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ApprovletS037.doc (clean copy 27March02)
Page 4 of 39
Rx only
VIDEX
(didanosine)
VIDEX (didanosine) Chewable/Dispersible Buffered Tablets
VIDEX (didanosine) Buffered Powder for Oral Solution
VIDEX (didanosine) Pediatric Powder for Oral Solution
(Patient Information Leaflet Included)
WARNING
FATAL AND NONFATAL PANCREATITIS HAVE OCCURRED DURING
THERAPY WITH VIDEX USED ALONE OR IN COMBINATION REGIMENS
IN
BOTH
TREATMENT-NAIVE
AND
TREATMENT-EXPERIENCED
PATIENTS, REGARDLESS OF DEGREE OF IMMUNOSUPPRESSION. VIDEX
SHOULD BE SUSPENDED IN PATIENTS WITH SUSPECTED PANCREATITIS
AND DISCONTINUED IN PATIENTS WITH CONFIRMED PANCREATITIS
(SEE WARNINGS).
LACTIC
ACIDOSIS
AND
SEVERE
HEPATOMEGALY
WITH
STEATOSIS, INCLUDING FATAL CASES, HAVE BEEN REPORTED WITH
THE USE OF NUCLEOSIDE ANALOGUES ALONE OR IN COMBINATION,
INCLUDING DIDANOSINE AND OTHER ANTIRETROVIRALS. FATAL
LACTIC ACIDOSIS HAS BEEN REPORTED IN PREGNANT WOMEN WHO
RECEIVED THE COMBINATION OF DIDANOSINE AND STAVUDINE WITH
OTHER
ANTIRETROVIRAL
AGENTS.
THE
COMBINATION
OF
DIDANOSINE AND STAVUDINE SHOULD BE USED WITH CAUTION
DURING PREGNANCY AND IS RECOMMENDED ONLY IF THE POTENTIAL
BENEFIT
CLEARLY
OUTWEIGHS
THE
POTENTIAL
RISK.
(SEE
WARNINGS AND PRECAUTIONS: PREGNANCY.)
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DESCRIPTION
VIDEX (didanosine) is a brand name for didanosine (ddI), a synthetic purine nucleoside
analogue active against the Human Immunodeficiency Virus (HIV). VIDEX
Chewable/Dispersible Buffered Tablets are available for oral administration in strengths of
25, 50, 100, 150, and 200 mg of didanosine. Each tablet is buffered with calcium
carbonate and magnesium hydroxide. VIDEX tablets also contain aspartame, sorbitol,
microcrystalline cellulose, polyplasdone, mandarin-orange flavor, and magnesium stearate.
VIDEX Buffered Powder for Oral Solution is supplied for oral administration in
single-dose packets containing 100, 167, or 250 mg of didanosine. Packets of each product
strength also contain a citrate-phosphate buffer (composed of dibasic sodium phosphate,
sodium citrate, and citric acid) and sucrose.
VIDEX Pediatric Powder for Oral Solution is supplied for oral administration in 4-
or 8-ounce glass bottles containing 2 or 4 grams of didanosine, respectively.
Didanosine is also available as an enteric-coated formulation (VIDEX® EC
Delayed-Release Capsules). Please consult the prescribing information for VIDEX EC
(didanosine).
The chemical name for didanosine is 2',3'-dideoxyinosine. The structural formula
is:
Didanosine is a white crystalline powder with the molecular formula C10H12N4O3
and a molecular weight of 236.2. The aqueous solubility of didanosine at 25°C and pH of
approximately 6 is 27.3 mg/mL. Didanosine is unstable in acidic solutions. For example,
at pH <3 and 37°C, 10% of didanosine decomposes to hypoxanthine in less than 2 minutes.
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Page 6 of 39
MICROBIOLOGY
Mechanism of Action
Didanosine is a synthetic nucleoside analogue of the naturally occurring nucleoside
deoxyadenosine in which the 3'-hydroxyl group is replaced by hydrogen. Intracellularly,
didanosine is converted by cellular enzymes to the active metabolite, dideoxyadenosine
5'-triphosphate. Dideoxyadenosine 5'-triphosphate inhibits the activity of HIV-1 reverse
transcriptase both by competing with the natural substrate, deoxyadenosine 5'-triphosphate,
and by its incorporation into viral DNA causing termination of viral DNA chain
elongation.
In Vitro HIV Susceptibility
The in vitro anti-HIV-1 activity of didanosine was evaluated in a variety of HIV-1 infected
lymphoblastic cell lines and monocyte/macrophage cell cultures. The concentration of drug
necessary to inhibit viral replication by 50% (IC50) ranged from 2.5 to 10 µM (1 µM = 0.24
µg/mL) in lymphoblastic cell lines and 0.01 to 0.1 µM in monocyte/macrophage cell
cultures. The relationship between in vitro susceptibility of HIV to didanosine and the
inhibition of HIV replication in humans has not been established.
Drug Resistance
HIV-1 isolates with reduced sensitivity to didanosine have been selected in vitro and were
also obtained from patients treated with didanosine. Genetic analysis of isolates from
didanosine-treated patients showed mutations in the reverse transcriptase gene that resulted
in the amino acid substitutions K65R, L74V, and M184V. The L74V mutation was most
frequently observed in clinical isolates. Phenotypic analysis of HIV-1 isolates from 60
patients (some with prior zidovudine treatment) receiving 6 to 24 months of didanosine
monotherapy showed that isolates from 10 of 60 patients exhibited an average of a 10-fold
decrease in susceptibility to didanosine in vitro compared to baseline isolates. Clinical
isolates that exhibited a decrease in didanosine susceptibility harbored one or more
didanosine-associated mutations. The clinical relevance of genotypic and phenotypic
changes associated with didanosine therapy has not been established.
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Page 7 of 39
Cross-resistance
HIV-1 isolates from 2 of 39 patients receiving combination therapy for up to 2 years with
zidovudine and didanosine exhibited decreased susceptibility to zidovudine, didanosine,
zalcitabine, stavudine, and lamivudine in vitro. These isolates harbored five mutations
(A62V, V75I, F77L, F116Y, and Q151M) in the reverse transcriptase gene. The clinical
relevance of these observations has not been established.
CLINICAL PHARMACOLOGY
Animal Toxicology
Evidence of a dose-limiting skeletal muscle toxicity has been observed in mice and rats
(but not in dogs) following long-term (greater than 90 days) dosing with didanosine at
doses that were approximately 1.2 to 12 times the estimated human exposure. The
relationship of this finding to the potential of VIDEX (didanosine) to cause myopathy in
humans is unclear. However, human myopathy has been associated with administration of
VIDEX and other nucleoside analogues.
Pharmacokinetics
The pharmacokinetic parameters of didanosine are summarized in Table 1. Didanosine is
rapidly absorbed, with peak plasma concentrations generally observed from 0.25 to 1.50
hours following oral dosing. Increases in plasma didanosine concentrations were dose
proportional over the range of 50 to 400 mg. Steady-state pharmacokinetic parameters did
not differ significantly from values obtained after a single dose. Binding of didanosine to
plasma proteins in vitro was low (<5%). Based on data from in vitro and animal studies, it
is presumed that the metabolism of didanosine in man occurs by the same pathways
responsible for the elimination of endogenous purines.
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Page 8 of 39
Table 1:
Mean ± SD Pharmacokinetic Parameters for Didanosine in Adult
and Pediatric Patients
Pediatric Patientsb
Parameter
Adult
Patientsa
n
8 months to 19 years
n
2 weeks to 4 months
n
Oral bioavailability (%)
42 ± 12
6
25 ± 20
46
ND
Apparent volume of
distributionc (L/m2)
43.70 ± 8.90
6
28 ± 15
49
ND
CSF-plasma ratiod
21 ± 0.03%e
5
46%
(range 12-85%)
7
ND
Systemic clearancec
(mL/min/m2)
526 ± 64.7
6
516 ± 184
49
ND
Renal clearancef
(mL/min/m2)
223 ± 85.0
6
240 ± 90
15
ND
Apparent oral
clearanceg (mL/min/m2)
1252 ± 154
6
2064 ± 736
48
1353 ± 759
41
Elimination half-lifef (h)
1.5 ± 0.4
6
0.8 ± 0.3
60
1.2 ± 0.3
21
Urinary recovery of
didanosinef (%)
18 ± 8
6
18 ± 10
15
ND
CSF = cerebrospinal fluid, ND = not determined.
a Parameter units for adults were converted to the same units in pediatric patients to facilitate comparisons
among populations: mean adult body weight = 70 kg and mean adult body surface area = 1.73 m2.
b In 1-day old infants (n=10), the mean ± SD apparent oral clearance was 1523 ± 1176 mL/min/m2 and half-
life was 2.0 ± 0.7 h.
c Following IV administration.
d Following IV administration in adults and IV or oral administration in pediatric patients.
e Mean ± SE.
f Following oral administration.
g Apparent oral clearance estimate was determined as the ratio of the mean systemic clearance and the mean
oral bioavailability estimate.
Effect of Food on Absorption of Didanosine: Didanosine peak plasma
concentrations (CMAX) and area under the plasma concentration time curve (AUC) were
decreased by approximately 55% when VIDEX tablets were administered up to 2 hours
after a meal. Administration of VIDEX tablets up to 30 minutes before a meal did not
result in any significant changes in bioavailability. VIDEX should be taken on an empty
stomach, at least 30 minutes before or 2 hours after eating. (See DOSAGE AND
ADMINISTRATION.)
Special Populations
Renal Insufficiency: It is recommended that the VIDEX (didanosine) dose be modified
in patients with reduced creatinine clearance and in patients receiving maintenance
hemodialysis (see DOSAGE AND ADMINISTRATION). Data from two studies in
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Page 9 of 39
adults indicated that the apparent oral clearance of didanosine decreased and the terminal
elimination half-life increased as creatinine clearance decreased (see Table 2). Following
oral administration, didanosine was not detectable in peritoneal dialysate fluid (n=6);
recovery in hemodialysate (n=5) ranged from 0.6% to 7.4% of the dose over a 3-4 hour
dialysis period. The absolute bioavailability of didanosine was not affected in patients
requiring dialysis.
Table 2:
Mean ± SD Pharmacokinetic Parameters for Didanosine
Following a Single Oral Dose
Creatinine Clearance (mL/min)
Parameter
≥ 90 (n=12)
60-90 (n=6)
30-59 (n=6)
10-29 (n=3)
Dialysis Patients
(n=11)
CLcr (mL/min)
112 ± 22
68 ± 8
46 ± 8
13 ± 5
NDa
CL/F (mL/min)
2164 ± 638
1566 ± 833
1023 ± 378
628 ± 104
543 ± 174
CLR (mL/min)
458 ± 164
247 ± 153
100 ± 44
20 ± 8
<10
T½ (h)
1.42 ± 0.33
1.59 ± 0.13
1.75 ± 0.43
2.0 ± 0.3
4.1 ± 1.2
a ND = not determined due to anuria
CLcr = creatinine clearance
CL/F = apparent oral clearance
CLR = renal clearance
Pediatric Patients: The pharmacokinetics of didanosine have been evaluated in
HIV-exposed and -infected pediatric patients from birth to 19 years of age (see Table 1).
Overall, the pharmacokinetics of didanosine in pediatric patients are similar to those of
didanosine in adults. Didanosine plasma concentrations appear to increase in proportion to
oral doses ranging from 25 to 120 mg/m2 in pediatric patients less than 5 months old and
from 80 to 180 mg/m2 in children above 8 months old. For information on controlled
clinical studies in pediatric patients, see PRECAUTIONS, Pediatric Use and Clinical
Studies.
Geriatric Patients: Didanosine pharmacokinetics have not been studied in
patients over 65 years of age.
Gender: The effects of gender on didanosine pharmacokinetics have not been
studied.
Drug Interactions: Tables 3 and 4 summarize the effects on AUC and CMAX,
with a 90% or 95% confidence interval (CI) when available, following coadministration of
VIDEX with a variety of drugs. For most of the listed drugs, no clinically significant
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Page 10 of 39
pharmacokinetic interactions were observed. Clinical recommendations based on drug
interaction studies for drugs in bold font are included in PRECAUTIONS: Drug
Interactions.
Table 3:
Results of Drug Interaction Studies: Effects of
Coadministered Drug on Didanosine Plasma AUC and CMAX
Values
Drugs With Clinical Recommendations Regarding Coadministration (see PRECAUTIONS: Drug Interactions)
Drug
Didanosine Dosage
n
AUC of
Didanosine
(95% CI)
CMAX of
Didanosine (95%
CI)
allopurinol
renally impaired, 300 mg/day
200 mg single dose
2
↑312%
↑232%
healthy volunteer, 300 mg/day
for 7 days
400 mg single dose
14
↑113%
↑69%
ciprofloxacin, 750 mg q12h for
3 days, 2 h before didanosine
200 mg q12h for 3
days
8a
↓16%
↓28%
ganciclovir, 1000 mg q8h, 2 h
after didanosine
200 mg q12h
12
↑111%
NA
indinavir, 800 mg single dose
simultaneous
1 h before didanosine
200 mg single dose
200 mg single dose
16
16
↔
↓17% (-27, - 7%)b
↔
↓13% (-28, 5%)b
ketoconazole, 200 mg/day for
4 days, 2 h before didanosine
375 mg q12h for 4
days
12a
↔
↓12%
methadone, chronic
maintenance dose
200 mg single dose
16,10c
↓57%
↓66%
No Clinically Significant Interaction Observed
Drug
Didanosine Dosage
n
AUC of
Didanosine
(95% CI)
CMAX of
Didanosine (95%
CI)
loperamide, 4 mg q6h for 1 day
300 mg single dose
12a
↔
↓23%
metoclopramide, 10 mg single
dose
300 mg single dose
12a
↔
↑13%
ranitidine, 150 mg single dose,
2 h before didanosine
375 mg single dose
12a
↑14%
↑13%
rifabutin, 300 or 600 mg/day
for 12 days
167 or 250 mg q12h
for 12 days
11
↑13% (-1, 27%)
↑17% (-4, 38%)
ritonavir, 600 mg q12h for 4
days
200 mg q12h for 4
days
12
↓13% (0, 23%)
↓16% (5, 26%)
stavudine, 40 mg q12h for 4
days
100 mg q12h for 4
days
10
↔
↔
sulfamethoxazole, 1000 mg
single dose
200 mg single dose
8a
↔
↔
trimethoprim, 200 mg single
dose
200 mg single dose
8a
↔
↑17% (-23, 77%)
zidovudine, 200 mg q8h for 3
days
200 mg q12h for 3
days
6a
↔
↔
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Table 3:
Results of Drug Interaction Studies: Effects of
Coadministered Drug on Didanosine Plasma AUC and CMAX
Values
↑ indicates increase.
↓ indicates decrease.
↔ indicates no change, or mean increase or decrease of <10%.
a HIV-infected patients.
b 90% CI.
c Parallel-group design; entries are subjects receiving combination and control regimens, respectively.
NA Not available.
Table 4:
Results of Drug Interaction Studies: Effects of Didanosine on
Coadministered Drug Plasma AUC and CMAX Values
Drugs With Clinical Recommendations Regarding Coadministration (see PRECAUTIONS: Drug Interactions)
Drug
Didanosine Dosage
n
AUC of
Coadministered
Drug (95% CI)
CMAX of
Coadministered
Drug (95% CI)
ciprofloxacin
750 mg q12h for 3 days, 2 h
before didanosine
750 mg single dose
200 mg q12h for 3 days
buffered placebo tablet
8a
12
↓26%
↓98%
↓16%
↓93%
delavirdine, 400 mg single dose
simultaneous
1 h before didanosine
125 or 200 mg q12h
125 or 200 mg q12h
12a
12a
↓32%
↑20%
↓53%
↑18%
ganciclovir, 1000 mg q8h, 2 h
after didanosine
200 mg q12h
12a
↓21%
NA
indinavir, 800 mg single dose
simultaneous
1 h before didanosine
200 mg single dose
200 mg single dose
16
16
↓84%
↓11%
↓82%
↓4%
ketoconazole, 200 mg/day for 4
days, 2 h before didanosine
375 mg q12h for 4 days
12a
↓14%
↓20%
nelfinavir, 750 mg single dose, 1
h after didanosine
200 mg single dose
10a
↑12%
↔
No Clinically Significant Interaction Observed
Drug
Didanosine Dosage
n
AUC of
Coadministered
Drug (95% CI)
CMAX of
Coadministered
Drug (95% CI)
dapsone, 100 mg single dose
200 mg q12h for 14
days
6a
↔
↔
ranitidine, 150 mg single dose, 2 h
before didanosine
375 mg single dose
12a
↓16%
↔
ritonavir, 600 mg q12h for 4 days
200 mg q12h for 4
days
12
↔
↔
stavudine, 40 mg q12h for 4 days
100 mg q12h for 4
days
10a
↔
↑17%
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Page 12 of 39
Table 4:
Results of Drug Interaction Studies: Effects of Didanosine on
Coadministered Drug Plasma AUC and CMAX Values
sulfamethoxazole, 1000 mg single
dose
200 mg single dose
8a
↓11% (-17, -4%)
↓12% (-28, 8%)
trimethoprim, 200 mg single dose
200 mg single dose
8a
↑10% (-9, 34%)
↓22% (-59, 49%)
zidovudine, 200 mg q8h for 3 days
200 mg q12h for 3
days
6a
↓10% (-27, 11%)
↓16.5% (-53, 47%)
↑ indicates increase.
↓ indicates decrease.
↔ indicates no change, or mean increase or decrease of <10%.
a HIV-infected patients.
NA Not available.
INDICATIONS AND USAGE
VIDEX in combination with other antiretroviral agents is indicated for the treatment
of HIV-1 infection (see Clinical Studies).
Clinical Studies
Combination Therapy
START 2 was a multicenter, randomized, open-label study comparing VIDEX (200 mg
twice daily)/stavudine/indinavir to zidovudine/lamivudine/indinavir in 205 treatment-naive
patients. Both regimens resulted in a similar magnitude of suppression of HIV RNA levels
and increases in CD4 cell counts through 48 weeks.
Study A1454-148 was a randomized, open-label, multicenter study comparing
treatment with VIDEX (400 mg once daily) plus stavudine (40 mg twice daily) and
nelfinavir (750 mg three times daily) versus zidovudine (300 mg twice daily) plus
lamivudine (150 mg twice daily) and nelfinavir (750 mg three times daily) in 756
treatment-naive patients, with a median CD4 cell count of 340 cells/mm3 (range 80 to 1568
cells/mm3) and a median plasma HIV-1 RNA of 4.69 log10 copies/mL (range 2.6 to 5.9
log10 copies/mL) at baseline. Median CD4 cell count increases at 48 weeks were 188
cells/mm3 in both treatment groups. Treatment response and outcomes through 48 weeks
are shown in Figure 1 and Table 5.
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Figure 1:
Treatment Response Through Week 48*, AI454-148
* Percent of patients at each time point who have HIV RNA <400 or <50 copies/mL, are on
their original study medication (except stavudine-zidovudine switches), and have not
experienced an AIDS-defining event.
Table 5:
Outcomes of Randomized Treatment through Week 48, AI454-148
Percent of Patients with HIV RNA <400 copies/mL (<50 copies/mL)
VIDEX/stavudine/nelfinavir
lamivudine/zidovudine/nelfinavir
Week 48 Status
n=503
n=253
Responder a
50* (34*)
59 (47)
Virologic failureb
36 (57)
32 (48)
Death or disease progression
<1 (<1)
1 (<1)
Discontinued due to adverse events
4 (2)
2 (<1)
Discontinued due to other reasonsc
6 (3)
4 (2)
Never initiated treatment
4 (4)
2 (2)
* <0.05 for the differences between treatment groups, by Cochran-Mantel-Haenszel test.
a Patients achieved virologic response [two consecutive viral load <400 (<50) copies/mL] and maintained it to
Week 48.
b Includes viral rebound and failing to achieve confirmed <400 (<50) copies/mL by Week 48.
c Includes lost to follow-up, noncompliance, withdrawal, and pregnancy.
Monotherapy
The efficacy of VIDEX was demonstrated in two randomized, double-blind studies
comparing VIDEX, given on a twice-daily schedule, to zidovudine, given three times
daily, in 617 (ACTG 116A, conducted 1989-1992) and 913 (ACTG116B/117, conducted
1989-1991) patients with symptomatic HIV infection or AIDS who were treated for more
than one year. In treatment-naive patients (ACTG 116A), the rate of HIV disease
0
20
40
60
80
100
0
8
16
24
32
40
48
Study Week
Percent of patients
] < 400 c/mL
] < 50 c/mL
VIDEX+stavudine+nelfinavir (n=503)
zidovudine+lamivudine+nelfinavir (n=253)
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progression or death was similar between the treatment groups; mortality rates were 26%
for patients receiving VIDEX and 21% for patients receiving zidovudine. Of the patients
who had received previous zidovudine treatment (ACTG 116B/117), those treated with
VIDEX had a lower rate of HIV disease progression or death (32%) compared to those
treated with zidovudine (41%); however, survival rates were similar between the treatment
groups.
Efficacy in pediatric patients was demonstrated in a randomized, double-blind,
controlled study (ACTG 152, conducted 1991-1995) involving 831 patients 3 months to 18
years of age treated for more than 1.5 years with zidovudine (180 mg/m2 q6h), VIDEX
(120 mg/m2 q12h), or zidovudine (120 mg/m2 q6h) plus VIDEX (90 mg/m2 q12h). Patients
treated with VIDEX or VIDEX plus zidovudine had lower rates of HIV disease
progression or death compared with those treated with zidovudine alone.
Studies have demonstrated that the clinical benefit of monotherapy with
antiretrovirals, including VIDEX, was time limited.
CONTRAINDICATION
VIDEX (didanosine) is contraindicated in patients with previously demonstrated clinically
significant hypersensitivity to any of the components of the formulations.
WARNINGS
1.
Pancreatitis
FATAL AND NONFATAL PANCREATITIS HAVE OCCURRED DURING
THERAPY WITH VIDEX USED ALONE OR IN COMBINATION REGIMENS IN
BOTH TREATMENT-NAIVE AND TREATMENT-EXPERIENCED PATIENTS,
REGARDLESS OF DEGREE OF IMMUNOSUPPRESSION. VIDEX SHOULD BE
SUSPENDED IN PATIENTS WITH SIGNS OR SYMPTOMS OF PANCREATITIS
AND DISCONTINUED IN PATIENTS WITH CONFIRMED PANCREATITIS.
PATIENTS TREATED WITH VIDEX IN COMBINATION WITH STAVUDINE,
WITH OR WITHOUT HYDROXYUREA, MAY BE AT INCREASED RISK FOR
PANCREATITIS.
When treatment with life-sustaining drugs known to cause pancreatic toxicity is
required, suspension of VIDEX (didanosine) therapy is recommended. In patients with risk
factors for pancreatitis, VIDEX should be used with extreme caution and only if clearly
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Page 15 of 39
indicated. Patients with advanced HIV infection, especially the elderly, are at increased
risk of pancreatitis and should be followed closely. Patients with renal impairment may be
at greater risk for pancreatitis if treated without dose adjustment.
The frequency of pancreatitis is dose related. In phase 3 studies, incidence ranged
from 1% to 10% with doses higher than are currently recommended and 1% to 7% with
recommended dose.
In pediatric phase 1 studies, pancreatitis occurred in 3% (2/60) of patients treated at
entry doses below 300 mg/m2/day and in 13% (5/38) of patients treated at higher doses. In
study ACTG 152, pancreatitis occurred in none of the 281 pediatric patients who received
didanosine 120 mg/m2 q12h and in <1% of the 274 pediatric patients who received
didanosine 90 mg/m2 q12h in combination with zidovudine. VIDEX use should be
suspended in pediatric patients with signs or symptoms of pancreatitis and discontinued in
pediatric patients with confirmed pancreatitis.
2.
Lactic Acidosis/Severe Hepatomegaly with Steatosis
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases,
have been reported with the use of nucleoside analogues alone or in combination,
including didanosine and other antiretrovirals. A majority of these cases have been in
women. Obesity and prolonged nucleoside exposure may be risk factors. Fatal lactic
acidosis has been reported in pregnant women who received the combination of didanosine
and stavudine with other antiretroviral agents. The combination of didanosine and
stavudine should be used with caution during pregnancy and is recommended only if the
potential benefit clearly outweighs the potential risk (see PRECAUTIONS: Pregnancy).
Particular caution should be exercised when administering VIDEX to any patient with
known risk factors for liver disease; however, cases have also been reported in patients
with no known risk factors. Treatment with VIDEX should be suspended in any patient
who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced
hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of
marked transaminase elevations).
3.
Retinal Changes and Optic Neuritis
Retinal changes and optic neuritis have been reported in adult and pediatric
patients. Periodic retinal examinations should be considered for patients receiving VIDEX.
(See ADVERSE REACTIONS.)
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PRECAUTIONS
Frequency of Dosing
The preferred dosing frequency of VIDEX is twice daily because there is more evidence to
support the effectiveness of this dosing frequency. Once-daily dosing should be considered
only for adult patients whose management requires once-daily dosing of VIDEX (see
Clinical Studies).
VIDEX should be taken on an empty stomach, at least 30 minutes before or 2
hours after eating.
Peripheral Neuropathy
Peripheral neuropathy, manifested by numbness, tingling, or pain in the hands or feet, has
been reported in patients receiving VIDEX therapy. Peripheral neuropathy has occurred
more frequently in patients with advanced HIV disease, in patients with a history of
neuropathy, or in patients being treated with neurotoxic drug therapy, including stavudine
(see ADVERSE REACTIONS).
Fat Redistribution
Redistribution/accumulation of body fat including central obesity, dorsocervical fat
enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and
“cushingoid appearance” have been observed in patients receiving antiretroviral therapy.
The mechanism and long-term consequences of these events are currently unknown. A
causal relationship has not been established.
General
Patients with Phenylketonuria: VIDEX Chewable/Dispersible Buffered Tablets
contain the following quantities of phenylalanine:
Table 6
All Strengths
Phenylalanine per 2-tablet dose
73 mg
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Table 6
All Strengths
Phenylalanine per tablet
36.5 mg
Patients on Sodium-Restricted Diets: VIDEX Buffered Powder for Oral
Solution: Each single-dose packet of VIDEX Buffered Powder for Oral Solution contains
1380 mg sodium.
Patients with Renal Impairment: Patients with renal impairment (creatinine
clearance <60 mL/min) may be at greater risk of toxicity from VIDEX due to decreased
drug clearance (see CLINICAL PHARMACOLOGY). A dose reduction is
recommended in these patients (see DOSAGE AND ADMINISTRATION). The
magnesium content of each buffered tablet of VIDEX is 8.6 mEq. This may present an
excessive load of magnesium to patients with significant renal impairment, particularly
after prolonged dosing.
Patients with Hepatic Impairment: It is unknown if hepatic impairment
significantly affects didanosine pharmacokinetics. Therefore, these patients should be
monitored closely for evidence of didanosine toxicity.
Hyperuricemia: VIDEX has been associated with asymptomatic hyperuricemia;
treatment suspension may be necessary if clinical measures aimed at reducing uric acid
levels fail.
Information for Patients (See Patient Information Leaflet.)
Patients should be informed that a serious toxicity of VIDEX used alone and in
combination regimens, is pancreatitis, which may be fatal.
Patients should be informed that the preferred dosing frequency of VIDEX is twice
daily because there is more evidence to support the effectiveness of this dosing frequency.
Once-daily dosing should be considered only for adult patients whose management
requires once-daily dosing of VIDEX.
Patients should also be aware that peripheral neuropathy, manifested by numbness,
tingling, or pain in hands or feet, may develop during therapy with VIDEX. Patients
should be counseled that peripheral neuropathy occurs with greatest frequency in patients
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with advanced HIV disease or a history of peripheral neuropathy, and that dose
modification and/or discontinuation of VIDEX may be required if toxicity develops.
Patients should be informed that when VIDEX is used in combination with other
agents with similar toxicities, the incidence of adverse events may be higher than when
VIDEX is used alone. These patients should be followed closely.
Patients should be cautioned about the use of medications or other substances,
including alcohol, that may exacerbate VIDEX toxicities.
Patients should be advised that to ensure proper acid neutralization in the stomach
they must take at least two of the appropriate strength VIDEX tablets at each dose. To
reduce the risk of gastrointestinal side effects from excess antacid, patients should take no
more than four VIDEX tablets at each dose.
VIDEX (didanosine) is not a cure for HIV infection, and patients may continue to
develop HIV-associated illnesses, including opportunistic infection. Therefore, patients
should remain under the care of a physician when using VIDEX. Patients should be
advised that VIDEX therapy has not been shown to reduce the risk of transmission of HIV
to others through sexual contact or blood contamination. Patients should be informed that
the long-term effects of VIDEX are unknown at this time.
Patients should be informed that redistribution or accumulation of body fat may
occur in patients receiving antiretroviral therapy and that the cause and long-term health
effects of these conditions are not known at this time.
Drug Interactions (see also CLINICAL PHARMACOLOGY: Drug
Interactions)
Drug interactions that have been established based on drug interaction studies are listed
with the pharmacokinetic results in CLINICAL PHARMACOLOGY: Drug
Interactions (Tables 3 and 4). The clinical recommendations based on the results of these
studies are listed in Table 7.
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Table 7:
Established Drug Interactions with VIDEX
Coadministration Not Recommended Based on Drug Interaction Studies (see CLINICAL
PHARMACOLOGY: Drug Interactions for Magnitude of Interaction)
Drug
Effect
Clinical Comment
allopurinol
↑ didanosine concentration
Coadministration not recommended.
Alteration in Dose or Regimen Recommended Based on Drug Interaction Studies (see CLINICAL
PHARMACOLOGY: Drug Interactions for Magnitude of Interaction)
Drug
Effect
Clinical Comment
ciprofloxacin
↓ ciprofloxacin concentration
Administer VIDEX at least 2 hours after or
6 hours before ciprofloxacin.
delavirdine
↓ delavirdine concentration
Administer VIDEX 1 hour after
delavirdine.
ganciclovir
↑ didanosine concentration
Appropriate doses for this combination,
with respect to efficacy and safety, have not
been established.
indinavir
↓ indinavir concentration
Administer VIDEX 1 hour after indinavir.
methadone
↓ didanosine concentration
Appropriate doses for this combination,
with respect to efficacy and safety, have not
been established.
nelfinavir
No interaction 1 hour after didanosine
Administer nelfinavir 1 hour after VIDEX.
↑ indicates increase.
↓ indicates decrease.
Coadministration of VIDEX with drugs that are known to cause pancreatitis
may increase the risk of this toxicity (see WARNINGS: Pancreatitis). Because VIDEX
formulations either contain buffers or are mixed with antacids before administration,
interactions may be anticipated with drugs whose absorption can be affected by the level of
acidity in the stomach and with drugs that have been demonstrated to interact with antacids
containing magnesium, calcium, or aluminum. Predicted drug interactions with VIDEX
are listed in Table 8.
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Table 8:
Predicted Drug Interactions with VIDEX
Use with Caution, Risk of Adverse Reactions May Be Increased
Drug Class
Effect
Clinical Comment
Drugs that may cause
pancreatic toxicity
↑ risk of pancreatitis
Use only with extreme caution.a
Neurotoxic drugs
↑ risk of neuropathy
Use with caution.b
Antacids containing
magnesium or aluminum
↑ side effects associated with
antacid components
Use caution with VIDEX
Chewable/Dispersible Buffered Tablets
and Pediatric Powder for Oral Solution.
Use with Caution, Plasma Concentrations May Be Decreased by Coadministration with VIDEX
Drug Class
Effect
Clinical Comment
Azole antifungals
↓ ketoconazole or itraconazole
concentration
Administer drugs such as ketoconazole or
itraconazole at least 2 hours before
VIDEX.
Quinolone antibiotics (see
also ciprofloxacin in Table 7)
↓ quinolone concentration
Consult package insert of the quinolone.
Tetracycline antibiotics
↓ antibiotic concentration
Consult package insert of the tetracycline.
↑ indicates increase.
↓ indicates decrease.
a Only if other drugs are not available and if clearly indicated. If treatment with life-sustaining drugs that
cause pancreatic toxicity is required, suspension of VIDEX is recommended (see WARNINGS:
Pancreatitis).
b See PRECAUTIONS: Peripheral Neuropathy.
Carcinogenesis and Mutagenesis
Lifetime carcinogenicity studies were conducted in mice and rats for 22 and 24 months,
respectively. In the mouse study, initial doses of 120, 800, and 1200 mg/kg/day for each
sex were lowered after 8 months to 120, 210, and 210 mg/kg/day for females and 120, 300,
and 600 mg/kg/day for males. The two higher doses exceeded the maximally tolerated
dose in females and the high dose exceeded the maximally tolerated dose in males. The
low dose in females represented 0.68-fold maximum human exposure and the intermediate
dose in males represented 1.7-fold maximum human exposure based on relative AUC
comparisons. In the rat study, initial doses were 100, 250, and 1000 mg/kg/day, and the
high dose was lowered to 500 mg/kg/day after 18 months. The upper dose in male and
female rats represented 3-fold maximum human exposure.
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Didanosine induced no significant increase in neoplastic lesions in mice or rats at
maximally tolerated doses.
Didanosine was positive in the following genetic toxicology assays: 1) the
Escherichia coli tester strain WP2 uvrA bacterial mutagenicity assay; 2) the
L5178Y/TK+/- mouse lymphoma mammalian cell gene mutation assay; 3) the in vitro
chromosomal aberrations assay in cultured human peripheral lymphocytes; 4) the in vitro
chromosomal aberrations assay in Chinese Hamster Lung cells; and 5) the BALB/c 3T3 in
vitro transformation assay. No evidence of mutagenicity was observed in an Ames
Salmonella bacterial mutagenicity assay or in rat and mouse in vivo micronucleus assays.
Pregnancy, Reproduction, and Fertility
Pregnancy Category B. Reproduction studies have been performed in rats and rabbits at
doses up to 12 and 14.2 times the estimated human exposure (based upon plasma levels),
respectively, and have revealed no evidence of impaired fertility or harm to the fetus due to
didanosine. At approximately 12 times the estimated human exposure, didanosine was
slightly toxic to female rats and their pups during mid and late lactation. These rats
showed reduced food intake and body weight gains but the physical and functional
development of the offspring was not impaired and there were no major changes in the F2
generation. A study in rats showed that didanosine and/or its metabolites are transferred to
the fetus through the placenta. Animal reproduction studies are not always predictive of
human response.
There are no adequate and well-controlled studies of didanosine in pregnant
women. Didanosine should be used during pregnancy only if the potential benefit justifies
the potential risk.
Fatal lactic acidosis has been reported in pregnant women who received the
combination of didanosine and stavudine with other antiretroviral agents. It is unclear if
pregnancy augments the risk of lactic acidosis/hepatic steatosis syndrome reported in
nonpregnant individuals receiving nucleoside analogues (see WARNINGS: Lactic
Acidosis/Severe Hepatomegaly with Steatosis). The combination of didanosine and
stavudine should be used with caution during pregnancy and is recommended only if
the potential benefit clearly outweighs the potential risk. Health care providers caring
for HIV-infected pregnant women receiving didanosine should be alert for early diagnosis
of lactic acidosis/hepatic steatosis syndrome.
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Antiretroviral Pregnancy Registry: To monitor maternal-fetal outcomes of
pregnant women exposed to didanosine and other antiretroviral agents, an Antiretroviral
Pregnancy Registry has been established. Physicians are encouraged to register patients by
calling 1-800-258-4263.
Nursing Mothers
The Centers for Disease Control and Prevention recommend that HIV-infected
mothers not breast-feed their infants to avoid risking postnatal transmission of HIV.
A study in rats showed that following oral administration, didanosine and/or its metabolites
were excreted into the milk of lactating rats. It is not known if didanosine is excreted in
human milk. Because of both the potential for HIV transmission and the potential for
serious adverse reactions in nursing infants, mothers should be instructed not to breast-
feed if they are receiving VIDEX.
Pediatric Use
Use of VIDEX in pediatric patients from 2 weeks of age through adolescence is supported
by evidence from adequate and well-controlled studies of VIDEX in adults and pediatric
patients (see Clinical Studies, CLINICAL PHARMACOLOGY, ADVERSE
REACTIONS, and DOSAGE AND ADMINISTRATION).
Dosing recommendations for VIDEX in patients less than 2 weeks of age cannot be
made because the pharmacokinetics of didanosine in these children are too variable to
determine an appropriate dose.
Geriatric Use
In an Expanded Access Program for patients with advanced HIV infection, patients aged
65 years and older had a higher frequency of pancreatitis (10%) than younger patients (5%)
(see WARNINGS). Clinical studies of didanosine did not include sufficient numbers of
subjects aged 65 years and over to determine whether they respond differently than
younger subjects. Didanosine is known to be substantially excreted by the kidney, and the
risk of toxic reactions to this drug may be greater in patients with impaired renal function.
Because elderly patients are more likely to have decreased renal function, care should be
taken in dose selection. In addition, renal function should be monitored and dosage
adjustments should be made accordingly (see DOSAGE AND ADMINISTRATION:
Dose Adjustment).
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ADVERSE REACTIONS
A SERIOUS TOXICITY OF VIDEX (didanosine) IS PANCREATITIS, WHICH MAY
BE FATAL (see WARNINGS). OTHER IMPORTANT TOXICITIES INCLUDE
LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS; RETINAL
CHANGES AND OPTIC NEURITIS; AND PERIPHERAL NEUROPATHY (see
WARNINGS and PRECAUTIONS).
When VIDEX is used in combination with other agents with similar toxicities,
the incidence of these toxicities may be higher than when VIDEX is used alone. Thus,
patients treated with VIDEX in combination with stavudine, with or without
hydroxyurea, may be at increased risk for pancreatitis, which may be fatal, and
hepatotoxicity (see WARNINGS). Patients treated with VIDEX in combination with
stavudine may also be at increased risk for peripheral neuropathy (see
PRECAUTIONS).
Adults: Selected clinical adverse events that occurred in adult patients in clinical
studies with VIDEX are provided in Tables 9 and 10.
Table 9:
Selected Clinical Adverse Events from Monotherapy
Studies
Percent of Patients
ACTG 116A
ACTG 116B/117
VIDEX
zidovudine
VIDEX
zidovudine
Adverse Events
n=197
n=212
n=298
n=304
Diarrhea
19
15
28
21
Peripheral Neurologic
Symptoms/Neuropathy
17
14
20
12
Rash/Pruritus
7
8
9
5
Abdominal Pain
13
8
7
8
Pancreatitis
7
3
6
2
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Table 10:
Selected Clinical Adverse Events from Combination
Studies
Percent of Patientsa
AI454-148b
START 2b
VIDEX +
stavudine +
nelfinavir
zidovudine +
lamivudine +
nelfinavir
VIDEX +
stavudine +
indinavir
zidovudine +
lamivudine +
indinavir
Adverse Events
n=482
n=248
n=102
n=103
Diarrhea
70
60
45
39
Nausea
28
40
53
67
Headache
21
30
46
37
Peripheral Neurologic
Symptoms/Neuropathy
26
6
21
10
Rash
13
16
30
18
Vomiting
12
14
30
35
Pancreatitis (see below)
1
*
<1
*
a Percentages based on treated subjects.
b Median duration of treatment 48 weeks.
* This event was not observed in this study arm.
Pancreatitis resulting in death was observed in one patient who received
VIDEX plus stavudine plus nelfinavir in Study Al454-148 and in one patient who
received VIDEX plus stavudine plus indinavir in the START 2 study. In addition,
pancreatitis resulting in death was observed in 2 of 68 patients who received VIDEX
plus stavudine plus indinavir plus hydroxyurea in an ACTG clinical trial (see
WARNINGS).
The frequency of pancreatitis is dose related. In phase 3 studies, incidence ranged
from 1% to 10% with doses higher than are currently recommended and from 1% to 7%
with recommended dose.
Selected laboratory abnormalities in clinical studies with VIDEX are shown in
Tables 11-13.
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Table 11:
Selected Laboratory Abnormalities from Monotherapy Studies
Percent of Patients
ACTG 116A
ACTG 116B/117
VIDEX
zidovudine
VIDEX
zidovudine
Parameter
n=197
n=212
n=298
n=304
SGOT (AST) (>5 x ULN)
9
4
7
6
SGPT (ALT) (>5 x ULN)
9
6
6
6
Alkaline phosphatase
(>5 x ULN)
4
1
1
1
Amylase (≥1.4 x ULN)
17
12
15
5
Uric acid (>12 mg/dL)
3
1
2
1
ULN = upper limit of normal.
Table 12:
Selected Laboratory Abnormalities from Combination
Studies (Grades 3-4)
Percent of Patientsa
AI454-148b
START 2b
VIDEX +
stavudine +
nelfinavir
zidovudine +
lamivudine +
nelfinavir
VIDEX +
stavudine +
indinavir
zidovudine +
lamivudine +
indinavir
Parameter
n=482
n=248
n=102
n=103
Bilirubin (>2.6 x ULN)
<1
<1
16
8
SGOT (AST) (>5 x ULN)
3
2
7
7
SGPT (ALT) (>5 x ULN)
3
3
8
5
GGT (>5 x ULN)
NC
NC
5
2
Lipase (>2 x ULN)
7
2
5
5
Amylase (>2 x ULN)
NC
NC
8
2
ULN = upper limit of normal.
NC=Not Collected
a Percentages based on treated subjects.
b Median duration of treatment 48 weeks.
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Table 13:
Selected Laboratory Abnormalities from Combination
Studies (All Grades)
Percent of Patientsa
I454-148b
START 2b
VIDEX +
stavudine +
nelfinavir
zidovudine +
lamivudine +
nelfinavir
VIDEX +
stavudine +
indinavir
zidovudine +
lamivudine +
indinavir
Parameter
n=482
n=248
n=102
n=103
Bilirubin
7
3
68
55
SGOT (AST)
42
23
53
20
SGPT (ALT)
37
24
50
18
GGT
NC
NC
28
12
Lipase
17
11
26
19
Amylase
NC
NC
31
17
NC = Not Collected
a Percentages based on treated subjects.
b Median duration of treatment 48 weeks.
Observed during Clinical Practice: The following events have been identified
during postapproval use of VIDEX (didanosine). Because they are reported voluntarily
from a population of unknown size, estimates of frequency cannot be made. These events
have been chosen for inclusion due to their seriousness, frequency of reporting, causal
connection to VIDEX, or a combination of these factors.
Body as a Whole - alopecia, anaphylactoid reaction, asthenia, chills/fever, pain, and
redistribution/accumulation
of
body
fat
(see
PRECAUTIONS:
Fat
Redistribution).
Digestive Disorders- anorexia, dyspepsia, and flatulence.
Exocrine
Gland
Disorders
–
pancreatitis
(including
fatal
cases)
(see
WARNINGS), sialoadenitis, parotid gland enlargement, dry mouth, and dry eyes.
Hematologic Disorders - anemia, leukopenia, and thrombocytopenia.
Liver - lactic acidosis and hepatic steatosis (see WARNINGS); hepatitis and liver
failure.
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Metabolic Disorders - diabetes mellitus, hypoglycemia, and hyperglycemia.
Musculoskeletal Disorders - myalgia (with or without increases in creatine kinase),
rhabdomyolysis including acute renal failure and hemodialysis, arthralgia, and
myopathy.
Ophthalmologic Disorders - Retinal depigmentation and optic neuritis (see
WARNINGS).
Pediatric Patients: In clinical trials, 743 pediatric patients between 2 weeks and
18 years of age have been treated with VIDEX. Adverse events and laboratory
abnormalities reported to occur in these patients were generally consistent with the safety
profile of didanosine in adults.
In pediatric phase 1 studies, pancreatitis occurred in 2 of 60 (3%) patients treated at
entry doses below 300 mg/m2/day and in 5 of 38 (13%) patients treated at higher doses. In
study ACTG 152, pancreatitis occurred in none of the 281 pediatric patients who received
didanosine 120 mg/m2 q12h and in <1% of the 274 pediatric patients who received
didanosine 90 mg/m2 q12h in combination with zidovudine (see Clinical Studies).
Retinal changes and optic neuritis have been reported in pediatric patients.
OVERDOSAGE
There is no known antidote for VIDEX (didanosine) overdosage. In phase 1 studies, in
which VIDEX was initially administered at doses ten times the currently recommended
dose, toxicities included: pancreatitis, peripheral neuropathy, diarrhea, hyperuricemia and
hepatic dysfunction. Didanosine is not dialyzable by peritoneal dialysis, although there is
some
clearance
by
hemodialysis
(see
CLINICAL
PHARMACOLOGY:
Pharmacokinetics).
DOSAGE AND ADMINISTRATION
Dosage
All VIDEX formulations should be administered on an empty stomach, at least 30
minutes before or 2 hours after eating. For either a once-daily or twice-daily regimen,
patients must take at least two of the appropriate strength tablets at each dose to
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provide adequate buffering and prevent gastric acid degradation of didanosine.
Because of the need for adequate buffering, the 200-mg strength tablet should only be
used as a component of a once-daily regimen. To reduce the risk of gastrointestinal
side effects, patients should take no more than four tablets at each dose.
Adults: The preferred dosing frequency of VIDEX is twice daily because there is
more evidence to support the effectiveness of this dosing regimen. Once-daily dosing
should be considered only for adult patients whose management requires once-daily dosing
of VIDEX (see Clinical Studies). The daily dose in adult patients is dependent on weight
as outlined in Table 14.
Table 14:
Adult Dosing
Patient Weight
VIDEX Tabletsa
VIDEX Buffered Powderb
Preferred dosing
≥60 kg
200 mg twice daily
250 mg twice daily
< 60 kg
125 mg twice daily
167 mg twice daily
Dosing for patients whose management requires once-daily frequency
≥ 60 kg
400 mg once daily
b
< 60 kg
250 mg once daily
b
a The 200-mg strength tablet should only be used as a component of a once-
daily regimen.
b Not suitable for once-daily dosing except for patients with renal impairment.
See Table 15.
Pediatric Patients: The recommended dose of VIDEX (didanosine) in pediatric
patients between 2 weeks and 8 months of age is 100 mg/m2 twice daily, and the
recommended VIDEX dose for pediatric patients older than 8 months is 120 mg/m2 twice
daily.
Dosing recommendations for VIDEX in patients less than 2 weeks of age cannot be
made because the pharmacokinetics of didanosine in these children are too variable to
determine an appropriate dose. There are no data on once-daily dosing of VIDEX in
pediatric patients.
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Dose Adjustment
Clinical and laboratory signs suggestive of pancreatitis should prompt dose
suspension and careful evaluation of the possibility of pancreatitis. VIDEX use should
be discontinued in patients with confirmed pancreatitis (see WARNINGS).
Patients with symptoms of peripheral neuropathy may tolerate a reduced dose of
VIDEX after resolution of the symptoms of peripheral neuropathy upon drug
discontinuation. If neuropathy recurs after resumption of VIDEX, permanent
discontinuation of VIDEX should be considered.
Renal Impairment: In adult patients with impaired renal function, the dose of
VIDEX should be adjusted to compensate for the slower rate of elimination. The
recommended doses and dosing intervals of VIDEX in adult patients with renal
insufficiency are presented in Table 15.
Table 15:
Recommended Dosage of VIDEX in Renal Impairment
≥ 60 kg
< 60 kg
Creatinine Clearance
(mL/min)
Tableta
(mg)
Buffered Powderb
(mg)
Tableta
(mg)
Buffered Powderb
(mg)
≥60
200 twice dailyc
250 twice daily
125 twice dailyc
167 twice daily
30-59
200 once daily
or 100 twice daily
100 twice daily
150 once daily
or 75 twice daily
100 twice daily
10-29
150 once daily
167 once daily
100 once daily
100 once daily
<10
100 once daily
100 once daily
75 once daily
100 once daily
a VIDEX Chewable/Dispersible Buffered Tablet. Two VIDEX tablets must be taken with each dose;
different strengths of tablets may be combined to yield the recommended dose.
b VIDEX Buffered Powder for Oral Solution.
c 400 mg once daily (≥60 kg) or 250 mg once daily (<60 kg) for patients whose management requires once-
daily frequency of administration.
Urinary excretion is also a major route of elimination of didanosine in pediatric
patients; therefore, the clearance of didanosine may be altered in children with renal
impairment. Although there are insufficient data to recommend a specific dose adjustment
of VIDEX in this patient population, a reduction in the dose and/or an increase in the
interval between doses should be considered.
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Patients Requiring Continuous Ambulatory Peritoneal Dialysis (CAPD)
or Hemodialysis: For patients requiring CAPD or hemodialysis, follow dosing
recommendations for patients with creatinine clearance less than 10 mL/min, shown in
Table 15. It is not necessary to administer a supplemental dose of VIDEX following
hemodialysis.
Hepatic Impairment: See WARNINGS and PRECAUTIONS.
Method of Preparation
VIDEX Chewable/Dispersible Buffered Tablets
Adult Dosing: To provide adequate buffering, at least two of the appropriate strength
tablets, but no more than four tablets, should be thoroughly chewed or dispersed in at least
1 ounce of water prior to consumption (see PRECAUTIONS: Information for Patients).
To disperse tablets, add 2 tablets to at least 1 ounce of drinking water. Stir until a uniform
dispersion forms, and drink the entire dispersion immediately. If additional flavoring is
desired, the dispersion may be diluted with one ounce of clear apple juice. Stir the further
diluted dispersion just prior to consumption. The dispersion with clear apple juice is stable
at room temperature, 62° to 73°F (17° to 23°C), for up to one hour.
VIDEX Buffered Powder for Oral Solution
1.
Open packet carefully and pour contents into a container with approximately 4
ounces of drinking water. Do not mix with fruit juice or other acid-containing liquid.
2.
Stir until the powder completely dissolves (approximately 2 to 3 minutes).
3.
Drink the entire solution immediately.
VIDEX Pediatric Powder for Oral Solution
Prior to dispensing, the pharmacist must constitute dry powder with Purified Water, USP,
to an initial concentration of 20 mg/mL and immediately mix the resulting solution with
antacid to a final concentration of 10 mg/mL as follows:
20 mg/mL Initial Solution: Constitute the product to 20 mg/mL by adding 100
mL or 200 mL of Purified Water, USP, to the 2 g or 4 g of VIDEX powder, respectively, in
the product bottle.
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10 mg/mL Final Admixture: 1. Immediately mix one part of the 20 mg/mL
initial solution with one part of either Mylanta® Double Strength Liquid, Extra Strength
Maalox® Plus Suspension, or Maalox ® TC Suspension for a final dispensing
concentration of 10 mg VIDEX per mL. For patient home use, the admixture should be
dispensed in appropriately sized, flint-glass or plastic (HDPE, PET, or PETG) bottles with
child-resistant closures. This admixture is stable for 30 days under refrigeration, 36° to
46° F (2° to 8° C).
2. Instruct the patient to shake the admixture thoroughly prior to use and to store
the tightly closed container in the refrigerator, 36° to 46° F (2° to 8° C), up to 30 days.
HOW SUPPLIED
VIDEX® (didanosine) Chewable/Dispersible Buffered Tablets are round, off white to
light orange/yellow with a mottled appearance, orange-flavored, tablets embossed with
"VIDEX" on one side and the product strength on the other. The tablets are available in
the following strengths of VIDEX: 25, 50, 100, 150, and 200 mg. Sixty tablets are
packaged in bottles with child-resistant closures.
The tablets should be stored in tightly closed bottles at 59° to 86° F (15° to
30 °C). If dispersed in water, the dose may be held for up to 1 hour at ambient
temperature.
VIDEX (didanosine) Buffered Powder for Oral Solution is supplied in single-
dose, child-resistant foil packets in the following strengths of VIDEX: 100, 167, or 250
mg. Each product strength provides a sweetened, buffered solution of VIDEX.
The packets should be stored at 59° to 86° F (15° to 30° C). After dissolving in
water, the solution may be stored at ambient room temperature for up to 4 hours.
VIDEX (didanosine) Pediatric Powder for Oral Solution is supplied in 4- and 8-
ounce glass bottles containing 2 g or 4 g of VIDEX, respectively.
The bottles of powder should be stored at 59° to 86° F (15° to 30° C). The VIDEX
admixture may be stored up to 30 days in a refrigerator, 36° to 46° F (2° to 8° C). Discard
any unused portion after 30 days.
Mylanta® is a registered trademark of Johnson & Johnson-Merck Consumer Pharmaceuticals Company.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
ApprovletS037.doc (clean copy 27March02)
Page 32 of 39
The NDC numbers for the previously described VIDEX products are:
Table 16
NDC NO.
Packaging Information
Product Strength
VIDEX
Chewable/Dispersible Buffered Tablets
0087-6650-01
60 tablets/bottle
25 mg/tablet
0087-6651-01
60 tablets/bottle
50 mg/tablet
0087-6652-01
60 tablets/bottle
100 mg/tablet
0087-6653-01
60 tablets/bottle
150 mg/tablet
0087-6665-15
60 tablets/bottle
200 mg/tablet
VIDEX
Buffered Powder for Oral Solution
0087-6614-43
One single-dose foil packet*
100 mg/packet
0087-6615-43
One single-dose foil packet*
167 mg/packet
0087-6616-43
One single-dose foil packet*
250 mg/packet
VIDEX
Pediatric Powder for Oral Solution
0087-6632-41
One bottle per carton
2 g/bottle
0087-6633-41
One bottle per carton
4 g/bottle
* Packaged as 30 packets per carton.
US Patent Nos.: 4,861,759 and 5,616,566.
HANDLING AND DISPOSAL
Spill, Leak, and Disposal Procedure
Avoid generating dust during clean-up of powdered products; use wet mop or damp
sponge. Clean surface with soap and water as necessary. Containerize larger spills.
There is no single preferred method of disposal of containerized waste. Disposal
options include incineration, landfill, or sewer as dictated by specific circumstances and
relevant national, state, and local regulations.
Maalox® is a registered trademark of Novartis Consumer Health, Inc.
This label may not be the latest approved by FDA.
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Page 33 of 39
Bristol-Myers Squibb Virology
A Bristol-Myers Squibb Company
Princeton, NJ 08543 USA
XXXXXX
Revised _____________________
PATIENT INFORMATION
Rx only
VIDEX®
(generic name = didanosine also known as ddI)
VIDEX® (didanosine) Chewable/Dispersible Buffered Tablets
VIDEX® (didanosine) Buffered Powder for Oral Solution
VIDEX® (didanosine) Pediatric Powder for Oral Solution
What is VIDEX?
VIDEX (pronounced VY dex) is a prescription medicine used in combination with other
drugs to treat children and adults who are infected with HIV (the human
immunodeficiency virus, the virus that causes AIDS). VIDEX belongs to a class of drugs
called nucleoside analogues. By reducing the growth of HIV, VIDEX helps your body
maintain its supply of CD4 cells, which are important for fighting HIV and other
infections.
VIDEX will not cure your HIV infection. At present there is no cure for HIV infection.
Even while taking VIDEX, you may continue to have HIV-related illnesses, including
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ApprovletS037.doc (clean copy 27March02)
Page 34 of 39
infections with other disease-producing organisms. Continue to see your doctor regularly and
report any medical problems that occur.
VIDEX does not prevent a patient infected with HIV from passing the virus to
other people. To protect others, you must continue to practice safe sex and take precautions
to prevent others from coming in contact with your blood and other body fluids.
There is limited information on the effects of long-term use of VIDEX.
Who should not take VIDEX?
Do not take VIDEX if you are allergic to any of its ingredients, including its active ingredient,
didanosine and the inactive ingredients. (See Inactive Ingredients at the end of this leaflet.)
Tell your doctor if you think you have had an allergic reaction to any of these ingredients.
How should I take VIDEX? How should I store it?
Your doctor will determine your dose based on your body weight, kidney and liver function,
and any side effects that you may have had with other medicines. Take VIDEX on an empty
stomach - that means at least 30 minutes before or 2 hours after eating. Do not take
VIDEX with food. Try not to miss a dose, but if you do, take it as soon as possible. If it is
almost time for the next dose, skip the missed dose and continue your regular dosing schedule.
Chewable/Dispersible Tablets: Each VIDEX tablet contains antacid. Each
time you take VIDEX, you must take at least two, but not more than four,
tablets. This is because VIDEX tablets contain an antacid to reduce the amount of
acid in your stomach. If you have too much acid, the medicine will break down.
However, too much antacid may cause stomach problems.
—DO NOT swallow VIDEX tablets whole. Chew the tablets well or mix them in
water. Many patients drop the tablets in at least one ounce of water and stir well
before swallowing. If you choose to mix the tablets in water, you may add one
ounce (2 tablespoons) of clear apple juice to the mixture for flavor (do not use any
other kind of juice).
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Page 35 of 39
—Store tablets in a tightly closed container at room temperature away from heat
and out of the reach of children and pets. Do NOT store the tablets in a damp place
such as a bathroom medicine cabinet or near the kitchen sink.
Buffered Powder for Oral Solution: Pour the contents of a packet into a glass
with 4 ounces (1/2 measuring cup) of water. Stir until completely dissolved. Drink
the entire solution right away. Do not mix with fruit juice. Store packets at room
temperature before use.
Pediatric Oral Solution: Your pharmacist will prepare the oral solution. Shake
the solution well before each use. Store in the refrigerator. Throw away any
unused portion after 30 days.
If you have kidney disease: If your kidneys are not working properly, your doctor
will need to do regular tests to check how they are working while you take VIDEX.
Your doctor may also lower your dosage of VIDEX.
What should I do if someone takes an overdose of VIDEX?
If someone may have taken an overdose of VIDEX, get medical help right away. Contact
their doctor or a poison control center.
What should I avoid while taking VIDEX?
Alcohol. Do not drink alcohol while taking VIDEX since alcohol may increase your risk of
pancreatitis (pain and inflammation of the pancreas) or liver damage.
Other medicines. Other medicines, including those you can buy without a prescription,
may interfere with the actions of VIDEX. Do not take any medicine, vitamin
supplement, or other health preparation without first checking with your doctor.
Antacids. Since VIDEX contains some of the same ingredients found in antacids,
any side effects related to VIDEX’s ingredients may get worse if you also take an
antacid.
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Page 36 of 39
Medicines at the same time you take your VIDEX dose. Some medicines should
not be taken at the same time of day that you take VIDEX. Check with your
doctor.
Pregnancy. It is not known if VIDEX can harm a human fetus. Also, pregnant women
have experienced serious side effects when taking VIDEX in combination with ZERIT
(stavudine), also known as d4T, and other HIV medicines. VIDEX should be used during
pregnancy only after discussion with your doctor. Tell your doctor if you become
pregnant or plan to become pregnant while taking VIDEX.
Nursing. Studies have shown VIDEX is in the breast milk of animals getting the drug. It
may also be in human breast milk. The Centers for Disease Control and Prevention (CDC)
recommends that HIV-infected mothers not breast-feed. This should reduce the risk of
passing HIV infection to their babies and the potential for serious adverse reactions in
nursing infants. Therefore, do not nurse a baby while taking VIDEX.
What are the possible side effects of VIDEX?
Pancreatitis. Pancreatitis is a dangerous inflammation of the pancreas that may cause
death. Tell your doctor right away if you or a child taking VIDEX develops stomach
pain, nausea, or vomiting. These can be signs of pancreatitis. Before starting VIDEX
therapy, let your doctor know if you or a child for whom it has been prescribed has ever had
pancreatitis. This condition is more likely to happen in people who have had it before. It is also
more likely in people with advanced HIV disease. However, it can occur at any stage of HIV
disease. It may be more common in patients with kidney problems, those who drink alcohol,
and those who are also treated with stavudine or hydroxyurea. If you get pancreatitis, your
doctor will tell you to stop taking VIDEX.
Lactic acidosis, severe liver enlargement, and liver failure, including deaths, have been
reported among patients taking VIDEX (including pregnant women). Symptoms that may
indicate a liver problem are:
• feeling very weak, tired, or uncomfortable,
• unusual or unexpected stomach discomfort,
• feeling cold,
• feeling dizzy or lightheaded,
• suddenly developing a slow or irregular heartbeat.
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Lactic acidosis is a medical emergency that must be treated in a hospital.
If you notice any of these symptoms or if your medical condition changes, stop taking
VIDEX and call your doctor right away. Women, overweight patients, and those who have
been treated for a long time with other medicines used to treat HIV infection are more likely to
develop lactic acidosis. Your doctor should check your liver function periodically while you
are taking VIDEX. You should be especially careful if you have a history of heavy alcohol use
or a liver problem.
Vision changes. VIDEX may affect the nerves in your eyes. Because of this, you should have
regular eye examinations. You should also report any changes in vision to your doctor right
away. This includes, for example, seeing colors abnormally or blurred vision.
Peripheral neuropathy. This is a problem with the nerves in your hands or feet. The nerve
problem may be serious. Tell your doctor right away if you or a child taking VIDEX has
continuing numbness, tingling, or pain in the feet or hands. A child may not recognize these
symptoms or know to tell you that his or her feet or hands are numb, burning, tingling, or
painful. Ask your child’s doctor how to find out if your child is developing peripheral
neuropathy.
Before starting VIDEX therapy, let your doctor know if you or a child for whom it has
been prescribed has ever had peripheral neuropathy. This condition is more likely to happen in
people who have had it before. It is also more likely in patients taking medicines that affect the
nerves and in people with advanced HIV disease. However, it can occur at any stage of HIV
disease. If you get peripheral neuropathy, your doctor will tell you to stop taking VIDEX.
After stopping VIDEX, the symptoms may get worse for a short time and then get better. Once
symptoms of peripheral neuropathy go away completely, you and your doctor should decide if
starting VIDEX is right for you. If so, you might be started at a lower dose.
Special note about other medicines. If you take VIDEX along with other medicines with
similar side effects, you may increase the chance of having these side effects. For example,
using VIDEX in combination with other medicines that may cause pancreatitis, peripheral
neuropathy, or liver problems (including stavudine and hydroxyurea) may increase your chance
of having these side effects.
Other side effects: The most common side effects in adults taking VIDEX are diarrhea,
neuropathy (nerve disorders), chills or fever, rash, abdominal pain, weakness, headache, and
nausea and vomiting. Children may have similar side effects as adults.
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Page 38 of 39
Changes in body fat have been seen in some patients taking antiretroviral therapy. These
changes may include increased amount of fat in the upper back and neck (“buffalo hump”),
breast, and around the trunk. Loss of fat from the legs, arms, and face may also happen. The
cause and long-term health effects of these conditions are not known at this time.
What else should I know about VIDEX?
If you should limit sodium (salt) intake: Each single-dose packet of Buffered Powder for
Oral Solution contains 1380 mg of sodium. Each Chewable/Dispersible Tablet contains
264.5 mg of sodium.
If you have phenylketonuria: Each Chewable/Dispersible Tablet contains 36.5 mg of
phenylalanine.
Inactive Ingredients:
Chewable/Dispersible Tablets: calcium carbonate, magnesium hydroxide,
aspartame, sorbitol, mandarin orange flavor, polyplasdone, microcrystalline
cellulose, and magnesium stearate.
Buffered Powder for Oral Solution: citrate-phosphate buffer (dibasic sodium
phosphate, sodium citrate, and citric acid) and sucrose.
Pediatric Oral Solution: Mylanta Double Strength Liquid, Extra Strength
Maalox Plus or Maalox TC Suspension.
This medicine was prescribed for your particular condition. Do not use VIDEX for another condition or give
it to others. Keep VIDEX and all medicines out of the reach of children. Throw away VIDEX when it is
outdated or no longer needed by flushing it down the toilet or pouring it down the sink.
This summary does not include everything there is to know about VIDEX. Medicines are sometimes
prescribed for purposes other than those listed in a Patient Information Leaflet. If you have questions or concerns, or
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For current labeling information, please visit https://www.fda.gov/drugsatfda
ApprovletS037.doc (clean copy 27March02)
Page 39 of 39
want more information about VIDEX, your physician and pharmacist have the complete prescribing information
upon which this leaflet is based. You may want to read it and discuss it with your doctor or other healthcare
professional. Remember, no written summary can replace careful discussion with your doctor.
Mylanta® is a registered trademark of Johnson & Johnson-Merck Consumer Pharmaceuticals Company.
Maalox® is a registered trademark of Novartis Consumer Health, Inc.
Bristol-Myers Squibb Virology
A Bristol-Myers Squibb Company
Princeton, NJ 08543 USA
This Patient Information Leaflet has been approved by the U.S. Food and Drug Administration.
xxxxxxxx
Revised __________________
Based on xxxxx (xx/02)
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
---------------------------------------------------------------------------------------------------------------------
This is a representation of an electronic record that was signed electronically and
this page is the manifestation of the electronic signature.
---------------------------------------------------------------------------------------------------------------------
/s/
---------------------
Jeffrey Murray
4/1/02 04:27:10 PM
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:46:54.087304
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2002/20154s37lbl.pdf', 'application_number': 20155, 'submission_type': 'SUPPL ', 'submission_number': 28}
|
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ApprovletS036.doc (clean copy 11/7/01)
Page 3 of 39
Rx only
VIDEX
(didanosine)
VIDEX (didanosine) Chewable/Dispersible Buffered Tablets
VIDEX (didanosine) Buffered Powder for Oral Solution
VIDEX (didanosine) Pediatric Powder for Oral Solution
(Patient Information Leaflet Included)
WARNING
FATAL AND NONFATAL PANCREATITIS HAVE OCCURRED DURING
THERAPY WITH VIDEX USED ALONE OR IN COMBINATION REGIMENS IN
BOTH TREATMENT-NAIVE AND TREATMENT-EXPERIENCED PATIENTS,
REGARDLESS OF DEGREE OF IMMUNOSUPPRESSION. VIDEX SHOULD BE
SUSPENDED IN PATIENTS WITH SUSPECTED PANCREATITIS AND
DISCONTINUED IN PATIENTS WITH CONFIRMED PANCREATITIS (SEE
WARNINGS).
LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS,
INCLUDING FATAL CASES, HAVE BEEN REPORTED WITH THE USE OF
NUCLEOSIDE ANALOGUES ALONE OR IN COMBINATION, INCLUDING
DIDANOSINE AND OTHER ANTIRETROVIRALS. FATAL LACTIC ACIDOSIS
HAS BEEN REPORTED IN PREGNANT WOMEN WHO RECEIVED THE
COMBINATION OF DIDANOSINE AND STAVUDINE WITH OTHER
ANTIRETROVIRAL AGENTS. THE COMBINATION OF DIDANOSINE AND
STAVUDINE SHOULD BE USED WITH CAUTION DURING PREGNANCY AND
IS RECOMMENDED ONLY IF THE POTENTIAL BENEFIT CLEARLY
OUTWEIGHS THE POTENTIAL RISK. (SEE WARNINGS AND PRECAUTIONS:
PREGNANCY.)
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DESCRIPTION
VIDEX (didanosine) is a brand name for didanosine (ddI), a synthetic purine nucleoside
analogue active against the Human Immunodeficiency Virus (HIV). VIDEX
Chewable/Dispersible Buffered Tablets are available for oral administration in strengths of 25,
50, 100, 150, and 200 mg of didanosine. Each tablet is buffered with calcium carbonate and
magnesium hydroxide. VIDEX tablets also contain aspartame, sorbitol, microcrystalline
cellulose, polyplasdone, mandarin-orange flavor, and magnesium stearate.
VIDEX Buffered Powder for Oral Solution is supplied for oral administration in single-
dose packets containing 100, 167, or 250 mg of didanosine. Packets of each product strength
also contain a citrate-phosphate buffer (composed of dibasic sodium phosphate, sodium citrate,
and citric acid) and sucrose.
VIDEX Pediatric Powder for Oral Solution is supplied for oral administration in 4- or
8-ounce glass bottles containing 2 or 4 grams of didanosine, respectively.
Didanosine is also available as an enteric-coated formulation (VIDEX® EC Delayed-
Release Capsules). Please consult the prescribing information for VIDEX EC (didanosine).
The chemical name for didanosine is 2',3'-dideoxyinosine. The structural formula is:
Didanosine is a white crystalline powder with the molecular formula C10H12N4O3 and a
molecular weight of 236.2. The aqueous solubility of didanosine at 25°C and pH of
approximately 6 is 27.3 mg/mL. Didanosine is unstable in acidic solutions. For example, at
pH <3 and 37°C, 10% of didanosine decomposes to hypoxanthine in less than 2 minutes.
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MICROBIOLOGY
Mechanism of Action
Didanosine is a synthetic nucleoside analogue of the naturally occurring nucleoside
deoxyadenosine in which the 3'-hydroxyl group is replaced by hydrogen. Intracellularly,
didanosine is converted by cellular enzymes to the active metabolite, dideoxyadenosine
5'-triphosphate. Dideoxyadenosine 5'-triphosphate inhibits the activity of HIV-1 reverse
transcriptase both by competing with the natural substrate, deoxyadenosine 5'-triphosphate,
and by its incorporation into viral DNA causing termination of viral DNA chain elongation.
In Vitro HIV Susceptibility
The in vitro anti-HIV-1 activity of didanosine was evaluated in a variety of HIV-1 infected
lymphoblastic cell lines and monocyte/macrophage cell cultures. The concentration of drug
necessary to inhibit viral replication by 50% (IC50) ranged from 2.5 to 10 µM (1 µM = 0.24
µg/mL) in lymphoblastic cell lines and 0.01 to 0.1 µM in monocyte/macrophage cell cultures.
The relationship between in vitro susceptibility of HIV to didanosine and the inhibition of HIV
replication in humans has not been established.
Drug Resistance
HIV-1 isolates with reduced sensitivity to didanosine have been selected in vitro and were also
obtained from patients treated with didanosine. Genetic analysis of isolates from didanosine-
treated patients showed mutations in the reverse transcriptase gene that resulted in the amino
acid substitutions K65R, L74V, and M184V. The L74V mutation was most frequently
observed in clinical isolates. Phenotypic analysis of HIV-1 isolates from 60 patients (some
with prior zidovudine treatment) receiving 6 to 24 months of didanosine monotherapy showed
that isolates from 10 of 60 patients exhibited an average of a 10-fold decrease in susceptibility
to didanosine in vitro compared to baseline isolates. Clinical isolates that exhibited a decrease
in didanosine susceptibility harbored one or more didanosine-associated mutations. The
clinical relevance of genotypic and phenotypic changes associated with didanosine therapy has
not been established.
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Cross-resistance
HIV-1 isolates from 2 of 39 patients receiving combination therapy for up to 2 years with
zidovudine and didanosine exhibited decreased susceptibility to zidovudine, didanosine,
zalcitabine, stavudine, and lamivudine in vitro. These isolates harbored five mutations (A62V,
V75I, F77L, F116Y, and Q151M) in the reverse transcriptase gene. The clinical relevance of
these observations has not been established.
CLINICAL PHARMACOLOGY
Animal Toxicology
Evidence of a dose-limiting skeletal muscle toxicity has been observed in mice and rats (but
not in dogs) following long-term (greater than 90 days) dosing with didanosine at doses that
were approximately 1.2 to 12 times the estimated human exposure. The relationship of this
finding to the potential of VIDEX (didanosine) to cause myopathy in humans is unclear.
However, human myopathy has been associated with administration of VIDEX and other
nucleoside analogues.
Pharmacokinetics
The pharmacokinetic parameters of didanosine are summarized in Table 1. Didanosine is
rapidly absorbed, with peak plasma concentrations generally observed from 0.25 to 1.50 hours
following oral dosing. Increases in plasma didanosine concentrations were dose proportional
over the range of 50 to 400 mg. Steady-state pharmacokinetic parameters did not differ
significantly from values obtained after a single dose. Binding of didanosine to plasma
proteins in vitro was low (<5%). Based on data from in vitro and animal studies, it is presumed
that the metabolism of didanosine in man occurs by the same pathways responsible for the
elimination of endogenous purines.
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Page 7 of 39
Table 1:
Mean ± SD Pharmacokinetic Parameters for Didanosine in
Adult and Pediatric Patients
Parameter
Adult Patients
n
Pediatric Patients
n
Oral bioavailability
42 ± 12%
6
25 ± 20%
46
Apparent volume of distributiona
1.08 ± 0.22 L/kg
6
28 ± 15 L/m2
49
CSF-plasma ratiob
21 ± 0.03%c
5
46% (range 12-85%)
7
Systemic clearancea
13.0 ± 1.6
mL/min/kg
6
516 ± 184
mL/min/m2
49
Renal clearanced
5.5 ± 2.1
mL/min/kg
6
240 ± 90 mL/min/m2
15
Elimination half-lifed
1.5 ± 0.4 h
6
0.8 ± 0.3 h
60
Urinary recovery of didanosined
18 ± 8%
6
18 ± 10%
15
CSF = cerebrospinal fluid
a following IV administration
b following IV administration in adults and IV or oral administration in pediatric patients
c mean ± SE
d following oral administration
Effect of Food on Absorption of Didanosine: Didanosine peak plasma
concentrations (CMAX) and area under the plasma concentration time curve (AUC) were
decreased by approximately 55% when VIDEX tablets were administered up to 2 hours after a
meal. Administration of VIDEX tablets up to 30 minutes before a meal did not result in any
significant changes in bioavailability. VIDEX should be taken on an empty stomach, at least
30 minutes before or 2 hours after eating. (See DOSAGE AND ADMINISTRATION.)
Special Populations
Renal Insufficiency: It is recommended that the VIDEX (didanosine) dose be modified in
patients with reduced creatinine clearance and in patients receiving maintenance hemodialysis
(see DOSAGE AND ADMINISTRATION). Data from two studies indicated that the
apparent oral clearance of didanosine decreased and the terminal elimination half-life
increased as creatinine clearance decreased (see Table 2). Following oral administration,
didanosine was not detectable in peritoneal dialysate fluid (n=6); recovery in hemodialysate
(n=5) ranged from 0.6% to 7.4% of the dose over a 3-4 hour dialysis period. The absolute
bioavailability of didanosine was not affected in patients requiring dialysis.
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Table 2:
Mean ± SD Pharmacokinetic Parameters for Didanosine
Following a Single Oral Dose
Creatinine Clearance (mL/min)
Parameter
≥ 90 (n=12)
60-90 (n=6)
30-59 (n=6)
10-29 (n=3)
Dialysis Patients
(n=11)
CLcr (mL/min)
112 ± 22
68 ± 8
46 ± 8
13 ± 5
NDa
CL/F (mL/min)
2164 ± 638
1566 ± 833
1023 ± 378
628 ± 104
543 ± 174
CLR (mL/min)
458 ± 164
247 ± 153
100 ± 44
20 ± 8
<10
T½ (h)
1.42 ± 0.33
1.59 ± 0.13
1.75 ± 0.43
2.0 ± 0.3
4.1 ± 1.2
a ND = not determined due to anuria
CLcr = creatinine clearance
CL/F = apparent oral clearance
CLR = renal clearance
Pediatric Patients: The pharmacokinetics of didanosine have been evaluated in
HIV-infected pediatric patients from 0.7 to 18.9 years of age (see Table 1). Overall, the
pharmacokinetics of didanosine in pediatric patients greater than 0.7 years of age are similar to
those of didanosine in adults. Didanosine plasma concentrations increased in proportion to oral
doses ranging from 80 to 180 mg/m2. For information on controlled clinical studies in
pediatric patients, see PRECAUTIONS: Pediatric Use and Clinical Studies.
Geriatric Patients: Didanosine pharmacokinetics have not been studied in patients
over 65 years of age.
Gender: The effects of gender on didanosine pharmacokinetics have not been studied.
Drug Interactions: Tables 3 and 4 summarize the effects on AUC and CMAX, with a
90% or 95% confidence interval (CI) when available, following coadministration of VIDEX
with a variety of drugs. For most of the listed drugs, no clinically significant pharmacokinetic
interactions were observed. Clinical recommendations based on drug interaction studies for
drugs in bold font are included in PRECAUTIONS: Drug Interactions.
Table 3:
Results of Drug Interaction Studies: Effects of
Coadministered Drug on Didanosine Plasma AUC and CMAX
Values
Drugs With Clinical Recommendations Regarding Coadministration (see PRECAUTIONS: Drug Interactions)
Drug
Didanosine Dosage
n
AUC of
Didanosine
(95% CI)
CMAX of
Didanosine (95%
CI)
allopurinol
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Table 3:
Results of Drug Interaction Studies: Effects of
Coadministered Drug on Didanosine Plasma AUC and CMAX
Values
renally impaired, 300 mg/day
200 mg single dose
2
↑312%
↑232%
healthy volunteer, 300 mg/day
for 7 days
400 mg single dose
14
↑113%
↑69%
ciprofloxacin, 750 mg q12h for
3 days, 2 h before didanosine
200 mg q12h for 3
days
8a
↓16%
↓28%
ganciclovir, 1000 mg q8h, 2 h
after didanosine
200 mg q12h
12
↑111%
NA
indinavir, 800 mg single dose
simultaneous
1 h before didanosine
200 mg single dose
200 mg single dose
16
16
↔
↓17% (-27, - 7%)b
↔
↓13% (-28, 5%)b
ketoconazole, 200 mg/day for 4
days, 2 h before didanosine
375 mg q12h for 4
days
12a
↔
↓12%
methadone, chronic
maintenance dose
200 mg single dose
16,10c
↓57%
↓66%
No Clinically Significant Interaction Observed
Drug
Didanosine Dosage
n
AUC of
Didanosine
(95% CI)
CMAX of
Didanosine (95%
CI)
loperamide, 4 mg q6h for 1 day
300 mg single dose
12a
↔
↓23%
metoclopramide, 10 mg single
dose
300 mg single dose
12a
↔
↑13%
ranitidine, 150 mg single dose,
2 h before didanosine
375 mg single dose
12a
↑14%
↑13%
rifabutin, 300 or 600 mg/day
for 12 days
167 or 250 mg q12h
for 12 days
11
↑13% (-1, 27%)
↑17% (-4, 38%)
ritonavir, 600 mg q12h for 4
days
200 mg q12h for 4
days
12
↓13% (0, 23%)
↓16% (5, 26%)
stavudine, 40 mg q12h for 4
days
100 mg q12h for 4
days
10
↔
↔
sulfamethoxazole, 1000 mg
single dose
200 mg single dose
8a
↔
↔
trimethoprim, 200 mg single
dose
200 mg single dose
8a
↔
↑17% (-23, 77%)
zidovudine, 200 mg q8h for 3
days
200 mg q12h for 3
days
6a
↔
↔
↑ indicates increase.
↓ indicates decrease.
↔ indicates no change, or mean increase or decrease of <10%.
a HIV-infected patients.
b 90% CI.
c Parallel-group design; entries are subjects receiving combination and control regimens, respectively.
NA Not available.
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Table 4:
Results of Drug Interaction Studies: Effects of Didanosine on
Coadministered Drug Plasma AUC and CMAX Values
Drugs With Clinical Recommendations Regarding Coadministration (see PRECAUTIONS: Drug Interactions)
Drug
Didanosine Dosage
n
AUC of
Coadministered
Drug (95% CI)
CMAX of
Coadministered
Drug (95% CI)
ciprofloxacin
750 mg q12h for 3 days, 2 h
before didanosine
750 mg single dose
200 mg q12h for 3 days
buffered placebo tablet
8a
12
↓26%
↓98%
↓16%
↓93%
delavirdine, 400 mg single dose
simultaneous
1 h before didanosine
125 or 200 mg q12h
125 or 200 mg q12h
12a
12a
↓32%
↑20%
↓53%
↑18%
ganciclovir, 1000 mg q8h, 2 h
after didanosine
200 mg q12h
12a
↓21%
NA
indinavir, 800 mg single dose
simultaneous
1 h before didanosine
200 mg single dose
200 mg single dose
16
16
↓84%
↓11%
↓82%
↓4%
ketoconazole, 200 mg/day for 4
days, 2 h before didanosine
375 mg q12h for 4 days
12a
↓14%
↓20%
nelfinavir, 750 mg single dose, 1
h after didanosine
200 mg single dose
10a
↑12%
↔
No Clinically Significant Interaction Observed
Drug
Didanosine Dosage
n
AUC of
Coadministered
Drug (95% CI)
CMAX of
Coadministered
Drug (95% CI)
dapsone, 100 mg single dose
200 mg q12h for 14
days
6a
↔
↔
ranitidine, 150 mg single dose, 2 h
before didanosine
375 mg single dose
12a
↓16%
↔
ritonavir, 600 mg q12h for 4 days
200 mg q12h for 4
days
12
↔
↔
stavudine, 40 mg q12h for 4 days
100 mg q12h for 4
days
10a
↔
↑17%
sulfamethoxazole, 1000 mg single
dose
200 mg single dose
8a
↓11% (-17, -4%)
↓12% (-28, 8%)
trimethoprim, 200 mg single dose
200 mg single dose
8a
↑10% (-9, 34%)
↓22% (-59, 49%)
zidovudine, 200 mg q8h for 3 days
200 mg q12h for 3
days
6a
↓10% (-27, 11%)
↓16.5% (-53, 47%)
↑ indicates increase.
↓ indicates decrease.
↔ indicates no change, or mean increase or decrease of <10%.
a HIV-infected patients.
NA Not available.
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INDICATIONS AND USAGE
VIDEX in combination with other antiretroviral agents is indicated for the treatment of
HIV-1 infection (see Clinical Studies).
Clinical Studies
Combination Therapy
START 2 was a multicenter, randomized, open-label study comparing VIDEX (200 mg twice
daily)/stavudine/indinavir to zidovudine/lamivudine/indinavir in 205 treatment-naive patients.
Both regimens resulted in a similar magnitude of suppression of HIV RNA levels and
increases in CD4 cell counts through 48 weeks.
Study A1454-148 was a randomized, open-label, multicenter study comparing
treatment with VIDEX (400 mg once daily) plus stavudine (40 mg twice daily) and nelfinavir
(750 mg three times daily) versus zidovudine (300 mg twice daily) plus lamivudine (150 mg
twice daily) and nelfinavir (750 mg three times daily) in 756 treatment-naive patients, with a
median CD4 cell count of 340 cells/mm3 (range 80 to 1568 cells/mm3) and a median plasma
HIV-1 RNA of 4.69 log10 copies/mL (range 2.6 to 5.9 log10 copies/mL) at baseline. Median
CD4 cell count increases at 48 weeks were 188 cells/mm3 in both treatment groups. Treatment
response and outcomes through 48 weeks are shown in Figure 1 and Table 5.
Figure 1:
Treatment Response Through Week 48*, AI454-148
* Percent of patients at each time point who have HIV RNA <400 or <50
copies/mL, are on their original study medication (except stavudine-
zidovudine switches), and have not experienced an AIDS-defining event.
0
20
40
60
80
100
0
8
16
24
32
40
48
Study Week
Percent of patients
] < 400 c/mL
] < 50 c/mL
VIDEX+stavudine+nelfinavir (n=503)
zidovudine+lamivudine+nelfinavir (n=253)
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Table 5:
Outcomes of Randomized Treatment through Week 48, AI454-148
Percent of Patients with HIV RNA <400 copies/mL (<50 copies/mL)
VIDEX/stavudine/nelfinavir
lamivudine/zidovudine/nelfinavir
Week 48 Status
n=503
n=253
Responder a
50* (34*)
59 (47)
Virologic failureb
36 (57)
32 (48)
Death or disease progression
<1 (<1)
1 (<1)
Discontinued due to adverse events
4 (2)
2 (<1)
Discontinued due to other reasonsc
6 (3)
4 (2)
Never initiated treatment
4 (4)
2 (2)
* <0.05 for the differences between treatment groups, by Cochran-Mantel-Haenszel test.
a Patients achieved virologic response [two consecutive viral load <400 (<50) copies/mL] and maintained it to
Week 48.
b Includes viral rebound and failing to achieve confirmed <400 (<50) copies/mL by Week 48.
c Includes lost to follow-up, noncompliance, withdrawal, and pregnancy.
Monotherapy
The efficacy of VIDEX was demonstrated in two randomized, double-blind studies comparing
VIDEX, given on a twice-daily schedule, to zidovudine, given three times daily, in 617
(ACTG 116A, conducted 1989-1992) and 913 (ACTG116B/117, conducted 1989-1991)
patients with symptomatic HIV infection or AIDS who were treated for more than one year. In
treatment-naive patients (ACTG 116A), the rate of HIV disease progression or death was
similar between the treatment groups; mortality rates were 26% for patients receiving VIDEX
and 21% for patients receiving zidovudine. Of the patients who had received previous
zidovudine treatment (ACTG 116B/117), those treated with VIDEX had a lower rate of HIV
disease progression or death (32%) compared to those treated with zidovudine (41%);
however, survival rates were similar between the treatment groups.
Efficacy in pediatric patients was demonstrated in a randomized, double-blind,
controlled study (ACTG 152, conducted 1991-1995) involving 831 patients treated for more
than 1.5 years with zidovudine (180 mg/m2 q6h), VIDEX (120 mg/m2 q12h), or zidovudine
(120 mg/m2 q6h) plus VIDEX (90 mg/m2 q12h). Patients treated with VIDEX or VIDEX plus
zidovudine had lower rates of HIV disease progression or death compared with those treated
with zidovudine alone.
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Studies have demonstrated that the clinical benefit of monotherapy with antiretrovirals,
including VIDEX, was time limited.
CONTRAINDICATION
VIDEX (didanosine) is contraindicated in patients with previously demonstrated clinically
significant hypersensitivity to any of the components of the formulations.
WARNINGS
1.
Pancreatitis
FATAL AND NONFATAL PANCREATITIS HAVE OCCURRED DURING
THERAPY WITH VIDEX USED ALONE OR IN COMBINATION REGIMENS IN
BOTH TREATMENT-NAIVE AND TREATMENT-EXPERIENCED PATIENTS,
REGARDLESS OF DEGREE OF IMMUNOSUPPRESSION. VIDEX SHOULD BE
SUSPENDED IN PATIENTS WITH SIGNS OR SYMPTOMS OF PANCREATITIS
AND DISCONTINUED IN PATIENTS WITH CONFIRMED PANCREATITIS.
PATIENTS TREATED WITH VIDEX IN COMBINATION WITH STAVUDINE,
WITH OR WITHOUT HYDROXYUREA, MAY BE AT INCREASED RISK FOR
PANCREATITIS.
When treatment with life-sustaining drugs known to cause pancreatic toxicity is
required, suspension of VIDEX (didanosine) therapy is recommended. In patients with risk
factors for pancreatitis, VIDEX should be used with extreme caution and only if clearly
indicated. Patients with advanced HIV infection, especially the elderly, are at increased risk of
pancreatitis and should be followed closely. Patients with renal impairment may be at greater
risk for pancreatitis if treated without dose adjustment.
The frequency of pancreatitis is dose related. In phase 3 studies, incidence ranged from
1% to 10% with doses higher than are currently recommended and 1% to 7% with
recommended dose.
In pediatric studies, pancreatitis occurred in 3% (2/60) of patients treated at entry doses
below 300 mg/m2/day and in 13% (5/38) of patients treated at higher doses. VIDEX use should
be suspended in pediatric patients with signs or symptoms of pancreatitis and discontinued in
pediatric patients with confirmed pancreatitis.
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2.
Lactic Acidosis/Severe Hepatomegaly with Steatosis
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have
been reported with the use of nucleoside analogues alone or in combination, including
didanosine and other antiretrovirals. A majority of these cases have been in women.
Obesity and prolonged nucleoside exposure may be risk factors. Fatal lactic acidosis has been
reported in pregnant women who received the combination of didanosine and stavudine with
other antiretroviral agents. The combination of didanosine and stavudine should be used with
caution during pregnancy and is recommended only if the potential benefit clearly outweighs
the potential risk (see PRECAUTIONS: Pregnancy). Particular caution should be exercised
when administering VIDEX to any patient with known risk factors for liver disease; however,
cases have also been reported in patients with no known risk factors. Treatment with VIDEX
should be suspended in any patient who develops clinical or laboratory findings suggestive of
lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis
even in the absence of marked transaminase elevations).
3.
Retinal Changes and Optic Neuritis
Retinal changes and optic neuritis have been reported in adult and pediatric patients.
Periodic retinal examinations should be considered for patients receiving VIDEX. (See
ADVERSE REACTIONS.)
PRECAUTIONS
Frequency of Dosing
The preferred dosing frequency of VIDEX is twice daily because there is more evidence to
support the effectiveness of this dosing frequency. Once-daily dosing should be considered
only for adult patients whose management requires once-daily dosing of VIDEX (see Clinical
Studies).
VIDEX should be taken on an empty stomach, at least 30 minutes before or 2
hours after eating.
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Peripheral Neuropathy
Peripheral neuropathy, manifested by numbness, tingling, or pain in the hands or feet, has been
reported in patients receiving VIDEX therapy. Peripheral neuropathy has occurred more
frequently in patients with advanced HIV disease, in patients with a history of neuropathy, or
in patients being treated with neurotoxic drug therapy, including stavudine (see ADVERSE
REACTIONS).
Fat Redistribution
Redistribution/accumulation of body fat including central obesity, dorsocervical fat
enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and
“cushingoid appearance” have been observed in patients receiving antiretroviral therapy. The
mechanism and long-term consequences of these events are currently unknown. A causal
relationship has not been established.
General
Patients with Phenylketonuria: VIDEX Chewable/Dispersible Buffered Tablets contain
the following quantities of phenylalanine:
Table 6
All Strengths
Phenylalanine per 2-tablet dose
73 mg
Phenylalanine per tablet
36.5 mg
Patients on Sodium-Restricted Diets: VIDEX Buffered Powder for Oral
Solution: Each single-dose packet of VIDEX Buffered Powder for Oral Solution contains 1380
mg sodium.
Patients with Renal Impairment: Patients with renal impairment (creatinine
clearance <60 mL/min) may be at greater risk of toxicity from VIDEX due to decreased drug
clearance (see CLINICAL PHARMACOLOGY). A dose reduction is recommended in these
patients (see DOSAGE AND ADMINISTRATION). The magnesium content of each
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buffered tablet of VIDEX is 8.6 mEq. This may present an excessive load of magnesium to
patients with significant renal impairment, particularly after prolonged dosing.
Patients with Hepatic Impairment: It is unknown if hepatic impairment
significantly affects didanosine pharmacokinetics. Therefore, these patients should be
monitored closely for evidence of didanosine toxicity.
Hyperuricemia: VIDEX has been associated with asymptomatic hyperuricemia;
treatment suspension may be necessary if clinical measures aimed at reducing uric acid levels
fail.
Information for Patients (See Patient Information Leaflet.)
Patients should be informed that a serious toxicity of VIDEX used alone and in combination
regimens, is pancreatitis, which may be fatal.
Patients should be informed that the preferred dosing frequency of VIDEX is twice
daily because there is more evidence to support the effectiveness of this dosing frequency.
Once-daily dosing should be considered only for adult patients whose management requires
once-daily dosing of VIDEX.
Patients should also be aware that peripheral neuropathy, manifested by numbness,
tingling, or pain in hands or feet, may develop during therapy with VIDEX. Patients should be
counseled that peripheral neuropathy occurs with greatest frequency in patients with advanced
HIV disease or a history of peripheral neuropathy, and that dose modification and/or
discontinuation of VIDEX may be required if toxicity develops.
Patients should be informed that when VIDEX is used in combination with other
agents with similar toxicities, the incidence of adverse events may be higher than when
VIDEX is used alone. These patients should be followed closely.
Patients should be cautioned about the use of medications or other substances,
including alcohol, that may exacerbate VIDEX toxicities.
Patients should be advised that to ensure proper acid neutralization in the stomach they
must take at least two of the appropriate strength VIDEX tablets at each dose. To reduce the
risk of gastrointestinal side effects from excess antacid, patients should take no more than four
VIDEX tablets at each dose.
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VIDEX (didanosine) is not a cure for HIV infection, and patients may continue to
develop HIV-associated illnesses, including opportunistic infection. Therefore, patients should
remain under the care of a physician when using VIDEX. Patients should be advised that
VIDEX therapy has not been shown to reduce the risk of transmission of HIV to others
through sexual contact or blood contamination. Patients should be informed that the long-term
effects of VIDEX are unknown at this time.
Patients should be informed that redistribution or accumulation of body fat may occur
in patients receiving antiretroviral therapy and that the cause and long-term health effects of
these conditions are not known at this time.
Drug Interactions (see also CLINICAL PHARMACOLOGY: Drug
Interactions)
Drug interactions that have been established based on drug interaction studies are listed with
the pharmacokinetic results in CLINICAL PHARMACOLOGY: Drug Interactions (Tables
3 and 4). The clinical recommendations based on the results of these studies are listed in Table
7.
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Table 7:
Established Drug Interactions with VIDEX
Coadministration Not Recommended Based on Drug Interaction Studies (see CLINICAL
PHARMACOLOGY: Drug Interactions for Magnitude of Interaction)
Drug
Effect
Clinical Comment
allopurinol
↑ didanosine concentration
Coadministration not recommended.
Alteration in Dose or Regimen Recommended Based on Drug Interaction Studies (see CLINICAL
PHARMACOLOGY: Drug Interactions for Magnitude of Interaction)
Drug
Effect
Clinical Comment
ciprofloxacin
↓ ciprofloxacin concentration
Administer VIDEX at least 2 hours after or
6 hours before ciprofloxacin.
delavirdine
↓ delavirdine concentration
Administer VIDEX 1 hour after delavirdine.
ganciclovir
↑ didanosine concentration
Appropriate doses for this combination,
with respect to efficacy and safety, have not
been established.
indinavir
↓ indinavir concentration
Administer VIDEX 1 hour after indinavir.
methadone
↓ didanosine concentration
Appropriate doses for this combination,
with respect to efficacy and safety, have not
been established.
nelfinavir
No interaction 1 hour after didanosine
Administer nelfinavir 1 hour after VIDEX.
↑ indicates increase.
↓ indicates decrease.
Coadministration of VIDEX with drugs that are known to cause pancreatitis may
increase the risk of this toxicity (see WARNINGS: Pancreatitis). Because VIDEX
formulations either contain buffers or are mixed with antacids before administration,
interactions may be anticipated with drugs whose absorption can be affected by the level of
acidity in the stomach and with drugs that have been demonstrated to interact with antacids
containing magnesium, calcium, or aluminum. Predicted drug interactions with VIDEX are
listed in Table 8.
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Table 8:
Predicted Drug Interactions with VIDEX
Use with Caution, Risk of Adverse Reactions May Be Increased
Drug Class
Effect
Clinical Comment
Drugs that may cause
pancreatic toxicity
↑ risk of pancreatitis
Use only with extreme caution.a
Neurotoxic drugs
↑ risk of neuropathy
Use with caution.b
Antacids containing
magnesium or aluminum
↑ side effects associated with
antacid components
Use caution with VIDEX
Chewable/Dispersible Buffered Tablets
and Pediatric Powder for Oral Solution.
Use with Caution, Plasma Concentrations May Be Decreased by Coadministration with VIDEX
Drug Class
Effect
Clinical Comment
Azole antifungals
↓ ketoconazole or itraconazole
concentration
Administer drugs such as ketoconazole or
itraconazole at least 2 hours before
VIDEX.
Quinolone antibiotics (see
also ciprofloxacin in Table 7)
↓ quinolone concentration
Consult package insert of the quinolone.
Tetracycline antibiotics
↓ antibiotic concentration
Consult package insert of the tetracycline.
↑ indicates increase.
↓ indicates decrease.
a Only if other drugs are not available and if clearly indicated. If treatment with life-sustaining drugs that
cause pancreatic toxicity is required, suspension of VIDEX is recommended (see WARNINGS:
Pancreatitis).
b See PRECAUTIONS: Peripheral Neuropathy.
Carcinogenesis and Mutagenesis
Lifetime carcinogenicity studies were conducted in mice and rats for 22 and 24 months,
respectively. In the mouse study, initial doses of 120, 800, and 1200 mg/kg/day for each sex
were lowered after 8 months to 120, 210, and 210 mg/kg/day for females and 120, 300, and
600 mg/kg/day for males. The two higher doses exceeded the maximally tolerated dose in
females and the high dose exceeded the maximally tolerated dose in males. The low dose in
females represented 0.68-fold maximum human exposure and the intermediate dose in males
represented 1.7-fold maximum human exposure based on relative AUC comparisons. In the
rat study, initial doses were 100, 250, and 1000 mg/kg/day, and the high dose was lowered to
500 mg/kg/day after 18 months. The upper dose in male and female rats represented 3-fold
maximum human exposure.
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Didanosine induced no significant increase in neoplastic lesions in mice or rats at
maximally tolerated doses.
Didanosine was positive in the following genetic toxicology assays: 1) the Escherichia
coli tester strain WP2 uvrA bacterial mutagenicity assay; 2) the L5178Y/TK+/- mouse
lymphoma mammalian cell gene mutation assay; 3) the in vitro chromosomal aberrations assay
in cultured human peripheral lymphocytes; 4) the in vitro chromosomal aberrations assay in
Chinese Hamster Lung cells; and 5) the BALB/c 3T3 in vitro transformation assay. No
evidence of mutagenicity was observed in an Ames Salmonella bacterial mutagenicity assay or
in rat and mouse in vivo micronucleus assays.
Pregnancy, Reproduction, and Fertility
Pregnancy Category B. Reproduction studies have been performed in rats and rabbits at doses
up to 12 and 14.2 times the estimated human exposure (based upon plasma levels),
respectively, and have revealed no evidence of impaired fertility or harm to the fetus due to
didanosine. At approximately 12 times the estimated human exposure, didanosine was slightly
toxic to female rats and their pups during mid and late lactation. These rats showed reduced
food intake and body weight gains but the physical and functional development of the
offspring was not impaired and there were no major changes in the F2 generation. A study in
rats showed that didanosine and/or its metabolites are transferred to the fetus through the
placenta. Animal reproduction studies are not always predictive of human response.
There are no adequate and well-controlled studies of didanosine in pregnant women.
Didanosine should be used during pregnancy only if the potential benefit justifies the potential
risk.
Fatal lactic acidosis has been reported in pregnant women who received the
combination of didanosine and stavudine with other antiretroviral agents. It is unclear if
pregnancy augments the risk of lactic acidosis/hepatic steatosis syndrome reported in
nonpregnant individuals receiving nucleoside analogues (see WARNINGS: Lactic
Acidosis/Severe Hepatomegaly with Steatosis). The combination of didanosine and
stavudine should be used with caution during pregnancy and is recommended only if the
potential benefit clearly outweighs the potential risk. Health care providers caring for HIV-
infected pregnant women receiving didanosine should be alert for early diagnosis of lactic
acidosis/hepatic steatosis syndrome.
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Antiretroviral Pregnancy Registry: To monitor maternal-fetal outcomes of
pregnant women exposed to didanosine and other antiretroviral agents, an Antiretroviral
Pregnancy Registry has been established. Physicians are encouraged to register patients by
calling 1-800-258-4263.
Nursing Mothers
The Centers for Disease Control and Prevention recommend that HIV-infected mothers
not breast-feed their infants to avoid risking postnatal transmission of HIV. A study in
rats showed that following oral administration, didanosine and/or its metabolites were excreted
into the milk of lactating rats. It is not known if didanosine is excreted in human milk.
Because of both the potential for HIV transmission and the potential for serious adverse
reactions in nursing infants, mothers should be instructed not to breast-feed if they are
receiving VIDEX.
Pediatric Use
Use of VIDEX in pediatric patients is supported by evidence from adequate and well-
controlled studies of VIDEX in adults and pediatric patients (see Clinical Studies,
CLINICAL PHARMACOLOGY, ADVERSE REACTIONS, and DOSAGE AND
ADMINISTRATION).
Geriatric Use
In an Expanded Access Program for patients with advanced HIV infection, patients aged 65
years and older had a higher frequency of pancreatitis (10%) than younger patients (5%) (see
WARNINGS). Clinical studies of didanosine did not include sufficient numbers of subjects
aged 65 years and over to determine whether they respond differently than younger subjects.
Didanosine is known to be substantially excreted by the kidney, and the risk of toxic reactions
to this drug may be greater in patients with impaired renal function. Because elderly patients
are more likely to have decreased renal function, care should be taken in dose selection. In
addition, renal function should be monitored and dosage adjustments should be made
accordingly (see DOSAGE AND ADMINISTRATION: Dose Adjustment).
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ADVERSE REACTIONS
A SERIOUS TOXICITY OF VIDEX (didanosine) IS PANCREATITIS, WHICH MAY BE
FATAL (see WARNINGS). OTHER IMPORTANT TOXICITIES INCLUDE LACTIC
ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS; RETINAL CHANGES AND
OPTIC NEURITIS; AND PERIPHERAL NEUROPATHY (see WARNINGS and
PRECAUTIONS).
When VIDEX is used in combination with other agents with similar toxicities, the
incidence of these toxicities may be higher than when VIDEX is used alone. Thus,
patients treated with VIDEX in combination with stavudine, with or without
hydroxyurea, may be at increased risk for pancreatitis, which may be fatal, and
hepatotoxicity (see WARNINGS). Patients treated with VIDEX in combination with
stavudine may also be at increased risk for peripheral neuropathy (see
PRECAUTIONS).
Adults: Selected clinical adverse events that occurred in adult patients in clinical
studies with VIDEX are provided in Tables 9 and 10.
Table 9:
Selected Clinical Adverse Events from Monotherapy
Studies
Percent of Patients
ACTG 116A
ACTG 116B/117
VIDEX
zidovudine
VIDEX
zidovudine
Adverse Events
n=197
n=212
n=298
n=304
Diarrhea
19
15
28
21
Peripheral Neurologic
Symptoms/Neuropathy
17
14
20
12
Rash/Pruritus
7
8
9
5
Abdominal Pain
13
8
7
8
Pancreatitis
7
3
6
2
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Table 10:
Selected Clinical Adverse Events from Combination
Studies
Percent of Patientsa
AI454-148b
START 2b
VIDEX +
stavudine +
nelfinavir
zidovudine +
lamivudine +
nelfinavir
VIDEX +
stavudine +
indinavir
zidovudine +
lamivudine +
indinavir
Adverse Events
n=482
n=248
n=102
n=103
Diarrhea
70
60
45
39
Nausea
28
40
53
67
Headache
21
30
46
37
Peripheral Neurologic
Symptoms/Neuropathy
26
6
21
10
Rash
13
16
30
18
Vomiting
12
14
30
35
Pancreatitis (see below)
1
*
<1
*
a Percentages based on treated subjects.
b Median duration of treatment 48 weeks.
* This event was not observed in this study arm.
Pancreatitis resulting in death was observed in one patient who received VIDEX
plus stavudine plus nelfinavir in Study Al454-148 and in one patient who received
VIDEX plus stavudine plus indinavir in the START 2 study. In addition, pancreatitis
resulting in death was observed in 2 of 68 patients who received VIDEX plus stavudine
plus indinavir plus hydroxyurea in an ACTG clinical trial (see WARNINGS).
The frequency of pancreatitis is dose related. In phase 3 studies, incidence ranged from
1% to 10% with doses higher than are currently recommended and from 1% to 7% with
recommended dose.
Selected laboratory abnormalities in clinical studies with VIDEX are shown in
Tables 11-13.
Table 11:
Selected Laboratory Abnormalities from Monotherapy Studies
Percent of Patients
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Table 11:
Selected Laboratory Abnormalities from Monotherapy Studies
ACTG 116A
ACTG 116B/117
VIDEX
zidovudine
VIDEX
zidovudine
Parameter
n=197
n=212
n=298
n=304
SGOT (AST) (>5 x ULN)
9
4
7
6
SGPT (ALT) (>5 x ULN)
9
6
6
6
Alkaline phosphatase
(>5 x ULN)
4
1
1
1
Amylase (≥1.4 x ULN)
17
12
15
5
Uric acid (>12 mg/dL)
3
1
2
1
ULN = upper limit of normal.
Table 12:
Selected Laboratory Abnormalities from Combination
Studies (Grades 3-4)
Percent of Patientsa
AI454-148b
START 2b
VIDEX +
stavudine +
nelfinavir
zidovudine +
lamivudine +
nelfinavir
VIDEX +
stavudine +
indinavir
zidovudine +
lamivudine +
indinavir
Parameter
n=482
n=248
n=102
n=103
Bilirubin (>2.6 x ULN)
<1
<1
16
8
SGOT (AST) (>5 x ULN)
3
2
7
7
SGPT (ALT) (>5 x ULN)
3
3
8
5
GGT (>5 x ULN)
NC
NC
5
2
Lipase (>2 x ULN)
7
2
5
5
Amylase (>2 x ULN)
NC
NC
8
2
ULN = upper limit of normal.
NC=Not Collected
a Percentages based on treated subjects.
b Median duration of treatment 48 weeks.
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Table 13:
Selected Laboratory Abnormalities from Combination
Studies (All Grades)
Percent of Patientsa
I454-148b
START 2b
VIDEX +
stavudine +
nelfinavir
zidovudine +
lamivudine +
nelfinavir
VIDEX +
stavudine +
indinavir
zidovudine +
lamivudine +
indinavir
Parameter
n=482
n=248
n=102
n=103
Bilirubin
7
3
68
55
SGOT (AST)
42
23
53
20
SGPT (ALT)
37
24
50
18
GGT
NC
NC
28
12
Lipase
17
11
26
19
Amylase
NC
NC
31
17
NC = Not Collected
a Percentages based on treated subjects.
b Median duration of treatment 48 weeks.
Observed during Clinical Practice: The following events have been identified
during postapproval use of VIDEX (didanosine). Because they are reported voluntarily from a
population of unknown size, estimates of frequency cannot be made. These events have been
chosen for inclusion due to their seriousness, frequency of reporting, causal connection to
VIDEX, or a combination of these factors.
Body as a Whole - alopecia, anaphylactoid reaction, asthenia, chills/fever, pain, and
redistribution/accumulation of body fat (see PRECAUTIONS: Fat Redistribution).
Digestive Disorders- anorexia, dyspepsia, and flatulence.
Exocrine Gland Disorders – pancreatitis (including fatal cases) (see WARNINGS),
sialoadenitis, parotid gland enlargement, dry mouth, and dry eyes.
Hematologic Disorders - anemia, leukopenia, and thrombocytopenia.
Liver - lactic acidosis and hepatic steatosis (see WARNINGS); hepatitis and liver
failure.
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Metabolic Disorders - diabetes mellitus, hypoglycemia, and hyperglycemia.
Musculoskeletal Disorders - myalgia (with or without increases in creatine kinase),
rhabdomyolysis including acute renal failure and hemodialysis, arthralgia, and
myopathy.
Ophthalmologic Disorders - Retinal depigmentation and optic neuritis (see
WARNINGS).
Pediatric Patients: Adverse events and laboratory abnormalities reported to occur
in the pediatric patients in ACTG 152 were generally similar to adverse events and laboratory
abnormalities reported in adult patients.
In pediatric phase 1 studies, pancreatitis occurred in 2 of 60 (3%) patients treated at
entry doses below 300 mg/m2/day and in 5 of 38 (13%) patients treated at higher doses.
Retinal changes and optic neuritis have been reported in pediatric patients.
OVERDOSAGE
There is no known antidote for VIDEX (didanosine) overdosage. In phase 1 studies, in which
VIDEX was initially administered at doses ten times the currently recommended dose,
toxicities included: pancreatitis, peripheral neuropathy, diarrhea, hyperuricemia and hepatic
dysfunction. Didanosine is not dialyzable by peritoneal dialysis, although there is some
clearance by hemodialysis (see CLINICAL PHARMACOLOGY: Pharmacokinetics).
DOSAGE AND ADMINISTRATION
Dosage
All VIDEX formulations should be administered on an empty stomach, at least 30
minutes before or 2 hours after eating. For either a once-daily or twice-daily regimen,
patients must take at least two of the appropriate strength tablets at each dose to provide
adequate buffering and prevent gastric acid degradation of didanosine. Because of the
need for adequate buffering, the 200-mg strength tablet should only be used as a
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component of a once-daily regimen. To reduce the risk of gastrointestinal side effects,
patients should take no more than four tablets at each dose.
Adults: The preferred dosing frequency of VIDEX is twice daily because there is
more evidence to support the effectiveness of this dosing regimen. Once-daily dosing should
be considered only for adult patients whose management requires once-daily dosing of VIDEX
(see Clinical Studies). The daily dose in adult patients is dependent on weight as outlined in
Table 14.
Table 14:
Adult Dosing
Patient Weight
VIDEX Tabletsa
VIDEX Buffered Powderb
Preferred dosing
≥60 kg
200 mg twice daily
250 mg twice daily
< 60 kg
125 mg twice daily
167 mg twice daily
Dosing for patients whose management requires once-daily frequency
≥ 60 kg
400 mg once daily
b
< 60 kg
250 mg once daily
b
a The 200-mg strength tablet should only be used as a component of a once-
daily regimen.
b Not suitable for once-daily dosing except for patients with renal impairment.
See Table 15.
Pediatric Patients: The recommended dose of VIDEX (didanosine) in pediatric
patients is 120 mg/m2 twice daily. There are no data on once-daily dosing of VIDEX in
pediatric patients.
Dose Adjustment
Clinical and laboratory signs suggestive of pancreatitis should prompt dose suspension
and careful evaluation of the possibility of pancreatitis. VIDEX use should be
discontinued in patients with confirmed pancreatitis (see WARNINGS).
Patients with symptoms of peripheral neuropathy may tolerate a reduced dose of
VIDEX after resolution of the symptoms of peripheral neuropathy upon drug discontinuation.
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If neuropathy recurs after resumption of VIDEX, permanent discontinuation of VIDEX should
be considered.
Renal Impairment: In adult patients with impaired renal function, the dose of
VIDEX should be adjusted to compensate for the slower rate of elimination. The
recommended doses and dosing intervals of VIDEX in adult patients with renal insufficiency
are presented in Table 15.
Table 15:
Recommended Dosage of VIDEX in Renal Impairment
≥ 60 kg
< 60 kg
Creatinine Clearance
(mL/min)
Tableta
(mg)
Buffered Powderb
(mg)
Tableta
(mg)
Buffered Powderb
(mg)
≥60
200 twice dailyc
250 twice daily
125 twice dailyc
167 twice daily
30-59
200 once daily
or 100 twice daily
100 twice daily
150 once daily
or 75 twice daily
100 twice daily
10-29
150 once daily
167 once daily
100 once daily
100 once daily
<10
100 once daily
100 once daily
75 once daily
100 once daily
a VIDEX Chewable/Dispersible Buffered Tablet. Two VIDEX tablets must be taken with each dose;
different strengths of tablets may be combined to yield the recommended dose.
b VIDEX Buffered Powder for Oral Solution.
c 400 mg once daily (≥60 kg) or 250 mg once daily (<60 kg) for patients whose management requires once-
daily frequency of administration.
Urinary excretion is also a major route of elimination of didanosine in pediatric
patients; therefore, the clearance of didanosine may be altered in children with renal
impairment. Although there are insufficient data to recommend a specific dose adjustment of
VIDEX in this patient population, a reduction in the dose and/or an increase in the interval
between doses should be considered.
Patients Requiring Continuous Ambulatory Peritoneal Dialysis (CAPD) or
Hemodialysis: For patients requiring CAPD or hemodialysis, follow dosing
recommendations for patients with creatinine clearance less than 10 mL/min, shown in Table
15. It is not necessary to administer a supplemental dose of VIDEX following hemodialysis.
Hepatic Impairment: See WARNINGS and PRECAUTIONS.
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Method of Preparation
VIDEX Chewable/Dispersible Buffered Tablets
Adult Dosing: To provide adequate buffering, at least two of the appropriate strength tablets,
but no more than four tablets, should be thoroughly chewed or dispersed in at least 1 ounce of
water prior to consumption (see PRECAUTIONS: Information for Patients). To disperse
tablets, add 2 tablets to at least 1 ounce of drinking water. Stir until a uniform dispersion
forms, and drink the entire dispersion immediately. If additional flavoring is desired, the
dispersion may be diluted with one ounce of clear apple juice. Stir the further diluted
dispersion just prior to consumption. The dispersion with clear apple juice is stable at room
temperature, 62° to 73°F (17° to 23°C), for up to one hour.
VIDEX Buffered Powder for Oral Solution
1.
Open packet carefully and pour contents into a container with approximately 4 ounces
of drinking water. Do not mix with fruit juice or other acid-containing liquid.
2.
Stir until the powder completely dissolves (approximately 2 to 3 minutes).
3.
Drink the entire solution immediately.
VIDEX Pediatric Powder for Oral Solution
Prior to dispensing, the pharmacist must constitute dry powder with Purified Water, USP, to an
initial concentration of 20 mg/mL and immediately mix the resulting solution with antacid to a
final concentration of 10 mg/mL as follows:
20 mg/mL Initial Solution: Constitute the product to 20 mg/mL by adding 100 mL or
200 mL of Purified Water, USP, to the 2 g or 4 g of VIDEX powder, respectively, in the
product bottle.
10 mg/mL Final Admixture: 1. Immediately mix one part of the 20 mg/mL initial
solution with one part of either Mylanta® Double Strength Liquid, Extra Strength Maalox®
Plus Suspension, or Maalox® TC Suspension for a final dispensing concentration of 10 mg
Mylanta® is a registered trademark of Johnson & Johnson-Merck Consumer
Pharmaceuticals Company.
Maalox® is a registered trademark of Novartis Consumer Health, Inc.
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VIDEX per mL. For patient home use, the admixture should be dispensed in appropriately
sized, flint-glass or plastic (HDPE, PET, or PETG) bottles with child-resistant closures. This
admixture is stable for 30 days under refrigeration, 36° to 46° F (2° to 8° C).
2. Instruct the patient to shake the admixture thoroughly prior to use and to store the
tightly closed container in the refrigerator, 36° to 46° F (2° to 8° C), up to 30 days.
HOW SUPPLIED
VIDEX® (didanosine) Chewable/Dispersible Buffered Tablets are round, off white to light
orange/yellow with a mottled appearance, orange-flavored, tablets embossed with "VIDEX" on
one side and the product strength on the other. The tablets are available in the following
strengths of VIDEX: 25, 50, 100, 150, and 200 mg. Sixty tablets are packaged in bottles with
child-resistant closures.
The tablets should be stored in tightly closed bottles at 59° to 86° F (15° to 30° C).
If dispersed in water, the dose may be held for up to 1 hour at ambient temperature.
VIDEX (didanosine) Buffered Powder for Oral Solution is supplied in single-dose,
child-resistant foil packets in the following strengths of VIDEX: 100, 167, or 250 mg. Each
product strength provides a sweetened, buffered solution of VIDEX.
The packets should be stored at 59° to 86° F (15° to 30° C). After dissolving in water,
the solution may be stored at ambient room temperature for up to 4 hours.
VIDEX (didanosine) Pediatric Powder for Oral Solution is supplied in 4- and 8-
ounce glass bottles containing 2 g or 4 g of VIDEX, respectively.
The bottles of powder should be stored at 59° to 86° F (15° to 30° C). The VIDEX
admixture may be stored up to 30 days in a refrigerator, 36° to 46° F (2° to 8° C). Discard any
unused portion after 30 days.
The NDC numbers for the previously described VIDEX products are:
Table 16
NDC NO.
Packaging Information
Product Strength
VIDEX
Chewable/Dispersible Buffered Tablets
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Table 16
0087-6650-01
60 tablets/bottle
25 mg/tablet
0087-6651-01
60 tablets/bottle
50 mg/tablet
0087-6652-01
60 tablets/bottle
100 mg/tablet
0087-6653-01
60 tablets/bottle
150 mg/tablet
0087-6665-15
60 tablets/bottle
200 mg/tablet
VIDEX
Buffered Powder for Oral Solution
0087-6614-43
One single-dose foil packet*
100 mg/packet
0087-6615-43
One single-dose foil packet*
167 mg/packet
0087-6616-43
One single-dose foil packet*
250 mg/packet
VIDEX
Pediatric Powder for Oral Solution
0087-6632-41
One bottle per carton
2 g/bottle
0087-6633-41
One bottle per carton
4 g/bottle
* Packaged as 30 packets per carton.
US Patent Nos.: 4,861,759 and 5,616,566.
HANDLING AND DISPOSAL
Spill, Leak, and Disposal Procedure
Avoid generating dust during clean-up of powdered products; use wet mop or damp sponge.
Clean surface with soap and water as necessary. Containerize larger spills.
There is no single preferred method of disposal of containerized waste. Disposal
options include incineration, landfill, or sewer as dictated by specific circumstances and
relevant national, state, and local regulations.
Bristol-Myers Squibb Virology
A Bristol-Myers Squibb Company
Princeton, NJ 08543 USA
1099814A7
Revised October 2001
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PATIENT INFORMATION
Rx only
VIDEX®
(generic name = didanosine also known as ddI)
VIDEX® (didanosine) Chewable/Dispersible Buffered Tablets
VIDEX® (didanosine) Buffered Powder for Oral Solution
VIDEX® (didanosine) Pediatric Powder for Oral Solution
What is VIDEX?
VIDEX (pronounced VY dex) is a prescription medicine used in combination with other drugs
to treat children and adults who are infected with HIV (the human immunodeficiency virus, the
virus that causes AIDS). VIDEX belongs to a class of drugs called nucleoside analogues. By
reducing the growth of HIV, VIDEX helps your body maintain its supply of CD4 cells, which
are important for fighting HIV and other infections.
VIDEX will not cure your HIV infection. At present there is no cure for HIV infection.
Even while taking VIDEX, you may continue to have HIV-related illnesses, including infections
with other disease-producing organisms. Continue to see your doctor regularly and report any
medical problems that occur.
VIDEX does not prevent a patient infected with HIV from passing the virus to other
people. To protect others, you must continue to practice safe sex and take precautions to
prevent others from coming in contact with your blood and other body fluids.
There is limited information on the effects of long-term use of VIDEX.
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Who should not take VIDEX?
Do not take VIDEX if you are allergic to any of its ingredients, including its active ingredient,
didanosine and the inactive ingredients. (See Inactive Ingredients at the end of this leaflet.) Tell
your doctor if you think you have had an allergic reaction to any of these ingredients.
How should I take VIDEX? How should I store it?
Your doctor will determine your dose based on your body weight, kidney and liver function, and
any side effects that you may have had with other medicines. Take VIDEX on an empty stomach -
that means at least 30 minutes before or 2 hours after eating. Do not take VIDEX with food.
Try not to miss a dose, but if you do, take it as soon as possible. If it is almost time for the next
dose, skip the missed dose and continue your regular dosing schedule.
Chewable/Dispersible Tablets: Each VIDEX tablet contains antacid. Each time
you take VIDEX, you must take at least two, but not more than four, tablets. This
is because VIDEX tablets contain an antacid to reduce the amount of acid in your
stomach. If you have too much acid, the medicine will break down. However, too
much antacid may cause stomach problems.
—DO NOT swallow VIDEX tablets whole. Chew the tablets well or mix them in
water. Many patients drop the tablets in at least one ounce of water and stir well
before swallowing. If you choose to mix the tablets in water, you may add one ounce
(2 tablespoons) of clear apple juice to the mixture for flavor (do not use any other kind
of juice).
—Store tablets in a tightly closed container at room temperature away from heat and
out of the reach of children and pets. Do NOT store the tablets in a damp place such as
a bathroom medicine cabinet or near the kitchen sink.
Buffered Powder for Oral Solution: Pour the contents of a packet into a glass with 4
ounces (1/2 measuring cup) of water. Stir until completely dissolved. Drink the entire
solution right away. Do not mix with fruit juice. Store packets at room temperature
before use.
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Pediatric Oral Solution: Your pharmacist will prepare the oral solution. Shake
the solution well before each use. Store in the refrigerator. Throw away any unused
portion after 30 days.
If you have kidney disease: If your kidneys are not working properly, your doctor will
need to do regular tests to check how they are working while you take VIDEX. Your
doctor may also lower your dosage of VIDEX.
What should I do if someone takes an overdose of VIDEX?
If someone may have taken an overdose of VIDEX, get medical help right away. Contact their
doctor or a poison control center.
What should I avoid while taking VIDEX?
Alcohol. Do not drink alcohol while taking VIDEX since alcohol may increase your risk of
pancreatitis (pain and inflammation of the pancreas) or liver damage.
Other medicines. Other medicines, including those you can buy without a prescription, may
interfere with the actions of VIDEX. Do not take any medicine, vitamin supplement, or
other health preparation without first checking with your doctor.
Antacids. Since VIDEX contains some of the same ingredients found in antacids, any
side effects related to VIDEX’s ingredients may get worse if you also take an antacid.
Medicines at the same time you take your VIDEX dose. Some medicines should not
be taken at the same time of day that you take VIDEX. Check with your doctor.
Pregnancy. It is not known if VIDEX can harm a human fetus. Also, pregnant women have
experienced serious side effects when taking VIDEX in combination with ZERIT (stavudine),
also known as d4T, and other HIV medicines. VIDEX should be used during pregnancy only
after discussion with your doctor. Tell your doctor if you become pregnant or plan to
become pregnant while taking VIDEX.
Nursing. Studies have shown VIDEX is in the breast milk of animals getting the drug. It may
also be in human breast milk. The Centers for Disease Control and Prevention (CDC)
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recommends that HIV-infected mothers not breast-feed. This should reduce the risk of
passing HIV infection to their babies and the potential for serious adverse reactions in nursing
infants. Therefore, do not nurse a baby while taking VIDEX.
What are the possible side effects of VIDEX?
Pancreatitis. Pancreatitis is a dangerous inflammation of the pancreas that may cause death.
Tell your doctor right away if you or a child taking VIDEX develops stomach pain, nausea,
or vomiting. These can be signs of pancreatitis. Before starting VIDEX therapy, let your
doctor know if you or a child for whom it has been prescribed has ever had pancreatitis. This
condition is more likely to happen in people who have had it before. It is also more likely in people
with advanced HIV disease. However, it can occur at any stage of HIV disease. It may be more
common in patients with kidney problems, those who drink alcohol, and those who are also treated
with stavudine or hydroxyurea. If you get pancreatitis, your doctor will tell you to stop taking
VIDEX.
Lactic acidosis, severe liver enlargement, and liver failure, including deaths, have been
reported among patients taking VIDEX (including pregnant women). Symptoms that may
indicate a liver problem are:
• feeling very weak, tired, or uncomfortable,
• unusual or unexpected stomach discomfort,
• feeling cold,
• feeling dizzy or lightheaded,
• suddenly developing a slow or irregular heartbeat.
Lactic acidosis is a medical emergency that must be treated in a hospital.
If you notice any of these symptoms or if your medical condition changes, stop taking
VIDEX and call your doctor right away. Women, overweight patients, and those who have been
treated for a long time with other medicines used to treat HIV infection are more likely to develop
lactic acidosis. Your doctor should check your liver function periodically while you are taking
VIDEX. You should be especially careful if you have a history of heavy alcohol use or a liver
problem.
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Vision changes. VIDEX may affect the nerves in your eyes. Because of this, you should have
regular eye examinations. You should also report any changes in vision to your doctor right away.
This includes, for example, seeing colors abnormally or blurred vision.
Peripheral neuropathy. This is a problem with the nerves in your hands or feet. The nerve
problem may be serious. Tell your doctor right away if you or a child taking VIDEX has
continuing numbness, tingling, or pain in the feet or hands. A child may not recognize these
symptoms or know to tell you that his or her feet or hands are numb, burning, tingling, or painful.
Ask your child’s doctor how to find out if your child is developing peripheral neuropathy.
Before starting VIDEX therapy, let your doctor know if you or a child for whom it has been
prescribed has ever had peripheral neuropathy. This condition is more likely to happen in people
who have had it before. It is also more likely in patients taking medicines that affect the nerves and
in people with advanced HIV disease. However, it can occur at any stage of HIV disease. If you
get peripheral neuropathy, your doctor will tell you to stop taking VIDEX. After stopping VIDEX,
the symptoms may get worse for a short time and then get better. Once symptoms of peripheral
neuropathy go away completely, you and your doctor should decide if starting VIDEX is right for
you. If so, you might be started at a lower dose.
Special note about other medicines. If you take VIDEX along with other medicines with similar
side effects, you may increase the chance of having these side effects. For example, using VIDEX
in combination with other medicines that may cause pancreatitis, peripheral neuropathy, or liver
problems (including stavudine and hydroxyurea) may increase your chance of having these side
effects.
Other side effects: The most common side effects in adults taking VIDEX are diarrhea,
neuropathy (nerve disorders), chills or fever, rash, abdominal pain, weakness, headache, and nausea
and vomiting. Children may have similar side effects as adults.
Changes in body fat have been seen in some patients taking antiretroviral therapy. These
changes may include increased amount of fat in the upper back and neck (“buffalo hump”), breast,
and around the trunk. Loss of fat from the legs, arms, and face may also happen. The cause and
long-term health effects of these conditions are not known at this time.
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What else should I know about VIDEX?
If you should limit sodium (salt) intake: Each single-dose packet of Buffered Powder for
Oral Solution contains 1380 mg of sodium. Each Chewable/Dispersible Tablet contains 264.5
mg of sodium.
If you have phenylketonuria: Each Chewable/Dispersible Tablet contains 36.5 mg of
phenylalanine.
Inactive Ingredients:
Chewable/Dispersible Tablets: calcium carbonate, magnesium hydroxide, aspartame,
sorbitol, mandarin orange flavor, polyplasdone, microcrystalline cellulose, and
magnesium stearate.
Buffered Powder for Oral Solution: citrate-phosphate buffer (dibasic sodium
phosphate, sodium citrate, and citric acid) and sucrose.
Pediatric Oral Solution: Mylanta Double Strength Liquid, Extra Strength
Maalox Plus or Maalox TC Suspension.
This medicine was prescribed for your particular condition. Do not use VIDEX for another condition or give it to
others. Keep VIDEX and all medicines out of the reach of children. Throw away VIDEX when it is outdated or
no longer needed by flushing it down the toilet or pouring it down the sink.
This summary does not include everything there is to know about VIDEX. Medicines are sometimes prescribed
for purposes other than those listed in a Patient Information Leaflet. If you have questions or concerns, or want more
information about VIDEX, your physician and pharmacist have the complete prescribing information upon which this
leaflet is based. You may want to read it and discuss it with your doctor or other healthcare professional. Remember, no
written summary can replace careful discussion with your doctor.
Mylanta® is a registered trademark of Johnson & Johnson-Merck Consumer Pharmaceuticals Company.
Maalox® is a registered trademark of Novartis Consumer Health, Inc.
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ApprovletS036.doc (clean copy 11/7/01)
Page 38 of 39
Bristol-Myers Squibb Virology
A Bristol-Myers Squibb Company
Princeton, NJ 08543 USA
This Patient Information Leaflet has been approved by the U.S. Food and Drug Administration.
1099814A7
Revised October 2001
Based on 1099814A7 (10/01)
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---------------------------------------------------------------------------------------------------------------------
This is a representation of an electronic record that was signed electronically and
this page is the manifestation of the electronic signature.
---------------------------------------------------------------------------------------------------------------------
/s/
---------------------
Debra Birnkrant
11/16/01 04:48:13 PM
NDA 20-156 SLR 028, NDA 20-155 SLR 027, NDA 20-154 SLR 036
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For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:46:54.116899
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2001/20155s27lbl.pdf', 'application_number': 20155, 'submission_type': 'SUPPL ', 'submission_number': 27}
|
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January 27, 2003
Page 4 of 70
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Rx only
VIDEX
(didanosine)
VIDEX (didanosine) Chewable/Dispersible Buffered Tablets
VIDEX (didanosine) Buffered Powder for Oral Solution
VIDEX (didanosine) Pediatric Powder for Oral Solution
(Patient Information Leaflet Included)
WARNING
FATAL AND NONFATAL PANCREATITIS HAVE OCCURRED DURING
THERAPY WITH VIDEX USED ALONE OR IN COMBINATION REGIMENS IN
BOTH TREATMENT-NAIVE AND TREATMENT-EXPERIENCED PATIENTS,
REGARDLESS OF DEGREE OF IMMUNOSUPPRESSION. VIDEX SHOULD BE
SUSPENDED IN PATIENTS WITH SUSPECTED PANCREATITIS AND
DISCONTINUED IN PATIENTS WITH CONFIRMED PANCREATITIS (SEE
WARNINGS).
LACTIC
ACIDOSIS
AND
SEVERE
HEPATOMEGALY
WITH
STEATOSIS, INCLUDING FATAL CASES, HAVE BEEN REPORTED WITH
THE USE OF NUCLEOSIDE ANALOGUES ALONE OR IN COMBINATION,
INCLUDING DIDANOSINE AND OTHER ANTIRETROVIRALS. FATAL
LACTIC ACIDOSIS HAS BEEN REPORTED IN PREGNANT WOMEN WHO
RECEIVED THE COMBINATION OF DIDANOSINE AND STAVUDINE WITH
OTHER ANTIRETROVIRAL AGENTS. THE COMBINATION OF DIDANOSINE
AND STAVUDINE SHOULD BE USED WITH CAUTION DURING PREGNANCY
AND IS RECOMMENDED ONLY IF THE POTENTIAL BENEFIT CLEARLY
OUTWEIGHS THE POTENTIAL RISK (SEE WARNINGS AND PRECAUTIONS:
PREGNANCY).
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DESCRIPTION
VIDEX (didanosine) is a brand name for didanosine (ddI), a synthetic purine nucleoside
analogue active against the Human Immunodeficiency Virus (HIV). VIDEX
Chewable/Dispersible Buffered Tablets are available for oral administration in strengths of
25, 50, 100, 150, and 200 mg of didanosine. Each tablet is buffered with calcium
carbonate and magnesium hydroxide. VIDEX tablets also contain aspartame, sorbitol,
microcrystalline cellulose, polyplasdone, mandarin-orange flavor, and magnesium stearate.
VIDEX Buffered Powder for Oral Solution is supplied for oral administration in
single-dose packets containing 100, 167, or 250 mg of didanosine. Packets of each product
strength also contain a citrate-phosphate buffer (composed of dibasic sodium phosphate,
sodium citrate, and citric acid) and sucrose.
VIDEX Pediatric Powder for Oral Solution is supplied for oral administration in 4-
or 8-ounce glass bottles containing 2 or 4 grams of didanosine, respectively.
Didanosine is also available as an enteric-coated formulation (VIDEX® EC
Delayed-Release Capsules). Please consult the prescribing information for VIDEX EC
(didanosine).
The chemical name for didanosine is 2',3'-dideoxyinosine. The structural formula
is:
Didanosine is a white crystalline powder with the molecular formula C10H12N4O3
and a molecular weight of 236.2. The aqueous solubility of didanosine at 25° C and pH of
approximately 6 is 27.3 mg/mL. Didanosine is unstable in acidic solutions. For example,
at pH <3 and 37° C, 10% of didanosine decomposes to hypoxanthine in less than 2
minutes.
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MICROBIOLOGY
Mechanism of Action
Didanosine is a synthetic nucleoside analogue of the naturally occurring nucleoside
deoxyadenosine in which the 3'-hydroxyl group is replaced by hydrogen. Intracellularly,
didanosine is converted by cellular enzymes to the active metabolite, dideoxyadenosine
5'-triphosphate. Dideoxyadenosine 5'-triphosphate inhibits the activity of HIV-1 reverse
transcriptase both by competing with the natural substrate, deoxyadenosine 5'-triphosphate,
and by its incorporation into viral DNA causing termination of viral DNA chain
elongation.
In Vitro HIV Susceptibility
The in vitro anti-HIV-1 activity of didanosine was evaluated in a variety of HIV-1 infected
lymphoblastic cell lines and monocyte/macrophage cell cultures. The concentration of drug
necessary to inhibit viral replication by 50% (IC50) ranged from 2.5 to 10 µM (1 µM =
0.24 µg/mL) in lymphoblastic cell lines and 0.01 to 0.1 µM in monocyte/macrophage cell
cultures. The relationship between in vitro susceptibility of HIV to didanosine and the
inhibition of HIV replication in humans has not been established.
Drug Resistance
HIV-1 isolates with reduced sensitivity to didanosine have been selected in vitro and were
also obtained from patients treated with didanosine. Genetic analysis of isolates from
didanosine-treated patients showed mutations in the reverse transcriptase gene that resulted
in the amino acid substitutions K65R, L74V, and M184V. The L74V mutation was most
frequently observed in clinical isolates. Phenotypic analysis of HIV-1 isolates from 60
patients (some with prior zidovudine treatment) receiving 6 to 24 months of didanosine
monotherapy showed that isolates from 10 of 60 patients exhibited an average of a 10-fold
decrease in susceptibility to didanosine in vitro compared to baseline isolates. Clinical
isolates that exhibited a decrease in didanosine susceptibility harbored one or more
didanosine-associated mutations. The clinical relevance of genotypic and phenotypic
changes associated with didanosine therapy has not been established.
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Cross-resistance
HIV-1 isolates from 2 of 39 patients receiving combination therapy for up to 2 years with
zidovudine and didanosine exhibited decreased susceptibility to zidovudine, didanosine,
zalcitabine, stavudine, and lamivudine in vitro. These isolates harbored five mutations
(A62V, V75I, F77L, F116Y, and Q151M) in the reverse transcriptase gene. The clinical
relevance of these observations has not been established.
CLINICAL PHARMACOLOGY
Animal Toxicology
Evidence of a dose-limiting skeletal muscle toxicity has been observed in mice and rats
(but not in dogs) following long-term (greater than 90 days) dosing with didanosine at
doses that were approximately 1.2 to 12 times the estimated human exposure. The
relationship of this finding to the potential of VIDEX (didanosine) to cause myopathy in
humans is unclear. However, human myopathy has been associated with administration of
VIDEX and other nucleoside analogues.
Pharmacokinetics
The pharmacokinetic parameters of didanosine are summarized in Table 1. Didanosine is
rapidly absorbed, with peak plasma concentrations generally observed from 0.25 to 1.50
hours following oral dosing. Increases in plasma didanosine concentrations were dose
proportional over the range of 50 to 400 mg. Steady-state pharmacokinetic parameters did
not differ significantly from values obtained after a single dose. Binding of didanosine to
plasma proteins in vitro was low (<5%). Based on data from in vitro and animal studies, it
is presumed that the metabolism of didanosine in man occurs by the same pathways
responsible for the elimination of endogenous purines.
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Table 1:
Mean ± SD Pharmacokinetic Parameters for Didanosine in
Adult and Pediatric Patients
Pediatric Patientsb
Parameter
Adult Patientsa
n
8 months to 19 years
n
2 weeks to 4 months
n
Oral bioavailability (%)
42 ± 12
6
25 ± 20
46
ND
Apparent volume of
distributionc (L/m2)
43.70 ± 8.90
6
28 ± 15
49
ND
CSF-plasma ratiod
21 ± 0.03%e
5
46%
(range 12-85%)
7
ND
Systemic clearancec
(mL/min/m2)
526 ± 64.7
6
516 ± 184
49
ND
Renal clearancef
(mL/min/m2)
223 ± 85.0
6
240 ± 90
15
ND
Apparent oral clearanceg
(mL/min/m2)
1252 ± 154
6
2064 ± 736
48
1353 ± 759
41
Elimination half-lifef (h)
1.5 ± 0.4
6
0.8 ± 0.3
60
1.2 ± 0.3
21
Urinary recovery of
didanosinef (%)
18 ± 8
6
18 ± 10
15
ND
CSF = cerebrospinal fluid, ND = not determined.
a Parameter units for adults were converted to the same units in pediatric patients to facilitate comparisons
among populations: mean adult body weight = 70 kg and mean adult body surface area = 1.73 m2.
b In 1-day old infants (n=10), the mean ± SD apparent oral clearance was 1523 ± 1176 mL/min/m2 and
half-life was 2.0 ± 0.7 h.
c Following IV administration.
d Following IV administration in adults and IV or oral administration in pediatric patients.
e
Mean ± SE.
f
Following oral administration.
g Apparent oral clearance estimate was determined as the ratio of the mean systemic clearance and the
mean oral bioavailability estimate.
Effect of Food on Absorption of Didanosine: Didanosine peak plasma
concentrations (CMAX) and area under the plasma concentration time curve (AUC) were
decreased by approximately 55% when VIDEX tablets were administered up to 2 hours
after a meal. Administration of VIDEX tablets up to 30 minutes before a meal did not
result in any significant changes in bioavailability. VIDEX should be taken on an empty
stomach, at least 30 minutes before or 2 hours after eating. (See DOSAGE AND
ADMINISTRATION.)
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Special Populations
Renal Insufficiency: It is recommended that the VIDEX (didanosine) dose be modified
in patients with reduced creatinine clearance and in patients receiving maintenance
hemodialysis (see DOSAGE AND ADMINISTRATION). Data from two studies in
adults indicated that the apparent oral clearance of didanosine decreased and the terminal
elimination half-life increased as creatinine clearance decreased (see Table 2). Following
oral administration, didanosine was not detectable in peritoneal dialysate fluid (n=6);
recovery in hemodialysate (n=5) ranged from 0.6% to 7.4% of the dose over a 3-4 hour
dialysis period. The absolute bioavailability of didanosine was not affected in patients
requiring dialysis.
Table 2:
Mean ± SD Pharmacokinetic Parameters for Didanosine
Following a Single Oral Dose
Creatinine Clearance (mL/min)
Parameter
≥ 90
(n=12)
60-90
(n=6)
30-59
(n=6)
10-29
(n=3)
Dialysis Patients
(n=11)
CLcr (mL/min)
112 ± 22
68 ± 8
46 ± 8
13 ± 5
ND
CL/F (mL/min)
2164 ± 638
1566 ± 833
1023 ± 378
628 ± 104
543 ± 174
CLR (mL/min)
458 ± 164
247 ± 153
100 ± 44
20 ± 8
<10
T½ (h)
1.42 ± 0.33
1.59 ± 0.13
1.75 ± 0.43
2.0 ± 0.3
4.1 ± 1.2
ND = not determined due to anuria.
CLcr = creatinine clearance.
CL/F = apparent oral clearance.
CLR = renal clearance.
Pediatric Patients: The pharmacokinetics of didanosine have been evaluated in
HIV-exposed and -infected pediatric patients from birth to 19 years of age (see Table 1).
Overall, the pharmacokinetics of didanosine in pediatric patients are similar to those of
didanosine in adults. Didanosine plasma concentrations appear to increase in proportion to
oral doses ranging from 25 to 120 mg/m2 in pediatric patients less than 5 months old and
from 80 to 180 mg/m2 in children above 8 months old. For information on controlled
clinical studies in pediatric patients, see INDICATIONS AND USAGE: Clinical Studies
and PRECAUTIONS: Pediatric Use.
Geriatric Patients: Didanosine pharmacokinetics have not been studied in
patients over 65 years of age.
Gender: The effects of gender on didanosine pharmacokinetics have not been
studied.
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Drug Interactions: Ribavirin has been shown in vitro to increase intracellular
triphosphate levels of didanosine, which could cause or worsen clinical toxicities (see
PRECAUTIONS: Drug Interactions).
Tables 3 and 4 summarize the effects on AUC and CMAX, with a 90% or 95%
confidence interval (CI) when available, following coadministration of VIDEX with a
variety of drugs. For most of the listed drugs, no clinically significant pharmacokinetic
interactions were observed. Clinical recommendations based on drug interaction studies for
drugs in bold font are included in PRECAUTIONS: Drug Interactions.
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Table 3:
Results of Drug Interaction Studies: Effects of Coadministered Drug on
Didanosine Plasma AUC and CMAX Values
Drugs With Clinical Recommendations Regarding Coadministration (see PRECAUTIONS: Drug Interactions)
Drug
Didanosine Dosage
n
AUC of
Didanosine
(95% CI)
CMAX of Didanosine
(95% CI)
allopurinol
renally impaired, 300 mg/day
200 mg single dose
2
↑ 312%
↑ 232%
healthy volunteer, 300 mg/day for
7 days
400 mg single dose
14
↑ 113%
↑ 69%
ciprofloxacin, 750 mg q12h for 3
days, 2 h before didanosine
200 mg q12h for 3 days
8a
↓ 16%
↓ 28%
ganciclovir, 1000 mg q8h, 2 h
after didanosine
200 mg q12h
12
↑ 111%
NA
indinavir, 800 mg single dose
simultaneous
1 h before didanosine
200 mg single dose
200 mg single dose
16
16
↔
↓ 17% (-27, - 7%)b
↔
↓ 13% (-28, 5%)b
ketoconazole, 200 mg/day for 4
days, 2 h before didanosine
375 mg q12h for 4 days
12a
↔
↓ 12%
methadone, chronic maintenance
dose
200 mg single dose
16,10c
↓ 57%
↓ 66%
tenofovir,d,e 300 mg once daily
1 h after didanosine
250f or 400 mg once
daily for 7 days
14
↑ 44%
(31, 59%)b
↑ 28%
(11, 48%)b
No Clinically Significant Interaction Observed
Drug
Didanosine Dosage
n
AUC of
Didanosine
(95% CI)
CMAX of Didanosine
(95% CI)
loperamide, 4 mg q6h for 1 day
300 mg single dose
12a
↔
↓ 23%
metoclopramide, 10 mg single dose
300 mg single dose
12a
↔
↑ 13%
ranitidine, 150 mg single dose, 2 h
before didanosine
375 mg single dose
12a
↑ 14%
↑ 13%
rifabutin, 300 or 600 mg/day for 12
days
167 or 250 mg q12h for
12 days
11
↑ 13% (-1, 27%)
↑ 17% (-4, 38%)
ritonavir, 600 mg q12h for 4 days
200 mg q12h for 4 days
12
↓ 13% (0, 23%)
↓ 16% (5, 26%)
stavudine, 40 mg q12h for 4 days
100 mg q12h for 4 days
10
↔
↔
sulfamethoxazole, 1000 mg single
dose
200 mg single dose
8a
↔
↔
trimethoprim, 200 mg single dose
200 mg single dose
8a
↔
↑ 17% (-23, 77%)
zidovudine, 200 mg q8h for 3 days
200 mg q12h for 3 days
6a
↔
↔
↑ indicates increase.
↓ indicates decrease.
↔ indicates no change, or mean increase or decrease of <10%.
a
HIV-infected patients.
b
90% CI.
c Parallel-group design; entries are subjects receiving combination and control regimens, respectively.
d tenofovir disoproxil fumarate.
e
In a drug interaction study with the enteric-coated formulation of didanosine (VIDEX EC) and tenofovir, the AUC and
CMAX of didanosine each increased 48% when VIDEX EC was administered in the fasting state 2 hours before
tenofovir with a light meal. The AUC and CMAX of didanosine increased 60% and 64%, respectively, when
VIDEX EC was administered together with tenofovir and a light meal.
f
patients less than 60 kg.
NA Not available.
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Table 4:
Results of Drug Interaction Studies: Effects of Didanosine on
Coadministered Drug Plasma AUC and CMAX Values
Drugs With Clinical Recommendations Regarding Coadministration (see PRECAUTIONS: Drug Interactions)
Drug
Didanosine Dosage
n
AUC of
Coadministered
Drug (95% CI)
CMAX of
Coadministered
Drug (95% CI)
ciprofloxacin
750 mg q12h for 3 days, 2 h
before didanosine
750 mg single dose
200 mg q12h for 3 days
buffered placebo tablet
8a
12
↓ 26%
↓ 98%
↓ 16%
↓ 93%
delavirdine, 400 mg single dose
simultaneous
1 h before didanosine
125 or 200 mg q12h
125 or 200 mg q12h
12a
12a
↓ 32%
↑ 20%
↓ 53%
↑ 18%
ganciclovir, 1000 mg q8h, 2 h
after didanosine
200 mg q12h
12a
↓ 21%
NA
indinavir, 800 mg single dose
simultaneous
1 h before didanosine
200 mg single dose
200 mg single dose
16
16
↓ 84%
↓ 11%
↓ 82%
↓ 4%
ketoconazole, 200 mg/day for 4
days, 2 h before didanosine
375 mg q12h for 4 days
12a
↓ 14%
↓ 20%
nelfinavir, 750 mg single dose,
1 h after didanosine
200 mg single dose
10a
↑ 12%
↔
No Clinically Significant Interaction Observed
Drug
Didanosine Dosage
n
AUC of
Coadministered
Drug (95% CI)
CMAX of
Coadministered
Drug (95% CI)
dapsone, 100 mg single dose
200 mg q12h for 14 days
6a
↔
↔
ranitidine, 150 mg single dose, 2 h
before didanosine
375 mg single dose
12a
↓ 16%
↔
ritonavir, 600 mg q12h for 4 days
200 mg q12h for 4 days
12
↔
↔
stavudine, 40 mg q12h for 4 days
100 mg q12h for 4 days
10a
↔
↑ 17%
sulfamethoxazole, 1000 mg single
dose
200 mg single dose
8a
↓ 11% (-17, -4%)
↓ 12% (-28, 8%)
tenofovir,b 300 mg once daily 1 h
after didanosine
250c or 400 mg once
daily for 7 days
14
↔
↔
trimethoprim, 200 mg single dose
200 mg single dose
8a
↑ 10% (-9, 34%)
↓ 22% (-59, 49%)
zidovudine, 200 mg q8h for 3
days
200 mg q12h for 3 days
6a
↓ 10% (-27, 11%)
↓ 16.5% (-53, 47%)
↑ indicates increase.
↓ indicates decrease.
↔ indicates no change, or mean increase or decrease of <10%.
a
HIV-infected patients.
b tenofovir disoproxil fumarate.
c
patients less than 60 kg.
NA Not available.
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INDICATIONS AND USAGE
VIDEX in combination with other antiretroviral agents is indicated for the treatment
of HIV-1 infection (see Clinical Studies).
Clinical Studies
Combination Therapy
START 2 was a multicenter, randomized, open-label study comparing VIDEX (200 mg
twice daily)/stavudine/indinavir to zidovudine/lamivudine/indinavir in 205 treatment-naive
patients. Both regimens resulted in a similar magnitude of suppression of HIV RNA levels
and increases in CD4 cell counts through 48 weeks.
Study A1454-148 was a randomized, open-label, multicenter study comparing
treatment with VIDEX (400 mg once daily) plus stavudine (40 mg twice daily) and
nelfinavir (750 mg three times daily) versus zidovudine (300 mg twice daily) plus
lamivudine (150 mg twice daily) and nelfinavir (750 mg three times daily) in 756
treatment-naive patients, with a median CD4 cell count of 340 cells/mm3 (range 80 to 1568
cells/mm3) and a median plasma HIV-1 RNA of 4.69 log10 copies/mL (range 2.6 to 5.9
log10 copies/mL) at baseline. Median CD4 cell count increases at 48 weeks were 188
cells/mm3 in both treatment groups. Treatment response and outcomes through 48 weeks
are shown in Figure 1 and Table 5.
Figure 1:
Treatment Response Through Week 48*, AI454-148
* Percent of patients at each time point who have HIV RNA <400 or <50 copies/mL, are on
their original study medication (except stavudine-zidovudine switches), and have not
experienced an AIDS-defining event.
0
20
40
60
80
100
0
8
16
24
32
40
48
Study Week
Percent of patients
] < 400 c/mL
] < 50 c/mL
VIDEX+stavudine+nelfinavir (n=503)
zidovudine+lamivudine+nelfinavir (n=253)
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Table 5:
Outcomes of Randomized Treatment through Week 48,
AI454-148
Percent of Patients with HIV RNA <400 copies/mL (<50 copies/mL)
VIDEX/stavudine/nelfinavir
lamivudine/zidovudine/nelfinavi
r
Week 48 Status
n=503
n=253
Responder a
50* (34*)
59 (47)
Virologic failureb
36 (57)
32 (48)
Death or disease progression
<1 (<1)
1 (<1)
Discontinued due to adverse events
4 (2)
2 (<1)
Discontinued due to other reasonsc
6 (3)
4 (2)
Never initiated treatment
4 (4)
2 (2)
* p <0.05 for the differences between treatment groups, by Cochran-Mantel-Haenszel test.
a Patients achieved virologic response [two consecutive viral loads <400 (<50) copies/mL] and maintained
it to Week 48.
b Includes viral rebound and failing to achieve confirmed <400 (<50) copies/mL by Week 48.
c Includes lost to follow-up, noncompliance, withdrawal, and pregnancy.
Monotherapy
The efficacy of VIDEX was demonstrated in two randomized, double-blind studies
comparing VIDEX, given on a twice-daily schedule, to zidovudine, given three times
daily, in 617 (ACTG 116A, conducted 1989-1992) and 913 (ACTG116B/117, conducted
1989-1991) patients with symptomatic HIV infection or AIDS who were treated for more
than one year. In treatment-naive patients (ACTG 116A), the rate of HIV disease
progression or death was similar between the treatment groups; mortality rates were 26%
for patients receiving VIDEX and 21% for patients receiving zidovudine. Of the patients
who had received previous zidovudine treatment (ACTG 116B/117), those treated with
VIDEX had a lower rate of HIV disease progression or death (32%) compared to those
treated with zidovudine (41%); however, survival rates were similar between the treatment
groups.
Efficacy in pediatric patients was demonstrated in a randomized, double-blind,
controlled study (ACTG 152, conducted 1991-1995) involving 831 patients 3 months to 18
years of age treated for more than 1.5 years with zidovudine (180 mg/m2 q6h), VIDEX
(120 mg/m2 q12h), or zidovudine (120 mg/m2 q6h) plus VIDEX (90 mg/m2 q12h). Patients
treated with VIDEX or VIDEX plus zidovudine had lower rates of HIV disease
progression or death compared with those treated with zidovudine alone.
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Studies have demonstrated that the clinical benefit of monotherapy with
antiretrovirals, including VIDEX, was time limited.
CONTRAINDICATION
VIDEX (didanosine) is contraindicated in patients with previously demonstrated clinically
significant hypersensitivity to any of the components of the formulations.
WARNINGS
1.
Pancreatitis
FATAL AND NONFATAL PANCREATITIS HAVE OCCURRED DURING
THERAPY WITH VIDEX USED ALONE OR IN COMBINATION REGIMENS IN
BOTH TREATMENT-NAIVE AND TREATMENT-EXPERIENCED PATIENTS,
REGARDLESS OF DEGREE OF IMMUNOSUPPRESSION. VIDEX SHOULD BE
SUSPENDED IN PATIENTS WITH SIGNS OR SYMPTOMS OF PANCREATITIS
AND DISCONTINUED IN PATIENTS WITH CONFIRMED PANCREATITIS.
PATIENTS TREATED WITH VIDEX IN COMBINATION WITH STAVUDINE,
WITH OR WITHOUT HYDROXYUREA, MAY BE AT INCREASED RISK FOR
PANCREATITIS.
When treatment with life-sustaining drugs known to cause pancreatic toxicity is
required, suspension of VIDEX (didanosine) therapy is recommended. In patients with risk
factors for pancreatitis, VIDEX should be used with extreme caution and only if clearly
indicated. Patients with advanced HIV infection, especially the elderly, are at increased
risk of pancreatitis and should be followed closely. Patients with renal impairment may be
at greater risk for pancreatitis if treated without dose adjustment.
The frequency of pancreatitis is dose related. In phase 3 studies, incidence ranged
from 1% to 10% with doses higher than are currently recommended and 1% to 7% with
recommended dose.
In pediatric phase 1 studies, pancreatitis occurred in 3% (2/60) of patients treated at
entry doses below 300 mg/m2/day and in 13% (5/38) of patients treated at higher doses. In
study ACTG 152, pancreatitis occurred in none of the 281 pediatric patients who received
didanosine 120 mg/m2 q12h and in <1% of the 274 pediatric patients who received
didanosine 90 mg/m2 q12h in combination with zidovudine. VIDEX use should be
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suspended in pediatric patients with signs or symptoms of pancreatitis and discontinued in
pediatric patients with confirmed pancreatitis.
2.
Lactic Acidosis/Severe Hepatomegaly with Steatosis
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases,
have been reported with the use of nucleoside analogues alone or in combination,
including didanosine and other antiretrovirals. A majority of these cases have been in
women. Obesity and prolonged nucleoside exposure may be risk factors. Fatal lactic
acidosis has been reported in pregnant women who received the combination of didanosine
and stavudine with other antiretroviral agents. The combination of didanosine and
stavudine should be used with caution during pregnancy and is recommended only if the
potential benefit clearly outweighs the potential risk (see PRECAUTIONS: Pregnancy).
Particular caution should be exercised when administering VIDEX to any patient with
known risk factors for liver disease; however, cases have also been reported in patients
with no known risk factors. Treatment with VIDEX should be suspended in any patient
who develops clinical or laboratory findings suggestive of symptomatic hyperlactatemia,
lactic acidosis, or pronounced hepatotoxicity (which may include hepatomegaly and
steatosis even in the absence of marked transaminase elevations).
3.
Retinal Changes and Optic Neuritis
Retinal changes and optic neuritis have been reported in adult and pediatric
patients. Periodic retinal examinations should be considered for patients receiving VIDEX.
(See ADVERSE REACTIONS.)
PRECAUTIONS
Frequency of Dosing
The preferred dosing frequency of VIDEX is twice daily because there is more evidence to
support the effectiveness of this dosing frequency. Once-daily dosing should be considered
only for adult patients whose management requires once-daily dosing of VIDEX (see
INDICATIONS AND USAGE: Clinical Studies).
VIDEX should be taken on an empty stomach, at least 30 minutes before or 2
hours after eating.
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Peripheral Neuropathy
Peripheral neuropathy, manifested by numbness, tingling, or pain in the hands or feet, has
been reported in patients receiving VIDEX therapy. Peripheral neuropathy has occurred
more frequently in patients with advanced HIV disease, in patients with a history of
neuropathy, or in patients being treated with neurotoxic drug therapy, including stavudine
(see ADVERSE REACTIONS).
Fat Redistribution
Redistribution/accumulation of body fat including central obesity, dorsocervical fat
enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and
“cushingoid appearance” have been observed in patients receiving antiretroviral therapy.
The mechanism and long-term consequences of these events are currently unknown. A
causal relationship has not been established.
General
Patients with Phenylketonuria: VIDEX Chewable/Dispersible Buffered Tablets
contain the following quantities of phenylalanine:
Table 6
All Strengths
Phenylalanine per 2-tablet dose
73 mg
Phenylalanine per tablet
36.5 mg
Patients on Sodium-Restricted Diets: VIDEX Buffered Powder for Oral
Solution: Each single-dose packet of VIDEX Buffered Powder for Oral Solution contains
1380 mg sodium.
Patients with Renal Impairment: Patients with renal impairment (creatinine
clearance <60 mL/min) may be at greater risk of toxicity from VIDEX due to decreased
drug clearance (see CLINICAL PHARMACOLOGY). A dose reduction is
recommended in these patients (see DOSAGE AND ADMINISTRATION). The
magnesium content of each buffered tablet of VIDEX is 8.6 mEq. This may present an
excessive load of magnesium to patients with significant renal impairment, particularly
after prolonged dosing.
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Patients with Hepatic Impairment: It is unknown if hepatic impairment
significantly affects didanosine pharmacokinetics. Therefore, these patients should be
monitored closely for evidence of didanosine toxicity.
Hyperuricemia: VIDEX has been associated with asymptomatic hyperuricemia;
treatment suspension may be necessary if clinical measures aimed at reducing uric acid
levels fail.
Information for Patients (See Patient Information Leaflet.)
Patients should be informed that a serious toxicity of VIDEX used alone and in
combination regimens, is pancreatitis, which may be fatal.
Patients should be informed that the preferred dosing frequency of VIDEX is twice
daily because there is more evidence to support the effectiveness of this dosing frequency.
Once-daily dosing should be considered only for adult patients whose management
requires once-daily dosing of VIDEX.
Patients should also be aware that peripheral neuropathy, manifested by numbness,
tingling, or pain in hands or feet, may develop during therapy with VIDEX. Patients
should be counseled that peripheral neuropathy occurs with greatest frequency in patients
with advanced HIV disease or a history of peripheral neuropathy, and that dose
modification and/or discontinuation of VIDEX may be required if toxicity develops.
Patients should be informed that when VIDEX is used in combination with other
agents with similar toxicities, the incidence of adverse events may be higher than when
VIDEX is used alone. These patients should be followed closely.
Patients should be cautioned about the use of medications or other substances,
including alcohol, that may exacerbate VIDEX toxicities.
Patients should be advised that to ensure proper acid neutralization in the stomach
they must take at least two of the appropriate strength VIDEX tablets at each dose. To
reduce the risk of gastrointestinal side effects from excess antacid, patients should take no
more than four VIDEX tablets at each dose.
VIDEX (didanosine) is not a cure for HIV infection, and patients may continue to
develop HIV-associated illnesses, including opportunistic infection. Therefore, patients
should remain under the care of a physician when using VIDEX. Patients should be
advised that VIDEX therapy has not been shown to reduce the risk of transmission of HIV
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to others through sexual contact or blood contamination. Patients should be informed that
the long-term effects of VIDEX are unknown at this time.
Patients should be informed that redistribution or accumulation of body fat may
occur in patients receiving antiretroviral therapy and that the cause and long-term health
effects of these conditions are not known at this time.
Drug Interactions (see also CLINICAL PHARMACOLOGY: Drug
Interactions)
Drug interactions that have been established based on drug interaction studies are listed
with the pharmacokinetic results in CLINICAL PHARMACOLOGY: Drug
Interactions (Tables 3 and 4). The clinical recommendations based on the results of these
studies are listed in Table 7.
Table 7:
Established Drug Interactions with VIDEX
Coadministration Not Recommended Based on Drug Interaction Studies (see CLINICAL
PHARMACOLOGY: Drug Interactions for Magnitude of Interaction)
Drug
Effect
Clinical Comment
allopurinol
↑ didanosine concentration
Coadministration not recommended.
Alteration in Dose or Regimen Recommended Based on Drug Interaction Studies (see CLINICAL
PHARMACOLOGY: Drug Interactions for Magnitude of Interaction)
Drug
Effect
Clinical Comment
ciprofloxacin
↓ ciprofloxacin concentration
Administer VIDEX at least 2 hours after or
6 hours before ciprofloxacin.
delavirdine
↓ delavirdine concentration
Administer VIDEX 1 hour after
delavirdine.
ganciclovir
↑ didanosine concentration
Appropriate doses for this combination,
with respect to efficacy and safety, have not
been established.
indinavir
↓ indinavir concentration
Administer VIDEX 1 hour after indinavir.
methadone
↓ didanosine concentration
Appropriate doses for this combination,
with respect to efficacy and safety, have not
been established.
nelfinavir
No interaction 1 hour after didanosine
Administer nelfinavir 1 hour after VIDEX.
tenofovir
disoproxil fumarate
↑ didanosine concentration
Appropriate doses for this combination,
with respect to efficacy and safety, have not
been established. Use with caution and
monitor closely for didanosine-associated
toxicities (see below).
↑ indicates increase.
↓ indicates decrease.
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Coadministration of VIDEX with drugs that are known to cause pancreatitis
may increase the risk of this toxicity (see WARNINGS: Pancreatitis). Because VIDEX
formulations either contain buffers or are mixed with antacids before administration,
interactions may be anticipated with drugs whose absorption can be affected by the level of
acidity in the stomach and with drugs that have been demonstrated to interact with antacids
containing magnesium, calcium, or aluminum. Predicted drug interactions with VIDEX
are listed in Table 8.
Table 8:
Predicted Drug Interactions with VIDEX
Use with Caution or Not Recommended, Risk of Adverse Reactions May Be Increased
Drug or Drug Class
Effect
Clinical Comment
Drugs that may cause
pancreatic toxicity
↑ risk of pancreatitis
Use only with extreme caution.a
Neurotoxic drugs
↑ risk of neuropathy
Use with caution.b
Antacids containing
magnesium or aluminum
↑ side effects associated with
antacid components
Use caution with VIDEX
Chewable/Dispersible Buffered Tablets
and Pediatric Powder for Oral Solution.
Ribavirin
↑ risk of toxicity
Ribavirin has been shown in vitro to
increase intracellular triphosphate levels of
didanosine. Coadministration is not
recommended (see below).
Use with Caution, Plasma Concentrations May Be Decreased by Coadministration with VIDEX
Drug Class
Effect
Clinical Comment
Azole antifungals
↓ ketoconazole or itraconazole
concentration
Administer drugs such as ketoconazole or
itraconazole at least 2 hours before
VIDEX.
Quinolone antibiotics (see
also ciprofloxacin in
Table 7)
↓ quinolone concentration
Consult package insert of the quinolone.
Tetracycline antibiotics
↓ antibiotic concentration
Consult package insert of the tetracycline.
↑ indicates increase.
↓ indicates decrease.
a Only if other drugs are not available and if clearly indicated. If treatment with life-sustaining drugs that
cause pancreatic toxicity is required, suspension of VIDEX is recommended (see WARNINGS:
Pancreatitis).
b See PRECAUTIONS: Peripheral Neuropathy.
Nucleoside/nucleotide analogues
Tenofovir disoproxil fumarate. Exposure to didanosine is increased when didanosine is
coadministered with tenofovir (see Tables 3 and 7). Increased exposure may cause or
worsen didanosine-related clinical toxicities, including pancreatitis, symptomatic
hyperlactatemia/lactic acidosis, and peripheral neuropathy. Coadministration of
tenofovir with VIDEX should be undertaken with caution, and patients should be
monitored closely for didanosine-related toxicities. VIDEX should be suspended if
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signs or symptoms of pancreatitis, symptomatic hyperlactatemia, or lactic acidosis
develop (see WARNINGS).
Ribavirin. Exposure to the active metabolite of didanosine (dideoxyadenosine 5’-
triphosphate) is increased when didanosine is coadministered with ribavirin (see Table 8).
Fatal hepatic failure, as well as peripheral neuropathy, pancreatitis, and symptomatic
hyperlactatemia/lactic acidosis have been reported in patients receiving both didanosine
and ribavirin. Coadministration of didanosine and ribavirin is not recommended.
Carcinogenesis and Mutagenesis
Lifetime carcinogenicity studies were conducted in mice and rats for 22 and 24 months,
respectively. In the mouse study, initial doses of 120, 800, and 1200 mg/kg/day for each
sex were lowered after 8 months to 120, 210, and 210 mg/kg/day for females and 120, 300,
and 600 mg/kg/day for males. The two higher doses exceeded the maximally tolerated
dose in females and the high dose exceeded the maximally tolerated dose in males. The
low dose in females represented 0.68-fold maximum human exposure and the intermediate
dose in males represented 1.7-fold maximum human exposure based on relative AUC
comparisons. In the rat study, initial doses were 100, 250, and 1000 mg/kg/day, and the
high dose was lowered to 500 mg/kg/day after 18 months. The upper dose in male and
female rats represented 3-fold maximum human exposure.
Didanosine induced no significant increase in neoplastic lesions in mice or rats at
maximally tolerated doses.
Didanosine was positive in the following genetic toxicology assays: 1) the
Escherichia coli tester strain WP2 uvrA bacterial mutagenicity assay; 2) the
L5178Y/TK+/- mouse lymphoma mammalian cell gene mutation assay; 3) the in vitro
chromosomal aberrations assay in cultured human peripheral lymphocytes; 4) the in vitro
chromosomal aberrations assay in Chinese Hamster Lung cells; and 5) the BALB/c 3T3 in
vitro transformation assay. No evidence of mutagenicity was observed in an Ames
Salmonella bacterial mutagenicity assay or in rat and mouse in vivo micronucleus assays.
Pregnancy, Reproduction, and Fertility
Pregnancy Category B. Reproduction studies have been performed in rats and rabbits at
doses up to 12 and 14.2 times the estimated human exposure (based upon plasma levels),
respectively, and have revealed no evidence of impaired fertility or harm to the fetus due to
didanosine. At approximately 12 times the estimated human exposure, didanosine was
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slightly toxic to female rats and their pups during mid and late lactation. These rats
showed reduced food intake and body weight gains but the physical and functional
development of the offspring was not impaired and there were no major changes in the F2
generation. A study in rats showed that didanosine and/or its metabolites are transferred to
the fetus through the placenta. Animal reproduction studies are not always predictive of
human response.
There are no adequate and well-controlled studies of didanosine in pregnant
women. Didanosine should be used during pregnancy only if the potential benefit justifies
the potential risk.
Fatal lactic acidosis has been reported in pregnant women who received the
combination of didanosine and stavudine with other antiretroviral agents. It is unclear if
pregnancy augments the risk of lactic acidosis/hepatic steatosis syndrome reported in
nonpregnant individuals receiving nucleoside analogues (see WARNINGS: Lactic
Acidosis/Severe Hepatomegaly with Steatosis). The combination of didanosine and
stavudine should be used with caution during pregnancy and is recommended only if
the potential benefit clearly outweighs the potential risk. Health care providers caring
for HIV-infected pregnant women receiving didanosine should be alert for early diagnosis
of lactic acidosis/hepatic steatosis syndrome.
Antiretroviral Pregnancy Registry: To monitor maternal-fetal outcomes of
pregnant women exposed to didanosine and other antiretroviral agents, an Antiretroviral
Pregnancy Registry has been established. Physicians are encouraged to register patients by
calling 1-800-258-4263.
Nursing Mothers
The Centers for Disease Control and Prevention recommend that HIV-infected
mothers not breast-feed their infants to avoid risking postnatal transmission of HIV.
A study in rats showed that following oral administration, didanosine and/or its metabolites
were excreted into the milk of lactating rats. It is not known if didanosine is excreted in
human milk. Because of both the potential for HIV transmission and the potential for
serious adverse reactions in nursing infants, mothers should be instructed not to breast-
feed if they are receiving VIDEX.
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Pediatric Use
Use of VIDEX in pediatric patients from 2 weeks of age through adolescence is supported
by evidence from adequate and well-controlled studies of VIDEX in adults and pediatric
patients
(see
INDICATIONS
AND
USAGE:
Clinical
Studies,
CLINICAL
PHARMACOLOGY,
ADVERSE
REACTIONS,
and
DOSAGE
AND
ADMINISTRATION).
Dosing recommendations for VIDEX in patients less than 2 weeks of age cannot be
made because the pharmacokinetics of didanosine in these children are too variable to
determine an appropriate dose.
Geriatric Use
In an Expanded Access Program for patients with advanced HIV infection, patients aged
65 years and older had a higher frequency of pancreatitis (10%) than younger patients (5%)
(see WARNINGS). Clinical studies of didanosine did not include sufficient numbers of
subjects aged 65 years and over to determine whether they respond differently than
younger subjects. Didanosine is known to be substantially excreted by the kidney, and the
risk of toxic reactions to this drug may be greater in patients with impaired renal function.
Because elderly patients are more likely to have decreased renal function, care should be
taken in dose selection. In addition, renal function should be monitored and dosage
adjustments should be made accordingly (see DOSAGE AND ADMINISTRATION:
Dose Adjustment).
ADVERSE REACTIONS
A SERIOUS TOXICITY OF VIDEX (didanosine) IS PANCREATITIS, WHICH MAY
BE FATAL (see WARNINGS). OTHER IMPORTANT TOXICITIES INCLUDE
LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS; RETINAL
CHANGES AND OPTIC NEURITIS; AND PERIPHERAL NEUROPATHY (see
WARNINGS and PRECAUTIONS).
When VIDEX is used in combination with other agents with similar toxicities,
the incidence of these toxicities may be higher than when VIDEX is used alone. Thus,
patients treated with VIDEX in combination with stavudine, with or without
hydroxyurea, may be at increased risk for pancreatitis, which may be fatal, and
hepatotoxicity (see WARNINGS). Patients treated with VIDEX in combination with
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stavudine may also be at increased risk for peripheral neuropathy (see
PRECAUTIONS).
Adults: Selected clinical adverse events that occurred in adult patients in clinical
studies with VIDEX are provided in Tables 9 and 10.
Table 9:
Selected Clinical Adverse Events from Monotherapy
Studies
Percent of Patients
ACTG 116A
ACTG 116B/117
Adverse Events
VIDEX
n=197
zidovudine
n=212
VIDEX
n=298
zidovudine
n=304
Diarrhea
19
15
28
21
Peripheral Neurologic
Symptoms/Neuropathy
17
14
20
12
Rash/Pruritus
7
8
9
5
Abdominal Pain
13
8
7
8
Pancreatitis
7
3
6
2
Table 10:
Selected Clinical Adverse Events from Combination
Studies
Percent of Patientsa
AI454-148b
START 2b
Adverse Events
VIDEX +
stavudine +
nelfinavir
n=482
zidovudine +
lamivudine +
nelfinavir
n=248
VIDEX +
stavudine +
indinavir
n=102
zidovudine +
lamivudine +
indinavir
n=103
Diarrhea
70
60
45
39
Nausea
28
40
53
67
Headache
21
30
46
37
Peripheral Neurologic
Symptoms/Neuropathy
26
6
21
10
Rash
13
16
30
18
Vomiting
12
14
30
35
Pancreatitis (see below)
1
*
<1
*
a Percentages based on treated subjects.
b Median duration of treatment 48 weeks.
* This event was not observed in this study arm.
Pancreatitis resulting in death was observed in one patient who received
VIDEX (didanosine) plus stavudine plus nelfinavir in Study Al454-148 and in one
patient who received VIDEX plus stavudine plus indinavir in the START 2 study. In
addition, pancreatitis resulting in death was observed in 2 of 68 patients who received
VIDEX plus stavudine plus indinavir plus hydroxyurea in an ACTG clinical trial (see
WARNINGS).
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The frequency of pancreatitis is dose related. In phase 3 studies, incidence ranged
from 1% to 10% with doses higher than are currently recommended and from 1% to 7%
with recommended dose.
Selected laboratory abnormalities in clinical studies with VIDEX are shown in
Tables 11-13.
Table 11:
Selected Laboratory Abnormalities from Monotherapy Studies
Percent of Patients
ACTG 116A
ACTG 116B/117
VIDEX
zidovudine
VIDEX
zidovudine
Parameter
n=197
n=212
n=298
n=304
SGOT (AST) (>5 x ULN)
9
4
7
6
SGPT (ALT) (>5 x ULN)
9
6
6
6
Alkaline phosphatase (>5 x ULN)
4
1
1
1
Amylase (≥1.4 x ULN)
17
12
15
5
Uric acid (>12 mg/dL)
3
1
2
1
ULN = upper limit of normal.
Table 12:
Selected Laboratory Abnormalities from Combination Studies
(Grades 3-4)
Percent of Patientsa
AI454-148b
START 2b
VIDEX +
stavudine +
nelfinavir
zidovudine +
lamivudine +
nelfinavir
VIDEX +
stavudine +
indinavir
zidovudine +
lamivudine +
indinavir
Parameter
n=482
n=248
n=102
n=103
Bilirubin (>2.6 x ULN)
<1
<1
16
8
SGOT (AST) (>5 x ULN)
3
2
7
7
SGPT (ALT) (>5 x ULN)
3
3
8
5
GGT (>5 x ULN)
NC
NC
5
2
Lipase (>2 x ULN)
7
2
5
5
Amylase (>2 x ULN)
NC
NC
8
2
ULN = upper limit of normal.
NC = Not Collected.
a Percentages based on treated subjects.
b Median duration of treatment 48 weeks.
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Table 13:
Selected Laboratory Abnormalities from Combination
Studies (All Grades)
Percent of Patientsa
I454-148b
START 2b
Parameter
VIDEX +
stavudine +
nelfinavir
n=482
zidovudine +
lamivudine +
nelfinavir
n=248
VIDEX +
stavudine +
indinavir
n=102
zidovudine +
lamivudine +
indinavir
n=103
Bilirubin
7
3
68
55
SGOT (AST)
42
23
53
20
SGPT (ALT)
37
24
50
18
GGT
NC
NC
28
12
Lipase
17
11
26
19
Amylase
NC
NC
31
17
NC = Not Collected.
a Percentages based on treated subjects.
b Median duration of treatment 48 weeks.
Observed during Clinical Practice: The following events have been identified
during postapproval use of VIDEX (didanosine). Because they are reported voluntarily
from a population of unknown size, estimates of frequency cannot be made. These events
have been chosen for inclusion due to their seriousness, frequency of reporting, causal
connection to VIDEX, or a combination of these factors.
Body as a Whole - alopecia, anaphylactoid reaction, asthenia, chills/fever, pain, and
redistribution/accumulation
of
body
fat
(see
PRECAUTIONS:
Fat
Redistribution).
Digestive Disorders- anorexia, dyspepsia, and flatulence.
Exocrine
Gland
Disorders
–
pancreatitis
(including
fatal
cases)
(see
WARNINGS), sialoadenitis, parotid gland enlargement, dry mouth, and dry eyes.
Hematologic Disorders - anemia, leukopenia, and thrombocytopenia.
Liver - symptomatic hyperlactatemia/lactic acidosis and hepatic steatosis (see
WARNINGS); hepatitis and liver failure.
Metabolic Disorders - diabetes mellitus, hypoglycemia, and hyperglycemia.
Musculoskeletal Disorders - myalgia (with or without increases in creatine kinase),
rhabdomyolysis including acute renal failure and hemodialysis, arthralgia, and
myopathy.
Ophthalmologic Disorders - Retinal depigmentation and optic neuritis (see
WARNINGS).
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Pediatric Patients: In clinical trials, 743 pediatric patients between 2 weeks and
18 years of age have been treated with VIDEX. Adverse events and laboratory
abnormalities reported to occur in these patients were generally consistent with the safety
profile of didanosine in adults.
In pediatric phase 1 studies, pancreatitis occurred in 2 of 60 (3%) patients treated at
entry doses below 300 mg/m2/day and in 5 of 38 (13%) patients treated at higher doses. In
study ACTG 152, pancreatitis occurred in none of the 281 pediatric patients who received
didanosine 120 mg/m2 q12h and in <1% of the 274 pediatric patients who received
didanosine 90 mg/m2 q12h in combination with zidovudine (see INDICATIONS AND
USAGE: Clinical Studies).
Retinal changes and optic neuritis have been reported in pediatric patients.
OVERDOSAGE
There is no known antidote for VIDEX (didanosine) overdosage. In phase 1 studies, in
which VIDEX was initially administered at doses ten times the currently recommended
dose, toxicities included: pancreatitis, peripheral neuropathy, diarrhea, hyperuricemia and
hepatic dysfunction. Didanosine is not dialyzable by peritoneal dialysis, although there is
some
clearance
by
hemodialysis
(see
CLINICAL
PHARMACOLOGY:
Pharmacokinetics).
DOSAGE AND ADMINISTRATION
Dosage
All VIDEX formulations should be administered on an empty stomach, at least 30
minutes before or 2 hours after eating. For either a once-daily or twice-daily regimen,
patients must take at least two of the appropriate strength tablets at each dose to
provide adequate buffering and prevent gastric acid degradation of didanosine.
Because of the need for adequate buffering, the 200-mg strength tablet should only be
used as a component of a once-daily regimen. To reduce the risk of gastrointestinal
side effects, patients should take no more than four tablets at each dose.
Adults: The preferred dosing frequency of VIDEX is twice daily because there is
more evidence to support the effectiveness of this dosing regimen. Once-daily dosing
should be considered only for adult patients whose management requires once-daily dosing
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of VIDEX (see INDICATIONS AND USAGE: Clinical Studies). The daily dose in adult
patients is dependent on weight as outlined in Table 14.
Table 14:
Adult Dosing
Patient Weight
VIDEX Tabletsa
VIDEX Buffered Powderb
Preferred dosing
≥60 kg
200 mg twice daily
250 mg twice daily
< 60 kg
125 mg twice daily
167 mg twice daily
Dosing for patients whose management requires once-daily frequency
≥ 60 kg
400 mg once daily
b
< 60 kg
250 mg once daily
b
a The 200-mg strength tablet should only be used as a component of a once-daily
regimen.
b Not suitable for once-daily dosing except for patients with renal impairment.
See Table 15.
Pediatric Patients: The recommended dose of VIDEX (didanosine) in pediatric
patients between 2 weeks and 8 months of age is 100 mg/m2 twice daily, and the
recommended VIDEX dose for pediatric patients older than 8 months is 120 mg/m2 twice
daily.
Dosing recommendations for VIDEX in patients less than 2 weeks of age cannot be
made because the pharmacokinetics of didanosine in these children are too variable to
determine an appropriate dose. There are no data on once-daily dosing of VIDEX in
pediatric patients.
Dose Adjustment
Clinical and laboratory signs suggestive of pancreatitis should prompt dose
suspension and careful evaluation of the possibility of pancreatitis. VIDEX use should
be discontinued in patients with confirmed pancreatitis (see WARNINGS and
PRECAUTIONS: Drug Interactions).
Patients with symptoms of peripheral neuropathy may tolerate a reduced dose of
VIDEX after resolution of the symptoms of peripheral neuropathy upon drug
discontinuation. If neuropathy recurs after resumption of VIDEX, permanent
discontinuation of VIDEX should be considered.
Renal Impairment: In adult patients with impaired renal function, the dose of
VIDEX should be adjusted to compensate for the slower rate of elimination. The
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recommended doses and dosing intervals of VIDEX in adult patients with renal
insufficiency are presented in Table 15.
Table 15:
Recommended Dosage of VIDEX in Renal Impairment
≥ 60 kg
< 60 kg
Creatinine Clearance
(mL/min)
Tableta
(mg)
Buffered Powderb
(mg)
Tableta
(mg)
Buffered Powderb
(mg)
≥60
200 twice dailyc
250 twice daily
125 twice dailyc
167 twice daily
30-59
200 once daily
or 100 twice daily
100 twice daily
150 once daily
or 75 twice daily
100 twice daily
10-29
150 once daily
167 once daily
100 once daily
100 once daily
<10
100 once daily
100 once daily
75 once daily
100 once daily
a VIDEX Chewable/Dispersible Buffered Tablet. Two VIDEX tablets must be taken with each dose;
different strengths of tablets may be combined to yield the recommended dose.
b VIDEX Buffered Powder for Oral Solution.
c 400 mg once daily (≥60 kg) or 250 mg once daily (<60 kg) for patients whose management requires once-
daily frequency of administration.
Urinary excretion is also a major route of elimination of didanosine in pediatric
patients; therefore, the clearance of didanosine may be altered in children with renal
impairment. Although there are insufficient data to recommend a specific dose adjustment
of VIDEX in this patient population, a reduction in the dose and/or an increase in the
interval between doses should be considered.
Patients Requiring Continuous Ambulatory Peritoneal Dialysis (CAPD)
or Hemodialysis: For patients requiring CAPD or hemodialysis, follow dosing
recommendations for patients with creatinine clearance less than 10 mL/min, shown in
Table 15. It is not necessary to administer a supplemental dose of VIDEX following
hemodialysis.
Hepatic Impairment: See WARNINGS and PRECAUTIONS.
Method of Preparation
VIDEX Chewable/Dispersible Buffered Tablets
Adult Dosing: To provide adequate buffering, at least two of the appropriate
strength tablets, but no more than four tablets, should be thoroughly chewed or dispersed
in at least 1 ounce of water prior to consumption (see PRECAUTIONS: Information for
Patients). To disperse tablets, add 2 tablets to at least 1 ounce of drinking water. Stir until
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a uniform dispersion forms, and drink the entire dispersion immediately. If additional
flavoring is desired, the dispersion may be diluted with one ounce of clear apple juice. Stir
the further diluted dispersion just prior to consumption. The dispersion with clear apple
juice is stable at room temperature, 62° to 73°F (17° to 23°C), for up to one hour.
VIDEX Buffered Powder for Oral Solution
1.
Open packet carefully and pour contents into a container with approximately 4
ounces of drinking water. Do not mix with fruit juice or other acid-containing
liquid.
2.
Stir until the powder completely dissolves (approximately 2 to 3 minutes).
3.
Drink the entire solution immediately.
VIDEX Pediatric Powder for Oral Solution
Prior to dispensing, the pharmacist must constitute dry powder with Purified Water, USP,
to an initial concentration of 20 mg/mL and immediately mix the resulting solution with
antacid to a final concentration of 10 mg/mL as follows:
20 mg/mL Initial Solution: Constitute the product to 20 mg/mL by adding 100
mL or 200 mL of Purified Water, USP, to the 2 g or 4 g of VIDEX powder, respectively, in
the product bottle.
10 mg/mL Final Admixture: 1. Immediately mix one part of the 20 mg/mL
initial solution with one part of either Extra Strength Mylanta® Liquid, Extra Strength
Maalox® Plus Suspension, or Maalox ® TC Suspension for a final dispensing
concentration of 10 mg VIDEX per mL. For patient home use, the admixture should be
dispensed in appropriately sized, flint-glass or plastic (HDPE, PET, or PETG) bottles with
child-resistant closures. This admixture is stable for 30 days under refrigeration, 36° to
46° F (2° to 8° C).
2. Instruct the patient to shake the admixture thoroughly prior to use and to store
the tightly closed container in the refrigerator, 36° to 46° F (2° to 8° C), up to 30 days.
Mylanta® is a registered trademark of Johnson & Johnson-Merck Consumer Pharmaceuticals Company.
Maalox® is a registered trademark of Novartis Consumer Health, Inc.
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HOW SUPPLIED
VIDEX® (didanosine) Chewable/Dispersible Buffered Tablets are round, off white to
light orange/yellow with a mottled appearance, orange-flavored, tablets embossed with
"VIDEX" on one side and the product strength on the other. The tablets are available in
the following strengths of VIDEX: 25, 50, 100, 150, and 200 mg. Sixty tablets are
packaged in bottles with child-resistant closures.
The tablets should be stored in tightly closed bottles at 59° to 86° F (15° to
30 °C). If dispersed in water, the dose may be held for up to 1 hour at ambient
temperature.
VIDEX (didanosine) Buffered Powder for Oral Solution is supplied in single-
dose, child-resistant foil packets in the following strengths of VIDEX: 100, 167, or 250
mg. Each product strength provides a sweetened, buffered solution of VIDEX.
The packets should be stored at 59° to 86° F (15° to 30° C). After dissolving in
water, the solution may be stored at ambient room temperature for up to 4 hours.
VIDEX (didanosine) Pediatric Powder for Oral Solution is supplied in 4- and 8-
ounce glass bottles containing 2 g or 4 g of VIDEX, respectively.
The bottles of powder should be stored at 59° to 86° F (15° to 30° C). The VIDEX
admixture may be stored up to 30 days in a refrigerator, 36° to 46° F (2° to 8° C). Discard
any unused portion after 30 days.
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The NDC numbers for the previously described VIDEX products are:
Table 16
NDC NO.
Packaging Information
Product Strength
VIDEX
Chewable/Dispersible Buffered Tablets
0087-6650-01
60 tablets/bottle
25 mg/tablet
0087-6651-01
60 tablets/bottle
50 mg/tablet
0087-6652-01
60 tablets/bottle
100 mg/tablet
0087-6653-01
60 tablets/bottle
150 mg/tablet
0087-6665-15
60 tablets/bottle
200 mg/tablet
VIDEX
Buffered Powder for Oral Solution
0087-6614-43
One single-dose foil packet*
100 mg/packet
0087-6615-43
One single-dose foil packet*
167 mg/packet
0087-6616-43
One single-dose foil packet*
250 mg/packet
VIDEX
Pediatric Powder for Oral Solution
0087-6632-41
One bottle per carton
2 g/bottle
0087-6633-41
One bottle per carton
4 g/bottle
* Packaged as 30 packets per carton.
US Patent Nos.: 4,861,759 and 5,616,566.
HANDLING AND DISPOSAL
Spill, Leak, and Disposal Procedure
Avoid generating dust during clean-up of powdered products; use wet mop or damp
sponge. Clean surface with soap and water as necessary. Containerize larger spills.
There is no single preferred method of disposal of containerized waste. Disposal
options include incineration, landfill, or sewer as dictated by specific circumstances and
relevant national, state, and local regulations.
Bristol-Myers Squibb Virology
Bristol-Myers Squibb Company
Princeton, NJ 08543 USA
xxxxxx
Revised
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PATIENT INFORMATION
Rx only
VIDEX®
(generic name = didanosine also known as ddI)
VIDEX® (didanosine) Chewable/Dispersible Buffered Tablets
VIDEX® (didanosine) Buffered Powder for Oral Solution
VIDEX® (didanosine) Pediatric Powder for Oral Solution
What is VIDEX?
VIDEX (pronounced VY dex) is a prescription medicine used in combination with other
drugs to treat children and adults who are infected with HIV (the human
immunodeficiency virus, the virus that causes AIDS). VIDEX belongs to a class of drugs
called nucleoside analogues. By reducing the growth of HIV, VIDEX helps your body
maintain its supply of CD4 cells, which are important for fighting HIV and other
infections.
VIDEX will not cure your HIV infection. At present there is no cure for HIV infection.
Even while taking VIDEX, you may continue to have HIV-related illnesses, including
infections with other disease-producing organisms. Continue to see your doctor regularly and
report any medical problems that occur.
VIDEX does not prevent a patient infected with HIV from passing the virus to
other people. To protect others, you must continue to practice safe sex and take precautions
to prevent others from coming in contact with your blood and other body fluids.
There is limited information on the effects of long-term use of VIDEX.
Who should not take VIDEX?
Do not take VIDEX if you are allergic to any of its ingredients, including its active ingredient,
didanosine and the inactive ingredients. (See Inactive Ingredients at the end of this leaflet.)
Tell your doctor if you think you have had an allergic reaction to any of these ingredients.
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How should I take VIDEX? How should I store it?
Your doctor will determine your dose based on your body weight, kidney and liver function,
other medicines you are taking, and any side effects that you may have had with VIDEX or
other medicines. Take VIDEX on an empty stomach - that means at least 30 minutes before
or 2 hours after eating. Do not take VIDEX with food. Try not to miss a dose, but if you do,
take it as soon as possible. If it is almost time for the next dose, skip the missed dose and
continue your regular dosing schedule.
Chewable/Dispersible Tablets: Each VIDEX tablet contains antacid. Each
time you take VIDEX, you must take at least two, but not more than four,
tablets. This is because VIDEX tablets contain an antacid to reduce the amount of
acid in your stomach. If you have too much acid, the medicine will break down.
However, too much antacid may cause stomach problems.
—DO NOT swallow VIDEX tablets whole. Chew the tablets well or mix them in
water. Many patients drop the tablets in at least one ounce of water and stir well
before swallowing. If you choose to mix the tablets in water, you may add one
ounce (2 tablespoons) of clear apple juice to the mixture for flavor (do not use any
other kind of juice).
—Store tablets in a tightly closed container at room temperature away from heat
and out of the reach of children and pets. Do NOT store the tablets in a damp place
such as a bathroom medicine cabinet or near the kitchen sink.
Buffered Powder for Oral Solution: Pour the contents of a packet into a glass
with 4 ounces (1/2 measuring cup) of water. Stir until completely dissolved. Drink
the entire solution right away. Do not mix with fruit juice. Store packets at room
temperature before use.
Pediatric Oral Solution: Your pharmacist will prepare the oral solution. Shake
the solution well before each use. Store in the refrigerator. Throw away any
unused portion after 30 days.
If you have kidney disease: If your kidneys are not working properly, your doctor
will need to do regular tests to check how they are working while you take VIDEX.
Your doctor may also lower your dosage of VIDEX.
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What should I do if someone takes an overdose of VIDEX?
If someone may have taken an overdose of VIDEX, get medical help right away. Contact
their doctor or a poison control center.
What should I avoid while taking VIDEX?
Alcohol. Do not drink alcohol while taking VIDEX since alcohol may increase your risk of
pancreatitis (pain and inflammation of the pancreas) or liver damage.
Other medicines. Other medicines, including those you can buy without a prescription,
may interfere with the actions of VIDEX. Do not take any medicine, vitamin
supplement, or other health preparation without first checking with your doctor.
Antacids. Since VIDEX contains some of the same ingredients found in antacids,
any side effects related to VIDEX’s ingredients may get worse if you also take an
antacid.
Medicines at the same time you take your VIDEX dose. Some medicines should
not be taken at the same time of day that you take VIDEX. Check with your
doctor.
Pregnancy. It is not known if VIDEX can harm a human fetus. Also, pregnant women
have experienced serious side effects when taking VIDEX in combination with ZERIT
(stavudine), also known as d4T, and other HIV medicines. VIDEX should be used during
pregnancy only after discussion with your doctor. Tell your doctor if you become
pregnant or plan to become pregnant while taking VIDEX.
Nursing. Studies have shown VIDEX is in the breast milk of animals getting the drug. It
may also be in human breast milk. The Centers for Disease Control and Prevention (CDC)
recommends that HIV-infected mothers not breast-feed. This should reduce the risk of
passing HIV infection to their babies and the potential for serious adverse reactions in
nursing infants. Therefore, do not nurse a baby while taking VIDEX.
What are the possible side effects of VIDEX?
Pancreatitis. Pancreatitis is a dangerous inflammation of the pancreas that may cause
death. Tell your doctor right away if you or a child taking VIDEX develops stomach
pain, nausea, or vomiting. These can be signs of pancreatitis. Before starting VIDEX
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therapy, let your doctor know if you or a child for whom it has been prescribed has ever had
pancreatitis. This condition is more likely to happen in people who have had it before. It is also
more likely in people with advanced HIV disease. However, it can occur at any stage of HIV
disease. It may be more common in patients with kidney problems, those who drink alcohol,
and those who are also treated with stavudine or hydroxyurea. If you get pancreatitis, your
doctor will tell you to stop taking VIDEX.
Lactic acidosis, severe liver enlargement, and liver failure, including deaths, have been
reported among patients taking VIDEX (including pregnant women). Symptoms that may
indicate a liver problem are:
• feeling very weak, tired, or uncomfortable,
• unusual or unexpected stomach discomfort,
• feeling cold,
• feeling dizzy or lightheaded,
• suddenly developing a slow or irregular heartbeat.
Lactic acidosis is a medical emergency that must be treated in a hospital.
If you notice any of these symptoms or if your medical condition changes, stop taking
VIDEX and call your doctor right away. Women, overweight patients, and those who have
been treated for a long time with other medicines used to treat HIV infection are more likely to
develop lactic acidosis. Your doctor should check your liver function periodically while you
are taking VIDEX. You should be especially careful if you have a history of heavy alcohol use
or a liver problem.
Vision changes. VIDEX may affect the nerves in your eyes. Because of this, you should have
regular eye examinations. You should also report any changes in vision to your doctor right
away. This includes, for example, seeing colors abnormally or blurred vision.
Peripheral neuropathy. This is a problem with the nerves in your hands or feet. The nerve
problem may be serious. Tell your doctor right away if you or a child taking VIDEX has
continuing numbness, tingling, or pain in the feet or hands. A child may not recognize these
symptoms or know to tell you that his or her feet or hands are numb, burning, tingling, or
painful. Ask your child’s doctor how to find out if your child is developing peripheral
neuropathy.
Before starting VIDEX therapy, let your doctor know if you or a child for whom it has
been prescribed has ever had peripheral neuropathy. This condition is more likely to happen in
people who have had it before. It is also more likely in patients taking medicines that affect the
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nerves and in people with advanced HIV disease. However, it can occur at any stage of HIV
disease. If you get peripheral neuropathy, your doctor will tell you to stop taking VIDEX.
After stopping VIDEX, the symptoms may get worse for a short time and then get better. Once
symptoms of peripheral neuropathy go away completely, you and your doctor should decide if
starting VIDEX is right for you. If so, you might be started at a lower dose.
Special note about other medicines. If you take VIDEX along with other medicines with
similar side effects, you may increase the chance of having these side effects. For example,
using VIDEX in combination with other medicines that may cause pancreatitis, peripheral
neuropathy, or liver problems (including stavudine and hydroxyurea) may increase your chance
of having these side effects.
Other side effects: The most common side effects in adults taking VIDEX are diarrhea,
neuropathy (nerve disorders), chills or fever, rash, abdominal pain, weakness, headache, and
nausea and vomiting. Children may have similar side effects as adults.
Changes in body fat have been seen in some patients taking antiretroviral therapy. These
changes may include increased amount of fat in the upper back and neck (“buffalo hump”),
breast, and around the trunk. Loss of fat from the legs, arms, and face may also happen. The
cause and long-term health effects of these conditions are not known at this time.
What else should I know about VIDEX?
If you should limit sodium (salt) intake: Each single-dose packet of Buffered Powder for
Oral Solution contains 1380 mg of sodium. Each Chewable/Dispersible Tablet contains
264.5 mg of sodium.
If you have phenylketonuria: Each Chewable/Dispersible Tablet contains 36.5 mg of
phenylalanine.
Inactive Ingredients:
Chewable/Dispersible Tablets: calcium carbonate, magnesium hydroxide,
aspartame, sorbitol, mandarin orange flavor, polyplasdone, microcrystalline
cellulose, and magnesium stearate.
Buffered Powder for Oral Solution: citrate-phosphate buffer (dibasic sodium
phosphate, sodium citrate, and citric acid) and sucrose.
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Pediatric Oral Solution: Extra Strength Mylanta Liquid, Extra Strength
Maalox Plus or Maalox TC Suspension.
This medicine was prescribed for your particular condition. Do not use VIDEX for another condition or give
it to others. Keep VIDEX and all medicines out of the reach of children. Throw away VIDEX when it is
outdated or no longer needed by flushing it down the toilet or pouring it down the sink.
This summary does not include everything there is to know about VIDEX. Medicines are sometimes
prescribed for purposes other than those listed in a Patient Information Leaflet. If you have questions or concerns, or
want more information about VIDEX, your physician and pharmacist have the complete prescribing information
upon which this leaflet is based. You may want to read it and discuss it with your doctor or other healthcare
professional. Remember, no written summary can replace careful discussion with your doctor.
Mylanta® is a registered trademark of Johnson & Johnson-Merck Consumer Pharmaceuticals Company.
Maalox® is a registered trademark of Novartis Consumer Health, Inc.
Bristol-Myers Squibb Virology
Bristol-Myers Squibb Company
Princeton, NJ 08543 USA
This Patient Information Leaflet has been approved by the U.S. Food and Drug Administration.
xxxxx
Revised
Based on xxxxx (x/xx)
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Rx only
VIDEX
EC (didanosine)
VIDEX EC (didanosine) Delayed-Release Capsules
Enteric-Coated Beadlets
(Patient Information Leaflet Included)
WARNING
FATAL AND NONFATAL PANCREATITIS HAVE OCCURRED DURING
THERAPY WITH DIDANOSINE USED ALONE OR IN COMBINATION
REGIMENS
IN
BOTH
TREATMENT-NAIVE
AND
TREATMENT-
EXPERIENCED
PATIENTS,
REGARDLESS
OF
DEGREE
OF
IMMUNOSUPPRESSION. VIDEX EC SHOULD BE SUSPENDED IN PATIENTS
WITH SUSPECTED PANCREATITIS AND DISCONTINUED IN PATIENTS
WITH CONFIRMED PANCREATITIS (SEE WARNINGS).
LACTIC
ACIDOSIS
AND
SEVERE
HEPATOMEGALY
WITH
STEATOSIS, INCLUDING FATAL CASES, HAVE BEEN REPORTED WITH
THE USE OF NUCLEOSIDE ANALOGUES ALONE OR IN COMBINATION,
INCLUDING DIDANOSINE AND OTHER ANTIRETROVIRALS. FATAL
LACTIC ACIDOSIS HAS BEEN REPORTED IN PREGNANT WOMEN WHO
RECEIVED THE COMBINATION OF DIDANOSINE AND STAVUDINE WITH
OTHER
ANTIRETROVIRAL
AGENTS.
THE
COMBINATION
OF
DIDANOSINE AND STAVUDINE SHOULD BE USED WITH CAUTION
DURING PREGNANCY AND IS RECOMMENDED ONLY IF THE POTENTIAL
BENEFIT CLEARLY OUTWEIGHS THE POTENTIAL RISK (SEE WARNINGS
AND PRECAUTIONS: PREGNANCY).
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DESCRIPTION
VIDEX® EC is the brand name for an enteric-coated formulation of didanosine (ddI), a
synthetic purine nucleoside analogue active against the Human Immunodeficiency Virus
(HIV). VIDEX EC (didanosine) Delayed-Release Capsules, containing enteric-coated
beadlets, are available for oral administration in strengths of 125, 200, 250, and 400 mg of
didanosine. The inactive ingredients in the beadlets include carboxymethylcellulose
sodium 12, diethyl phthalate, methacrylic acid copolymer, sodium hydroxide, sodium
starch glycolate, and talc. The capsule shells contain colloidal silicon dioxide, gelatin,
sodium lauryl sulfate, and titanium dioxide. The capsules are imprinted with edible inks.
Didanosine is also available as buffered formulations. Please consult the
prescribing information for VIDEX (didanosine) buffered formulations and Pediatric
Powder for Oral Solution for additional information.
The chemical name for didanosine is 2',3'-dideoxyinosine. The structural formula
is:
Didanosine is a white crystalline powder with the molecular formula C10H12N4O3
and a molecular weight of 236.2. The aqueous solubility of didanosine at 25° C and pH of
approximately 6 is 27.3 mg/mL. Didanosine is unstable in acidic solutions. For example, at
pH <3 and 37° C, 10% of didanosine decomposes to hypoxanthine in less than 2 minutes.
In VIDEX EC, an enteric coating is used to protect didanosine from degradation by
stomach acid.
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MICROBIOLOGY
Mechanism of Action
Didanosine is a synthetic nucleoside analogue of the naturally occurring nucleoside
deoxyadenosine in which the 3'–hydroxyl group is replaced by hydrogen. Intracellularly,
didanosine is converted by cellular enzymes to the active metabolite, dideoxyadenosine
5'-triphosphate. Dideoxyadenosine 5'–triphosphate inhibits the activity of HIV–1 reverse
transcriptase both by competing with the natural substrate, deoxyadenosine 5'–
triphosphate, and by its incorporation into viral DNA causing termination of viral DNA
chain elongation.
In Vitro HIV Susceptibility
The in vitro anti-HIV-1 activity of didanosine was evaluated in a variety of HIV-1 infected
lymphoblastic cell lines and monocyte/macrophage cell cultures. The concentration of drug
necessary to inhibit viral replication by 50% (IC50) ranged from 2.5 to 10 µM (1 µM = 0.24
µg/mL) in lymphoblastic cell lines and 0.01 to 0.1 µM in monocyte/macrophage cell
cultures. The relationship between in vitro susceptibility of HIV to didanosine and the
inhibition of HIV replication in humans has not been established.
Drug Resistance
HIV-1 isolates with reduced sensitivity to didanosine have been selected in vitro and were
also obtained from patients treated with didanosine. Genetic analysis of isolates from
didanosine-treated patients showed mutations in the reverse transcriptase gene that resulted
in the amino acid substitutions K65R, L74V, and M184V. The L74V mutation was most
frequently observed in clinical isolates. Phenotypic analysis of HIV-1 isolates from 60
patients (some with prior zidovudine treatment) receiving 6 to 24 months of didanosine
monotherapy showed that isolates from 10 of 60 patients exhibited an average of a 10-fold
decrease in susceptibility to didanosine in vitro compared to baseline isolates. Clinical
isolates that exhibited a decrease in didanosine susceptibility harbored one or more
didanosine-associated mutations. The clinical relevance of genotypic and phenotypic
changes associated with didanosine therapy has not been established.
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Cross-resistance
HIV-1 isolates from 2 of 39 patients receiving combination therapy for up to 2 years with
zidovudine and didanosine exhibited decreased susceptibility to zidovudine, didanosine,
zalcitabine, stavudine, and lamivudine in vitro. These isolates harbored five mutations
(A62V, V75I, F77L, F116Y, and Q151M) in the reverse transcriptase gene. The clinical
relevance of these observations has not been established.
CLINICAL PHARMACOLOGY
Animal Toxicology
Evidence of a dose-limiting skeletal muscle toxicity has been observed in mice and rats
(but not in dogs) following long-term (greater than 90 days) dosing with didanosine at
doses that were approximately 1.2 to 12 times the estimated human exposure. The
relationship of this finding to the potential of didanosine to cause myopathy in humans is
unclear. However, human myopathy has been associated with administration of
didanosine and other nucleoside analogues.
Pharmacokinetics
The pharmacokinetic parameters of didanosine are summarized in Table 1. Didanosine is
rapidly absorbed, with peak plasma concentrations generally observed from 0.25 to 1.50
hours following oral dosing with a buffered formulation. Increases in plasma didanosine
concentrations were dose proportional over the range of 50 to 400 mg. Steady-state
pharmacokinetic parameters did not differ significantly from values obtained after a single
dose. Binding of didanosine to plasma proteins in vitro was low (<5%). Based on data
from in vitro and animal studies, it is presumed that the metabolism of didanosine in man
occurs by the same pathways responsible for the elimination of endogenous purines.
Table 1:
Pharmacokinetic Parameters for Didanosine in Adults
Parameter
Mean ± SD
n
Oral bioavailabilitya
42 ± 12%
6
Apparent volume of distributionb
1.08 ± 0.22 L/kg
6
CSF-plasma ratiob
21 ± 0.03%c
5
Systemic clearanceb
13.0 ± 1.6 mL/min/kg
6
Renal clearancea
5.5 ± 2.1 mL/min/kg
6
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Table 1:
Pharmacokinetic Parameters for Didanosine in Adults
Parameter
Mean ± SD
n
Elimination half-lifea
1.5 ± 0.4 h
6
Urinary recovery of didanosinea
18 ± 8%
6
CSF = cerebrospinal fluid.
a following oral administration of a buffered formulation.
b following IV administration.
c mean ± SE.
Comparison of Didanosine Formulations
In VIDEX EC, the active ingredient, didanosine, is protected against degradation by
stomach acid by the use of an enteric coating on the beadlets in the capsule. The enteric
coating dissolves when the beadlets empty into the small intestine, the site of drug
absorption. With buffered formulations of didanosine, administration with antacid
provides protection from degradation by stomach acid.
In healthy volunteers, as well as subjects infected with HIV, the area under the
plasma concentration time curve (AUC) is equivalent for didanosine administered as the
VIDEX EC formulation relative to a buffered tablet formulation. The peak plasma
concentration (CMAX) of didanosine, administered as VIDEX EC, is reduced approximately
40% relative to didanosine buffered tablets. The time to the peak concentration (TMAX)
increases from approximately 0.67 hours for didanosine buffered tablets to 2.0 hours for
VIDEX EC.
Effect of Food on Absorption of Didanosine
In the presence of food, the CMAX and AUC for VIDEX EC were reduced by
approximately 46% and 19%, respectively, compared to the fasting state. VIDEX EC
should be taken on an empty stomach.
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Special Populations
Renal Insufficiency
It is recommended that the VIDEX EC (didanosine) dose be modified in patients with
reduced creatinine clearance and in patients receiving maintenance hemodialysis (see
DOSAGE AND ADMINISTRATION). Data from two studies using a buffered
formulation of didanosine indicated that the apparent oral clearance of didanosine
decreased and the terminal elimination half-life increased as creatinine clearance decreased
(see Table 2). Following oral administration, didanosine was not detectable in peritoneal
dialysate fluid (n=6); recovery in hemodialysate (n=5) ranged from 0.6% to 7.4% of the
dose over a 3-4 hour dialysis period. The absolute bioavailability of didanosine was not
affected in patients requiring dialysis.
Table 2:
Mean ± SD Pharmacokinetic Parameters for Didanosine
Following a Single Oral Dose of a Buffered Formulation
Creatinine Clearance (mL/min)
Parameter
≥ 90
(n=12)
60-90
(n=6)
30-59
(n=6)
10-29
(n=3)
Dialysis
Patients
(n=11)
CLcr (mL/min)
112 ± 22
68 ± 8
46 ± 8
13 ± 5
NDa
CL/F (mL/min)
2164 ± 638
1566 ± 833
1023 ± 378
628 ± 104
543 ± 174
CLR (mL/min)
458 ± 164
247 ± 153
100 ± 44
20 ± 8
<10
T½ (h)
1.42 ± 0.33
1.59 ± 0.13
1.75 ± 0.43
2.0 ± 0.3
4.1 ± 1.2
a ND = not determined due to anuria.
CLcr = creatinine clearance.
CL/F = apparent oral clearance.
CLR = renal clearance.
Pediatric Patients
The pharmacokinetics of didanosine administered as VIDEX EC have not been studied in
pediatric patients.
Geriatric Patients
Didanosine pharmacokinetics have not been studied in patients over 65 years of age (see
PRECAUTIONS: Geriatric Use).
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Gender
The effects of gender on didanosine pharmacokinetics have not been studied.
Drug Interactions (See also PRECAUTIONS: Drug Interactions.)
Ribavirin has been shown in vitro to increase intracellular triphosphate levels of
didanosine, which could cause or worsen clinical toxicities (see PRECAUTIONS: Drug
Interactions).
VIDEX EC
Tables 3 and 4 summarize the effects on AUC and CMAX, with a 90% confidence interval
(CI) when available, following coadministration of VIDEX EC with a variety of drugs.
Clinical recommendations based on drug interaction studies for drugs in bold font are
included in PRECAUTIONS: Drug Interactions.
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Table 3:
Results of Drug Interaction Studies with VIDEX EC: Effects of
Coadministered Drug on Didanosine Plasma AUC and CMAX
Valuesa
Drug
Didanosine Dosage
n
AUC of Didanosine
(90% CI)
CMAX of Didanosine
(90% CI)
tenofovir,b 300 mg
once daily with a
light mealc
400 mg single dose
fasting 2 h before
tenofovir
26
↑ 48% (31, 67%)
↑ 48% (25, 76%)
tenofovir,b 300 mg
once daily with a
light mealc
400 mg single dose
together with
tenofovir and a
light meal
25
↑ 60% (44, 79%)
↑ 64% (41, 89%)
↑ indicates increase.
a All studies conducted in healthy volunteers.
b tenofovir disoproxil fumarate.
c 373 kcalories, 8.2 grams fat.
Table 4:
Results of Drug Interaction Studies with VIDEX EC: Effects of
Didanosine on Coadministered Drug Plasma AUC and CMAX
Valuesa
Drug
Didanosine Dosage
n
AUC of
Coadministered Drug
CMAX of Coadministered
Drug
ciprofloxacin, 750 mg
single dose
400 mg single dose
16
↔
↔
indinavir, 800 mg
single dose
400 mg single dose
23
↔
↔
ketoconazole, 200 mg
single dose
400 mg single dose
21
↔
↔
tenofovir,b 300 mg
once daily with a
light mealc
400 mg single dose
fasting 2 h before
tenofovir
25
↔
↔
tenofovir,b 300 mg
once daily with a
light mealc
400 mg single dose
together with
tenofovir and a
light meal
25
↔
↔
↔ indicates no change, or mean increase or decrease of <10%.
a All studies conducted in healthy volunteers.
b tenofovir disoproxil fumarate.
c 373 kcalories, 8.2 grams fat.
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Didanosine Buffered Formulations
Tables 5 and 6 summarize the effects on AUC and CMAX, with a 90% or 95% CI when
available, following coadministration of buffered formulations of didanosine with a variety
of drugs. Except as noted in table footnotes, the results of these studies may be expected to
apply to VIDEX EC. For most of the listed drugs, no clinically significant
pharmacokinetic interactions were noted. Clinical recommendations based on drug
interaction studies for drugs in bold font are included in PRECAUTIONS: Drug
Interactions.
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Table 5:
Results of Drug Interaction Studies with Buffered
Formulations of Didanosine: Effects of Coadministered Drug
on Didanosine Plasma AUC and CMAX Values
Drugs With Clinical Recommendations Regarding Coadministration (see PRECAUTIONS: Drug
Interactions)
Drug
Didanosine Dosage
n
AUC of Didanosine
(95% CI)
CMAX of Didanosine
(95% CI)
allopurinol
renally impaired, 300 mg/day
200 mg single dose
2
↑ 312%
↑ 232%
healthy volunteer, 300 mg/day for
7 days
400 mg single dose
14
↑ 113%
↑ 69%
ganciclovir, 1000 mg q8h,
2 h after didanosine
200 mg q12h
12
↑ 111%
NA
methadone, chronic maintenance
dose
200 mg single dose
16,10a
↓ 57%
↓ 66%
tenofovir,b 300 mg once daily 1 h
after didanosine
250c or 400 mg once
daily for 7 days
14
↑ 44%
(31, 59%)d
↑ 28%
(11, 48%)d
No Clinically Significant Interaction Observed
Drug
Didanosine Dosage
n
AUC of Didanosine
(95% CI)
CMAX of Didanosine
(95% CI)
ciprofloxacin, 750 mg q12h for 3
days, 2 h before didanosine
200 mg q12h for 3 days
8e
↓ 16%
↓ 28%
indinavir, 800 mg single dose
simultaneous
200 mg single dose
16
↔
↔
1 h before didanosine
200 mg single dose
16
↓ 17% (-27, -7%)d
↓ 13% (-28, 5%)d
ketoconazole, 200 mg/day for 4
days, 2 h before didanosine
375 mg q12h for 4 days
12e
↔
↓12%
loperamide, 4 mg q6h for 1 day
300 mg single dose
12e
↔
↓23%
metoclopramide, 10 mg single dose
300 mg single dose
12e
↔
↑13%
ranitidine, 150 mg single dose, 2 h
before didanosine
375 mg single dose
12e
↑14%
↑13%
rifabutin, 300 or 600 mg/day for 12
days
167 or 250 mg q12h for
12 days
11
↑ 13% (-1, 27%)
↑ 17% (-4, 38%)
ritonavir, 600 mg q12h for 4 days
200 mg q12h for 4 days
12
↓ 13% (0, 23%)
↓ 16% (5, 26%)
stavudine, 40 mg q12h for 4 days
100 mg q12h for 4 days
10
↔
↔
sulfamethoxazole, 1000 mg single
dose
200 mg single dose
8e
↔
↔
trimethoprim, 200 mg single dose
200 mg single dose
8e
↔
↑ 17% (-23, 77%)
zidovudine, 200 mg q8h for 3 days
200 mg q12h for 3 days
6e
↔
↔
↑
indicates increase.
↓
indicates decrease.
↔ indicates no change, or mean increase or decrease of <10%.
a
Parallel-group design; entries are subjects receiving combination and control regimens, respectively.
b
tenofovir disoproxil fumarate.
c
patients less than 60 kg.
d
90% Cl.
e
HIV-infected patients.
NA Not available.
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Table 6:
Results of Drug Interaction Studies with Buffered
Formulations of Didanosine: Effects of Didanosine on
Coadministered Drug Plasma AUC and CMAX Values
No Clinically Significant Interaction Observed
Drug
Didanosine Dosage
n
AUC of
Coadministered Drug
(95% CI)
CMAX of
Coadministered Drug
(95% CI)
dapsone, 100 mg single dose
200 mg q12h for 14 days
6a
↔
↔
delavirdine, 400 mg single
dose
simultaneous
1 h before didanosine
125 or 200 mg q12h
125 or 200 mg q12h
12a
12a
↓ 32%b
↑ 20%
↓ 53%b
↑ 18%
ganciclovir, 1000 mg q8h,
2 h after didanosine
200 mg q12h
12a
↓21%
NA
nelfinavir, 750 mg single
dose, 1 h after didanosine
200 mg single dose
10a
↑12%
↔
ranitidine, 150 mg single
dose, 2 h before didanosine
375 mg single dose
12a
↓16%
↔
ritonavir, 600 mg q12h for
4 days
200 mg q12h for 4 days
12
↔
↔
stavudine, 40 mg q12h for
4 days
100 mg q12h for 4 days
10a
↔
↑17%
sulfamethoxazole, 1000 mg
single dose
200 mg single dose
8a
↓ 11% (-17, -4%)
↓ 12% (-28, 8%)
tenofovir,c 300 mg once daily
1 h after didanosine
250d or 400 mg once daily
for 7 days
14
↔
↔
trimethoprim, 200 mg single
dose
200 mg single dose
8a
↑ 10% (-9, 34%)
↓ 22% (-59, 49%)
zidovudine, 200 mg q8h for 3
days
200 mg q12h for 3 days
6a
↓ 10% (-27, 11%)
↓ 16.5% (-53, 47%)
↑
indicates increase.
↓
indicates decrease.
↔ indicates no change, or mean increase or decrease of <10%.
a
HIV-infected patients.
b
This result is probably related to the buffer and is not expected to occur with VIDEX EC.
c
tenofovir disoproxil fumarate.
d
patients less than 60 kg.
NA Not available.
INDICATIONS AND USAGE
VIDEX EC (didanosine) in combination with other antiretroviral agents is indicated
for the treatment of HIV-1 infection in adults. (See Clinical Studies.)
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Clinical Studies
Study Al454-152 was a 48-week, randomized, open-label study comparing VIDEX EC
(400 mg once daily) plus stavudine (40 mg twice daily) plus nelfinavir (750 mg three times
daily) to zidovudine (300 mg) plus lamivudine (150 mg) combination tablets twice daily
plus nelfinavir (750 mg three times daily) in 511 treatment-naive patients, with a mean
CD4 cell count of 411 cells/mm3 (range 39 to 1105 cells/mm3) and a mean plasma HIV-1
RNA of 4.71 log10 copies/mL (range 2.8 to 5.9 log10 copies/mL) at baseline. Patients were
primarily males (72%) and Caucasian (53%) with a mean age of 35 years (range 18 to 73
years). The percentages of patients with HIV RNA <400 and <50 copies/mL and outcomes
of patients through 48 weeks are summarized in Figure 1 and Table 7, respectively.
Figure 1
Treatment Response Through Week 48*, AI454-152
*Percent of patients at each time point who have HIV RNA <400 or
<50 copies/mL and do not meet any criteria for treatment failure (eg,
virologic failure or discontinuation for any reason).
0
20
40
60
80
100
0
12
24
36
48
Study Week
Percent of Patients
] < 400 c/mL
] < 50 c/mL
VIDEX EC+stavudine+nelfinavir, n=258
zidovudine/lamivudine+nelfinavir, n=253
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Table 7:
Outcomes of Randomized Treatment Through Week 48, AI454-152
Percent of Patients with HIV RNA <400 copies/mL (<50 copies/mL)
VIDEX EC + stavudine +
zidovudine/lamivudinea +
nelfinavir
nelfinavir
Outcome
n=258
n=253
Responderb,c
55% (33%)
56% (33%)
Virologic failured
22% (45%)
21% (43%)
Death or discontinued due to
disease progression
1% (1%)
2% (2%)
Discontinued due to adverse event
6% (6%)
7% (7%)
Discontinued due to other reasonse
16% (16%)
15% (16%)
a Zidovudine/lamivudine combination tablet.
b Corresponds to rates at Week 48 in Figure 1.
c Subjects achieved and maintained confirmed HIV RNA <400 copies/mL (<50 copies/mL) through
Week 48.
d Includes viral rebound at or before Week 48 and failure to achieve confirmed HIV RNA <400 copies/mL
(<50 copies/mL) through Week 48.
e Includes lost to follow-up, subject’s withdrawal, discontinuation due to physician’s decision, never treated,
and other reasons.
CONTRAINDICATION
VIDEX EC (didanosine) is contraindicated in patients with previously demonstrated
clinically significant hypersensitivity to any component of the formulation.
WARNINGS
1. Pancreatitis
FATAL AND NONFATAL PANCREATITIS HAVE OCCURRED DURING
THERAPY WITH DIDANOSINE USED ALONE OR IN COMBINATION
REGIMENS
IN
BOTH
TREATMENT-NAIVE
AND
TREATMENT-
EXPERIENCED
PATIENTS,
REGARDLESS
OF
DEGREE
OF
IMMUNOSUPPRESSION. VIDEX EC SHOULD BE SUSPENDED IN PATIENTS
WITH SIGNS OR SYMPTOMS OF PANCREATITIS AND DISCONTINUED IN
PATIENTS WITH CONFIRMED PANCREATITIS. PATIENTS TREATED WITH
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VIDEX EC IN COMBINATION WITH STAVUDINE, WITH OR WITHOUT
HYDROXYUREA, MAY BE AT INCREASED RISK FOR PANCREATITIS.
When treatment with life-sustaining drugs known to cause pancreatic toxicity is
required, suspension of VIDEX EC therapy is recommended. In patients with risk factors
for pancreatitis, VIDEX EC should be used with extreme caution and only if clearly
indicated. Patients with advanced HIV infection, especially the elderly, are at increased
risk of pancreatitis and should be followed closely. Patients with renal impairment may be
at greater risk for pancreatitis if treated without dose adjustment.
The frequency of pancreatitis is dose related. In phase 3 studies with buffered
formulations of didanosine, incidence ranged from 1% to 10% with doses higher than are
currently recommended and 1% to 7% with recommended dose.
2. Lactic Acidosis/Severe Hepatomegaly with Steatosis
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases,
have been reported with the use of nucleoside analogues alone or in combination,
including didanosine and other antiretrovirals. A majority of these cases have been in
women. Obesity and prolonged nucleoside exposure may be risk factors. Fatal lactic
acidosis has been reported in pregnant women who received the combination of didanosine
and stavudine with other antiretroviral agents. The combination of didanosine and
stavudine should be used with caution during pregnancy and is recommended only if the
potential benefit clearly outweighs the potential risk (see PRECAUTIONS: Pregnancy).
Particular caution should be exercised when administering VIDEX EC to any patient with
known risk factors for liver disease; however, cases have also been reported in patients
with no known risk factors. Treatment with VIDEX EC should be suspended in any
patient who develops clinical or laboratory findings suggestive of symptomatic
hyperlactatemia, lactic acidosis, or pronounced hepatotoxicity (which may include
hepatomegaly and steatosis even in the absence of marked transaminase elevations).
3. Retinal Changes and Optic Neuritis
Retinal changes and optic neuritis have been reported in patients taking didanosine.
Periodic retinal examinations should be considered for patients receiving VIDEX EC. (See
ADVERSE REACTIONS.)
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PRECAUTIONS
Dosing
VIDEX EC should be administered once daily on an empty stomach.
Peripheral Neuropathy
Peripheral neuropathy, manifested by numbness, tingling, or pain in the hands or feet, has
been reported in patients receiving didanosine therapy. Peripheral neuropathy has occurred
more frequently in patients with advanced HIV disease, in patients with a history of
neuropathy, or in patients being treated with neurotoxic drug therapy, including stavudine
(see ADVERSE REACTIONS).
Fat Redistribution
Redistribution/accumulation of body fat including central obesity, dorsocervical fat
enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and
“cushingoid appearance” have been observed in patients receiving antiretroviral therapy.
The mechanism and long-term consequences of these events are currently unknown. A
causal relationship has not been established.
General
Patients with Renal Impairment
Patients with renal impairment (creatinine clearance <60 mL/min) may be at greater risk of
toxicity from didanosine due to decreased drug clearance (see CLINICAL
PHARMACOLOGY). A dose reduction is recommended in these patients (see
DOSAGE AND ADMINISTRATION).
Patients with Hepatic Impairment
It is unknown if hepatic impairment significantly affects didanosine pharmacokinetics.
Therefore, these patients should be monitored closely for evidence of didanosine toxicity.
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Hyperuricemia
Didanosine has been associated with asymptomatic hyperuricemia; treatment suspension
may be necessary if clinical measures aimed at reducing uric acid levels fail.
Information for Patients (See Patient Information Leaflet.)
Patients should be informed that a serious toxicity of didanosine, used alone and in
combination regimens, is pancreatitis, which may be fatal.
Patients should also be aware that peripheral neuropathy, manifested by numbness,
tingling, or pain in hands or feet, may develop during therapy with VIDEX EC
(didanosine). Patients should be counseled that peripheral neuropathy occurs with greatest
frequency in patients with advanced HIV disease or a history of peripheral neuropathy, and
that dose modification and/or discontinuation of VIDEX EC may be required if toxicity
develops.
Patients should be informed that when didanosine is used in combination with other
agents with similar toxicities, the incidence of adverse events may be higher than when
didanosine is used alone. These patients should be followed closely.
Patients should be cautioned about the use of medications or other substances,
including alcohol, that may exacerbate VIDEX EC toxicities.
VIDEX EC is not a cure for HIV infection, and patients may continue to develop
HIV-associated illnesses, including opportunistic infection. Therefore, patients should
remain under the care of a physician when using VIDEX EC. Patients should be advised
that VIDEX EC therapy has not been shown to reduce the risk of transmission of HIV to
others through sexual contact or blood contamination. Patients should be informed that the
long-term effects of VIDEX EC are unknown at this time.
Patients should be informed that redistribution or accumulation of body fat may
occur in patients receiving antiretroviral therapy and that the cause and long-term health
effects of these conditions are not known at this time.
Drug Interactions (see also CLINICAL PHARMACOLOGY: Drug
Interactions)
Drug interactions that have been established based on drug interaction studies are listed
with the pharmacokinetic results in CLINICAL PHARMACOLOGY: Drug
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Interactions (Tables 3-6). The clinical recommendations based on the results of these
studies are listed in Table 8.
Table 8:
Established Drug Interactions Based on Studies with
VIDEX EC or Studies with Buffered Formulations of
Didanosine and Expected to Occur with VIDEX EC
Coadministration Not Recommended Based on Drug Interaction Studies (see CLINICAL
PHARMACOLOGY: Drug Interactions for Magnitude of Interaction)
Drug
Effect
Clinical Comment
allopurinol
↑ didanosine concentration
Coadministration not recommended.
Alteration in Dose or Regimen Recommended Based on Drug Interaction Studies (see CLINICAL
PHARMACOLOGY: Drug Interactions for Magnitude of Interaction)
Drug
Effect
Clinical Comment
ganciclovir
↑ didanosine concentration
Appropriate doses for this combination, with
respect to efficacy and safety, have not been
established.
methadone
↓ didanosine concentration
Appropriate doses for this combination, with
respect to efficacy and safety, have not been
established.
tenofovir disoproxil
fumarate
↑ didanosine concentration
Appropriate doses for this combination, with
respect to efficacy and safety, have not been
established. Use with caution and monitor
closely for didanosine-associated toxicities
(see below).
↑ indicates increase.
↓ indicates decrease.
Coadministration of VIDEX EC with drugs that are known to cause
pancreatitis may increase the risk of this toxicity (see WARNINGS: Pancreatitis).
Predicted drug interactions with VIDEX EC are listed in Table 9.
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Table 9:
Predicted Drug Interactions with VIDEX EC
Drug or Drug Class
Effect
Clinical Comment
Drugs that may cause
pancreatic toxicity
↑ risk of pancreatitis
Use only with extreme caution.a
Neurotoxic drugs
↑ risk of neuropathy
Use with caution.b
Ribavirin
↑ risk of toxicity
Ribavirin has been shown in vitro to increase
intracellular triphosphate levels of didanosine.
Coadministration is not recommended (see
below).
↑ indicates increase.
a Only if other drugs are not available and if clearly indicated. If treatment with life-sustaining drugs that
cause pancreatic toxicity is required, suspension of VIDEX EC is recommended (see WARNINGS:
Pancreatitis).
b See PRECAUTIONS: Peripheral Neuropathy.
Nucleoside/nucleotide analogues
Tenofovir disoproxil fumarate. Exposure to didanosine is increased when didanosine is
coadministered with tenofovir (see Tables 3, 5, and 8). Increased exposure may cause or
worsen didanosine-related clinical toxicities, including pancreatitis, symptomatic
hyperlactatemia/lactic acidosis, and peripheral neuropathy. Coadministration of
tenofovir with VIDEX EC should be undertaken with caution, and patients should be
monitored closely for didanosine-related toxicities. VIDEX EC should be suspended if
signs or symptoms of pancreatitis, symptomatic hyperlactatemia, or lactic acidosis
develop (see WARNINGS).
Ribavirin. Exposure to the active metabolite of didanosine (dideoxyadenosine 5’-
triphosphate) is increased when didanosine is coadministered with ribavirin (see Table 9).
Fatal hepatic failure, as well as peripheral neuropathy, pancreatitis, and symptomatic
hyperlactatemia/lactic acidosis have been reported in patients receiving both didanosine
and ribavirin. Coadministration of didanosine and ribavirin is not recommended.
Carcinogenesis and Mutagenesis
Lifetime carcinogenicity studies were conducted in mice and rats for 22 and 24 months,
respectively. In the mouse study, initial doses of 120, 800, and 1200 mg/kg/day for each
sex were lowered after 8 months to 120, 210, and 210 mg/kg/day for females and 120, 300,
and 600 mg/kg/day for males. The two higher doses exceeded the maximally tolerated
dose in females and the high dose exceeded the maximally tolerated dose in males. The
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low dose in females represented 0.68-fold maximum human exposure and the intermediate
dose in males represented 1.7-fold maximum human exposure based on relative AUC
comparisons. In the rat study, initial doses were 100, 250, and 1000 mg/kg/day, and the
high dose was lowered to 500 mg/kg/day after 18 months. The upper dose in male and
female rats represented 3-fold maximum human exposure.
Didanosine induced no significant increase in neoplastic lesions in mice or rats at
maximally tolerated doses.
Didanosine was positive in the following genetic toxicology assays: 1) the
Escherichia coli tester strain WP2 uvrA bacterial mutagenicity assay; 2) the
L5178Y/TK+/- mouse lymphoma mammalian cell gene mutation assay; 3) the in vitro
chromosomal aberrations assay in cultured human peripheral lymphocytes; 4) the in vitro
chromosomal aberrations assay in Chinese Hamster Lung cells; and 5) the BALB/c 3T3 in
vitro transformation assay. No evidence of mutagenicity was observed in an Ames
Salmonella bacterial mutagenicity assay or in rat and mouse in vivo micronucleus assays.
Pregnancy, Reproduction, and Fertility
Pregnancy Category B. Reproduction studies have been performed in rats and rabbits at
doses up to 12 and 14.2 times the estimated human exposure (based upon plasma levels),
respectively, and have revealed no evidence of impaired fertility or harm to the fetus due to
didanosine. At approximately 12 times the estimated human exposure, didanosine was
slightly toxic to female rats and their pups during mid and late lactation. These rats showed
reduced food intake and body weight gains but the physical and functional development of
the offspring was not impaired and there were no major changes in the F2 generation. A
study in rats showed that didanosine and/or its metabolites are transferred to the fetus
through the placenta. Animal reproduction studies are not always predictive of human
response.
There are no adequate and well-controlled studies of didanosine in pregnant
women. Didanosine should be used during pregnancy only if the potential benefit justifies
the potential risk.
Fatal lactic acidosis has been reported in pregnant women who received the
combination of didanosine and stavudine with other antiretroviral agents. It is unclear if
pregnancy augments the risk of lactic acidosis/hepatic steatosis syndrome reported in
nonpregnant individuals receiving nucleoside analogues (see WARNINGS: Lactic
Acidosis/Severe Hepatomegaly with Steatosis). The combination of didanosine and
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stavudine should be used with caution during pregnancy and is recommended only if
the potential benefit clearly outweighs the potential risk. Health care providers caring
for HIV-infected pregnant women receiving didanosine should be alert for early diagnosis
of lactic acidosis/hepatic steatosis syndrome.
Antiretroviral Pregnancy Registry: To monitor maternal-fetal outcomes of
pregnant women exposed to didanosine and other antiretroviral agents, an Antiretroviral
Pregnancy Registry has been established. Physicians are encouraged to register patients by
calling 1-800-258-4263.
Nursing Mothers
The Centers for Disease Control and Prevention recommend that HIV-infected
mothers not breast-feed their infants to avoid risking postnatal transmission of HIV.
A study in rats showed that following oral administration, didanosine and/or its metabolites
were excreted into the milk of lactating rats. It is not known if didanosine is excreted in
human milk. Because of both the potential for HIV transmission and the potential for
serious adverse reactions in nursing infants, mothers should be instructed not to breast-
feed if they are receiving VIDEX EC (didanosine).
Pediatric Use
The safety and efficacy of VIDEX EC in pediatric patients have not been established.
Please consult the complete prescribing information for VIDEX (didanosine) buffered
formulations and Pediatric Powder for Oral Solution for dosage and administration of
didanosine to pediatric patients.
Geriatric Use
In an Expanded Access Program using a buffered formulation of didanosine for the
treatment of advanced HIV infection, patients aged 65 years and older had a higher
frequency of pancreatitis (10%) than younger patients (5%) (see WARNINGS). Clinical
studies of didanosine, including those for VIDEX EC, did not include sufficient numbers
of subjects aged 65 years and over to determine whether they respond differently than
younger subjects. Didanosine is known to be substantially excreted by the kidney, and the
risk of toxic reactions to this drug may be greater in patients with impaired renal function.
Because elderly patients are more likely to have decreased renal function, care should be
taken in dose selection. In addition, renal function should be monitored and dosage
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adjustments should be made accordingly (see DOSAGE AND ADMINISTRATION:
Dose Adjustment).
ADVERSE REACTIONS
A SERIOUS TOXICITY OF DIDANOSINE IS PANCREATITIS, WHICH MAY BE
FATAL (see WARNINGS). OTHER IMPORTANT TOXICITIES INCLUDE LACTIC
ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS; RETINAL CHANGES
AND OPTIC NEURITIS; AND PERIPHERAL NEUROPATHY (see WARNINGS and
PRECAUTIONS).
When didanosine is used in combination with other agents with similar
toxicities, the incidence of these toxicities may be higher than when didanosine is used
alone. Thus, patients treated with VIDEX EC in combination with stavudine, with or
without hydroxyurea, may be at increased risk for pancreatitis, which may be fatal,
and hepatotoxicity (see WARNINGS). Patients treated with VIDEX EC in
combination with stavudine may also be at increased risk for peripheral neuropathy
(see PRECAUTIONS).
Selected clinical adverse events that occurred in a study of VIDEX EC in
combination with other antiretroviral agents are provided in Table 10.
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Table 10:
Selected Clinical Adverse Events, Study AI454-152a
Percent of Patientsb
VIDEX EC +
stavudine +
nelfinavir
zidovudine/
lamivudinec +
nelfinavir
Adverse Events
n=258
n=253
Diarrhea
57
58
Peripheral Neurologic
Symptoms/Neuropathy
25
11
Nausea
24
36
Headache
22
17
Rash
14
12
Vomiting
14
19
Pancreatitis (see below)
<1
*
a Median duration of treatment was 62 weeks in the VIDEX EC + stavudine + nelfinavir group and
61 weeks in the zidovudine/lamivudine + nelfinavir group.
b Percentages based on treated patients.
c Zidovudine/lamivudine combination tablet.
* This event was not observed in this study arm.
In clinical trials using a buffered formulation of didanosine, pancreatitis
resulting in death was observed in one patient who received didanosine plus
stavudine plus nelfinavir, one patient who received didanosine plus stavudine plus
indinavir, and 2 of 68 patients who received didanosine plus stavudine plus indinavir
plus hydroxyurea. In an early access program, pancreatitis resulting in death was
observed in one patient who received VIDEX EC plus stavudine plus hydroxyurea
plus ritonavir plus indinavir plus efavirenz (see WARNINGS).
The frequency of pancreatitis is dose related. In phase 3 studies with buffered
formulations of didanosine, incidence ranged from 1% to 10% with doses higher than are
currently recommended and 1% to 7% with recommended dose.
Selected laboratory abnormalities that occurred in a study of VIDEX EC in
combination with other antiretroviral agents are shown in Table 11.
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Table 11:
Selected Laboratory Abnormalities, Study AI454-152a
Percent of Patientsb
VIDEX EC + stavudine
+ nelfinavir
n=258
zidovudine/lamivudinec
+ nelfinavir
n=253
Parameter
Grades 3-4d
All Grades
Grades 3-4d
All Grades
SGOT (AST)
5
46
5
19
SGPT (ALT)
6
44
5
22
Lipase
5
23
2
13
Bilirubin
<1
9
<1
3
a Median duration of treatment was 62 weeks in the VIDEX EC + stavudine + nelfinavir group
and 61 weeks in the zidovudine/lamivudine + nelfinavir group.
b Percentages based on treated patients.
c Zidovudine/lamivudine combination tablet.
d >5 x ULN for SGOT and SGPT, ≥2.1 x ULN for lipase, and ≥2.6 x ULN for bilirubin (ULN =
upper limit of normal).
Observed During Clinical Practice
The following events have been identified during postapproval use of didanosine buffered
formulations. Because they are reported voluntarily from a population of unknown size,
estimates of frequency cannot be made. These events have been chosen for inclusion due
to their seriousness, frequency of reporting, causal connection to didanosine, or a
combination of these factors.
Body as a Whole – abdominal pain, alopecia, anaphylactoid reaction, asthenia,
chills/fever,
pain,
and
redistribution/accumulation
of
body
fat
(see
PRECAUTIONS: Fat Redistribution).
Digestive Disorders- anorexia, dyspepsia, and flatulence.
Exocrine
Gland
Disorders
–
pancreatitis
(including
fatal
cases)
(see
WARNINGS), sialoadenitis, parotid gland enlargement, dry mouth, and dry eyes.
Hematologic Disorders - anemia, leukopenia, and thrombocytopenia.
Liver - symptomatic hyperlactatemia/lactic acidosis and hepatic steatosis (see
WARNINGS); hepatitis and liver failure.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
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Metabolic Disorders - diabetes mellitus, elevated serum alkaline phosphatase level,
elevated serum amylase level, elevated serum gamma-glutamyltransferase level,
elevated serum uric acid level, hypoglycemia, and hyperglycemia.
Musculoskeletal Disorders - myalgia (with or without increases in creatine kinase),
rhabdomyolysis including acute renal failure and hemodialysis, arthralgia, and
myopathy.
Ophthalmologic Disorders - Retinal depigmentation and optic neuritis (see
WARNINGS).
OVERDOSAGE
There is no known antidote for didanosine overdosage. In phase 1 studies, in which
buffered formulations of didanosine were initially administered at doses ten times the
currently recommended dose, toxicities included: pancreatitis, peripheral neuropathy,
diarrhea, hyperuricemia and hepatic dysfunction. Didanosine is not dialyzable by
peritoneal dialysis, although there is some clearance by hemodialysis (see CLINICAL
PHARMACOLOGY: Pharmacokinetics).
DOSAGE AND ADMINISTRATION
Dosage
Adults
VIDEX EC (didanosine) should be administered on an empty stomach.
VIDEX EC Delayed-Release Capsules should be swallowed intact.
The recommended daily dose is dependent on body weight and is administered as
one capsule given on a once-daily schedule as outlined in Table 12.
Table 12:
Dosing of VIDEX EC Delayed-Release Capsules
Patient Weight
Dosage
≥60 kg
400 mg once daily
<60 kg
250 mg once daily
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Pediatric Patients
VIDEX EC has not been studied in pediatric patients. Please consult the complete
prescribing information for VIDEX (didanosine) buffered formulations and Pediatric
Powder for Oral Solution for dosage and administration of didanosine to pediatric patients.
Dose Adjustment
Clinical and laboratory signs suggestive of pancreatitis should prompt dose
suspension and careful evaluation of the possibility of pancreatitis. VIDEX EC use
should be discontinued in patients with confirmed pancreatitis (see WARNINGS and
PRECAUTIONS: Drug Interactions).
Based on data with buffered didanosine formulations, patients with symptoms of
peripheral neuropathy may tolerate a reduced dose of VIDEX EC after resolution of the
symptoms of peripheral neuropathy upon drug interruption. If neuropathy recurs after
resumption of VIDEX EC, permanent discontinuation of VIDEX EC should be considered.
Renal Impairment
Dosing recommendations for VIDEX EC and VIDEX buffered formulations are different
for patients with renal impairment. Please consult the complete prescribing information on
administration of VIDEX (didanosine) buffered formulations to patients with renal
impairment.
In adult patients with impaired renal function, the dose of VIDEX EC should be
adjusted to compensate for the slower rate of elimination. The recommended doses and
dosing intervals of VIDEX EC in adult patients with renal insufficiency are presented in
Table 13.
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Table 13:
Recommended Dosage of VIDEX EC in Renal
Impairment by Body Weighta
Dosage
Creatinine
Clearance
(mL/min)
≥60 kg
<60 kg
≥60
400 once daily
250 once daily
30-59
200 once daily
125 once daily
10-29
125 once daily
125 once daily
<10
125 once daily
b
a Based on studies using a buffered formulation of didanosine.
b Not suitable for use in patients <60 kg with CLcr <10 mL/min. An alternate formulation of
didanosine should be used.
Patients Requiring Continuous Ambulatory Peritoneal Dialysis (CAPD) or
Hemodialysis
For patients requiring CAPD or hemodialysis, follow dosing recommendations for patients
with creatinine clearance less than 10 mL/min, shown in Table 13. It is not necessary to
administer a supplemental dose of didanosine following hemodialysis.
Hepatic Impairment (See WARNINGS and PRECAUTIONS.)
HOW SUPPLIED
VIDEX® EC (didanosine) Delayed-Release Capsules are white, opaque capsules that are
packaged in bottles with child-resistant closures as described in Table 14.
Table 14:
VIDEX EC Delayed-Release Capsules
125 mg capsule imprinted with BMS 125 mg 6671 in Tan
NDC No. 0087-6671-17
30 capsules/bottle
200 mg capsule imprinted with BMS 200 mg 6672 in Green
NDC No. 0087-6672-17
30 capsules/bottle
250 mg capsule imprinted with BMS 250 mg 6673 in Blue
NDC No. 0087-6673-17
30 capsules/bottle
400 mg capsule imprinted with BMS 400 mg 6674 in Red
NDC No. 0087-6674-17
30 capsules/bottle
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The capsules should be stored in tightly closed containers at 25° C (77° F).
Excursions between 15° and 30° C (59° and 86° F) are permitted [see USP Controlled
Room Temperature].
HANDLING AND DISPOSAL
Disposal options include incineration, landfill, or sewer as dictated by specific
circumstances and relevant national, state, and local regulations.
US Patent Nos: 4,861,759 and 5,616,566 (didanosine).
Patent also Pending (didanosine capsules).
Bristol-Myers Squibb Virology
Bristol-Myers Squibb Company
Princeton, NJ 08543 USA
xxxxxx
Revised
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
January 27, 2003
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PATIENT INFORMATION
Rx only
VIDEX® EC
(generic name = didanosine also known as ddI)
VIDEX® EC (didanosine) Delayed-Release Capsules
Enteric-Coated Beadlets
What is VIDEX EC?
VIDEX EC (pronounced VY dex ee see) is a prescription medicine used in combination
with other drugs to treat adults who are infected with HIV (the human immunodeficiency
virus, the virus that causes AIDS). VIDEX EC belongs to a class of drugs called
nucleoside analogues. By reducing the growth of HIV, VIDEX EC helps your body
maintain its supply of CD4 cells, which are important for fighting HIV and other
infections.
VIDEX EC will not cure your HIV infection. At present there is no cure for HIV
infection. Even while taking VIDEX EC, you may continue to have HIV-related illnesses,
including infections with other disease-producing organisms. Continue to see your doctor
regularly and report any medical problems that occur.
VIDEX EC does not prevent a patient infected with HIV from passing the virus to
other people. To protect others, you must continue to practice safe sex and take precautions
to prevent others from coming in contact with your blood and other body fluids.
There is limited information on the antiviral response of long-term use of
VIDEX EC.
In VIDEX EC, an enteric coating is used to protect the medicine while it is in your
stomach since stomach acids can break it down. The enteric coating dissolves when the
medicine reaches your small intestine.
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Who should not take VIDEX EC?
Do not take VIDEX EC if you are allergic to any of its ingredients, including its active
ingredient, didanosine, and the inactive ingredients. (See Inactive Ingredients at the end
of this leaflet.) Tell your doctor if you think you have had an allergic reaction to any of
these ingredients.
Because it has only been studied in adults, VIDEX EC is not recommended for
children.
How should I take VIDEX EC?
How should I store it?
VIDEX EC should only be taken once daily. Your doctor will determine your dose based
on your body weight, kidney and liver function, other medicines you are taking, and any
side effects that you may have had with VIDEX EC or other medicines. Take VIDEX EC
on an empty stomach. Do not take VIDEX EC with food. Swallow the capsule whole;
do not open it. Try not to miss a dose, but if you do, take it as soon as possible. If it is
almost time for the next dose, skip the missed dose and continue your regular dosing
schedule.
Store capsules in a tightly closed container at room temperature away from heat
and out of the reach of children and pets.
If you have kidney disease: If your kidneys are not working properly, your doctor will
need to do regular tests to check how they are working while you take VIDEX EC. Your
doctor may also lower your dosage of VIDEX EC.
What should I do if someone takes an overdose of VIDEX EC?
If someone may have taken an overdose of VIDEX EC, get medical help right away.
Contact their doctor or a poison control center.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
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What should I avoid while taking VIDEX EC?
Alcohol. Do not drink alcohol while taking VIDEX EC since alcohol may increase your
risk of pancreatitis (pain and inflammation of the pancreas) or liver damage.
Other medicines. Other medicines, including those you can buy without a prescription,
may interfere with the actions of VIDEX EC. Do not take any medicine, vitamin
supplement, or other health preparation without first checking with your doctor.
Pregnancy. It is not known if VIDEX EC can harm a human fetus. Also, pregnant women
have experienced serious side effects when taking didanosine (the active ingredient in
VIDEX EC) in combination with ZERIT (stavudine), also known as d4T, and other HIV
medicines. VIDEX EC should be used during pregnancy only after discussion with your
doctor. Tell your doctor if you become pregnant or plan to become pregnant while
taking VIDEX EC.
Nursing. Studies have shown didanosine (the active ingredient in VIDEX EC) is in the
breast milk of animals getting the drug. It may also be in human breast milk. The Centers
for Disease Control and Prevention (CDC) recommends that HIV-infected mothers not
breast-feed. This should reduce the risk of passing HIV infection to their babies and the
potential for serious adverse reactions in nursing infants. Therefore, do not nurse a baby
while taking VIDEX EC.
What are the possible side effects of VIDEX EC?
Pancreatitis. Pancreatitis is a dangerous inflammation of the pancreas that may cause
death. Tell your doctor right away if you develop stomach pain, nausea, or vomiting.
These can be signs of pancreatitis. Before starting VIDEX EC therapy, let your doctor
know if you have ever had pancreatitis. This condition is more likely to happen in people who
have had it before. It is also more likely in people with advanced HIV disease. However, it can
occur at any stage of HIV disease. It may be more common in patients with kidney problems,
those who drink alcohol, and those who are also treated with stavudine or hydroxyurea. If you
get pancreatitis, your doctor will tell you to stop taking VIDEX EC.
Lactic acidosis, severe liver enlargement, and liver failure, including deaths, have been
reported among patients taking VIDEX EC (including pregnant women). Symptoms that
may indicate a liver problem are:
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•
feeling very weak, tired, or uncomfortable,
•
unusual or unexpected stomach discomfort,
•
feeling cold,
•
feeling dizzy or lightheaded,
•
suddenly developing a slow or irregular heartbeat.
Lactic acidosis is a medical emergency that must be treated in a hospital.
If you notice any of these symptoms or if your medical condition changes, stop
taking VIDEX EC and call your doctor right away. Women, overweight patients, and
those who have been treated for a long time with other medicines used to treat HIV
infection are more likely to develop lactic acidosis. Your doctor should check your liver
function periodically while you are taking VIDEX EC. You should be especially careful if
you have a history of heavy alcohol use or a liver problem.
Vision changes. VIDEX EC may affect the nerves in your eyes. Because of this, you
should have regular eye examinations. You should also report any changes in vision to
your doctor right away. This includes, for example, seeing colors abnormally or blurred
vision.
Peripheral neuropathy. This is a problem with the nerves in your hands or feet. The
nerve problem may be serious. Tell your doctor right away if you have continuing
numbness, tingling, or pain in the feet or hands.
Before starting VIDEX EC therapy, let your doctor know if you have ever had
peripheral neuropathy. This condition is more likely to happen in people who have had it
before. It is also more likely in patients taking medicines that affect the nerves and in
people with advanced HIV disease. However, it can occur at any stage of HIV disease. If
you get peripheral neuropathy, your doctor will tell you to stop taking VIDEX EC. After
stopping VIDEX EC, the symptoms may get worse for a short time and then get better.
Once symptoms of peripheral neuropathy go away completely, you and your doctor should
decide if starting VIDEX EC is right for you. If so, you might be started at a lower dose.
Special note about other medicines. If you take VIDEX EC along with other medicines
with similar side effects, you may increase the chance of having these side effects. For
example, using VIDEX EC in combination with other medicines that may cause
pancreatitis, peripheral neuropathy, or liver problems (including stavudine and
hydroxyurea) may increase your chance of having these side effects.
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Other side effects: The most common side effects in adults taking VIDEX EC in
combination with other HIV drugs included diarrhea, nausea, headache, vomiting, and
rash.
Changes in body fat have been seen in some patients taking antiretroviral therapy.
These changes may include increased amount of fat in the upper back and neck (“buffalo
hump”), breast, and around the trunk. Loss of fat from the legs, arms, and face may also
happen. The cause and long-term health effects of these conditions are not known at this
time.
Inactive Ingredients:
Carboxymethylcellulose sodium 12, diethyl phthalate, methacrylic acid copolymer, sodium
hydroxide, sodium starch glycolate, talc, colloidal silicon dioxide, gelatin, sodium lauryl
sulfate, and titanium dioxide.
This medicine was prescribed for your particular condition. Do not use VIDEX EC for another condition or
give it to others. Keep VIDEX EC and all medicines out of the reach of children. Throw away VIDEX EC
when it is outdated or no longer needed by flushing it down the toilet or pouring it down the sink.
This summary does not include everything there is to know about VIDEX EC. Medicines are sometimes
prescribed for purposes other than those listed in a Patient Information Leaflet. If you have questions or concerns, or
want more information about VIDEX EC, your physician and pharmacist have the complete prescribing information
upon which this leaflet is based. You may want to read it and discuss it with your doctor or other healthcare
professional. Remember, no written summary can replace careful discussion with your doctor.
Bristol-Myers Squibb Virology
Bristol-Myers Squibb Company
Princeton, NJ 08543 USA
This Patient Information Leaflet has been approved by the U.S. Food and Drug Administration.
xxxxxx
Revised
Based on xxxxxx (x/xx)
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:46:54.360892
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/20154slr042,20156slr033,20155slr032,21183slr007videx_lbl.pdf', 'application_number': 20155, 'submission_type': 'SUPPL ', 'submission_number': 32}
|
12,272
|
NDA 20-154/S-049
NDA 20-155/S-038
NDA 20-156/S-039
NDA 21-183/S-015
Page 4 of 75
Rx only
VIDEX® (didanosine)
VIDEX® (didanosine) Chewable/Dispersible Buffered Tablets
VIDEX® (didanosine) Pediatric Powder for Oral Solution
(Patient Information Leaflet Included)
WARNING
FATAL AND NONFATAL PANCREATITIS HAVE OCCURRED DURING
THERAPY WITH VIDEX USED ALONE OR IN COMBINATION REGIMENS IN
BOTH TREATMENT-NAIVE AND TREATMENT-EXPERIENCED PATIENTS,
REGARDLESS OF DEGREE OF IMMUNOSUPPRESSION. VIDEX SHOULD BE
SUSPENDED IN PATIENTS WITH SUSPECTED PANCREATITIS AND
DISCONTINUED IN PATIENTS WITH CONFIRMED PANCREATITIS (SEE
WARNINGS).
LACTIC
ACIDOSIS
AND
SEVERE
HEPATOMEGALY
WITH
STEATOSIS, INCLUDING FATAL CASES, HAVE BEEN REPORTED WITH THE
USE OF NUCLEOSIDE ANALOGUES ALONE OR IN COMBINATION,
INCLUDING DIDANOSINE AND OTHER ANTIRETROVIRALS. FATAL
LACTIC ACIDOSIS HAS BEEN REPORTED IN PREGNANT WOMEN WHO
RECEIVED THE COMBINATION OF DIDANOSINE AND STAVUDINE WITH
OTHER ANTIRETROVIRAL AGENTS. THE COMBINATION OF DIDANOSINE
AND STAVUDINE SHOULD BE USED WITH CAUTION DURING PREGNANCY
AND IS RECOMMENDED ONLY IF THE POTENTIAL BENEFIT CLEARLY
OUTWEIGHS THE POTENTIAL RISK (SEE WARNINGS AND PRECAUTIONS:
PREGNANCY).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-154/S-049
NDA 20-155/S-038
NDA 20-156/S-039
NDA 21-183/S-015
Page 5 of 75
DESCRIPTION
VIDEX® (didanosine) is a brand name for didanosine (ddI), a synthetic purine nucleoside
analogue active against the Human Immunodeficiency Virus (HIV). VIDEX
Chewable/Dispersible Buffered Tablets are available for oral administration in strengths of
25, 50, 100, 150, and 200 mg of didanosine. Each tablet is buffered with calcium
carbonate and magnesium hydroxide. VIDEX tablets also contain aspartame, sorbitol,
microcrystalline cellulose, polyplasdone, mandarin-orange flavor, and magnesium stearate.
VIDEX Pediatric Powder for Oral Solution is supplied for oral administration in 4-
or 8-ounce glass bottles containing 2 or 4 grams of didanosine, respectively.
Didanosine is also available as an enteric-coated formulation (VIDEX® EC
Delayed-Release Capsules). Please consult the prescribing information for VIDEX EC
(didanosine).
The chemical name for didanosine is 2',3'-dideoxyinosine. The structural formula is:
Didanosine is a white crystalline powder with the molecular formula C10H12N4O3
and a molecular weight of 236.2. The aqueous solubility of didanosine at 25° C and pH of
approximately 6 is 27.3 mg/mL. Didanosine is unstable in acidic solutions. For example,
at pH <3 and 37° C, 10% of didanosine decomposes to hypoxanthine in less than 2
minutes.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-154/S-049
NDA 20-155/S-038
NDA 20-156/S-039
NDA 21-183/S-015
Page 6 of 75
MICROBIOLOGY
Mechanism of Action
Didanosine is a synthetic nucleoside analogue of the naturally occurring nucleoside
deoxyadenosine in which the 3'-hydroxyl group is replaced by hydrogen. Intracellularly,
didanosine is converted by cellular enzymes to the active metabolite, dideoxyadenosine
5'-triphosphate. Dideoxyadenosine 5'-triphosphate inhibits the activity of HIV-1 reverse
transcriptase both by competing with the natural substrate, deoxyadenosine 5'-triphosphate,
and by its incorporation into viral DNA causing termination of viral DNA chain
elongation.
In Vitro HIV Susceptibility
The in vitro anti-HIV-1 activity of didanosine was evaluated in a variety of HIV-1 infected
lymphoblastic cell lines and monocyte/macrophage cell cultures. The concentration of
drug necessary to inhibit viral replication by 50% (IC50) ranged from 2.5 to 10 µM (1 µM
= 0.24 µg/mL) in lymphoblastic cell lines and 0.01 to 0.1 µM in monocyte/macrophage
cell cultures. The relationship between in vitro susceptibility of HIV to didanosine and the
inhibition of HIV replication in humans has not been established.
Drug Resistance
HIV-1 isolates with reduced sensitivity to didanosine have been selected in vitro and were
also obtained from patients treated with didanosine. Genetic analysis of isolates from
didanosine-treated patients showed mutations in the reverse transcriptase gene that resulted
in the amino acid substitutions K65R, L74V, and M184V. The L74V mutation was most
frequently observed in clinical isolates. Phenotypic analysis of HIV-1 isolates from 60
patients (some with prior zidovudine treatment) receiving 6 to 24 months of didanosine
monotherapy showed that isolates from 10 of 60 patients exhibited an average of a 10-fold
decrease in susceptibility to didanosine in vitro compared to baseline isolates. Clinical
isolates that exhibited a decrease in didanosine susceptibility harbored one or more
didanosine-associated mutations. The clinical relevance of genotypic and phenotypic
changes associated with didanosine therapy has not been established.
This label may not be the latest approved by FDA.
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Cross-resistance
HIV-1 isolates from 2 of 39 patients receiving combination therapy for up to 2 years with
zidovudine and didanosine exhibited decreased susceptibility to zidovudine, didanosine,
zalcitabine, stavudine, and lamivudine in vitro. These isolates harbored five mutations
(A62V, V75I, F77L, F116Y, and Q151M) in the reverse transcriptase gene. The clinical
relevance of these observations has not been established.
CLINICAL PHARMACOLOGY
Animal Toxicology
Evidence of a dose-limiting skeletal muscle toxicity has been observed in mice and rats
(but not in dogs) following long-term (greater than 90 days) dosing with didanosine at
doses that were approximately 1.2 to 12 times the estimated human exposure. The
relationship of this finding to the potential of VIDEX (didanosine) to cause myopathy in
humans is unclear. However, human myopathy has been associated with administration of
VIDEX and other nucleoside analogues.
Pharmacokinetics
The pharmacokinetic parameters of didanosine are summarized in Table 1. Didanosine is
rapidly absorbed, with peak plasma concentrations generally observed from 0.25 to 1.50
hours following oral dosing. Increases in plasma didanosine concentrations were dose
proportional over the range of 50 to 400 mg. Steady-state pharmacokinetic parameters did
not differ significantly from values obtained after a single dose. Binding of didanosine to
plasma proteins in vitro was low (<5%). Based on data from in vitro and animal studies, it
is presumed that the metabolism of didanosine in man occurs by the same pathways
responsible for the elimination of endogenous purines.
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Table 1:
Mean ± SD Pharmacokinetic Parameters for Didanosine in
Adult and Pediatric Patients
Pediatric Patientsb
Parameter
Adult Patientsa
n
8 months to 19 years
n
2 weeks to 4 months
n
Oral bioavailability (%)
42 ± 12
6
25 ± 20
46
ND
Apparent volume of
distributionc (L/m2)
43.70 ± 8.90
6
28 ± 15
49
ND
CSF-plasma ratiod
21 ± 0.03%e
5
46%
(range 12-85%)
7
ND
Systemic clearancec
(mL/min/m2)
526 ± 64.7
6
516 ± 184
49
ND
Renal clearancef
(mL/min/m2)
223 ± 85.0
6
240 ± 90
15
ND
Apparent oral clearanceg
(mL/min/m2)
1252 ± 154
6
2064 ± 736
48
1353 ± 759
41
Elimination half-lifef (h)
1.5 ± 0.4
6
0.8 ± 0.3
60
1.2 ± 0.3
21
Urinary recovery of
didanosinef (%)
18 ± 8
6
18 ± 10
15
ND
CSF = cerebrospinal fluid, ND = not determined.
a Parameter units for adults were converted to the same units in pediatric patients to facilitate comparisons
among populations: mean adult body weight = 70 kg and mean adult body surface area = 1.73 m2.
b In 1-day old infants (n=10), the mean ± SD apparent oral clearance was 1523 ± 1176 mL/min/m2 and
half-life was 2.0 ± 0.7 h.
c Following IV administration.
d Following IV administration in adults and IV or oral administration in pediatric patients.
e Mean ± SE.
f
Following oral administration.
g Apparent oral clearance estimate was determined as the ratio of the mean systemic clearance and the
mean oral bioavailability estimate.
Effect of Food on Absorption of Didanosine: Didanosine peak plasma
concentrations (CMAX) and area under the plasma concentration time curve (AUC) were
decreased by approximately 55% when VIDEX tablets were administered up to 2 hours
after a meal. Administration of VIDEX tablets up to 30 minutes before a meal did not
result in any significant changes in bioavailability. VIDEX should be taken on an empty
stomach, at least 30 minutes before or 2 hours after eating. (See DOSAGE AND
ADMINISTRATION.)
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Special Populations
Renal Insufficiency: It is recommended that the VIDEX (didanosine) dose be modified
in patients with reduced creatinine clearance and in patients receiving maintenance
hemodialysis (see DOSAGE AND ADMINISTRATION). Data from two studies in
adults indicated that the apparent oral clearance of didanosine decreased and the terminal
elimination half-life increased as creatinine clearance decreased (see Table 2). Following
oral administration, didanosine was not detectable in peritoneal dialysate fluid (n=6);
recovery in hemodialysate (n=5) ranged from 0.6% to 7.4% of the dose over a 3-4 hour
dialysis period. The absolute bioavailability of didanosine was not affected in patients
requiring dialysis.
Table 2:
Mean ± SD Pharmacokinetic Parameters for Didanosine
Following a Single Oral Dose
Creatinine Clearance (mL/min)
Parameter
≥ 90
(n=12)
60-90
(n=6)
30-59
(n=6)
10-29
(n=3)
Dialysis Patients
(n=11)
CLcr (mL/min)
112 ± 22
68 ± 8
46 ± 8
13 ± 5
ND
CL/F (mL/min)
2164 ± 638
1566 ± 833
1023 ± 378
628 ± 104
543 ± 174
CLR (mL/min)
458 ± 164
247 ± 153
100 ± 44
20 ± 8
<10
T½ (h)
1.42 ± 0.33
1.59 ± 0.13
1.75 ± 0.43
2.0 ± 0.3
4.1 ± 1.2
ND = not determined due to anuria.
CLcr = creatinine clearance.
CL/F = apparent oral clearance.
CLR = renal clearance.
Pediatric Patients: The pharmacokinetics of didanosine have been evaluated in
HIV-exposed and -infected pediatric patients from birth to 19 years of age (see Table 1).
Overall, the pharmacokinetics of didanosine in pediatric patients are similar to those of
didanosine in adults. Didanosine plasma concentrations appear to increase in proportion to
oral doses ranging from 25 to 120 mg/m2 in pediatric patients less than 5 months old and
from 80 to 180 mg/m2 in children above 8 months old. For information on controlled
clinical studies in pediatric patients, see INDICATIONS AND USAGE: Clinical Studies
and PRECAUTIONS: Pediatric Use.
Geriatric Patients: Didanosine pharmacokinetics have not been studied in
patients over 65 years of age.
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Gender: The effects of gender on didanosine pharmacokinetics have not been
studied.
Drug Interactions: Ribavirin has been shown in vitro to increase intracellular
triphosphate levels of didanosine, which could cause or worsen clinical toxicities (see
PRECAUTIONS: Drug Interactions).
Tables 3 and 4 summarize the effects on AUC and CMAX, with a 90% or 95%
confidence interval (CI) when available, following coadministration of VIDEX with a
variety of drugs. For most of the listed drugs, no clinically significant pharmacokinetic
interactions were observed. Clinical recommendations based on drug interaction studies
for drugs in bold font are included in PRECAUTIONS: Drug Interactions and
DOSAGE AND ADMINISTRATION (for tenofovir).
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Table 3:
Results of Drug Interaction Studies with VIDEX: Effects of Coadministered
Drug on Didanosine Plasma AUC and CMAX Values
Drugs With Clinical Recommendations Regarding Coadministration (see PRECAUTIONS: Drug Interactions)
Drug
Didanosine Dosage
n
AUC of
Didanosine
(95% CI)
CMAX of Didanosine
(95% CI)
allopurinol
renally impaired, 300 mg/day
200 mg single dose
2
↑ 312%
↑ 232%
healthy volunteer, 300 mg/day for
7 days
400 mg single dose
14
↑ 113%
↑ 69%
ciprofloxacin, 750 mg q12h for 3
days, 2 h before didanosine
200 mg q12h for 3 days
8a
↓ 16%
↓ 28%
ganciclovir, 1000 mg q8h, 2 h
after didanosine
200 mg q12h
12
↑ 111%
NA
indinavir, 800 mg single dose
simultaneous
1 h before didanosine
200 mg single dose
200 mg single dose
16
16
↔
↓ 17% (-27, - 7%)b
↔
↓ 13% (-28, 5%)b
ketoconazole, 200 mg/day for 4
days, 2 h before didanosine
375 mg q12h for 4 days
12a
↔
↓ 12%
methadone, chronic maintenance
dose
200 mg single dose
16, 10c
↓ 57%
↓ 66%
tenofovir,d,e 300 mg once daily
1 h after didanosine
250f or 400 mg once
daily for 7 days
14
↑ 44%
(31, 59%)b
↑ 28%
(11, 48%)b
No Clinically Significant Interaction Observed
Drug
Didanosine Dosage
n
AUC of
Didanosine
(95% CI)
CMAX of Didanosine
(95% CI)
loperamide, 4 mg q6h for 1 day
300 mg single dose
12a
↔
↓ 23%
metoclopramide, 10 mg single dose
300 mg single dose
12a
↔
↑ 13%
ranitidine, 150 mg single dose, 2 h
before didanosine
375 mg single dose
12a
↑ 14%
↑ 13%
rifabutin, 300 or 600 mg/day for 12
days
167 or 250 mg q12h for
12 days
11
↑ 13% (-1, 27%)
↑ 17% (-4, 38%)
ritonavir, 600 mg q12h for 4 days
200 mg q12h for 4 days
12
↓ 13% (0, 23%)
↓ 16% (5, 26%)
stavudine, 40 mg q12h for 4 days
100 mg q12h for 4 days
10
↔
↔
sulfamethoxazole, 1000 mg single
dose
200 mg single dose
8a
↔
↔
trimethoprim, 200 mg single dose
200 mg single dose
8a
↔
↑ 17% (-23, 77%)
zidovudine, 200 mg q8h for 3 days
200 mg q12h for 3 days
6a
↔
↔
↑ indicates increase.
↓ indicates decrease.
↔ indicates no change, or mean increase or decrease of <10%.
a
HIV-infected patients.
b
90% CI.
c Parallel-group design; entries are subjects receiving combination and control regimens, respectively.
d tenofovir disoproxil fumarate.
e
For results of drug interaction studies between the enteric-coated formulation of didanosine (VIDEX EC) and
tenofovir, see the complete prescribing information for VIDEX EC.
f
patients <60 kg with creatinine clearance ≥60 mL/min.
NA Not available.
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Table 4:
Results of Drug Interaction Studies with VIDEX: Effects of
Didanosine on Coadministered Drug Plasma AUC and CMAX
Values
Drugs With Clinical Recommendations Regarding Coadministration (see PRECAUTIONS: Drug Interactions)
Drug
Didanosine Dosage
n
AUC of
Coadministered
Drug (95% CI)
CMAX of
Coadministered
Drug (95% CI)
ciprofloxacin
750 mg q12h for 3 days, 2 h
before didanosine
750 mg single dose
200 mg q12h for 3 days
buffered placebo tablet
8a
12
↓ 26%
↓ 98%
↓ 16%
↓ 93%
delavirdine, 400 mg single dose
simultaneous
1 h before didanosine
125 or 200 mg q12h
125 or 200 mg q12h
12a
12a
↓ 32%
↑ 20%
↓ 53%
↑ 18%
ganciclovir, 1000 mg q8h, 2 h
after didanosine
200 mg q12h
12a
↓ 21%
NA
indinavir, 800 mg single dose
simultaneous
1 h before didanosine
200 mg single dose
200 mg single dose
16
16
↓ 84%
↓ 11%
↓ 82%
↓ 4%
ketoconazole, 200 mg/day for 4
days, 2 h before didanosine
375 mg q12h for 4 days
12a
↓ 14%
↓ 20%
nelfinavir, 750 mg single dose,
1 h after didanosine
200 mg single dose
10a
↑ 12%
↔
No Clinically Significant Interaction Observed
Drug
Didanosine Dosage
n
AUC of
Coadministered
Drug (95% CI)
CMAX of
Coadministered
Drug (95% CI)
dapsone, 100 mg single dose
200 mg q12h for 14 days
6a
↔
↔
ranitidine, 150 mg single dose, 2 h
before didanosine
375 mg single dose
12a
↓ 16%
↔
ritonavir, 600 mg q12h for 4 days
200 mg q12h for 4 days
12
↔
↔
stavudine, 40 mg q12h for 4 days
100 mg q12h for 4 days
10a
↔
↑ 17%
sulfamethoxazole, 1000 mg single
dose
200 mg single dose
8a
↓ 11% (-17, -4%)
↓ 12% (-28, 8%)
tenofovir,b 300 mg once daily 1 h
after didanosine
250c or 400 mg once
daily for 7 days
14
↔
↔
trimethoprim, 200 mg single dose
200 mg single dose
8a
↑ 10% (-9, 34%)
↓ 22% (-59, 49%)
zidovudine, 200 mg q8h for 3
days
200 mg q12h for 3 days
6a
↓ 10% (-27, 11%)
↓ 16.5% (-53, 47%)
↑ indicates increase.
↓ indicates decrease.
↔ indicates no change, or mean increase or decrease of <10%.
a
HIV-infected patients.
b
tenofovir disoproxil fumarate.
c
patients <60 kg with creatinine clearance ≥60 mL/min.
NA Not available.
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INDICATIONS AND USAGE
VIDEX (didanosine) in combination with other antiretroviral agents is indicated for
the treatment of HIV-1 infection (see Clinical Studies).
Clinical Studies
Combination Therapy
START 2 was a multicenter, randomized, open-label study comparing VIDEX (200 mg
twice daily)/stavudine/indinavir to zidovudine/lamivudine/indinavir in 205 treatment-naive
patients. Both regimens resulted in a similar magnitude of suppression of HIV RNA levels
and increases in CD4 cell counts through 48 weeks.
Study A1454-148 was a randomized, open-label, multicenter study comparing
treatment with VIDEX (400 mg once daily) plus stavudine (40 mg twice daily) and
nelfinavir (750 mg three times daily) versus zidovudine (300 mg twice daily) plus
lamivudine (150 mg twice daily) and nelfinavir (750 mg three times daily) in 756
treatment-naive patients, with a median CD4 cell count of 340 cells/mm3 (range 80 to 1568
cells/mm3) and a median plasma HIV-1 RNA of 4.69 log10 copies/mL (range 2.6 to 5.9
log10 copies/mL) at baseline. Median CD4 cell count increases at 48 weeks were 188
cells/mm3 in both treatment groups. Treatment response and outcomes through 48 weeks
are shown in Figure 1 and Table 5.
Figure 1:
Treatment Response Through Week 48*, AI454-148
0
20
40
60
80
100
0
8
16
24
32
40
48
Study Week
Percent of patients
] < 400 c/mL
] < 50 c/mL
VIDEX+stavudine+nelfinavir (n=503)
zidovudine+lamivudine+nelfinavir (n=253)
* Percent of patients at each time point who have HIV RNA <400 or <50 copies/mL, are on
their original study medication (except stavudine-zidovudine switches), and have not
experienced an AIDS-defining event.
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Table 5:
Outcomes of Randomized Treatment through Week 48,
AI454-148
Percent of Patients with HIV RNA <400 copies/mL (<50 copies/mL)
VIDEX/stavudine/nelfinavir
lamivudine/zidovudine/nelfinavir
Week 48 Status
n=503
n=253
Responder a
50* (34*)
59 (47)
Virologic failureb
36 (57)
32 (48)
Death or disease progression
<1 (<1)
1 (<1)
Discontinued due to adverse events
4 (2)
2 (<1)
Discontinued due to other reasonsc
6 (3)
4 (2)
Never initiated treatment
4 (4)
2 (2)
* p <0.05 for the differences between treatment groups, by Cochran-Mantel-Haenszel test.
a Patients achieved virologic response [two consecutive viral loads <400 (<50) copies/mL] and maintained
it to Week 48.
b Includes viral rebound and failing to achieve confirmed <400 (<50) copies/mL by Week 48.
c Includes lost to follow-up, noncompliance, withdrawal, and pregnancy.
Monotherapy
The efficacy of VIDEX was demonstrated in two randomized, double-blind studies
comparing VIDEX, given on a twice-daily schedule, to zidovudine, given three times
daily, in 617 (ACTG 116A, conducted 1989-1992) and 913 (ACTG 116B/117, conducted
1989-1991) patients with symptomatic HIV infection or AIDS who were treated for more
than one year. In treatment-naive patients (ACTG 116A), the rate of HIV disease
progression or death was similar between the treatment groups; mortality rates were 26%
for patients receiving VIDEX and 21% for patients receiving zidovudine. Of the patients
who had received previous zidovudine treatment (ACTG 116B/117), those treated with
VIDEX had a lower rate of HIV disease progression or death (32%) compared to those
treated with zidovudine (41%); however, survival rates were similar between the treatment
groups.
Efficacy in pediatric patients was demonstrated in a randomized, double-blind,
controlled study (ACTG 152, conducted 1991-1995) involving 831 patients 3 months to 18
years of age treated for more than 1.5 years with zidovudine (180 mg/m2 q6h), VIDEX
(120 mg/m2 q12h), or zidovudine (120 mg/m2q6h) plus VIDEX (90 mg/m2 q12h). Patients
treated with VIDEX or VIDEX plus zidovudine had lower rates of HIV disease
progression or death compared with those treated with zidovudine alone.
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Studies have demonstrated that the clinical benefit of monotherapy with
antiretrovirals, including VIDEX, was time limited.
CONTRAINDICATION
VIDEX (didanosine) is contraindicated in patients with previously demonstrated clinically
significant hypersensitivity to any of the components of the formulations.
WARNINGS
1.
Pancreatitis
FATAL AND NONFATAL PANCREATITIS HAVE OCCURRED DURING
THERAPY WITH VIDEX USED ALONE OR IN COMBINATION REGIMENS IN
BOTH TREATMENT-NAIVE AND TREATMENT-EXPERIENCED PATIENTS,
REGARDLESS OF DEGREE OF IMMUNOSUPPRESSION. VIDEX SHOULD BE
SUSPENDED IN PATIENTS WITH SIGNS OR SYMPTOMS OF PANCREATITIS
AND DISCONTINUED IN PATIENTS WITH CONFIRMED PANCREATITIS.
PATIENTS TREATED WITH VIDEX IN COMBINATION WITH STAVUDINE,
WITH OR WITHOUT HYDROXYUREA, MAY BE AT INCREASED RISK FOR
PANCREATITIS.
When treatment with life-sustaining drugs known to cause pancreatic toxicity is
required, suspension of VIDEX (didanosine) therapy is recommended. In patients with risk
factors for pancreatitis, VIDEX should be used with extreme caution and only if clearly
indicated. Patients with advanced HIV infection, especially the elderly, are at increased
risk of pancreatitis and should be followed closely. Patients with renal impairment may be
at greater risk for pancreatitis if treated without dose adjustment.
The frequency of pancreatitis is dose related. In phase 3 studies, incidence ranged
from 1% to 10% with doses higher than are currently recommended and 1% to 7% with
recommended dose.
In pediatric phase 1 studies, pancreatitis occurred in 3% (2/60) of patients treated at
entry doses below 300 mg/m2/day and in 13% (5/38) of patients treated at higher doses. In
study ACTG 152, pancreatitis occurred in none of the 281 pediatric patients who received
didanosine 120 mg/m2 q12h and in <1% of the 274 pediatric patients who received
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didanosine 90 mg/m2 q12h in combination with zidovudine. VIDEX (didanosine) use
should be suspended in pediatric patients with signs or symptoms of pancreatitis and
discontinued in pediatric patients with confirmed pancreatitis.
2.
Lactic Acidosis/Severe Hepatomegaly with Steatosis
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases,
have been reported with the use of nucleoside analogues alone or in combination,
including didanosine and other antiretrovirals. A majority of these cases have been in
women. Obesity and prolonged nucleoside exposure may be risk factors. Fatal lactic
acidosis has been reported in pregnant women who received the combination of didanosine
and stavudine with other antiretroviral agents. The combination of didanosine and
stavudine should be used with caution during pregnancy and is recommended only if the
potential benefit clearly outweighs the potential risk (see PRECAUTIONS: Pregnancy).
Particular caution should be exercised when administering VIDEX to any patient with
known risk factors for liver disease; however, cases have also been reported in patients
with no known risk factors. Treatment with VIDEX should be suspended in any patient
who develops clinical or laboratory findings suggestive of symptomatic hyperlactatemia,
lactic acidosis, or pronounced hepatotoxicity (which may include hepatomegaly and
steatosis even in the absence of marked transaminase elevations).
3.
Retinal Changes and Optic Neuritis
Retinal changes and optic neuritis have been reported in adult and pediatric
patients. Periodic retinal examinations should be considered for patients receiving VIDEX.
(See ADVERSE REACTIONS.)
4.
Hepatic Impairment and Toxicity
It
is
unknown
if
hepatic
impairment
significantly
affects
didanosine
pharmacokinetics. Therefore, these patients should be monitored closely for evidence of
didanosine toxicity. The safety and efficacy of VIDEX have not been established in HIV-
infected patients with significant underlying liver disease. During combination
antiretroviral therapy, patients with preexisting liver dysfunction, including chronic active
hepatitis, have an increased frequency of liver function abnormalities, including severe and
potentially fatal hepatic adverse events, and should be monitored according to standard
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practice. If there is evidence of worsening liver disease in such patients, interruption or
discontinuation of treatment must be considered.
Hepatotoxicity and hepatic failure resulting in death were reported during
postmarketing surveillance in HIV-infected patients treated with hydroxyurea and other
antiretroviral agents. Fatal hepatic events were reported most often in patients treated with
the combination of hydroxyurea, didanosine, and stavudine. This combination should be
avoided.
PRECAUTIONS
Frequency of Dosing
The preferred dosing frequency of VIDEX is twice daily because there is more evidence to
support the effectiveness of this dosing frequency. Once-daily dosing should be considered
only for adult patients whose management requires once-daily dosing of VIDEX (see
INDICATIONS AND USAGE: Clinical Studies).
VIDEX should be taken on an empty stomach, at least 30 minutes before or 2
hours after eating.
Peripheral Neuropathy
Peripheral neuropathy, manifested by numbness, tingling, or pain in the hands or feet, has
been reported in patients receiving VIDEX therapy. Peripheral neuropathy has occurred
more frequently in patients with advanced HIV disease, in patients with a history of
neuropathy, or in patients being treated with neurotoxic drug therapy, including stavudine.
Peripheral neuropathy, which was severe in some cases, has been reported in HIV-infected
patients receiving hydroxyurea in combination with antiretroviral agents, including
didanosine, with or without stavudine (see ADVERSE REACTIONS).
Fat Redistribution
Redistribution/accumulation of body fat including central obesity, dorsocervical fat
enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and
“cushingoid appearance” have been observed in patients receiving antiretroviral therapy.
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The mechanism and long-term consequences of these events are currently unknown. A
causal relationship has not been established.
Immune Reconstitution Syndrome
Immune reconstitution syndrome has been reported in patients treated with combination
antiretroviral therapy, including VIDEX. During the initial phase of combination
antiretroviral treatment, patients whose immune system responds may develop an
inflammatory response to indolent or residual opportunistic infections (such as
Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia
[PCP], or tuberculosis), which may necessitate further evaluation and treatment.
General
Patients with Phenylketonuria: VIDEX Chewable/Dispersible Buffered Tablets
contain the following quantities of phenylalanine:
Table 6
All Strengths
Phenylalanine per 2-tablet dose
73 mg
Phenylalanine per tablet
36.5 mg
Patients with Renal Impairment: Patients with renal impairment (creatinine
clearance <60 mL/min) may be at greater risk of toxicity from VIDEX due to decreased
drug clearance (see CLINICAL PHARMACOLOGY). A dose reduction is
recommended in these patients (see DOSAGE AND ADMINISTRATION). The
magnesium content of each buffered tablet of VIDEX is 8.6 mEq. This may present an
excessive load of magnesium to patients with significant renal impairment, particularly
after prolonged dosing.
Hyperuricemia: VIDEX has been associated with asymptomatic hyperuricemia;
treatment suspension may be necessary if clinical measures aimed at reducing uric acid
levels fail.
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Information for Patients (see Patient Information Leaflet)
Patients should be informed that a serious toxicity of VIDEX used alone and in
combination regimens is pancreatitis, which may be fatal.
Patients should be informed that the preferred dosing frequency of VIDEX is twice
daily because there is more evidence to support the effectiveness of this dosing frequency.
Once-daily dosing should be considered only for adult patients whose management
requires once-daily dosing of VIDEX.
Patients should also be aware that peripheral neuropathy, manifested by numbness,
tingling, or pain in hands or feet, may develop during therapy with VIDEX. Patients
should be counseled that peripheral neuropathy occurs with greatest frequency in patients
with advanced HIV disease or a history of peripheral neuropathy, and that dose
modification and/or discontinuation of VIDEX may be required if toxicity develops.
Patients should be informed that when VIDEX is used in combination with other
agents with similar toxicities, the incidence of adverse events may be higher than when
VIDEX is used alone. These patients should be followed closely.
Patients should be cautioned about the use of medications or other substances,
including alcohol, that may exacerbate VIDEX toxicities.
Patients should be advised that to ensure proper acid neutralization in the stomach
they must take at least two of the appropriate strength VIDEX tablets at each dose. To
reduce the risk of gastrointestinal side effects from excess antacid, patients should take no
more than four VIDEX tablets at each dose.
VIDEX (didanosine) is not a cure for HIV infection, and patients may continue to
develop HIV-associated illnesses, including opportunistic infection. Therefore, patients
should remain under the care of a physician when using VIDEX. Patients should be
advised that VIDEX therapy has not been shown to reduce the risk of transmission of HIV
to others through sexual contact or blood contamination. Patients should be informed that
the long-term effects of VIDEX are unknown at this time.
Patients should be informed that redistribution or accumulation of body fat may
occur in patients receiving antiretroviral therapy and that the cause and long-term health
effects of these conditions are not known at this time.
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Drug Interactions (see also CLINICAL PHARMACOLOGY: Drug
Interactions)
Drug interactions that have been established based on drug interaction studies are listed
with the pharmacokinetic results in CLINICAL PHARMACOLOGY: Drug
Interactions (Tables 3 and 4). The clinical recommendations based on the results of these
studies are listed in Table 7.
Table 7:
Established Drug Interactions with VIDEX
Coadministration Not Recommended Based on Drug Interaction Studies (see CLINICAL
PHARMACOLOGY: Drug Interactions for Magnitude of Interaction)
Drug
Effect
Clinical Comment
allopurinol
↑ didanosine concentration
Coadministration not recommended.
Alteration in Dose or Regimen Recommended Based on Drug Interaction Studies (see CLINICAL
PHARMACOLOGY: Drug Interactions for Magnitude of Interaction)
Drug
Effect
Clinical Comment
ciprofloxacin
↓ ciprofloxacin concentration
Administer VIDEX at least 2 hours after or
6 hours before ciprofloxacin.
delavirdine
↓ delavirdine concentration
Administer VIDEX 1 hour after delavirdine.
ganciclovir
↑ didanosine concentration
Appropriate doses for this combination,
with respect to efficacy and safety, have not
been established.
indinavir
↓ indinavir concentration
Administer VIDEX 1 hour after indinavir.
methadone
↓ didanosine concentration
Appropriate doses for this combination,
with respect to efficacy and safety, have not
been established.
nelfinavir
No interaction 1 hour after didanosine
Administer nelfinavir 1 hour after VIDEX.
tenofovir
disoproxil fumarate
↑ didanosine concentration
A dose reduction of VIDEX to 250 mg
(adults weighing ≥60 kg with creatinine
clearance ≥60 mL/min) or 200 mg (adults
weighing <60 kg with creatinine clearance ≥60
mL/min) once daily is recommended. VIDEX
and tenofovir may be taken together in the fasted
state. Alternatively, if tenofovir is taken with
food, VIDEX should be taken on an empty
stomach (at least 30 minutes before food or 2
hours after food). Patients should be monitored
for didanosine-associated toxicities and
clinical response (see below).
↑ indicates increase.
↓ indicates decrease.
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Coadministration of VIDEX with drugs that are known to cause pancreatitis
may increase the risk of this toxicity (see WARNINGS: Pancreatitis). Because VIDEX
formulations either contain buffers or are mixed with antacids before administration,
interactions may be anticipated with drugs whose absorption can be affected by the level of
acidity in the stomach and with drugs that have been demonstrated to interact with antacids
containing magnesium, calcium, or aluminum. Predicted drug interactions with VIDEX
are listed in Table 8.
Table 8:
Predicted Drug Interactions with VIDEX
Use with Caution or Not Recommended, Risk of Adverse Reactions May Be Increased
Drug or Drug Class
Effect
Clinical Comment
Drugs that may cause
pancreatic toxicity
↑ risk of pancreatitis
Use only with extreme caution.a
Neurotoxic drugs
↑ risk of neuropathy
Use with caution.b
Antacids containing
magnesium or aluminum
↑ side effects associated with
antacid components
Use caution with VIDEX
Chewable/Dispersible Buffered Tablets
and Pediatric Powder for Oral Solution.
Ribavirin
↑ risk of toxicity
Ribavirin has been shown in vitro to
increase intracellular triphosphate levels of
didanosine. Coadministration is not
recommended (see below).
Use with Caution, Plasma Concentrations May Be Decreased by Coadministration with VIDEX
Drug Class
Effect
Clinical Comment
Azole antifungals
↓ ketoconazole or itraconazole
concentration
Administer drugs such as ketoconazole or
itraconazole at least 2 hours before
VIDEX.
Quinolone antibiotics (see
also ciprofloxacin in
Table 7)
↓ quinolone concentration
Consult package insert of the quinolone.
Tetracycline antibiotics
↓ antibiotic concentration
Consult package insert of the tetracycline.
↑ indicates increase.
↓ indicates decrease.
a Only if other drugs are not available and if clearly indicated. If treatment with life-sustaining drugs that
cause pancreatic toxicity is required, suspension of VIDEX is recommended (see WARNINGS:
Pancreatitis).
b See PRECAUTIONS: Peripheral Neuropathy.
Nucleoside/nucleotide analogues
Tenofovir disoproxil fumarate. Exposure to didanosine is increased when coadministered
with tenofovir (see Table 3). Increased exposure may cause or worsen didanosine-
related clinical toxicities, including pancreatitis, symptomatic hyperlactatemia/lactic
acidosis, and peripheral neuropathy. Coadministration of tenofovir with VIDEX
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should be undertaken with caution, and patients should be monitored closely for
didanosine-related toxicities and clinical response. VIDEX should be suspended if
signs or symptoms of pancreatitis, symptomatic hyperlactatemia, or lactic acidosis
develop (see WARNINGS). A dose reduction of VIDEX to 250 mg (adults weighing ≥60
kg with creatinine clearance ≥60 mL/min) or 200 mg (adults weighing <60 kg with
creatinine clearance ≥60 mL/min) once daily is recommended. VIDEX and tenofovir may
be taken together in the fasted state. Alternatively, if tenofovir is taken with food, VIDEX
should be taken on an empty stomach, at least 30 minutes before food or 2 hours after food
(see DOSAGE AND ADMINISTRATION). (The dosing recommendation for
coadministration of VIDEX EC and tenofovir disoproxil fumarate with respect to meal
consumption differs from that of VIDEX. See the complete prescribing information for
VIDEX EC.)
Ribavirin. Exposure to the active metabolite of didanosine (dideoxyadenosine 5’-
triphosphate) is increased when didanosine is coadministered with ribavirin (see Table 8).
Fatal hepatic failure, as well as peripheral neuropathy, pancreatitis, and symptomatic
hyperlactatemia/lactic acidosis have been reported in patients receiving both didanosine
and ribavirin. Coadministration of didanosine and ribavirin is not recommended.
Carcinogenesis and Mutagenesis
Lifetime carcinogenicity studies were conducted in mice and rats for 22 and 24 months,
respectively. In the mouse study, initial doses of 120, 800, and 1200 mg/kg/day for each
sex were lowered after 8 months to 120, 210, and 210 mg/kg/day for females and 120, 300,
and 600 mg/kg/day for males. The two higher doses exceeded the maximally tolerated
dose in females and the high dose exceeded the maximally tolerated dose in males. The
low dose in females represented 0.68-fold maximum human exposure and the intermediate
dose in males represented 1.7-fold maximum human exposure based on relative AUC
comparisons. In the rat study, initial doses were 100, 250, and 1000 mg/kg/day, and the
high dose was lowered to 500 mg/kg/day after 18 months. The upper dose in male and
female rats represented 3-fold maximum human exposure.
Didanosine induced no significant increase in neoplastic lesions in mice or rats at
maximally tolerated doses.
Didanosine was positive in the following genetic toxicology assays: 1) the
Escherichia coli tester strain WP2 uvrA bacterial mutagenicity assay; 2) the
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L5178Y/TK+/-mouse lymphoma mammalian cell gene mutation assay; 3) the in vitro
chromosomal aberrations assay in cultured human peripheral lymphocytes; 4) the in vitro
chromosomal aberrations assay in Chinese Hamster Lung cells; and 5) the BALB/c 3T3 in
vitro transformation assay. No evidence of mutagenicity was observed in an Ames
Salmonella bacterial mutagenicity assay or in rat and mouse in vivo micronucleus assays.
Pregnancy, Reproduction, and Fertility
Pregnancy Category B. Reproduction studies have been performed in rats and rabbits at
doses up to 12 and 14.2 times the estimated human exposure (based upon plasma levels),
respectively, and have revealed no evidence of impaired fertility or harm to the fetus due to
didanosine. At approximately 12 times the estimated human exposure, didanosine was
slightly toxic to female rats and their pups during mid and late lactation. These rats
showed reduced food intake and body weight gains but the physical and functional
development of the offspring was not impaired and there were no major changes in the F2
generation. A study in rats showed that didanosine and/or its metabolites are transferred to
the fetus through the placenta. Animal reproduction studies are not always predictive of
human response.
There are no adequate and well-controlled studies of didanosine in pregnant
women. Didanosine should be used during pregnancy only if the potential benefit justifies
the potential risk.
Fatal lactic acidosis has been reported in pregnant women who received the
combination of didanosine and stavudine with other antiretroviral agents. It is unclear if
pregnancy augments the risk of lactic acidosis/hepatic steatosis syndrome reported in
nonpregnant individuals receiving nucleoside analogues (see WARNINGS: Lactic
Acidosis/Severe Hepatomegaly with Steatosis). The combination of didanosine and
stavudine should be used with caution during pregnancy and is recommended only if
the potential benefit clearly outweighs the potential risk. Health care providers caring
for HIV-infected pregnant women receiving didanosine should be alert for early diagnosis
of lactic acidosis/hepatic steatosis syndrome.
Antiretroviral Pregnancy Registry: To monitor maternal-fetal outcomes of
pregnant women exposed to didanosine and other antiretroviral agents, an Antiretroviral
Pregnancy Registry has been established. Physicians are encouraged to register patients by
calling 1-800-258-4263.
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Nursing Mothers
The Centers for Disease Control and Prevention recommend that HIV-infected
mothers not breast-feed their infants to avoid risking postnatal transmission of HIV.
A study in rats showed that following oral administration, didanosine and/or its
metabolites were excreted into the milk of lactating rats. It is not known if didanosine is
excreted in human milk. Because of both the potential for HIV transmission and the
potential for serious adverse reactions in nursing infants, mothers should be instructed
not to breast-feed if they are receiving VIDEX.
Pediatric Use
Use of VIDEX in pediatric patients from 2 weeks of age through adolescence is supported
by evidence from adequate and well-controlled studies of VIDEX in adults and pediatric
patients
(see
INDICATIONS
AND
USAGE:
Clinical
Studies,
CLINICAL
PHARMACOLOGY,
ADVERSE
REACTIONS,
and
DOSAGE
AND
ADMINISTRATION).
Dosing recommendations for VIDEX in patients less than 2 weeks of age cannot be
made because the pharmacokinetics of didanosine in these children are too variable to
determine an appropriate dose.
Geriatric Use
In an Expanded Access Program for patients with advanced HIV infection, patients aged
65 years and older had a higher frequency of pancreatitis (10%) than younger patients
(5%) (see WARNINGS). Clinical studies of didanosine did not include sufficient numbers
of subjects aged 65 years and over to determine whether they respond differently than
younger subjects. Didanosine is known to be substantially excreted by the kidney, and the
risk of toxic reactions to this drug may be greater in patients with impaired renal function.
Because elderly patients are more likely to have decreased renal function, care should be
taken in dose selection. In addition, renal function should be monitored and dosage
adjustments should be made accordingly (see DOSAGE AND ADMINISTRATION:
Dose Adjustment).
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ADVERSE REACTIONS
A SERIOUS TOXICITY OF VIDEX (didanosine) IS PANCREATITIS, WHICH MAY
BE FATAL (see WARNINGS). OTHER IMPORTANT TOXICITIES INCLUDE
LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS; RETINAL
CHANGES AND OPTIC NEURITIS; AND PERIPHERAL NEUROPATHY (see
WARNINGS and PRECAUTIONS).
When VIDEX is used in combination with other agents with similar toxicities,
the incidence of these toxicities may be higher than when VIDEX is used alone. Thus,
patients treated with VIDEX in combination with stavudine, with or without
hydroxyurea, may be at increased risk for pancreatitis and hepatotoxicity, which may
be fatal, and severe peripheral neuropathy (see WARNINGS and PRECAUTIONS).
Adults: Selected clinical adverse events that occurred in adult patients in clinical
studies with VIDEX are provided in Tables 9 and 10.
Table 9:
Selected Clinical Adverse Events from Monotherapy
Studies
Percent of Patients
ACTG 116A
ACTG 116B/117
Adverse Events
VIDEX
n=197
zidovudine
n=212
VIDEX
n=298
zidovudine
n=304
Diarrhea
19
15
28
21
Peripheral Neurologic
Symptoms/Neuropathy
17
14
20
12
Rash/Pruritus
7
8
9
5
Abdominal Pain
13
8
7
8
Pancreatitis
7
3
6
2
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Table 10:
Selected Clinical Adverse Events from Combination
Studies
Percent of Patientsa
AI454-148b
START 2b
Adverse Events
VIDEX +
stavudine +
nelfinavir
n=482
zidovudine +
lamivudine +
nelfinavir
n=248
VIDEX +
stavudine +
indinavir
n=102
zidovudine +
lamivudine +
indinavir
n=103
Diarrhea
70
60
45
39
Nausea
28
40
53
67
Headache
21
30
46
37
Peripheral Neurologic
Symptoms/Neuropathy
26
6
21
10
Rash
13
16
30
18
Vomiting
12
14
30
35
Pancreatitis (see below)
1
*
<1
*
a Percentages based on treated subjects.
b Median duration of treatment 48 weeks.
* This event was not observed in this study arm.
Pancreatitis resulting in death was observed in one patient who received
VIDEX (didanosine) plus stavudine plus nelfinavir in Study Al454-148 and in one
patient who received VIDEX plus stavudine plus indinavir in the START 2 study. In
addition, pancreatitis resulting in death was observed in 2 of 68 patients who received
VIDEX plus stavudine plus indinavir plus hydroxyurea in an ACTG clinical trial (see
WARNINGS).
The frequency of pancreatitis is dose related. In phase 3 studies, incidence ranged
from 1% to 10% with doses higher than are currently recommended and from 1% to 7%
with recommended dose.
Selected laboratory abnormalities in clinical studies with VIDEX are shown in
Tables 11-13.
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Table 11:
Selected Laboratory Abnormalities from Monotherapy Studies
Percent of Patients
ACTG 116A
ACTG 116B/117
VIDEX
zidovudine
VIDEX
zidovudine
Parameter
n=197
n=212
n=298
n=304
SGOT (AST) (>5 x ULN)
9
4
7
6
SGPT (ALT) (>5 x ULN)
9
6
6
6
Alkaline phosphatase (>5 x ULN)
4
1
1
1
Amylase (≥1.4 x ULN)
17
12
15
5
Uric acid (>12 mg/dL)
3
1
2
1
ULN = upper limit of normal.
Table 12:
Selected Laboratory Abnormalities from Combination Studies
(Grades 3-4)
Percent of Patientsa
AI454-148b
START 2b
VIDEX +
stavudine +
nelfinavir
zidovudine +
lamivudine +
nelfinavir
VIDEX +
stavudine +
indinavir
zidovudine +
lamivudine +
indinavir
Parameter
n=482
n=248
n=102
n=103
Bilirubin (>2.6 x ULN)
<1
<1
16
8
SGOT (AST) (>5 x ULN)
3
2
7
7
SGPT (ALT) (>5 x ULN)
3
3
8
5
GGT (>5 x ULN)
NC
NC
5
2
Lipase (>2 x ULN)
7
2
5
5
Amylase (>2 x ULN)
NC
NC
8
2
ULN = upper limit of normal.
NC = Not Collected.
a Percentages based on treated subjects.
b Median duration of treatment 48 weeks.
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Table 13:
Selected Laboratory Abnormalities from Combination
Studies (All Grades)
Percent of Patientsa
AI454-148b
START 2b
Parameter
VIDEX +
stavudine +
nelfinavir
n=482
zidovudine +
lamivudine +
nelfinavir
n=248
VIDEX +
stavudine +
indinavir
n=102
zidovudine +
lamivudine +
indinavir
n=103
Bilirubin
7
3
68
55
SGOT (AST)
42
23
53
20
SGPT (ALT)
37
24
50
18
GGT
NC
NC
28
12
Lipase
17
11
26
19
Amylase
NC
NC
31
17
NC = Not Collected.
a Percentages based on treated subjects.
b Median duration of treatment 48 weeks.
Observed during Clinical Practice: The following events have been identified
during postapproval use of VIDEX (didanosine). Because they are reported voluntarily
from a population of unknown size, estimates of frequency cannot be made. These events
have been chosen for inclusion due to their seriousness, frequency of reporting, causal
connection to VIDEX, or a combination of these factors.
Body as a Whole – alopecia, anaphylactoid reaction, asthenia, chills/fever, pain,
and redistribution/accumulation of body fat (see PRECAUTIONS: Fat
Redistribution).
Digestive Disorders – anorexia, dyspepsia, and flatulence.
Exocrine Gland Disorders – pancreatitis (including fatal cases) (see
WARNINGS), sialoadenitis, parotid gland enlargement, dry mouth, and dry eyes.
Hematologic Disorders – anemia, leukopenia, and thrombocytopenia.
Liver – symptomatic hyperlactatemia/lactic acidosis and hepatic steatosis (see
WARNINGS); hepatitis and liver failure.
Metabolic Disorders – diabetes mellitus, hypoglycemia, and hyperglycemia.
Musculoskeletal Disorders – myalgia (with or without increases in creatine kinase),
rhabdomyolysis including acute renal failure and hemodialysis, arthralgia, and
myopathy.
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Ophthalmologic Disorders – Retinal depigmentation and optic neuritis (see
WARNINGS).
Pediatric Patients: In clinical trials, 743 pediatric patients between 2 weeks and
18 years of age have been treated with VIDEX. Adverse events and laboratory
abnormalities reported to occur in these patients were generally consistent with the safety
profile of didanosine in adults.
In pediatric phase 1 studies, pancreatitis occurred in 2 of 60 (3%) patients treated at
entry doses below 300 mg/m2/day and in 5 of 38 (13%) patients treated at higher doses. In
study ACTG 152, pancreatitis occurred in none of the 281 pediatric patients who received
didanosine 120 mg/m2 q12h and in <1% of the 274 pediatric patients who received
didanosine 90 mg/m2 q12h in combination with zidovudine (see INDICATIONS AND
USAGE: Clinical Studies).
Retinal changes and optic neuritis have been reported in pediatric patients.
OVERDOSAGE
There is no known antidote for VIDEX (didanosine) overdosage. In phase 1 studies, in
which VIDEX was initially administered at doses ten times the currently recommended
dose, toxicities included: pancreatitis, peripheral neuropathy, diarrhea, hyperuricemia, and
hepatic dysfunction. Didanosine is not dialyzable by peritoneal dialysis, although there is
some
clearance
by
hemodialysis
(see
CLINICAL
PHARMACOLOGY:
Pharmacokinetics).
DOSAGE AND ADMINISTRATION
Dosage
All VIDEX formulations should be administered on an empty stomach, at least 30
minutes before or 2 hours after eating. For either a once-daily or twice-daily regimen,
patients must take at least two of the appropriate strength tablets at each dose to
provide adequate buffering and prevent gastric acid degradation of didanosine.
Because of the need for adequate buffering, the 200-mg strength tablet should only be
used as a component of a once-daily regimen. To reduce the risk of gastrointestinal
side effects, patients should take no more than four tablets at each dose.
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Adults: The preferred dosing frequency of VIDEX is twice daily because there is
more evidence to support the effectiveness of this dosing regimen. Once-daily dosing
should be considered only for adult patients whose management requires once-daily dosing
of VIDEX (see INDICATIONS AND USAGE: Clinical Studies). The daily dose in adult
patients is dependent on weight as outlined in Table 14.
Table 14:
Adult Dosinga
Recommended VIDEX Dose by Patient Weight
≥60 kg
<60 kg
Preferred dosing
200 mg twice daily
125 mg twice daily
Dosing for patients whose
management requires once-daily
frequency
400 mg once daily
250 mg once daily
a The 200-mg strength tablet should only be used as a component of a once-daily regimen.
Pediatric Patients: The recommended dose of VIDEX (didanosine) in pediatric
patients between 2 weeks and 8 months of age is 100 mg/m2 twice daily, and the
recommended VIDEX dose for pediatric patients older than 8 months is 120 mg/m2 twice
daily.
Dosing recommendations for VIDEX in patients less than 2 weeks of age cannot be
made because the pharmacokinetics of didanosine in these children are too variable to
determine an appropriate dose. There are no data on once-daily dosing of VIDEX in
pediatric patients.
Dose Adjustment
Clinical and laboratory signs suggestive of pancreatitis should prompt dose
suspension and careful evaluation of the possibility of pancreatitis. VIDEX use should
be discontinued in patients with confirmed pancreatitis (see WARNINGS and
PRECAUTIONS: Drug Interactions).
Patients with symptoms of peripheral neuropathy may tolerate a reduced dose of
VIDEX after resolution of the symptoms of peripheral neuropathy upon drug
discontinuation. If neuropathy recurs after resumption of VIDEX, permanent
discontinuation of VIDEX should be considered.
Concomitant Therapy: Tenofovir disoproxil fumarate. A dose reduction of
VIDEX to 250 mg (adults weighing ≥60 kg with creatinine clearance ≥60 mL/min) or 200
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mg (adults weighing <60 kg with creatinine clearance ≥60 mL/min) once daily is
recommended. VIDEX and tenofovir may be taken together in the fasted state.
Alternatively, if tenofovir is taken with food, VIDEX should be taken on an empty
stomach (at least 30 minutes before food or 2 hours after food). The appropriate dose of
VIDEX coadministered with tenofovir in patients with creatinine clearance <60
mL/min has not been established. [See CLINICAL PHARMACOLOGY: Drug
Interactions and PRECAUTIONS: Drug Interactions; see the complete prescribing
information for VIDEX EC (enteric-coated formulation of didanosine) for results of drug
interaction studies of tenofovir with reduced doses of the enteric-coated formulation of
didanosine.]
Renal Impairment: In adult patients with impaired renal function, the dose of
VIDEX should be adjusted to compensate for the slower rate of elimination. The
recommended doses and dosing intervals of VIDEX in adult patients with renal
insufficiency are presented in Table 15.
Table 15:
Recommended Dosage of VIDEX in Renal Impairmenta
Recommended VIDEX Dose by Patient Weight
Creatinine Clearance
(mL/min)
≥60 kg
<60 kg
≥60
200 mg twice dailyb
125 twice dailyb
30-59
200 mg once daily
or 100 mg twice daily
150 mg once daily
or 75 mg twice daily
10-29
150 mg once daily
100 mg once daily
<10
100 mg once daily
75 mg once daily
a Two VIDEX Chewable/Dispersible Buffered tablets must be taken with each dose; different strengths of
tablets may be combined to yield the recommended dose.
b 400 mg once daily (≥60 kg) or 250 mg once daily (<60 kg) for patients whose management requires once-
daily frequency of administration.
Urinary excretion is also a major route of elimination of didanosine in pediatric
patients; therefore, the clearance of didanosine may be altered in children with renal
impairment. Although there are insufficient data to recommend a specific dose adjustment
of VIDEX in this patient population, a reduction in the dose and/or an increase in the
interval between doses should be considered.
Patients Requiring Continuous Ambulatory Peritoneal Dialysis (CAPD) or
Hemodialysis:
For
patients
requiring
CAPD
or
hemodialysis,
follow
dosing
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Page 32 of 75
recommendations for patients with creatinine clearance less than 10 mL/min, shown in Table
15. It is not necessary to administer a supplemental dose of VIDEX following hemodialysis.
Hepatic Impairment and Toxicity: See WARNINGS.
Method of Preparation
VIDEX Chewable/Dispersible Buffered Tablets
Adult Dosing: To provide adequate buffering, at least two of the appropriate
strength tablets, but no more than four tablets, should be thoroughly chewed or dispersed
in at least 1 ounce of water prior to consumption (see PRECAUTIONS: Information for
Patients). To disperse tablets, add 2 tablets to at least 1 ounce of drinking water. Stir until
a uniform dispersion forms, and drink the entire dispersion immediately. If additional
flavoring is desired, the dispersion may be diluted with one ounce of clear apple juice. Stir
the further diluted dispersion just prior to consumption. The dispersion with clear apple
juice is stable at room temperature, 62° to 73°F (17° to 23°C), for up to one hour.
VIDEX Pediatric Powder for Oral Solution
Prior to dispensing, the pharmacist must constitute dry powder with Purified Water, USP,
to an initial concentration of 20 mg/mL and immediately mix the resulting solution with
antacid to a final concentration of 10 mg/mL as follows:
20 mg/mL Initial Solution: Constitute the product to 20 mg/mL by adding 100
mL or 200 mL of Purified Water, USP, to the 2 g or 4 g of VIDEX powder, respectively, in
the product bottle.
10 mg/mL Final Admixture: 1. Immediately mix one part of the 20 mg/mL initial
solution with one part of Maximum Strength Mylanta® Liquid for a final dispensing
concentration of 10 mg VIDEX per mL. For patient home use, the admixture should be
dispensed in appropriately sized, flint-glass or plastic (HDPE, PET, or PETG) bottles with
child-resistant closures. This admixture is stable for 30 days under refrigeration, 36° to 46°
F (2° to 8° C).
2. Instruct the patient to shake the admixture thoroughly prior to use and to store
the tightly closed container in the refrigerator, 36° to 46° F (2° to 8° C), up to 30 days.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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Page 33 of 75
HOW SUPPLIED
VIDEX® (didanosine) Chewable/Dispersible Buffered Tablets are round, off white to
light orange/yellow with a mottled appearance, orange-flavored, tablets embossed with
"VIDEX" on one side and the product strength on the other. The tablets are available in
the following strengths of VIDEX: 25, 50, 100, 150, and 200 mg. Sixty tablets are
packaged in bottles with child-resistant closures.
The tablets should be stored in tightly closed bottles at 59° to 86° F (15° to
30° C). If dispersed in water, the dose may be held for up to 1 hour at ambient
temperature.
VIDEX (didanosine) Pediatric Powder for Oral Solution is supplied in 4- and 8-
ounce glass bottles containing 2 g or 4 g of VIDEX, respectively.
The bottles of powder should be stored at 59° to 86° F (15° to 30° C). The VIDEX
admixture may be stored up to 30 days in a refrigerator, 36° to 46° F (2° to 8° C). Discard
any unused portion after 30 days.
The NDC numbers for the previously described VIDEX products are:
Table 16
NDC NO.
Packaging Information
Product Strength
VIDEX® Chewable/Dispersible Buffered Tablets
0087-6650-01
60 tablets/bottle
25 mg/tablet
0087-6651-01
60 tablets/bottle
50 mg/tablet
0087-6652-01
60 tablets/bottle
100 mg/tablet
0087-6653-01
60 tablets/bottle
150 mg/tablet
0087-6665-15
60 tablets/bottle
200 mg/tablet
VIDEX® Pediatric Powder for Oral Solution
0087-6632-41
One bottle per carton
2 g/bottle
0087-6633-41
One bottle per carton
4 g/bottle
US Patent Nos.: 4,861,759, 5,254,539, 5,616,566 and 5,880,106.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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Page 34 of 75
HANDLING AND DISPOSAL
Spill, Leak, and Disposal Procedure
Avoid generating dust during clean-up of powdered products; use wet mop or damp
sponge. Clean surface with soap and water as necessary. Containerize larger spills.
There is no single preferred method of disposal of containerized waste. Disposal
options include incineration, landfill, or sewer as dictated by specific circumstances and
relevant national, state, and local regulations.
Mylanta® is a registered trademark of Johnson & Johnson-Merck Consumer Pharmaceuticals Company.
Bristol-Myers Squibb Virology
Bristol-Myers Squibb Company
Princeton, NJ 08543 USA
1196181A2
Revised July 2006
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For current labeling information, please visit https://www.fda.gov/drugsatfda
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Patient Information
Rx only
VIDEX®
(generic name = didanosine also known as ddI)
VIDEX® (didanosine) Chewable/Dispersible Buffered Tablets
VIDEX® (didanosine) Pediatric Powder for Oral Solution
What is VIDEX?
VIDEX (pronounced VY dex) is a prescription medicine used in combination with other
drugs to treat children and adults who are infected with HIV (the human
immunodeficiency virus, the virus that causes AIDS). VIDEX belongs to a class of drugs
called nucleoside analogues. By reducing the growth of HIV, VIDEX helps your body
maintain its supply of CD4 cells, which are important for fighting HIV and other
infections.
VIDEX will not cure your HIV infection. At present there is no cure for HIV infection.
Even while taking VIDEX, you may continue to have HIV-related illnesses, including
infections with other disease-producing organisms. Continue to see your doctor regularly and
report any medical problems that occur.
VIDEX does not prevent a patient infected with HIV from passing the virus to
other people. To protect others, you must continue to practice safe sex and take precautions
to prevent others from coming in contact with your blood and other body fluids.
There is limited information on the effects of long-term use of VIDEX.
Who should not take VIDEX?
Do not take VIDEX if you are allergic to any of its ingredients, including its active ingredient,
didanosine and the inactive ingredients. (See Inactive Ingredients at the end of this leaflet.)
Tell your doctor if you think you have had an allergic reaction to any of these ingredients.
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Page 36 of 75
How should I take VIDEX? How should I store it?
Your doctor will determine your dose based on your body weight, kidney and liver function,
other medicines you are taking, and any side effects that you may have had with VIDEX or
other medicines. Take VIDEX on an empty stomach - that means at least 30 minutes before
or 2 hours after eating. Do not take VIDEX with food. Try not to miss a dose, but if you do,
take it as soon as possible. If it is almost time for the next dose, skip the missed dose and
continue your regular dosing schedule.
Chewable/Dispersible Tablets: Each VIDEX tablet contains antacid. Each
time you take VIDEX, you must take at least two, but not more than four,
tablets. This is because VIDEX tablets contain an antacid to reduce the amount of
acid in your stomach. If you have too much acid, the medicine will break down.
However, too much antacid may cause stomach problems.
—DO NOT swallow VIDEX tablets whole. Chew the tablets well or mix them in
water. Many patients drop the tablets in at least one ounce of water and stir well
before swallowing. If you choose to mix the tablets in water, you may add one
ounce (2 tablespoons) of clear apple juice to the mixture for flavor (do not use any
other kind of juice).
—Store tablets in a tightly closed container at room temperature away from heat
and out of the reach of children and pets. Do NOT store the tablets in a damp place
such as a bathroom medicine cabinet or near the kitchen sink.
Pediatric Oral Solution: Your pharmacist will prepare the oral solution. Shake
the solution well before each use. Store in the refrigerator. Throw away any
unused portion after 30 days.
If you have kidney disease: If your kidneys are not working properly, your doctor
will need to do regular tests to check how they are working while you take VIDEX.
Your doctor may also lower your dosage of VIDEX.
What should I do if someone takes an overdose of VIDEX?
If someone may have taken an overdose of VIDEX, get medical help right away. Contact
their doctor or a poison control center.
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What should I avoid while taking VIDEX?
Alcohol. Do not drink alcohol while taking VIDEX since alcohol may increase your risk
of pancreatitis (pain and inflammation of the pancreas) or liver damage.
Other medicines. Other medicines, including those you can buy without a prescription,
may interfere with the actions of VIDEX or may increase the possibility or severity of side
effects. Do not take any medicine, vitamin supplement, or other health preparation
without first checking with your doctor.
Antacids. Since VIDEX contains some of the same ingredients found in antacids,
any side effects related to VIDEX’s ingredients may get worse if you also take an
antacid.
Medicines at the same time you take your VIDEX dose. Some medicines should
not be taken at the same time of day that you take VIDEX. Check with your
doctor.
Pregnancy. It is not known if VIDEX can harm a human fetus. Also, pregnant women
have experienced serious side effects when taking VIDEX in combination with ZERIT
(stavudine), also known as d4T, and other HIV medicines. VIDEX should be used during
pregnancy only after discussion with your doctor. Tell your doctor if you become
pregnant or plan to become pregnant while taking VIDEX.
Nursing. Studies have shown VIDEX is in the breast milk of animals getting the drug. It
may also be in human breast milk. The Centers for Disease Control and Prevention (CDC)
recommends that HIV-infected mothers not breast-feed. This should reduce the risk of
passing HIV infection to their babies and the potential for serious adverse reactions in
nursing infants. Therefore, do not nurse a baby while taking VIDEX.
What are the possible side effects of VIDEX?
Pancreatitis. Pancreatitis is a dangerous inflammation of the pancreas that may cause
death. Tell your doctor right away if you or a child taking VIDEX develops stomach
pain, nausea, or vomiting. These can be signs of pancreatitis. Before starting VIDEX
therapy, let your doctor know if you or a child for whom it has been prescribed has ever had
pancreatitis. This condition is more likely to happen in people who have had it before. It is
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Page 38 of 75
also more likely in people with advanced HIV disease. However, it can occur at any stage of
HIV disease. It may be more common in patients with kidney problems, those who drink
alcohol, and those who are also treated with stavudine or hydroxyurea. If you get pancreatitis,
your doctor will tell you to stop taking VIDEX.
Lactic acidosis, severe liver enlargement, and liver failure, including deaths, have been
reported among patients taking VIDEX (including pregnant women). Symptoms that may
indicate a liver problem are:
• feeling very weak, tired, or uncomfortable,
• unusual or unexpected stomach discomfort,
• feeling cold,
• feeling dizzy or lightheaded,
• suddenly developing a slow or irregular heartbeat.
Lactic acidosis is a medical emergency that must be treated in a hospital.
If you notice any of these symptoms or if your medical condition changes, stop taking
VIDEX and call your doctor right away. Women, overweight patients, and those who have
been treated for a long time with other medicines used to treat HIV infection are more likely to
develop lactic acidosis. Your doctor should check your liver function periodically while you
are taking VIDEX. You should be especially careful if you have a history of heavy alcohol use
or a liver problem.
Vision changes. VIDEX may affect the nerves in your eyes. Because of this, you should have
regular eye examinations. You should also report any changes in vision to your doctor right
away. This includes, for example, seeing colors abnormally or blurred vision.
Peripheral neuropathy. This is a problem with the nerves in your hands or feet. The nerve
problem may be serious. Tell your doctor right away if you or a child taking VIDEX has
continuing numbness, tingling, or pain in the feet or hands. A child may not recognize these
symptoms or know to tell you that his or her feet or hands are numb, burning, tingling, or
painful. Ask your child’s doctor how to find out if your child is developing peripheral
neuropathy.
Before starting VIDEX therapy, let your doctor know if you or a child for whom it has
been prescribed has ever had peripheral neuropathy. This condition is more likely to happen in
people who have had it before. It is also more likely in patients taking medicines that affect the
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nerves and in people with advanced HIV disease. However, it can occur at any stage of HIV
disease. If you get peripheral neuropathy, your doctor will tell you to stop taking VIDEX.
After stopping VIDEX, the symptoms may get worse for a short time and then get better. Once
symptoms of peripheral neuropathy go away completely, you and your doctor should decide if
starting VIDEX is right for you. If so, you might be started at a lower dose.
Special note about other medicines. If you take VIDEX along with other medicines with
similar side effects, you may increase the chance of having these side effects. For example,
using VIDEX in combination with other medicines that may cause pancreatitis, peripheral
neuropathy, or liver problems (including stavudine and hydroxyurea) may increase your chance
of having these side effects.
Other side effects: The most common side effects in adults taking VIDEX are diarrhea,
neuropathy (nerve disorders), chills or fever, rash, abdominal pain, weakness, headache, and
nausea and vomiting. Children may have similar side effects as adults.
Changes in body fat have been seen in some patients taking antiretroviral therapy.
These changes may include increased amount of fat in the upper back and neck (“buffalo
hump”), breast, and around the trunk. Loss of fat from the legs, arms, and face may also
happen. The cause and long-term health effects of these conditions are not known at this time.
What else should I know about VIDEX?
If you have phenylketonuria: Each Chewable/Dispersible Tablet contains 36.5 mg of
phenylalanine.
Inactive Ingredients:
Chewable/Dispersible Tablets: calcium carbonate, magnesium hydroxide,
aspartame, sorbitol, mandarin orange flavor, polyplasdone, microcrystalline
cellulose, and magnesium stearate.
Pediatric Oral Solution: Maximum Strength Mylanta® Liquid.
This medicine was prescribed for your particular condition. Do not use VIDEX for another condition or give
it to others. Keep VIDEX and all medicines out of the reach of children. Throw away VIDEX when it is
outdated or no longer needed by flushing it down the toilet or pouring it down the sink.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
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This summary does not include everything there is to know about VIDEX. Medicines are sometimes
prescribed for purposes other than those listed in a Patient Information Leaflet. If you have questions or concerns, or
want more information about VIDEX, your physician and pharmacist have the complete prescribing information
upon which this leaflet is based. You may want to read it and discuss it with your doctor or other healthcare
professional. Remember, no written summary can replace careful discussion with your doctor.
Mylanta® is a registered trademark of Johnson & Johnson-Merck Consumer Pharmaceuticals Company.
Bristol-Myers Squibb Virology
Bristol-Myers Squibb Company
Princeton, NJ 08543 USA
This Patient Information Leaflet has been approved by the U.S. Food and Drug Administration.
Revised July 2006
1196181A2
Based on package insert dated July 2006
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-154/S-049
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Page 41 of 75
Rx only
VIDEX® EC (didanosine)
VIDEX® EC (didanosine) Delayed-Release Capsules
Enteric-Coated Beadlets
(Patient Information Leaflet Included)
WARNING
FATAL AND NONFATAL PANCREATITIS HAVE OCCURRED DURING
THERAPY WITH DIDANOSINE USED ALONE OR IN COMBINATION
REGIMENS
IN
BOTH
TREATMENT-NAIVE
AND
TREATMENT-
EXPERIENCED
PATIENTS,
REGARDLESS
OF
DEGREE
OF
IMMUNOSUPPRESSION. VIDEX EC SHOULD BE SUSPENDED IN PATIENTS
WITH SUSPECTED PANCREATITIS AND DISCONTINUED IN PATIENTS
WITH CONFIRMED PANCREATITIS (SEE WARNINGS).
LACTIC
ACIDOSIS
AND
SEVERE
HEPATOMEGALY
WITH
STEATOSIS, INCLUDING FATAL CASES, HAVE BEEN REPORTED WITH
THE USE OF NUCLEOSIDE ANALOGUES ALONE OR IN COMBINATION,
INCLUDING DIDANOSINE AND OTHER ANTIRETROVIRALS. FATAL
LACTIC ACIDOSIS HAS BEEN REPORTED IN PREGNANT WOMEN WHO
RECEIVED THE COMBINATION OF DIDANOSINE AND STAVUDINE WITH
OTHER
ANTIRETROVIRAL
AGENTS.
THE
COMBINATION
OF
DIDANOSINE AND STAVUDINE SHOULD BE USED WITH CAUTION
DURING PREGNANCY AND IS RECOMMENDED ONLY IF THE POTENTIAL
BENEFIT CLEARLY OUTWEIGHS THE POTENTIAL RISK (SEE WARNINGS
AND PRECAUTIONS: PREGNANCY).
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DESCRIPTION
VIDEX® EC is the brand name for an enteric-coated formulation of didanosine (ddI), a
synthetic purine nucleoside analogue active against the Human Immunodeficiency Virus
(HIV). VIDEX EC (didanosine) Delayed-Release Capsules, containing enteric-coated
beadlets, are available for oral administration in strengths of 125, 200, 250, and 400 mg of
didanosine. The inactive ingredients in the beadlets include carboxymethylcellulose
sodium 12, diethyl phthalate, methacrylic acid copolymer, sodium hydroxide, sodium
starch glycolate, and talc. The capsule shells contain colloidal silicon dioxide, gelatin,
sodium lauryl sulfate, and titanium dioxide. The capsules are imprinted with edible inks.
Didanosine is also available as buffered formulations. Please consult the
prescribing information for VIDEX (didanosine) Chewable/Dispersible Buffered Tablets
and Pediatric Powder for Oral Solution for additional information.
The chemical name for didanosine is 2',3'-dideoxyinosine. The structural formula
is:
Didanosine is a white crystalline powder with the molecular formula C10H12N4O3
and a molecular weight of 236.2. The aqueous solubility of didanosine at 25° C and pH of
approximately 6 is 27.3 mg/mL. Didanosine is unstable in acidic solutions. For example, at
pH <3 and 37° C, 10% of didanosine decomposes to hypoxanthine in less than 2 minutes.
In VIDEX EC, an enteric coating is used to protect didanosine from degradation by
stomach acid.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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Page 43 of 75
MICROBIOLOGY
Mechanism of Action
Didanosine is a synthetic nucleoside analogue of the naturally occurring nucleoside
deoxyadenosine in which the 3'-hydroxyl group is replaced by hydrogen. Intracellularly,
didanosine is converted by cellular enzymes to the active metabolite, dideoxyadenosine
5'-triphosphate. Dideoxyadenosine 5'-triphosphate inhibits the activity of HIV-1 reverse
transcriptase both by competing with the natural substrate, deoxyadenosine 5'-triphosphate,
and by its incorporation into viral DNA causing termination of viral DNA chain
elongation.
In Vitro HIV Susceptibility
The in vitro anti-HIV-1 activity of didanosine was evaluated in a variety of HIV-1 infected
lymphoblastic cell lines and monocyte/macrophage cell cultures. The concentration of
drug necessary to inhibit viral replication by 50% (IC50) ranged from 2.5 to 10 µM (1 µM
= 0.24 µg/mL) in lymphoblastic cell lines and 0.01 to 0.1 µM in monocyte/macrophage
cell cultures. The relationship between in vitro susceptibility of HIV to didanosine and the
inhibition of HIV replication in humans has not been established.
Drug Resistance
HIV-1 isolates with reduced sensitivity to didanosine have been selected in vitro and were
also obtained from patients treated with didanosine. Genetic analysis of isolates from
didanosine-treated patients showed mutations in the reverse transcriptase gene that resulted
in the amino acid substitutions K65R, L74V, and M184V. The L74V mutation was most
frequently observed in clinical isolates. Phenotypic analysis of HIV-1 isolates from 60
patients (some with prior zidovudine treatment) receiving 6 to 24 months of didanosine
monotherapy showed that isolates from 10 of 60 patients exhibited an average of a 10-fold
decrease in susceptibility to didanosine in vitro compared to baseline isolates. Clinical
isolates that exhibited a decrease in didanosine susceptibility harbored one or more
didanosine-associated mutations. The clinical relevance of genotypic and phenotypic
changes associated with didanosine therapy has not been established.
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Cross-resistance
HIV-1 isolates from 2 of 39 patients receiving combination therapy for up to 2 years with
zidovudine and didanosine exhibited decreased susceptibility to zidovudine, didanosine,
zalcitabine, stavudine, and lamivudine in vitro. These isolates harbored five mutations
(A62V, V75I, F77L, F116Y, and Q151M) in the reverse transcriptase gene. The clinical
relevance of these observations has not been established.
CLINICAL PHARMACOLOGY
Animal Toxicology
Evidence of a dose-limiting skeletal muscle toxicity has been observed in mice and rats
(but not in dogs) following long-term (greater than 90 days) dosing with didanosine at
doses that were approximately 1.2 to 12 times the estimated human exposure. The
relationship of this finding to the potential of didanosine to cause myopathy in humans is
unclear. However, human myopathy has been associated with administration of
didanosine and other nucleoside analogues.
Pharmacokinetics
The pharmacokinetic parameters of didanosine are summarized in Table 1. Didanosine is
rapidly absorbed, with peak plasma concentrations generally observed from 0.25 to 1.50
hours following oral dosing with a buffered formulation. Increases in plasma didanosine
concentrations were dose proportional over the range of 50 to 400 mg. Steady-state
pharmacokinetic parameters did not differ significantly from values obtained after a single
dose. Binding of didanosine to plasma proteins in vitro was low (<5%). Based on data
from in vitro and animal studies, it is presumed that the metabolism of didanosine in man
occurs by the same pathways responsible for the elimination of endogenous purines.
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Table 1:
Pharmacokinetic Parameters for Didanosine in Adults
Parameter
Mean ± SD
n
Oral bioavailability
42 ± 12%
6
Apparent volume of distribution
1.08 ± 0.22 L/kg
6
CSF-plasma ratiob
21 ± 0.03%
5
Systemic clearanceb
13.0 ± 1.6 mL/min/kg
6
Renal clearancea
5.5 ± 2.1 mL/min/kg
6
Elimination half-lifea
1.5 ± 0.4 h
6
Urinary recovery of didanosinea
18 ± 8%
6
CSF = cerebrospinal fluid.
a following oral administration of a buffered formulation.
b following IV administration.
c mean ± SE.
Comparison of Didanosine Formulations
In VIDEX EC, the active ingredient, didanosine, is protected against degradation by
stomach acid by the use of an enteric coating on the beadlets in the capsule. The enteric
coating dissolves when the beadlets empty into the small intestine, the site of drug
absorption. With buffered formulations of didanosine, administration with antacid provides
protection from degradation by stomach acid.
In healthy volunteers, as well as subjects infected with HIV, the area under the
plasma concentration time curve (AUC) is equivalent for didanosine administered as the
VIDEX EC formulation relative to a buffered tablet formulation. The peak plasma
concentration (CMAX) of didanosine, administered as VIDEX EC, is reduced approximately
40% relative to didanosine buffered tablets. The time to the peak concentration (TMAX)
increases from approximately 0.67 hours for didanosine buffered tablets to 2.0 hours for
VIDEX EC.
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Effect of Food on Absorption of Didanosine
In the presence of food, the CMAX and AUC for VIDEX EC were reduced by
approximately 46% and 19%, respectively, compared to the fasting state. VIDEX EC
should be taken on an empty stomach.
Special Populations
Renal Insufficiency
It is recommended that the VIDEX EC (didanosine) dose be modified in patients with
reduced creatinine clearance and in patients receiving maintenance hemodialysis (see
DOSAGE AND ADMINISTRATION). Data from two studies using a buffered
formulation of didanosine indicated that the apparent oral clearance of didanosine
decreased and the terminal elimination half-life increased as creatinine clearance decreased
(see Table 2). Following oral administration, didanosine was not detectable in peritoneal
dialysate fluid (n=6); recovery in hemodialysate (n=5) ranged from 0.6% to 7.4% of the
dose over a 3-4 hour dialysis period. The absolute bioavailability of didanosine was not
affected in patients requiring dialysis.
Table 2:
Mean ± SD Pharmacokinetic Parameters for Didanosine
Following a Single Oral Dose of a Buffered Formulation
Creatinine Clearance (mL/min)
Parameter
≥ 90
(n=12)
60-90
(n=6)
30-59
(n=6)
10-29
(n=3)
Dialysis
Patients
(n=11)
CLcr (mL/min)
112 ± 22
68 ± 8
46 ± 8
13 ± 5
ND
CL/F (mL/min)
2164 ± 638
1566 ± 833
1023 ± 378
628 ± 104
543 ± 174
CLR (mL/min)
458 ± 164
247 ± 153
100 ± 44
20 ± 8
<10
T½ (h)
1.42 ± 0.33
1.59 ± 0.13
1.75 ± 0.43
2.0 ± 0.3
4.1 ± 1.2
ND = not determined due to anuria.
CLcr = creatinine clearance.
CL/F = apparent oral clearance.
CLR = renal clearance.
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Pediatric Patients
The pharmacokinetics of didanosine administered as VIDEX EC have not been studied in
pediatric patients.
Geriatric Patients
Didanosine pharmacokinetics have not been studied in patients over 65 years of age (see
PRECAUTIONS: Geriatric Use).
Gender
The effects of gender on didanosine pharmacokinetics have not been studied.
Drug Interactions (See also PRECAUTIONS: Drug Interactions.)
Ribavirin has been shown in vitro to increase intracellular triphosphate levels of
didanosine, which could cause or worsen clinical toxicities (see PRECAUTIONS: Drug
Interactions).
VIDEX EC
Tables 3 and 4 summarize the effects on AUC and CMAX, with a 90% confidence interval
(CI) when available, following coadministration of VIDEX EC with a variety of drugs.
Clinical recommendations based on drug interaction studies for drugs in bold font are
included
in
PRECAUTIONS:
Drug
Interactions
and
DOSAGE
AND
ADMINISTRATION.
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Table 3:
Results of Drug Interaction Studies with VIDEX EC: Effects of
Coadministered Drug on Didanosine Plasma AUC and CMAX
Valuesa
Drug
Didanosine Dosage
n
AUC of Didanosine
(90% CI)
CMAX of Didanosine
(90% CI)
tenofovir,b 300 mg
once daily with a
light mealc
400 mg single dose
fasting 2 h before
tenofovir
26
↑ 48% (31, 67%)
↑ 48% (25, 76%)
tenofovir,b 300 mg
once daily with a
light mealc
400 mg single dose
with tenofovir and
a light meal
25
↑ 60% (44, 79%)
↑ 64% (41, 89%)
tenofovir,b 300 mg
once daily with a
light mealc
200 mg single dose
with tenofovir and
a light meal
33
↑ 16% (6, 27%)d
↓ 12% (−25, 3%)d
250 mg single dose
with tenofovir and
a light meal
33
↔ (−13, 5%)e
↓ 20% (−32, −7%)e
325 mg single dose
with tenofovir and
a light meal
33
↑ 13% (3, 24%)e
↓ 11% (−24, 4%)e
↑ indicates increase.
↓ indicates decrease.
↔ indicates no change, or mean increase or decrease of <10%.
a All studies conducted in healthy volunteers ≥60 kg with creatinine clearance ≥60 mL/min.
b tenofovir disoproxil fumarate.
c 373 kcalories, 8.2 grams fat.
d Compared with VIDEX EC 250 mg administered alone under fasting conditions.
e Compared with VIDEX EC 400 mg administered alone under fasting conditions.
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Table 4:
Results of Drug Interaction Studies with VIDEX EC: Effects of
Didanosine on Coadministered Drug Plasma AUC and CMAX
Valuesa
Drug
Didanosine Dosage
n
AUC of
Coadministered Drug
CMAX of Coadministered
Drug
ciprofloxacin, 750 mg
single dose
400 mg single dose
16
↔
↔
indinavir, 800 mg
single dose
400 mg single dose
23
↔
↔
ketoconazole, 200 mg
single dose
400 mg single dose
21
↔
↔
tenofovir,b 300 mg
once daily with a
light mealc
400 mg single dose
fasting 2 h before
tenofovir
25
↔
↔
tenofovir,b 300 mg
once daily with a
light mealc
400 mg single dose
with tenofovir and
a light meal
25
↔
↔
↔ indicates no change, or mean increase or decrease of <10%.
a All studies conducted in healthy volunteers ≥60 kg with creatinine clearance ≥60 mL/min.
b tenofovir disoproxil fumarate.
c 373 kcalories, 8.2 grams fat.
Didanosine Buffered Formulations
Tables 5 and 6 summarize the effects on AUC and CMAX, with a 90% or 95% CI when
available, following coadministration of buffered formulations of didanosine with a variety
of drugs. Except as noted in table footnotes, the results of these studies may be expected to
apply to VIDEX EC. For most of the listed drugs, no clinically significant
pharmacokinetic interactions were noted. Clinical recommendations based on drug
interaction studies for drugs in bold font are included in PRECAUTIONS: Drug
Interactions and DOSAGE AND ADMINISTRATION (for tenofovir).
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Table 5:
Results of Drug Interaction Studies with Buffered
Formulations of Didanosine: Effects of Coadministered Drug
on Didanosine Plasma AUC and CMAX Values
Drugs With Clinical Recommendations Regarding Coadministration (see PRECAUTIONS: Drug
Interactions)
Drug
Didanosine Dosage
n
AUC of Didanosine
(95% CI)
CMAX of Didanosine
(95% CI)
allopurinol
renally impaired, 300 mg/day
200 mg single dose
2
↑ 312%
↑ 232%
healthy volunteer, 300 mg/day for
7 days
400 mg single dose
14
↑ 113%
↑ 69%
ganciclovir, 1000 mg q8h,
2 h after didanosine
200 mg q12h
12
↑ 111%
NA
methadone, chronic maintenance
dose
200 mg single dose
16, 10a
↓ 57%
↓ 66%
tenofovir,b 300 mg once daily 1 h
after didanosine
250c or 400 mg once
daily for 7 days
14
↑ 44%
(31, 59%)d
↑ 28%
(11, 48%)d
No Clinically Significant Interaction Observed
Drug
Didanosine Dosage
n
AUC of Didanosine
(95% CI)
CMAX of Didanosine
(95% CI)
ciprofloxacin, 750 mg q12h for 3
days, 2 h before didanosine
200 mg q12h for 3 days
8e
↓ 16%
↓ 28%
indinavir, 800 mg single dose
simultaneous
200 mg single dose
16
↔
↔
1 h before didanosine
200 mg single dose
16
↓ 17% (-27, -7%)d
↓ 13% (-28, 5%)d
ketoconazole, 200 mg/day for 4
days, 2 h before didanosine
375 mg q12h for 4 days
12e
↔
↓12%
loperamide, 4 mg q6h for 1 day
300 mg single dose
12e
↔
↓23%
metoclopramide, 10 mg single dose
300 mg single dose
12e
↔
↑13%
ranitidine, 150 mg single dose, 2 h
before didanosine
375 mg single dose
12e
↑14%
↑13%
rifabutin, 300 or 600 mg/day for 12
days
167 or 250 mg q12h for
12 days
11
↑ 13% (-1, 27%)
↑ 17% (-4, 38%)
ritonavir, 600 mg q12h for 4 days
200 mg q12h for 4 days
12
↓ 13% (0, 23%)
↓ 16% (5, 26%)
stavudine, 40 mg q12h for 4 days
100 mg q12h for 4 days
10
↔
↔
sulfamethoxazole, 1000 mg single
dose
200 mg single dose
8e
↔
↔
trimethoprim, 200 mg single dose
200 mg single dose
8e
↔
↑ 17% (-23, 77%)
zidovudine, 200 mg q8h for 3 days
200 mg q12h for 3 days
6e
↔
↔
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Table 5:
Results of Drug Interaction Studies with Buffered
Formulations of Didanosine: Effects of Coadministered Drug
on Didanosine Plasma AUC and CMAX Values
↑
indicates increase.
↓
indicates decrease.
↔ indicates no change, or mean increase or decrease of <10%.
a
Parallel-group design; entries are subjects receiving combination and control regimens, respectively.
b
tenofovir disoproxil fumarate.
c
patients <60 kg with creatinine clearance ≥60 mL/min.
d
90% Cl.
e
HIV-infected patients.
NA Not available.
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Table 6:
Results of Drug Interaction Studies with Buffered
Formulations of Didanosine: Effects of Didanosine on
Coadministered Drug Plasma AUC and CMAX Values
No Clinically Significant Interaction Observed
Drug
Didanosine Dosage
n
AUC of
Coadministered Drug
(95% CI)
CMAX of
Coadministered Drug
(95% CI)
dapsone, 100 mg single dose
200 mg q12h for 14 days
6a
↔
↔
delavirdine, 400 mg single
dose
simultaneous
1 h before didanosine
125 or 200 mg q12h
125 or 200 mg q12h
12a
12a
↓ 32%b
↑ 20%
↓ 53%b
↑ 18%
ganciclovir, 1000 mg q8h,
2 h after didanosine
200 mg q12h
12a
↓21%
NA
nelfinavir, 750 mg single
dose, 1 h after didanosine
200 mg single dose
10a
↑12%
↔
ranitidine, 150 mg single
dose, 2 h before didanosine
375 mg single dose
12a
↓16%
↔
ritonavir, 600 mg q12h for
4 days
200 mg q12h for 4 days
12
↔
↔
stavudine, 40 mg q12h for
4 days
100 mg q12h for 4 days
10a
↔
↑17%
sulfamethoxazole, 1000 mg
single dose
200 mg single dose
8a
↓ 11% (-17, -4%)
↓ 12% (-28, 8%)
tenofovir,c 300 mg once
daily 1 h after didanosine
250d or 400 mg once daily
for 7 days
14
↔
↔
trimethoprim, 200 mg single
dose
200 mg single dose
8a
↑ 10% (-9, 34%)
↓ 22% (-59, 49%)
zidovudine, 200 mg q8h for
3 days
200 mg q12h for 3 days
6a
↓ 10% (-27, 11%)
↓ 16.5% (-53, 47%)
↑
indicates increase.
↓
indicates decrease.
↔ indicates no change, or mean increase or decrease of <10%.
a
HIV-infected patients.
b
This result is probably related to the buffer and is not expected to occur with VIDEX EC.
c
tenofovir disoproxil fumarate.
d
patients <60 kg with creatinine clearance ≥60 mL/min.
NA Not available.
INDICATIONS AND USAGE
VIDEX EC (didanosine) in combination with other antiretroviral agents is indicated
for the treatment of HIV-1 infection in adults. (See Clinical Studies.)
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Clinical Studies
Study Al454-152 was a 48-week, randomized, open-label study comparing VIDEX EC
(400 mg once daily) plus stavudine (40 mg twice daily) plus nelfinavir (750 mg three times
daily) to zidovudine (300 mg) plus lamivudine (150 mg) combination tablets twice daily
plus nelfinavir (750 mg three times daily) in 511 treatment-naive patients, with a mean
CD4 cell count of 411 cells/mm3 (range 39 to 1105 cells/mm3) and a mean plasma HIV-1
RNA of 4.71 log10 copies/mL (range 2.8 to 5.9 log10 copies/mL) at baseline. Patients were
primarily males (72%) and Caucasian (53%) with a mean age of 35 years (range 18 to 73
years). The percentages of patients with HIV RNA <400 and <50 copies/mL and outcomes
of patients through 48 weeks are summarized in Figure 1 and Table 7, respectively.
Figure 1
Treatment Response Through Week 48*, AI454-152
0
20
40
60
80
100
0
12
24
36
48
Study Week
Percent of Patients
] < 400 c/mL
] < 50 c/mL
VIDEX EC+stavudine+nelfinavir, n=258
zidovudine/lamivudine+nelfinavir, n=253
*Percent of patients at each time point who have HIV RNA <400 or
<50 copies/mL and do not meet any criteria for treatment failure (eg,
virologic failure or discontinuation for any reason).
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Table 7:
Outcomes of Randomized Treatment Through Week 48, AI454-152
Percent of Patients with HIV RNA <400 copies/mL (<50 copies/mL)
VIDEX EC + stavudine +
zidovudine/lamivudinea +
nelfinavir
nelfinavir
Outcome
n=258
n=253
Responderb,c
55% (33%)
56% (33%)
Virologic failured
22% (45%)
21% (43%)
Death or discontinued due to
disease progression
1% (1%)
2% (2%)
Discontinued due to adverse event
6% (6%)
7% (7%)
Discontinued due to other reasonse
16% (16%)
15% (16%)
a Zidovudine/lamivudine combination tablet.
b Corresponds to rates at Week 48 in Figure 1.
c Subjects achieved and maintained confirmed HIV RNA <400 copies/mL (<50 copies/mL) through
Week 48.
d Includes viral rebound at or before Week 48 and failure to achieve confirmed HIV RNA <400 copies/mL
(<50 copies/mL) through Week 48.
e Includes lost to follow-up, subject’s withdrawal, discontinuation due to physician’s decision, never treated,
and other reasons.
CONTRAINDICATION
VIDEX EC (didanosine) is contraindicated in patients with previously demonstrated
clinically significant hypersensitivity to any component of the formulation.
WARNINGS
1. Pancreatitis
FATAL AND NONFATAL PANCREATITIS HAVE OCCURRED DURING
THERAPY WITH DIDANOSINE USED ALONE OR IN COMBINATION
REGIMENS
IN
BOTH
TREATMENT-NAIVE
AND
TREATMENT-
EXPERIENCED
PATIENTS,
REGARDLESS
OF
DEGREE
OF
IMMUNOSUPPRESSION. VIDEX EC SHOULD BE SUSPENDED IN PATIENTS
WITH SIGNS OR SYMPTOMS OF PANCREATITIS AND DISCONTINUED IN
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PATIENTS WITH CONFIRMED PANCREATITIS. PATIENTS TREATED WITH
VIDEX EC IN COMBINATION WITH STAVUDINE, WITH OR WITHOUT
HYDROXYUREA, MAY BE AT INCREASED RISK FOR PANCREATITIS.
When treatment with life-sustaining drugs known to cause pancreatic toxicity is
required, suspension of VIDEX EC therapy is recommended. In patients with risk factors
for pancreatitis, VIDEX EC should be used with extreme caution and only if clearly
indicated. Patients with advanced HIV infection, especially the elderly, are at increased
risk of pancreatitis and should be followed closely. Patients with renal impairment may be
at greater risk for pancreatitis if treated without dose adjustment.
The frequency of pancreatitis is dose related. In phase 3 studies with buffered
formulations of didanosine, incidence ranged from 1% to 10% with doses higher than are
currently recommended and 1% to 7% with recommended dose.
2. Lactic Acidosis/Severe Hepatomegaly with Steatosis
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases,
have been reported with the use of nucleoside analogues alone or in combination,
including didanosine and other antiretrovirals. A majority of these cases have been in
women. Obesity and prolonged nucleoside exposure may be risk factors. Fatal lactic
acidosis has been reported in pregnant women who received the combination of didanosine
and stavudine with other antiretroviral agents. The combination of didanosine and
stavudine should be used with caution during pregnancy and is recommended only if the
potential benefit clearly outweighs the potential risk (see PRECAUTIONS: Pregnancy).
Particular caution should be exercised when administering VIDEX EC to any patient with
known risk factors for liver disease; however, cases have also been reported in patients
with no known risk factors. Treatment with VIDEX EC should be suspended in any
patient who develops clinical or laboratory findings suggestive of symptomatic
hyperlactatemia, lactic acidosis, or pronounced hepatotoxicity (which may include
hepatomegaly and steatosis even in the absence of marked transaminase elevations).
3. Retinal Changes and Optic Neuritis
Retinal changes and optic neuritis have been reported in patients taking didanosine.
Periodic retinal examinations should be considered for patients receiving VIDEX EC. (See
ADVERSE REACTIONS.)
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4. Hepatic Impairment and Toxicity
It is unknown if hepatic impairment significantly affects didanosine pharmaco-
kinetics. Therefore, these patients should be monitored closely for evidence of didanosine
toxicity. The safety and efficacy of VIDEX EC have not been established in HIV-infected
patients with significant underlying liver disease. During combination antiretroviral
therapy, patients with preexisting liver dysfunction, including chronic active hepatitis,
have an increased frequency of liver function abnormalities, including severe and
potentially fatal hepatic adverse events, and should be monitored according to standard
practice. If there is evidence of worsening liver disease in such patients, interruption or
discontinuation of treatment must be considered.
Hepatotoxicity and hepatic failure resulting in death were reported during
postmarketing surveillance in HIV-infected patients treated with hydroxyurea and other
antiretroviral agents. Fatal hepatic events were reported most often in patients treated with
the combination of hydroxyurea, didanosine, and stavudine. This combination should be
avoided.
PRECAUTIONS
Dosing
VIDEX EC should be administered once daily on an empty stomach.
Peripheral Neuropathy
Peripheral neuropathy, manifested by numbness, tingling, or pain in the hands or feet, has
been reported in patients receiving didanosine therapy. Peripheral neuropathy has occurred
more frequently in patients with advanced HIV disease, in patients with a history of
neuropathy, or in patients being treated with neurotoxic drug therapy, including stavudine.
Peripheral neuropathy, which was severe in some cases, has been reported in HIV-infected
patients receiving hydroxyurea in combination with antiretroviral agents, including
didanosine, with or without stavudine (see ADVERSE REACTIONS).
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Fat Redistribution
Redistribution/accumulation of body fat including central obesity, dorsocervical fat
enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and
“cushingoid appearance” have been observed in patients receiving antiretroviral therapy.
The mechanism and long-term consequences of these events are currently unknown. A
causal relationship has not been established.
Immune Reconstitution Syndrome
Immune reconstitution syndrome has been reported in patients treated with combination
antiretroviral therapy, including VIDEX EC. During the initial phase of combination
antiretroviral treatment, patients whose immune system responds may develop an
inflammatory response to indolent or residual opportunistic infections (such as
Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia
[PCP], or tuberculosis), which may necessitate further evaluation and treatment.
General
Patients with Renal Impairment
Patients with renal impairment (creatinine clearance <60 mL/min) may be at greater risk of
toxicity from didanosine due to decreased drug clearance (see CLINICAL
PHARMACOLOGY). A dose reduction is recommended in these patients (see DOSAGE
AND ADMINISTRATION).
Hyperuricemia
Didanosine has been associated with asymptomatic hyperuricemia; treatment suspension
may be necessary if clinical measures aimed at reducing uric acid levels fail.
Information for Patients (See Patient Information Leaflet)
Patients should be informed that a serious toxicity of didanosine, used alone and in
combination regimens, is pancreatitis, which may be fatal.
Patients should also be aware that peripheral neuropathy, manifested by numbness,
tingling, or pain in hands or feet, may develop during therapy with VIDEX EC
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(didanosine). Patients should be counseled that peripheral neuropathy occurs with greatest
frequency in patients with advanced HIV disease or a history of peripheral neuropathy, and
that dose modification and/or discontinuation of VIDEX EC may be required if toxicity
develops.
Patients should be informed that when didanosine is used in combination with other
agents with similar toxicities, the incidence of adverse events may be higher than when
didanosine is used alone. These patients should be followed closely.
Patients should be cautioned about the use of medications or other substances,
including alcohol, that may exacerbate VIDEX EC toxicities.
VIDEX EC is not a cure for HIV infection, and patients may continue to develop
HIV-associated illnesses, including opportunistic infection. Therefore, patients should
remain under the care of a physician when using VIDEX EC. Patients should be advised
that VIDEX EC therapy has not been shown to reduce the risk of transmission of HIV to
others through sexual contact or blood contamination. Patients should be informed that the
long-term effects of VIDEX EC are unknown at this time.
Patients should be informed that redistribution or accumulation of body fat may
occur in patients receiving antiretroviral therapy and that the cause and long-term health
effects of these conditions are not known at this time.
Drug Interactions (see also CLINICAL PHARMACOLOGY: Drug
Interactions)
Drug interactions that have been established based on drug interaction studies are listed
with the pharmacokinetic results in CLINICAL PHARMACOLOGY: Drug
Interactions (Tables 3-6). The clinical recommendations based on the results of these
studies are listed in Table 8.
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Table 8:
Established Drug Interactions Based on Studies with
VIDEX EC or Studies with Buffered Formulations of
Didanosine and Expected to Occur with VIDEX EC
Coadministration Not Recommended Based on Drug Interaction Studies (see CLINICAL
PHARMACOLOGY: Drug Interactions for Magnitude of Interaction)
Drug
Effect
Clinical Comment
allopurinol
↑ didanosine concentration
Coadministration not recommended.
Alteration in Dose or Regimen Recommended Based on Drug Interaction Studies (see CLINICAL
PHARMACOLOGY: Drug Interactions for Magnitude of Interaction)
Drug
Effect
Clinical Comment
ganciclovir
↑ didanosine concentration
Appropriate doses for this combination, with
respect to efficacy and safety, have not been
established.
methadone
↓ didanosine concentration
Appropriate doses for this combination, with
respect to efficacy and safety, have not been
established.
tenofovir disoproxil
fumarate
↑ didanosine concentration
A dose reduction of VIDEX EC to 250 mg
(adults weighing ≥60 kg with creatinine
clearance ≥60 mL/min) or 200 mg (adults
weighing <60 kg with creatinine clearance
≥60 mL/min) once daily taken together with
tenofovir and a light meal (≤400 kcalories and
≤20% fat) or in the fasted state is
recommended. Patients should be monitored
for didanosine-associated toxicities and
clinical response (see below).
↑ indicates increase.
↓ indicates decrease.
Coadministration of VIDEX EC with drugs that are known to cause
pancreatitis may increase the risk of this toxicity (see WARNINGS: Pancreatitis).
Predicted drug interactions with VIDEX EC are listed in Table 9.
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Table 9:
Predicted Drug Interactions with VIDEX EC
Drug or Drug Class
Effect
Clinical Comment
Drugs that may cause
pancreatic toxicity
↑ risk of pancreatitis
Use only with extreme caution.a
Neurotoxic drugs
↑ risk of neuropathy
Use with caution.b
Ribavirin
↑ risk of toxicity
Ribavirin has been shown in vitro to increase
intracellular triphosphate levels of didanosine.
Coadministration is not recommended (see
below).
↑ indicates increase.
a Only if other drugs are not available and if clearly indicated. If treatment with life-sustaining drugs that
cause pancreatic toxicity is required, suspension of VIDEX EC is recommended (see WARNINGS:
Pancreatitis).
b See PRECAUTIONS: Peripheral Neuropathy.
Nucleoside/nucleotide analogues
Tenofovir disoproxil fumarate. Exposure to didanosine is increased when coadministered
with tenofovir (see Tables 3, 5, and 8). Increased exposure may cause or worsen
didanosine-related
clinical
toxicities,
including
pancreatitis,
symptomatic
hyperlactatemia/lactic acidosis, and peripheral neuropathy. Coadministration of
tenofovir with VIDEX EC should be undertaken with caution, and patients should be
monitored closely for didanosine-related toxicities and clinical response. VIDEX EC
should be suspended if signs or symptoms of pancreatitis, symptomatic
hyperlactatemia, or lactic acidosis develop (see WARNINGS). Administration of
reduced doses of VIDEX EC with tenofovir and a light meal resulted in didanosine
exposures (AUC) similar to the recommended doses of VIDEX EC given alone in the
fasted state (see Table 3). Therefore, when administered with tenofovir, a dose reduction
of VIDEX EC to 250 mg (adults weighing ≥60 kg with creatinine clearance ≥60 mL/min)
or 200 mg (adults weighing <60 kg with creatinine clearance ≥60 mL/min) once daily is
recommended, and both drugs may be taken together with a light meal (≤400 kcalories,
≤20% fat) or in the fasted state (see DOSAGE AND ADMINISTRATION).
Coadministration of didanosine with food decreases didanosine concentrations. Thus,
although not studied, it is possible that coadministration with heavier meals could reduce
didanosine concentrations further.
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Ribavirin. Exposure to the active metabolite of didanosine (dideoxyadenosine 5'-
triphosphate) is increased when didanosine is coadministered with ribavirin (see Table 9).
Fatal hepatic failure, as well as peripheral neuropathy, pancreatitis, and symptomatic
hyperlactatemia/lactic acidosis have been reported in patients receiving both didanosine
and ribavirin. Coadministration of didanosine and ribavirin is not recommended.
Carcinogenesis and Mutagenesis
Lifetime carcinogenicity studies were conducted in mice and rats for 22 and 24 months,
respectively. In the mouse study, initial doses of 120, 800, and 1200 mg/kg/day for each
sex were lowered after 8 months to 120, 210, and 210 mg/kg/day for females and 120, 300,
and 600 mg/kg/day for males. The two higher doses exceeded the maximally tolerated
dose in females and the high dose exceeded the maximally tolerated dose in males. The
low dose in females represented 0.68-fold maximum human exposure and the intermediate
dose in males represented 1.7-fold maximum human exposure based on relative AUC
comparisons. In the rat study, initial doses were 100, 250, and 1000 mg/kg/day, and the
high dose was lowered to 500 mg/kg/day after 18 months. The upper dose in male and
female rats represented 3-fold maximum human exposure.
Didanosine induced no significant increase in neoplastic lesions in mice or rats at
maximally tolerated doses.
Didanosine was positive in the following genetic toxicology assays: 1) the
Escherichia coli tester strain WP2 uvrA bacterial mutagenicity assay; 2) the
L5178Y/TK+/- mouse lymphoma mammalian cell gene mutation assay; 3) the in vitro
chromosomal aberrations assay in cultured human peripheral lymphocytes; 4) the in vitro
chromosomal aberrations assay in Chinese Hamster Lung cells; and 5) the BALB/c 3T3 in
vitro transformation assay. No evidence of mutagenicity was observed in an Ames
Salmonella bacterial mutagenicity assay or in rat and mouse in vivo micronucleus assays.
Pregnancy, Reproduction, and Fertility
Pregnancy Category B. Reproduction studies have been performed in rats and rabbits at
doses up to 12 and 14.2 times the estimated human exposure (based upon plasma levels),
respectively, and have revealed no evidence of impaired fertility or harm to the fetus due to
didanosine. At approximately 12 times the estimated human exposure, didanosine was
slightly toxic to female rats and their pups during mid and late lactation. These rats showed
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-154/S-049
NDA 20-155/S-038
NDA 20-156/S-039
NDA 21-183/S-015
Page 62 of 75
reduced food intake and body weight gains but the physical and functional development of
the offspring was not impaired and there were no major changes in the F2 generation. A
study in rats showed that didanosine and/or its metabolites are transferred to the fetus
through the placenta. Animal reproduction studies are not always predictive of human
response.
There are no adequate and well-controlled studies of didanosine in pregnant
women. Didanosine should be used during pregnancy only if the potential benefit justifies
the potential risk.
Fatal lactic acidosis has been reported in pregnant women who received the
combination of didanosine and stavudine with other antiretroviral agents. It is unclear if
pregnancy augments the risk of lactic acidosis/hepatic steatosis syndrome reported in
nonpregnant individuals receiving nucleoside analogues (see WARNINGS: Lactic
Acidosis/Severe Hepatomegaly with Steatosis). The combination of didanosine and
stavudine should be used with caution during pregnancy and is recommended only if
the potential benefit clearly outweighs the potential risk. Health care providers caring
for HIV-infected pregnant women receiving didanosine should be alert for early diagnosis
of lactic acidosis/hepatic steatosis syndrome.
Antiretroviral Pregnancy Registry: To monitor maternal-fetal outcomes of
pregnant women exposed to didanosine and other antiretroviral agents, an Antiretroviral
Pregnancy Registry has been established. Physicians are encouraged to register patients by
calling 1-800-258-4263.
Nursing Mothers
The Centers for Disease Control and Prevention recommend that HIV-infected
mothers not breast-feed their infants to avoid risking postnatal transmission of HIV.
A study in rats showed that following oral administration, didanosine and/or its
metabolites were excreted into the milk of lactating rats. It is not known if didanosine is
excreted in human milk. Because of both the potential for HIV transmission and the
potential for serious adverse reactions in nursing infants, mothers should be instructed
not to breast-feed if they are receiving VIDEX EC (didanosine).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-154/S-049
NDA 20-155/S-038
NDA 20-156/S-039
NDA 21-183/S-015
Page 63 of 75
Pediatric Use
The safety and efficacy of VIDEX EC in pediatric patients have not been established.
Please consult the complete prescribing information for VIDEX (didanosine)
Chewable/Dispersible Buffered Tablets and Pediatric Powder for Oral Solution for dosage
and administration of didanosine to pediatric patients.
Geriatric Use
In an Expanded Access Program using a buffered formulation of didanosine for the
treatment of advanced HIV infection, patients aged 65 years and older had a higher
frequency of pancreatitis (10%) than younger patients (5%) (see WARNINGS). Clinical
studies of didanosine, including those for VIDEX EC, did not include sufficient numbers
of subjects aged 65 years and over to determine whether they respond differently than
younger subjects. Didanosine is known to be substantially excreted by the kidney, and the
risk of toxic reactions to this drug may be greater in patients with impaired renal function.
Because elderly patients are more likely to have decreased renal function, care should be
taken in dose selection. In addition, renal function should be monitored and dosage
adjustments should be made accordingly (see DOSAGE AND ADMINISTRATION:
Dose Adjustment).
ADVERSE REACTIONS
A SERIOUS TOXICITY OF DIDANOSINE IS PANCREATITIS, WHICH MAY BE
FATAL (see WARNINGS). OTHER IMPORTANT TOXICITIES INCLUDE LACTIC
ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS; RETINAL CHANGES
AND OPTIC NEURITIS; AND PERIPHERAL NEUROPATHY (see WARNINGS and
PRECAUTIONS).
When didanosine is used in combination with other agents with similar
toxicities, the incidence of these toxicities may be higher than when didanosine is used
alone. Thus, patients treated with VIDEX EC in combination with stavudine, with or
without hydroxyurea, may be at increased risk for pancreatitis and hepatotoxicity,
which may be fatal, and severe peripheral neuropathy (see WARNINGS and
PRECAUTIONS).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-154/S-049
NDA 20-155/S-038
NDA 20-156/S-039
NDA 21-183/S-015
Page 64 of 75
Selected clinical adverse events that occurred in a study of VIDEX EC in
combination with other antiretroviral agents are provided in Table 10.
Table 10:
Selected Clinical Adverse Events, Study AI454-152a
Percent of Patientsb
VIDEX EC +
stavudine +
nelfinavir
zidovudine/
lamivudinec +
nelfinavir
Adverse Events
n=258
n=253
Diarrhea
57
58
Peripheral Neurologic
Symptoms/Neuropathy
25
11
Nausea
24
36
Headache
22
17
Rash
14
12
Vomiting
14
19
Pancreatitis (see below)
<1
*
a Median duration of treatment was 62 weeks in the VIDEX EC + stavudine + nelfinavir group and
61 weeks in the zidovudine/lamivudine + nelfinavir group.
b Percentages based on treated patients.
c Zidovudine/lamivudine combination tablet.
* This event was not observed in this study arm.
In clinical trials using a buffered formulation of didanosine, pancreatitis
resulting in death was observed in one patient who received didanosine plus
stavudine plus nelfinavir, one patient who received didanosine plus stavudine plus
indinavir, and 2 of 68 patients who received didanosine plus stavudine plus indinavir
plus hydroxyurea. In an early access program, pancreatitis resulting in death was
observed in one patient who received VIDEX EC plus stavudine plus hydroxyurea
plus ritonavir plus indinavir plus efavirenz (see WARNINGS).
The frequency of pancreatitis is dose related. In phase 3 studies with buffered
formulations of didanosine, incidence ranged from 1% to 10% with doses higher than are
currently recommended and 1% to 7% with recommended dose.
Selected laboratory abnormalities that occurred in a study of VIDEX EC in
combination with other antiretroviral agents are shown in Table 11.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-154/S-049
NDA 20-155/S-038
NDA 20-156/S-039
NDA 21-183/S-015
Page 65 of 75
Table 11:
Selected Laboratory Abnormalities, Study AI454-152a
Percent of Patientsb
VIDEX EC + stavudine
+ nelfinavir
n=258
zidovudine/lamivudinec
+ nelfinavir
n=253
Parameter
Grades 3-4d
All Grades
Grades 3-4d
All Grades
SGOT (AST)
5
46
5
19
SGPT (ALT)
6
44
5
22
Lipase
5
23
2
13
Bilirubin
<1
9
<1
3
a Median duration of treatment was 62 weeks in the VIDEX EC + stavudine + nelfinavir group
and 61 weeks in the zidovudine/lamivudine + nelfinavir group.
b Percentages based on treated patients.
c Zidovudine/lamivudine combination tablet.
d >5 x ULN for SGOT and SGPT, ≥2.1 x ULN for lipase, and ≥2.6 x ULN for bilirubin (ULN =
upper limit of normal).
Observed During Clinical Practice
The following events have been identified during postapproval use of didanosine buffered
formulations. Because they are reported voluntarily from a population of unknown size,
estimates of frequency cannot be made. These events have been chosen for inclusion due
to their seriousness, frequency of reporting, causal connection to didanosine, or a
combination of these factors.
Body as a Whole – abdominal pain, alopecia, anaphylactoid reaction, asthenia,
chills/fever,
pain,
and
redistribution/accumulation
of
body
fat
(see
PRECAUTIONS: Fat Redistribution).
Digestive Disorders – anorexia, dyspepsia, and flatulence.
Exocrine Gland Disorders – pancreatitis (including fatal cases) (see
WARNINGS), sialoadenitis, parotid gland enlargement, dry mouth, and dry eyes.
Hematologic Disorders – anemia, leukopenia, and thrombocytopenia.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-154/S-049
NDA 20-155/S-038
NDA 20-156/S-039
NDA 21-183/S-015
Page 66 of 75
Liver – symptomatic hyperlactatemia/lactic acidosis and hepatic steatosis (see
WARNINGS); hepatitis and liver failure.
Metabolic Disorders – diabetes mellitus, elevated serum alkaline phosphatase
level, elevated serum amylase level, elevated serum gamma-glutamyltransferase
level, elevated serum uric acid level, hypoglycemia, and hyperglycemia.
Musculoskeletal Disorders – myalgia (with or without increases in creatine kinase),
rhabdomyolysis including acute renal failure and hemodialysis, arthralgia, and
myopathy.
Ophthalmologic Disorders – Retinal depigmentation and optic neuritis (see
WARNINGS).
OVERDOSAGE
There is no known antidote for didanosine overdosage. In phase 1 studies, in which
buffered formulations of didanosine were initially administered at doses ten times the
currently recommended dose, toxicities included: pancreatitis, peripheral neuropathy,
diarrhea, hyperuricemia, and hepatic dysfunction. Didanosine is not dialyzable by
peritoneal dialysis, although there is some clearance by hemodialysis (see CLINICAL
PHARMACOLOGY: Pharmacokinetics).
DOSAGE AND ADMINISTRATION
Dosage
Adults
VIDEX EC (didanosine) should be administered on an empty stomach.
VIDEX EC Delayed-Release Capsules should be swallowed intact.
The recommended daily dose is dependent on body weight and is administered as
one capsule given on a once-daily schedule as outlined in Table 12.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-154/S-049
NDA 20-155/S-038
NDA 20-156/S-039
NDA 21-183/S-015
Page 67 of 75
Table 12:
Dosing of VIDEX EC Delayed-Release Capsules
Patient Weight
Dosage
≥60 kg
400 mg once daily
<60 kg
250 mg once daily
Pediatric Patients
VIDEX EC has not been studied in pediatric patients. Please consult the complete
prescribing information for VIDEX (didanosine) Chewable/Dispersible Buffered Tablets
and Pediatric Powder for Oral Solution for dosage and administration of didanosine to
pediatric patients.
Dose Adjustment
Clinical and laboratory signs suggestive of pancreatitis should prompt dose
suspension and careful evaluation of the possibility of pancreatitis. VIDEX EC use
should be discontinued in patients with confirmed pancreatitis (see WARNINGS and
PRECAUTIONS: Drug Interactions).
Based on data with buffered didanosine formulations, patients with symptoms of
peripheral neuropathy may tolerate a reduced dose of VIDEX EC after resolution of the
symptoms of peripheral neuropathy upon drug interruption. If neuropathy recurs after
resumption of VIDEX EC, permanent discontinuation of VIDEX EC should be considered.
Concomitant Therapy
Tenofovir disoproxil fumarate. A dose reduction of VIDEX EC to 250 mg (adults
weighing ≥60 kg with creatinine clearance ≥60 mL/min) or 200 mg (adults weighing <60
kg with creatinine clearance ≥60 mL/min) once daily taken together with tenofovir and a
light meal (≤400 kcalories, ≤20% fat) or in the fasted state is recommended. The
appropriate dose of VIDEX EC coadministered with tenofovir in patients with
creatinine clearance <60 mL/min has not been established. (See CLINICAL
PHARMACOLOGY: Drug Interactions and PRECAUTIONS: Drug Interactions.)
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-154/S-049
NDA 20-155/S-038
NDA 20-156/S-039
NDA 21-183/S-015
Page 68 of 75
Renal Impairment
Dosing recommendations for VIDEX EC and VIDEX buffered formulations are different
for patients with renal impairment. Please consult the complete prescribing information on
administration of VIDEX (didanosine) buffered formulations to patients with renal
impairment.
In adult patients with impaired renal function, the dose of VIDEX EC should be
adjusted to compensate for the slower rate of elimination. The recommended doses and
dosing intervals of VIDEX EC in adult patients with renal insufficiency are presented in
Table 13.
Table 13:
Recommended Dosage of VIDEX EC in Renal
Impairment by Body Weighta
Dosage
Creatinine
Clearance
(mL/min)
≥60 kg
<60 kg
≥60
400 once daily
250 once daily
30-59
200 once daily
125 once daily
10-29
125 once daily
125 once daily
<10
125 once daily
b
a Based on studies using a buffered formulation of didanosine.
b Not suitable for use in patients <60 kg with CLcr <10 mL/min. An alternate formulation of
didanosine should be used.
Patients Requiring Continuous Ambulatory Peritoneal Dialysis (CAPD) or
Hemodialysis
For patients requiring CAPD or hemodialysis, follow dosing recommendations for patients
with creatinine clearance less than 10 mL/min, shown in Table 13. It is not necessary to
administer a supplemental dose of didanosine following hemodialysis.
Hepatic Impairment and Toxicity: See WARNINGS.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-154/S-049
NDA 20-155/S-038
NDA 20-156/S-039
NDA 21-183/S-015
Page 69 of 75
HOW SUPPLIED
VIDEX® EC (didanosine) Delayed-Release Capsules are white, opaque capsules that are
packaged in bottles with child-resistant closures as described in Table 14.
Table 14:
VIDEX EC Delayed-Release Capsules
125 mg capsule imprinted with BMS 125 mg 6671 in Tan
NDC No. 0087-6671-17
30 capsules/bottle
200 mg capsule imprinted with BMS 200 mg 6672 in Green
NDC No. 0087-6672-17
30 capsules/bottle
250 mg capsule imprinted with BMS 250 mg 6673 in Blue
NDC No. 0087-6673-17
30 capsules/bottle
400 mg capsule imprinted with BMS 400 mg 6674 in Red
NDC No. 0087-6674-17
30 capsules/bottle
The capsules should be stored in tightly closed containers at 25° C (77° F).
Excursions between 15° and 30° C (59° and 86° F) are permitted [see USP Controlled
Room Temperature].
HANDLING AND DISPOSAL
Disposal options include incineration, landfill, or sewer as dictated by specific
circumstances and relevant national, state, and local regulations.
US Patent Nos: 4,861,759, 5,254,539, 5,616,566, and 5,880,106 (didanosine).
Patent also Pending (didanosine capsules).
Bristol-Myers Squibb Virology
Bristol-Myers Squibb Company
Princeton, NJ 08543 USA
1196180A2
Revised July 2006
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-154/S-049
NDA 20-155/S-038
NDA 20-156/S-039
NDA 21-183/S-015
Page 70 of 75
PATIENT INFORMATION
Rx only
VIDEX® EC
(generic name = didanosine also known as ddI)
VIDEX® EC (didanosine) Delayed-Release Capsules
Enteric-Coated Beadlets
What is VIDEX EC?
VIDEX EC (pronounced VY dex ee see) is a prescription medicine used in combination
with other drugs to treat adults who are infected with HIV (the human immunodeficiency
virus, the virus that causes AIDS). VIDEX EC belongs to a class of drugs called
nucleoside analogues. By reducing the growth of HIV, VIDEX EC helps your body
maintain its supply of CD4 cells, which are important for fighting HIV and other
infections.
VIDEX EC will not cure your HIV infection. At present there is no cure for HIV
infection. Even while taking VIDEX EC, you may continue to have HIV-related illnesses,
including infections with other disease-producing organisms. Continue to see your doctor
regularly and report any medical problems that occur.
VIDEX EC does not prevent a patient infected with HIV from passing the virus to
other people. To protect others, you must continue to practice safe sex and take precautions
to prevent others from coming in contact with your blood and other body fluids.
There is limited information on the antiviral response of long-term use of
VIDEX EC.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-154/S-049
NDA 20-155/S-038
NDA 20-156/S-039
NDA 21-183/S-015
Page 71 of 75
In VIDEX EC, an enteric coating is used to protect the medicine while it is in your
stomach since stomach acids can break it down. The enteric coating dissolves when the
medicine reaches your small intestine.
Who should not take VIDEX EC?
Do not take VIDEX EC if you are allergic to any of its ingredients, including its active
ingredient, didanosine, and the inactive ingredients. (See Inactive Ingredients at the end
of this leaflet.) Tell your doctor if you think you have had an allergic reaction to any of
these ingredients.
Because it has only been studied in adults, VIDEX EC is not recommended for
children.
How should I take VIDEX EC?
How should I store it?
VIDEX EC should only be taken once daily. Your doctor will determine your dose based
on your body weight, kidney and liver function, other medicines you are taking, and any
side effects that you may have had with VIDEX EC or other medicines. Take VIDEX EC
on an empty stomach. Do not take VIDEX EC with food. Swallow the capsule whole;
do not open it. Try not to miss a dose, but if you do, take it as soon as possible. If it is
almost time for the next dose, skip the missed dose and continue your regular dosing
schedule.
Store capsules in a tightly closed container at room temperature away from heat
and out of the reach of children and pets.
If you have kidney disease: If your kidneys are not working properly, your doctor will
need to do regular tests to check how they are working while you take VIDEX EC. Your
doctor may also lower your dosage of VIDEX EC.
What should I do if someone takes an overdose of VIDEX EC?
If someone may have taken an overdose of VIDEX EC, get medical help right away.
Contact their doctor or a poison control center.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-154/S-049
NDA 20-155/S-038
NDA 20-156/S-039
NDA 21-183/S-015
Page 72 of 75
What should I avoid while taking VIDEX EC?
Alcohol. Do not drink alcohol while taking VIDEX EC since alcohol may increase your
risk of pancreatitis (pain and inflammation of the pancreas) or liver damage.
Other medicines. Other medicines, including those you can buy without a prescription,
may interfere with the actions of VIDEX EC or may increase the possibility or severity of
side effects. Do not take any medicine, vitamin supplement, or other health
preparation without first checking with your doctor.
Pregnancy. It is not known if VIDEX EC can harm a human fetus. Also, pregnant women
have experienced serious side effects when taking didanosine (the active ingredient in
VIDEX EC) in combination with ZERIT (stavudine), also known as d4T, and other HIV
medicines. VIDEX EC should be used during pregnancy only after discussion with your
doctor. Tell your doctor if you become pregnant or plan to become pregnant while
taking VIDEX EC.
Nursing. Studies have shown didanosine (the active ingredient in VIDEX EC) is in the
breast milk of animals getting the drug. It may also be in human breast milk. The Centers
for Disease Control and Prevention (CDC) recommends that HIV-infected mothers not
breast-feed. This should reduce the risk of passing HIV infection to their babies and the
potential for serious adverse reactions in nursing infants. Therefore, do not nurse a baby
while taking VIDEX EC.
What are the possible side effects of VIDEX EC?
Pancreatitis. Pancreatitis is a dangerous inflammation of the pancreas that may cause
death. Tell your doctor right away if you develop stomach pain, nausea, or vomiting.
These can be signs of pancreatitis. Before starting VIDEX EC therapy, let your doctor
know if you have ever had pancreatitis. This condition is more likely to happen in people who
have had it before. It is also more likely in people with advanced HIV disease. However, it can
occur at any stage of HIV disease. It may be more common in patients with kidney problems,
those who drink alcohol, and those who are also treated with stavudine or hydroxyurea. If you
get pancreatitis, your doctor will tell you to stop taking VIDEX EC.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-154/S-049
NDA 20-155/S-038
NDA 20-156/S-039
NDA 21-183/S-015
Page 73 of 75
Lactic acidosis, severe liver enlargement, and liver failure, including deaths, have been
reported among patients taking VIDEX EC (including pregnant women). Symptoms that
may indicate a liver problem are:
•
feeling very weak, tired, or uncomfortable,
•
unusual or unexpected stomach discomfort,
•
feeling cold,
•
feeling dizzy or lightheaded,
•
suddenly developing a slow or irregular heartbeat.
Lactic acidosis is a medical emergency that must be treated in a hospital.
If you notice any of these symptoms or if your medical condition changes, stop
taking VIDEX EC and call your doctor right away. Women, overweight patients, and
those who have been treated for a long time with other medicines used to treat HIV
infection are more likely to develop lactic acidosis. Your doctor should check your liver
function periodically while you are taking VIDEX EC. You should be especially careful if
you have a history of heavy alcohol use or a liver problem.
Vision changes. VIDEX EC may affect the nerves in your eyes. Because of this, you
should have regular eye examinations. You should also report any changes in vision to
your doctor right away. This includes, for example, seeing colors abnormally or blurred
vision.
Peripheral neuropathy. This is a problem with the nerves in your hands or feet. The
nerve problem may be serious. Tell your doctor right away if you have continuing
numbness, tingling, or pain in the feet or hands.
Before starting VIDEX EC therapy, let your doctor know if you have ever had
peripheral neuropathy. This condition is more likely to happen in people who have had it
before. It is also more likely in patients taking medicines that affect the nerves and in
people with advanced HIV disease. However, it can occur at any stage of HIV disease. If
you get peripheral neuropathy, your doctor will tell you to stop taking VIDEX EC. After
stopping VIDEX EC, the symptoms may get worse for a short time and then get better.
Once symptoms of peripheral neuropathy go away completely, you and your doctor should
decide if starting VIDEX EC is right for you. If so, you might be started at a lower dose.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-154/S-049
NDA 20-155/S-038
NDA 20-156/S-039
NDA 21-183/S-015
Page 74 of 75
Special note about other medicines. If you take VIDEX EC along with other medicines
with similar side effects, you may increase the chance of having these side effects. For
example, using VIDEX EC in combination with other medicines that may cause
pancreatitis, peripheral neuropathy, or liver problems (including stavudine and
hydroxyurea) may increase your chance of having these side effects.
Other side effects: The most common side effects in adults taking VIDEX EC in
combination with other HIV drugs included diarrhea, nausea, headache, vomiting, and
rash.
Changes in body fat have been seen in some patients taking antiretroviral therapy.
These changes may include increased amount of fat in the upper back and neck (“buffalo
hump”), breast, and around the trunk. Loss of fat from the legs, arms, and face may also
happen. The cause and long-term health effects of these conditions are not known at this
time.
Inactive Ingredients:
Carboxymethylcellulose sodium 12, diethyl phthalate, methacrylic acid copolymer, sodium
hydroxide, sodium starch glycolate, talc, colloidal silicon dioxide, gelatin, sodium lauryl
sulfate, and titanium dioxide.
This medicine was prescribed for your particular condition. Do not use VIDEX EC for another condition or
give it to others. Keep VIDEX EC and all medicines out of the reach of children. Throw away VIDEX EC
when it is outdated or no longer needed by flushing it down the toilet or pouring it down the sink.
This summary does not include everything there is to know about VIDEX EC. Medicines are sometimes
prescribed for purposes other than those listed in a Patient Information Leaflet. If you have questions or concerns, or
want more information about VIDEX EC, your physician and pharmacist have the complete prescribing information
upon which this leaflet is based. You may want to read it and discuss it with your doctor or other healthcare
professional. Remember, no written summary can replace careful discussion with your doctor.
Bristol-Myers Squibb Virology
Bristol-Myers Squibb Company
Princeton, NJ 08543 USA
This Patient Information Leaflet has been approved by the U.S. Food and Drug Administration.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-154/S-049
NDA 20-155/S-038
NDA 20-156/S-039
NDA 21-183/S-015
Page 75 of 75
1196180A2
Revised July 2006
Based on package insert dated July 2006
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:46:54.578090
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/020154s49,20155s38,20156s39,21183s15lbl.pdf', 'application_number': 20155, 'submission_type': 'SUPPL ', 'submission_number': 38}
|
12,274
|
ApprovletS037.doc (clean copy 27March02)
Page 4 of 39
Rx only
VIDEX
(didanosine)
VIDEX (didanosine) Chewable/Dispersible Buffered Tablets
VIDEX (didanosine) Buffered Powder for Oral Solution
VIDEX (didanosine) Pediatric Powder for Oral Solution
(Patient Information Leaflet Included)
WARNING
FATAL AND NONFATAL PANCREATITIS HAVE OCCURRED DURING
THERAPY WITH VIDEX USED ALONE OR IN COMBINATION REGIMENS
IN
BOTH
TREATMENT-NAIVE
AND
TREATMENT-EXPERIENCED
PATIENTS, REGARDLESS OF DEGREE OF IMMUNOSUPPRESSION. VIDEX
SHOULD BE SUSPENDED IN PATIENTS WITH SUSPECTED PANCREATITIS
AND DISCONTINUED IN PATIENTS WITH CONFIRMED PANCREATITIS
(SEE WARNINGS).
LACTIC
ACIDOSIS
AND
SEVERE
HEPATOMEGALY
WITH
STEATOSIS, INCLUDING FATAL CASES, HAVE BEEN REPORTED WITH
THE USE OF NUCLEOSIDE ANALOGUES ALONE OR IN COMBINATION,
INCLUDING DIDANOSINE AND OTHER ANTIRETROVIRALS. FATAL
LACTIC ACIDOSIS HAS BEEN REPORTED IN PREGNANT WOMEN WHO
RECEIVED THE COMBINATION OF DIDANOSINE AND STAVUDINE WITH
OTHER
ANTIRETROVIRAL
AGENTS.
THE
COMBINATION
OF
DIDANOSINE AND STAVUDINE SHOULD BE USED WITH CAUTION
DURING PREGNANCY AND IS RECOMMENDED ONLY IF THE POTENTIAL
BENEFIT
CLEARLY
OUTWEIGHS
THE
POTENTIAL
RISK.
(SEE
WARNINGS AND PRECAUTIONS: PREGNANCY.)
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
ApprovletS037.doc (clean copy 27March02)
Page 5 of 39
DESCRIPTION
VIDEX (didanosine) is a brand name for didanosine (ddI), a synthetic purine nucleoside
analogue active against the Human Immunodeficiency Virus (HIV). VIDEX
Chewable/Dispersible Buffered Tablets are available for oral administration in strengths of
25, 50, 100, 150, and 200 mg of didanosine. Each tablet is buffered with calcium
carbonate and magnesium hydroxide. VIDEX tablets also contain aspartame, sorbitol,
microcrystalline cellulose, polyplasdone, mandarin-orange flavor, and magnesium stearate.
VIDEX Buffered Powder for Oral Solution is supplied for oral administration in
single-dose packets containing 100, 167, or 250 mg of didanosine. Packets of each product
strength also contain a citrate-phosphate buffer (composed of dibasic sodium phosphate,
sodium citrate, and citric acid) and sucrose.
VIDEX Pediatric Powder for Oral Solution is supplied for oral administration in 4-
or 8-ounce glass bottles containing 2 or 4 grams of didanosine, respectively.
Didanosine is also available as an enteric-coated formulation (VIDEX® EC
Delayed-Release Capsules). Please consult the prescribing information for VIDEX EC
(didanosine).
The chemical name for didanosine is 2',3'-dideoxyinosine. The structural formula
is:
Didanosine is a white crystalline powder with the molecular formula C10H12N4O3
and a molecular weight of 236.2. The aqueous solubility of didanosine at 25°C and pH of
approximately 6 is 27.3 mg/mL. Didanosine is unstable in acidic solutions. For example,
at pH <3 and 37°C, 10% of didanosine decomposes to hypoxanthine in less than 2 minutes.
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MICROBIOLOGY
Mechanism of Action
Didanosine is a synthetic nucleoside analogue of the naturally occurring nucleoside
deoxyadenosine in which the 3'-hydroxyl group is replaced by hydrogen. Intracellularly,
didanosine is converted by cellular enzymes to the active metabolite, dideoxyadenosine
5'-triphosphate. Dideoxyadenosine 5'-triphosphate inhibits the activity of HIV-1 reverse
transcriptase both by competing with the natural substrate, deoxyadenosine 5'-triphosphate,
and by its incorporation into viral DNA causing termination of viral DNA chain
elongation.
In Vitro HIV Susceptibility
The in vitro anti-HIV-1 activity of didanosine was evaluated in a variety of HIV-1 infected
lymphoblastic cell lines and monocyte/macrophage cell cultures. The concentration of drug
necessary to inhibit viral replication by 50% (IC50) ranged from 2.5 to 10 µM (1 µM = 0.24
µg/mL) in lymphoblastic cell lines and 0.01 to 0.1 µM in monocyte/macrophage cell
cultures. The relationship between in vitro susceptibility of HIV to didanosine and the
inhibition of HIV replication in humans has not been established.
Drug Resistance
HIV-1 isolates with reduced sensitivity to didanosine have been selected in vitro and were
also obtained from patients treated with didanosine. Genetic analysis of isolates from
didanosine-treated patients showed mutations in the reverse transcriptase gene that resulted
in the amino acid substitutions K65R, L74V, and M184V. The L74V mutation was most
frequently observed in clinical isolates. Phenotypic analysis of HIV-1 isolates from 60
patients (some with prior zidovudine treatment) receiving 6 to 24 months of didanosine
monotherapy showed that isolates from 10 of 60 patients exhibited an average of a 10-fold
decrease in susceptibility to didanosine in vitro compared to baseline isolates. Clinical
isolates that exhibited a decrease in didanosine susceptibility harbored one or more
didanosine-associated mutations. The clinical relevance of genotypic and phenotypic
changes associated with didanosine therapy has not been established.
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Cross-resistance
HIV-1 isolates from 2 of 39 patients receiving combination therapy for up to 2 years with
zidovudine and didanosine exhibited decreased susceptibility to zidovudine, didanosine,
zalcitabine, stavudine, and lamivudine in vitro. These isolates harbored five mutations
(A62V, V75I, F77L, F116Y, and Q151M) in the reverse transcriptase gene. The clinical
relevance of these observations has not been established.
CLINICAL PHARMACOLOGY
Animal Toxicology
Evidence of a dose-limiting skeletal muscle toxicity has been observed in mice and rats
(but not in dogs) following long-term (greater than 90 days) dosing with didanosine at
doses that were approximately 1.2 to 12 times the estimated human exposure. The
relationship of this finding to the potential of VIDEX (didanosine) to cause myopathy in
humans is unclear. However, human myopathy has been associated with administration of
VIDEX and other nucleoside analogues.
Pharmacokinetics
The pharmacokinetic parameters of didanosine are summarized in Table 1. Didanosine is
rapidly absorbed, with peak plasma concentrations generally observed from 0.25 to 1.50
hours following oral dosing. Increases in plasma didanosine concentrations were dose
proportional over the range of 50 to 400 mg. Steady-state pharmacokinetic parameters did
not differ significantly from values obtained after a single dose. Binding of didanosine to
plasma proteins in vitro was low (<5%). Based on data from in vitro and animal studies, it
is presumed that the metabolism of didanosine in man occurs by the same pathways
responsible for the elimination of endogenous purines.
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Table 1:
Mean ± SD Pharmacokinetic Parameters for Didanosine in Adult
and Pediatric Patients
Pediatric Patientsb
Parameter
Adult
Patientsa
n
8 months to 19 years
n
2 weeks to 4 months
n
Oral bioavailability (%)
42 ± 12
6
25 ± 20
46
ND
Apparent volume of
distributionc (L/m2)
43.70 ± 8.90
6
28 ± 15
49
ND
CSF-plasma ratiod
21 ± 0.03%e
5
46%
(range 12-85%)
7
ND
Systemic clearancec
(mL/min/m2)
526 ± 64.7
6
516 ± 184
49
ND
Renal clearancef
(mL/min/m2)
223 ± 85.0
6
240 ± 90
15
ND
Apparent oral
clearanceg (mL/min/m2)
1252 ± 154
6
2064 ± 736
48
1353 ± 759
41
Elimination half-lifef (h)
1.5 ± 0.4
6
0.8 ± 0.3
60
1.2 ± 0.3
21
Urinary recovery of
didanosinef (%)
18 ± 8
6
18 ± 10
15
ND
CSF = cerebrospinal fluid, ND = not determined.
a Parameter units for adults were converted to the same units in pediatric patients to facilitate comparisons
among populations: mean adult body weight = 70 kg and mean adult body surface area = 1.73 m2.
b In 1-day old infants (n=10), the mean ± SD apparent oral clearance was 1523 ± 1176 mL/min/m2 and half-
life was 2.0 ± 0.7 h.
c Following IV administration.
d Following IV administration in adults and IV or oral administration in pediatric patients.
e Mean ± SE.
f Following oral administration.
g Apparent oral clearance estimate was determined as the ratio of the mean systemic clearance and the mean
oral bioavailability estimate.
Effect of Food on Absorption of Didanosine: Didanosine peak plasma
concentrations (CMAX) and area under the plasma concentration time curve (AUC) were
decreased by approximately 55% when VIDEX tablets were administered up to 2 hours
after a meal. Administration of VIDEX tablets up to 30 minutes before a meal did not
result in any significant changes in bioavailability. VIDEX should be taken on an empty
stomach, at least 30 minutes before or 2 hours after eating. (See DOSAGE AND
ADMINISTRATION.)
Special Populations
Renal Insufficiency: It is recommended that the VIDEX (didanosine) dose be modified
in patients with reduced creatinine clearance and in patients receiving maintenance
hemodialysis (see DOSAGE AND ADMINISTRATION). Data from two studies in
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adults indicated that the apparent oral clearance of didanosine decreased and the terminal
elimination half-life increased as creatinine clearance decreased (see Table 2). Following
oral administration, didanosine was not detectable in peritoneal dialysate fluid (n=6);
recovery in hemodialysate (n=5) ranged from 0.6% to 7.4% of the dose over a 3-4 hour
dialysis period. The absolute bioavailability of didanosine was not affected in patients
requiring dialysis.
Table 2:
Mean ± SD Pharmacokinetic Parameters for Didanosine
Following a Single Oral Dose
Creatinine Clearance (mL/min)
Parameter
≥ 90 (n=12)
60-90 (n=6)
30-59 (n=6)
10-29 (n=3)
Dialysis Patients
(n=11)
CLcr (mL/min)
112 ± 22
68 ± 8
46 ± 8
13 ± 5
NDa
CL/F (mL/min)
2164 ± 638
1566 ± 833
1023 ± 378
628 ± 104
543 ± 174
CLR (mL/min)
458 ± 164
247 ± 153
100 ± 44
20 ± 8
<10
T½ (h)
1.42 ± 0.33
1.59 ± 0.13
1.75 ± 0.43
2.0 ± 0.3
4.1 ± 1.2
a ND = not determined due to anuria
CLcr = creatinine clearance
CL/F = apparent oral clearance
CLR = renal clearance
Pediatric Patients: The pharmacokinetics of didanosine have been evaluated in
HIV-exposed and -infected pediatric patients from birth to 19 years of age (see Table 1).
Overall, the pharmacokinetics of didanosine in pediatric patients are similar to those of
didanosine in adults. Didanosine plasma concentrations appear to increase in proportion to
oral doses ranging from 25 to 120 mg/m2 in pediatric patients less than 5 months old and
from 80 to 180 mg/m2 in children above 8 months old. For information on controlled
clinical studies in pediatric patients, see PRECAUTIONS, Pediatric Use and Clinical
Studies.
Geriatric Patients: Didanosine pharmacokinetics have not been studied in
patients over 65 years of age.
Gender: The effects of gender on didanosine pharmacokinetics have not been
studied.
Drug Interactions: Tables 3 and 4 summarize the effects on AUC and CMAX,
with a 90% or 95% confidence interval (CI) when available, following coadministration of
VIDEX with a variety of drugs. For most of the listed drugs, no clinically significant
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pharmacokinetic interactions were observed. Clinical recommendations based on drug
interaction studies for drugs in bold font are included in PRECAUTIONS: Drug
Interactions.
Table 3:
Results of Drug Interaction Studies: Effects of
Coadministered Drug on Didanosine Plasma AUC and CMAX
Values
Drugs With Clinical Recommendations Regarding Coadministration (see PRECAUTIONS: Drug Interactions)
Drug
Didanosine Dosage
n
AUC of
Didanosine
(95% CI)
CMAX of
Didanosine (95%
CI)
allopurinol
renally impaired, 300 mg/day
200 mg single dose
2
↑312%
↑232%
healthy volunteer, 300 mg/day
for 7 days
400 mg single dose
14
↑113%
↑69%
ciprofloxacin, 750 mg q12h for
3 days, 2 h before didanosine
200 mg q12h for 3
days
8a
↓16%
↓28%
ganciclovir, 1000 mg q8h, 2 h
after didanosine
200 mg q12h
12
↑111%
NA
indinavir, 800 mg single dose
simultaneous
1 h before didanosine
200 mg single dose
200 mg single dose
16
16
↔
↓17% (-27, - 7%)b
↔
↓13% (-28, 5%)b
ketoconazole, 200 mg/day for
4 days, 2 h before didanosine
375 mg q12h for 4
days
12a
↔
↓12%
methadone, chronic
maintenance dose
200 mg single dose
16,10c
↓57%
↓66%
No Clinically Significant Interaction Observed
Drug
Didanosine Dosage
n
AUC of
Didanosine
(95% CI)
CMAX of
Didanosine (95%
CI)
loperamide, 4 mg q6h for 1 day
300 mg single dose
12a
↔
↓23%
metoclopramide, 10 mg single
dose
300 mg single dose
12a
↔
↑13%
ranitidine, 150 mg single dose,
2 h before didanosine
375 mg single dose
12a
↑14%
↑13%
rifabutin, 300 or 600 mg/day
for 12 days
167 or 250 mg q12h
for 12 days
11
↑13% (-1, 27%)
↑17% (-4, 38%)
ritonavir, 600 mg q12h for 4
days
200 mg q12h for 4
days
12
↓13% (0, 23%)
↓16% (5, 26%)
stavudine, 40 mg q12h for 4
days
100 mg q12h for 4
days
10
↔
↔
sulfamethoxazole, 1000 mg
single dose
200 mg single dose
8a
↔
↔
trimethoprim, 200 mg single
dose
200 mg single dose
8a
↔
↑17% (-23, 77%)
zidovudine, 200 mg q8h for 3
days
200 mg q12h for 3
days
6a
↔
↔
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Table 3:
Results of Drug Interaction Studies: Effects of
Coadministered Drug on Didanosine Plasma AUC and CMAX
Values
↑ indicates increase.
↓ indicates decrease.
↔ indicates no change, or mean increase or decrease of <10%.
a HIV-infected patients.
b 90% CI.
c Parallel-group design; entries are subjects receiving combination and control regimens, respectively.
NA Not available.
Table 4:
Results of Drug Interaction Studies: Effects of Didanosine on
Coadministered Drug Plasma AUC and CMAX Values
Drugs With Clinical Recommendations Regarding Coadministration (see PRECAUTIONS: Drug Interactions)
Drug
Didanosine Dosage
n
AUC of
Coadministered
Drug (95% CI)
CMAX of
Coadministered
Drug (95% CI)
ciprofloxacin
750 mg q12h for 3 days, 2 h
before didanosine
750 mg single dose
200 mg q12h for 3 days
buffered placebo tablet
8a
12
↓26%
↓98%
↓16%
↓93%
delavirdine, 400 mg single dose
simultaneous
1 h before didanosine
125 or 200 mg q12h
125 or 200 mg q12h
12a
12a
↓32%
↑20%
↓53%
↑18%
ganciclovir, 1000 mg q8h, 2 h
after didanosine
200 mg q12h
12a
↓21%
NA
indinavir, 800 mg single dose
simultaneous
1 h before didanosine
200 mg single dose
200 mg single dose
16
16
↓84%
↓11%
↓82%
↓4%
ketoconazole, 200 mg/day for 4
days, 2 h before didanosine
375 mg q12h for 4 days
12a
↓14%
↓20%
nelfinavir, 750 mg single dose, 1
h after didanosine
200 mg single dose
10a
↑12%
↔
No Clinically Significant Interaction Observed
Drug
Didanosine Dosage
n
AUC of
Coadministered
Drug (95% CI)
CMAX of
Coadministered
Drug (95% CI)
dapsone, 100 mg single dose
200 mg q12h for 14
days
6a
↔
↔
ranitidine, 150 mg single dose, 2 h
before didanosine
375 mg single dose
12a
↓16%
↔
ritonavir, 600 mg q12h for 4 days
200 mg q12h for 4
days
12
↔
↔
stavudine, 40 mg q12h for 4 days
100 mg q12h for 4
days
10a
↔
↑17%
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Table 4:
Results of Drug Interaction Studies: Effects of Didanosine on
Coadministered Drug Plasma AUC and CMAX Values
sulfamethoxazole, 1000 mg single
dose
200 mg single dose
8a
↓11% (-17, -4%)
↓12% (-28, 8%)
trimethoprim, 200 mg single dose
200 mg single dose
8a
↑10% (-9, 34%)
↓22% (-59, 49%)
zidovudine, 200 mg q8h for 3 days
200 mg q12h for 3
days
6a
↓10% (-27, 11%)
↓16.5% (-53, 47%)
↑ indicates increase.
↓ indicates decrease.
↔ indicates no change, or mean increase or decrease of <10%.
a HIV-infected patients.
NA Not available.
INDICATIONS AND USAGE
VIDEX in combination with other antiretroviral agents is indicated for the treatment
of HIV-1 infection (see Clinical Studies).
Clinical Studies
Combination Therapy
START 2 was a multicenter, randomized, open-label study comparing VIDEX (200 mg
twice daily)/stavudine/indinavir to zidovudine/lamivudine/indinavir in 205 treatment-naive
patients. Both regimens resulted in a similar magnitude of suppression of HIV RNA levels
and increases in CD4 cell counts through 48 weeks.
Study A1454-148 was a randomized, open-label, multicenter study comparing
treatment with VIDEX (400 mg once daily) plus stavudine (40 mg twice daily) and
nelfinavir (750 mg three times daily) versus zidovudine (300 mg twice daily) plus
lamivudine (150 mg twice daily) and nelfinavir (750 mg three times daily) in 756
treatment-naive patients, with a median CD4 cell count of 340 cells/mm3 (range 80 to 1568
cells/mm3) and a median plasma HIV-1 RNA of 4.69 log10 copies/mL (range 2.6 to 5.9
log10 copies/mL) at baseline. Median CD4 cell count increases at 48 weeks were 188
cells/mm3 in both treatment groups. Treatment response and outcomes through 48 weeks
are shown in Figure 1 and Table 5.
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Figure 1:
Treatment Response Through Week 48*, AI454-148
* Percent of patients at each time point who have HIV RNA <400 or <50 copies/mL, are on
their original study medication (except stavudine-zidovudine switches), and have not
experienced an AIDS-defining event.
Table 5:
Outcomes of Randomized Treatment through Week 48, AI454-148
Percent of Patients with HIV RNA <400 copies/mL (<50 copies/mL)
VIDEX/stavudine/nelfinavir
lamivudine/zidovudine/nelfinavir
Week 48 Status
n=503
n=253
Responder a
50* (34*)
59 (47)
Virologic failureb
36 (57)
32 (48)
Death or disease progression
<1 (<1)
1 (<1)
Discontinued due to adverse events
4 (2)
2 (<1)
Discontinued due to other reasonsc
6 (3)
4 (2)
Never initiated treatment
4 (4)
2 (2)
* <0.05 for the differences between treatment groups, by Cochran-Mantel-Haenszel test.
a Patients achieved virologic response [two consecutive viral load <400 (<50) copies/mL] and maintained it to
Week 48.
b Includes viral rebound and failing to achieve confirmed <400 (<50) copies/mL by Week 48.
c Includes lost to follow-up, noncompliance, withdrawal, and pregnancy.
Monotherapy
The efficacy of VIDEX was demonstrated in two randomized, double-blind studies
comparing VIDEX, given on a twice-daily schedule, to zidovudine, given three times
daily, in 617 (ACTG 116A, conducted 1989-1992) and 913 (ACTG116B/117, conducted
1989-1991) patients with symptomatic HIV infection or AIDS who were treated for more
than one year. In treatment-naive patients (ACTG 116A), the rate of HIV disease
0
20
40
60
80
100
0
8
16
24
32
40
48
Study Week
Percent of patients
] < 400 c/mL
] < 50 c/mL
VIDEX+stavudine+nelfinavir (n=503)
zidovudine+lamivudine+nelfinavir (n=253)
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progression or death was similar between the treatment groups; mortality rates were 26%
for patients receiving VIDEX and 21% for patients receiving zidovudine. Of the patients
who had received previous zidovudine treatment (ACTG 116B/117), those treated with
VIDEX had a lower rate of HIV disease progression or death (32%) compared to those
treated with zidovudine (41%); however, survival rates were similar between the treatment
groups.
Efficacy in pediatric patients was demonstrated in a randomized, double-blind,
controlled study (ACTG 152, conducted 1991-1995) involving 831 patients 3 months to 18
years of age treated for more than 1.5 years with zidovudine (180 mg/m2 q6h), VIDEX
(120 mg/m2 q12h), or zidovudine (120 mg/m2 q6h) plus VIDEX (90 mg/m2 q12h). Patients
treated with VIDEX or VIDEX plus zidovudine had lower rates of HIV disease
progression or death compared with those treated with zidovudine alone.
Studies have demonstrated that the clinical benefit of monotherapy with
antiretrovirals, including VIDEX, was time limited.
CONTRAINDICATION
VIDEX (didanosine) is contraindicated in patients with previously demonstrated clinically
significant hypersensitivity to any of the components of the formulations.
WARNINGS
1.
Pancreatitis
FATAL AND NONFATAL PANCREATITIS HAVE OCCURRED DURING
THERAPY WITH VIDEX USED ALONE OR IN COMBINATION REGIMENS IN
BOTH TREATMENT-NAIVE AND TREATMENT-EXPERIENCED PATIENTS,
REGARDLESS OF DEGREE OF IMMUNOSUPPRESSION. VIDEX SHOULD BE
SUSPENDED IN PATIENTS WITH SIGNS OR SYMPTOMS OF PANCREATITIS
AND DISCONTINUED IN PATIENTS WITH CONFIRMED PANCREATITIS.
PATIENTS TREATED WITH VIDEX IN COMBINATION WITH STAVUDINE,
WITH OR WITHOUT HYDROXYUREA, MAY BE AT INCREASED RISK FOR
PANCREATITIS.
When treatment with life-sustaining drugs known to cause pancreatic toxicity is
required, suspension of VIDEX (didanosine) therapy is recommended. In patients with risk
factors for pancreatitis, VIDEX should be used with extreme caution and only if clearly
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indicated. Patients with advanced HIV infection, especially the elderly, are at increased
risk of pancreatitis and should be followed closely. Patients with renal impairment may be
at greater risk for pancreatitis if treated without dose adjustment.
The frequency of pancreatitis is dose related. In phase 3 studies, incidence ranged
from 1% to 10% with doses higher than are currently recommended and 1% to 7% with
recommended dose.
In pediatric phase 1 studies, pancreatitis occurred in 3% (2/60) of patients treated at
entry doses below 300 mg/m2/day and in 13% (5/38) of patients treated at higher doses. In
study ACTG 152, pancreatitis occurred in none of the 281 pediatric patients who received
didanosine 120 mg/m2 q12h and in <1% of the 274 pediatric patients who received
didanosine 90 mg/m2 q12h in combination with zidovudine. VIDEX use should be
suspended in pediatric patients with signs or symptoms of pancreatitis and discontinued in
pediatric patients with confirmed pancreatitis.
2.
Lactic Acidosis/Severe Hepatomegaly with Steatosis
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases,
have been reported with the use of nucleoside analogues alone or in combination,
including didanosine and other antiretrovirals. A majority of these cases have been in
women. Obesity and prolonged nucleoside exposure may be risk factors. Fatal lactic
acidosis has been reported in pregnant women who received the combination of didanosine
and stavudine with other antiretroviral agents. The combination of didanosine and
stavudine should be used with caution during pregnancy and is recommended only if the
potential benefit clearly outweighs the potential risk (see PRECAUTIONS: Pregnancy).
Particular caution should be exercised when administering VIDEX to any patient with
known risk factors for liver disease; however, cases have also been reported in patients
with no known risk factors. Treatment with VIDEX should be suspended in any patient
who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced
hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of
marked transaminase elevations).
3.
Retinal Changes and Optic Neuritis
Retinal changes and optic neuritis have been reported in adult and pediatric
patients. Periodic retinal examinations should be considered for patients receiving VIDEX.
(See ADVERSE REACTIONS.)
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PRECAUTIONS
Frequency of Dosing
The preferred dosing frequency of VIDEX is twice daily because there is more evidence to
support the effectiveness of this dosing frequency. Once-daily dosing should be considered
only for adult patients whose management requires once-daily dosing of VIDEX (see
Clinical Studies).
VIDEX should be taken on an empty stomach, at least 30 minutes before or 2
hours after eating.
Peripheral Neuropathy
Peripheral neuropathy, manifested by numbness, tingling, or pain in the hands or feet, has
been reported in patients receiving VIDEX therapy. Peripheral neuropathy has occurred
more frequently in patients with advanced HIV disease, in patients with a history of
neuropathy, or in patients being treated with neurotoxic drug therapy, including stavudine
(see ADVERSE REACTIONS).
Fat Redistribution
Redistribution/accumulation of body fat including central obesity, dorsocervical fat
enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and
“cushingoid appearance” have been observed in patients receiving antiretroviral therapy.
The mechanism and long-term consequences of these events are currently unknown. A
causal relationship has not been established.
General
Patients with Phenylketonuria: VIDEX Chewable/Dispersible Buffered Tablets
contain the following quantities of phenylalanine:
Table 6
All Strengths
Phenylalanine per 2-tablet dose
73 mg
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Table 6
All Strengths
Phenylalanine per tablet
36.5 mg
Patients on Sodium-Restricted Diets: VIDEX Buffered Powder for Oral
Solution: Each single-dose packet of VIDEX Buffered Powder for Oral Solution contains
1380 mg sodium.
Patients with Renal Impairment: Patients with renal impairment (creatinine
clearance <60 mL/min) may be at greater risk of toxicity from VIDEX due to decreased
drug clearance (see CLINICAL PHARMACOLOGY). A dose reduction is
recommended in these patients (see DOSAGE AND ADMINISTRATION). The
magnesium content of each buffered tablet of VIDEX is 8.6 mEq. This may present an
excessive load of magnesium to patients with significant renal impairment, particularly
after prolonged dosing.
Patients with Hepatic Impairment: It is unknown if hepatic impairment
significantly affects didanosine pharmacokinetics. Therefore, these patients should be
monitored closely for evidence of didanosine toxicity.
Hyperuricemia: VIDEX has been associated with asymptomatic hyperuricemia;
treatment suspension may be necessary if clinical measures aimed at reducing uric acid
levels fail.
Information for Patients (See Patient Information Leaflet.)
Patients should be informed that a serious toxicity of VIDEX used alone and in
combination regimens, is pancreatitis, which may be fatal.
Patients should be informed that the preferred dosing frequency of VIDEX is twice
daily because there is more evidence to support the effectiveness of this dosing frequency.
Once-daily dosing should be considered only for adult patients whose management
requires once-daily dosing of VIDEX.
Patients should also be aware that peripheral neuropathy, manifested by numbness,
tingling, or pain in hands or feet, may develop during therapy with VIDEX. Patients
should be counseled that peripheral neuropathy occurs with greatest frequency in patients
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with advanced HIV disease or a history of peripheral neuropathy, and that dose
modification and/or discontinuation of VIDEX may be required if toxicity develops.
Patients should be informed that when VIDEX is used in combination with other
agents with similar toxicities, the incidence of adverse events may be higher than when
VIDEX is used alone. These patients should be followed closely.
Patients should be cautioned about the use of medications or other substances,
including alcohol, that may exacerbate VIDEX toxicities.
Patients should be advised that to ensure proper acid neutralization in the stomach
they must take at least two of the appropriate strength VIDEX tablets at each dose. To
reduce the risk of gastrointestinal side effects from excess antacid, patients should take no
more than four VIDEX tablets at each dose.
VIDEX (didanosine) is not a cure for HIV infection, and patients may continue to
develop HIV-associated illnesses, including opportunistic infection. Therefore, patients
should remain under the care of a physician when using VIDEX. Patients should be
advised that VIDEX therapy has not been shown to reduce the risk of transmission of HIV
to others through sexual contact or blood contamination. Patients should be informed that
the long-term effects of VIDEX are unknown at this time.
Patients should be informed that redistribution or accumulation of body fat may
occur in patients receiving antiretroviral therapy and that the cause and long-term health
effects of these conditions are not known at this time.
Drug Interactions (see also CLINICAL PHARMACOLOGY: Drug
Interactions)
Drug interactions that have been established based on drug interaction studies are listed
with the pharmacokinetic results in CLINICAL PHARMACOLOGY: Drug
Interactions (Tables 3 and 4). The clinical recommendations based on the results of these
studies are listed in Table 7.
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Table 7:
Established Drug Interactions with VIDEX
Coadministration Not Recommended Based on Drug Interaction Studies (see CLINICAL
PHARMACOLOGY: Drug Interactions for Magnitude of Interaction)
Drug
Effect
Clinical Comment
allopurinol
↑ didanosine concentration
Coadministration not recommended.
Alteration in Dose or Regimen Recommended Based on Drug Interaction Studies (see CLINICAL
PHARMACOLOGY: Drug Interactions for Magnitude of Interaction)
Drug
Effect
Clinical Comment
ciprofloxacin
↓ ciprofloxacin concentration
Administer VIDEX at least 2 hours after or
6 hours before ciprofloxacin.
delavirdine
↓ delavirdine concentration
Administer VIDEX 1 hour after
delavirdine.
ganciclovir
↑ didanosine concentration
Appropriate doses for this combination,
with respect to efficacy and safety, have not
been established.
indinavir
↓ indinavir concentration
Administer VIDEX 1 hour after indinavir.
methadone
↓ didanosine concentration
Appropriate doses for this combination,
with respect to efficacy and safety, have not
been established.
nelfinavir
No interaction 1 hour after didanosine
Administer nelfinavir 1 hour after VIDEX.
↑ indicates increase.
↓ indicates decrease.
Coadministration of VIDEX with drugs that are known to cause pancreatitis
may increase the risk of this toxicity (see WARNINGS: Pancreatitis). Because VIDEX
formulations either contain buffers or are mixed with antacids before administration,
interactions may be anticipated with drugs whose absorption can be affected by the level of
acidity in the stomach and with drugs that have been demonstrated to interact with antacids
containing magnesium, calcium, or aluminum. Predicted drug interactions with VIDEX
are listed in Table 8.
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Table 8:
Predicted Drug Interactions with VIDEX
Use with Caution, Risk of Adverse Reactions May Be Increased
Drug Class
Effect
Clinical Comment
Drugs that may cause
pancreatic toxicity
↑ risk of pancreatitis
Use only with extreme caution.a
Neurotoxic drugs
↑ risk of neuropathy
Use with caution.b
Antacids containing
magnesium or aluminum
↑ side effects associated with
antacid components
Use caution with VIDEX
Chewable/Dispersible Buffered Tablets
and Pediatric Powder for Oral Solution.
Use with Caution, Plasma Concentrations May Be Decreased by Coadministration with VIDEX
Drug Class
Effect
Clinical Comment
Azole antifungals
↓ ketoconazole or itraconazole
concentration
Administer drugs such as ketoconazole or
itraconazole at least 2 hours before
VIDEX.
Quinolone antibiotics (see
also ciprofloxacin in Table 7)
↓ quinolone concentration
Consult package insert of the quinolone.
Tetracycline antibiotics
↓ antibiotic concentration
Consult package insert of the tetracycline.
↑ indicates increase.
↓ indicates decrease.
a Only if other drugs are not available and if clearly indicated. If treatment with life-sustaining drugs that
cause pancreatic toxicity is required, suspension of VIDEX is recommended (see WARNINGS:
Pancreatitis).
b See PRECAUTIONS: Peripheral Neuropathy.
Carcinogenesis and Mutagenesis
Lifetime carcinogenicity studies were conducted in mice and rats for 22 and 24 months,
respectively. In the mouse study, initial doses of 120, 800, and 1200 mg/kg/day for each
sex were lowered after 8 months to 120, 210, and 210 mg/kg/day for females and 120, 300,
and 600 mg/kg/day for males. The two higher doses exceeded the maximally tolerated
dose in females and the high dose exceeded the maximally tolerated dose in males. The
low dose in females represented 0.68-fold maximum human exposure and the intermediate
dose in males represented 1.7-fold maximum human exposure based on relative AUC
comparisons. In the rat study, initial doses were 100, 250, and 1000 mg/kg/day, and the
high dose was lowered to 500 mg/kg/day after 18 months. The upper dose in male and
female rats represented 3-fold maximum human exposure.
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Didanosine induced no significant increase in neoplastic lesions in mice or rats at
maximally tolerated doses.
Didanosine was positive in the following genetic toxicology assays: 1) the
Escherichia coli tester strain WP2 uvrA bacterial mutagenicity assay; 2) the
L5178Y/TK+/- mouse lymphoma mammalian cell gene mutation assay; 3) the in vitro
chromosomal aberrations assay in cultured human peripheral lymphocytes; 4) the in vitro
chromosomal aberrations assay in Chinese Hamster Lung cells; and 5) the BALB/c 3T3 in
vitro transformation assay. No evidence of mutagenicity was observed in an Ames
Salmonella bacterial mutagenicity assay or in rat and mouse in vivo micronucleus assays.
Pregnancy, Reproduction, and Fertility
Pregnancy Category B. Reproduction studies have been performed in rats and rabbits at
doses up to 12 and 14.2 times the estimated human exposure (based upon plasma levels),
respectively, and have revealed no evidence of impaired fertility or harm to the fetus due to
didanosine. At approximately 12 times the estimated human exposure, didanosine was
slightly toxic to female rats and their pups during mid and late lactation. These rats
showed reduced food intake and body weight gains but the physical and functional
development of the offspring was not impaired and there were no major changes in the F2
generation. A study in rats showed that didanosine and/or its metabolites are transferred to
the fetus through the placenta. Animal reproduction studies are not always predictive of
human response.
There are no adequate and well-controlled studies of didanosine in pregnant
women. Didanosine should be used during pregnancy only if the potential benefit justifies
the potential risk.
Fatal lactic acidosis has been reported in pregnant women who received the
combination of didanosine and stavudine with other antiretroviral agents. It is unclear if
pregnancy augments the risk of lactic acidosis/hepatic steatosis syndrome reported in
nonpregnant individuals receiving nucleoside analogues (see WARNINGS: Lactic
Acidosis/Severe Hepatomegaly with Steatosis). The combination of didanosine and
stavudine should be used with caution during pregnancy and is recommended only if
the potential benefit clearly outweighs the potential risk. Health care providers caring
for HIV-infected pregnant women receiving didanosine should be alert for early diagnosis
of lactic acidosis/hepatic steatosis syndrome.
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Antiretroviral Pregnancy Registry: To monitor maternal-fetal outcomes of
pregnant women exposed to didanosine and other antiretroviral agents, an Antiretroviral
Pregnancy Registry has been established. Physicians are encouraged to register patients by
calling 1-800-258-4263.
Nursing Mothers
The Centers for Disease Control and Prevention recommend that HIV-infected
mothers not breast-feed their infants to avoid risking postnatal transmission of HIV.
A study in rats showed that following oral administration, didanosine and/or its metabolites
were excreted into the milk of lactating rats. It is not known if didanosine is excreted in
human milk. Because of both the potential for HIV transmission and the potential for
serious adverse reactions in nursing infants, mothers should be instructed not to breast-
feed if they are receiving VIDEX.
Pediatric Use
Use of VIDEX in pediatric patients from 2 weeks of age through adolescence is supported
by evidence from adequate and well-controlled studies of VIDEX in adults and pediatric
patients (see Clinical Studies, CLINICAL PHARMACOLOGY, ADVERSE
REACTIONS, and DOSAGE AND ADMINISTRATION).
Dosing recommendations for VIDEX in patients less than 2 weeks of age cannot be
made because the pharmacokinetics of didanosine in these children are too variable to
determine an appropriate dose.
Geriatric Use
In an Expanded Access Program for patients with advanced HIV infection, patients aged
65 years and older had a higher frequency of pancreatitis (10%) than younger patients (5%)
(see WARNINGS). Clinical studies of didanosine did not include sufficient numbers of
subjects aged 65 years and over to determine whether they respond differently than
younger subjects. Didanosine is known to be substantially excreted by the kidney, and the
risk of toxic reactions to this drug may be greater in patients with impaired renal function.
Because elderly patients are more likely to have decreased renal function, care should be
taken in dose selection. In addition, renal function should be monitored and dosage
adjustments should be made accordingly (see DOSAGE AND ADMINISTRATION:
Dose Adjustment).
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ADVERSE REACTIONS
A SERIOUS TOXICITY OF VIDEX (didanosine) IS PANCREATITIS, WHICH MAY
BE FATAL (see WARNINGS). OTHER IMPORTANT TOXICITIES INCLUDE
LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS; RETINAL
CHANGES AND OPTIC NEURITIS; AND PERIPHERAL NEUROPATHY (see
WARNINGS and PRECAUTIONS).
When VIDEX is used in combination with other agents with similar toxicities,
the incidence of these toxicities may be higher than when VIDEX is used alone. Thus,
patients treated with VIDEX in combination with stavudine, with or without
hydroxyurea, may be at increased risk for pancreatitis, which may be fatal, and
hepatotoxicity (see WARNINGS). Patients treated with VIDEX in combination with
stavudine may also be at increased risk for peripheral neuropathy (see
PRECAUTIONS).
Adults: Selected clinical adverse events that occurred in adult patients in clinical
studies with VIDEX are provided in Tables 9 and 10.
Table 9:
Selected Clinical Adverse Events from Monotherapy
Studies
Percent of Patients
ACTG 116A
ACTG 116B/117
VIDEX
zidovudine
VIDEX
zidovudine
Adverse Events
n=197
n=212
n=298
n=304
Diarrhea
19
15
28
21
Peripheral Neurologic
Symptoms/Neuropathy
17
14
20
12
Rash/Pruritus
7
8
9
5
Abdominal Pain
13
8
7
8
Pancreatitis
7
3
6
2
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Table 10:
Selected Clinical Adverse Events from Combination
Studies
Percent of Patientsa
AI454-148b
START 2b
VIDEX +
stavudine +
nelfinavir
zidovudine +
lamivudine +
nelfinavir
VIDEX +
stavudine +
indinavir
zidovudine +
lamivudine +
indinavir
Adverse Events
n=482
n=248
n=102
n=103
Diarrhea
70
60
45
39
Nausea
28
40
53
67
Headache
21
30
46
37
Peripheral Neurologic
Symptoms/Neuropathy
26
6
21
10
Rash
13
16
30
18
Vomiting
12
14
30
35
Pancreatitis (see below)
1
*
<1
*
a Percentages based on treated subjects.
b Median duration of treatment 48 weeks.
* This event was not observed in this study arm.
Pancreatitis resulting in death was observed in one patient who received
VIDEX plus stavudine plus nelfinavir in Study Al454-148 and in one patient who
received VIDEX plus stavudine plus indinavir in the START 2 study. In addition,
pancreatitis resulting in death was observed in 2 of 68 patients who received VIDEX
plus stavudine plus indinavir plus hydroxyurea in an ACTG clinical trial (see
WARNINGS).
The frequency of pancreatitis is dose related. In phase 3 studies, incidence ranged
from 1% to 10% with doses higher than are currently recommended and from 1% to 7%
with recommended dose.
Selected laboratory abnormalities in clinical studies with VIDEX are shown in
Tables 11-13.
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Table 11:
Selected Laboratory Abnormalities from Monotherapy Studies
Percent of Patients
ACTG 116A
ACTG 116B/117
VIDEX
zidovudine
VIDEX
zidovudine
Parameter
n=197
n=212
n=298
n=304
SGOT (AST) (>5 x ULN)
9
4
7
6
SGPT (ALT) (>5 x ULN)
9
6
6
6
Alkaline phosphatase
(>5 x ULN)
4
1
1
1
Amylase (≥1.4 x ULN)
17
12
15
5
Uric acid (>12 mg/dL)
3
1
2
1
ULN = upper limit of normal.
Table 12:
Selected Laboratory Abnormalities from Combination
Studies (Grades 3-4)
Percent of Patientsa
AI454-148b
START 2b
VIDEX +
stavudine +
nelfinavir
zidovudine +
lamivudine +
nelfinavir
VIDEX +
stavudine +
indinavir
zidovudine +
lamivudine +
indinavir
Parameter
n=482
n=248
n=102
n=103
Bilirubin (>2.6 x ULN)
<1
<1
16
8
SGOT (AST) (>5 x ULN)
3
2
7
7
SGPT (ALT) (>5 x ULN)
3
3
8
5
GGT (>5 x ULN)
NC
NC
5
2
Lipase (>2 x ULN)
7
2
5
5
Amylase (>2 x ULN)
NC
NC
8
2
ULN = upper limit of normal.
NC=Not Collected
a Percentages based on treated subjects.
b Median duration of treatment 48 weeks.
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Table 13:
Selected Laboratory Abnormalities from Combination
Studies (All Grades)
Percent of Patientsa
I454-148b
START 2b
VIDEX +
stavudine +
nelfinavir
zidovudine +
lamivudine +
nelfinavir
VIDEX +
stavudine +
indinavir
zidovudine +
lamivudine +
indinavir
Parameter
n=482
n=248
n=102
n=103
Bilirubin
7
3
68
55
SGOT (AST)
42
23
53
20
SGPT (ALT)
37
24
50
18
GGT
NC
NC
28
12
Lipase
17
11
26
19
Amylase
NC
NC
31
17
NC = Not Collected
a Percentages based on treated subjects.
b Median duration of treatment 48 weeks.
Observed during Clinical Practice: The following events have been identified
during postapproval use of VIDEX (didanosine). Because they are reported voluntarily
from a population of unknown size, estimates of frequency cannot be made. These events
have been chosen for inclusion due to their seriousness, frequency of reporting, causal
connection to VIDEX, or a combination of these factors.
Body as a Whole - alopecia, anaphylactoid reaction, asthenia, chills/fever, pain, and
redistribution/accumulation
of
body
fat
(see
PRECAUTIONS:
Fat
Redistribution).
Digestive Disorders- anorexia, dyspepsia, and flatulence.
Exocrine
Gland
Disorders
–
pancreatitis
(including
fatal
cases)
(see
WARNINGS), sialoadenitis, parotid gland enlargement, dry mouth, and dry eyes.
Hematologic Disorders - anemia, leukopenia, and thrombocytopenia.
Liver - lactic acidosis and hepatic steatosis (see WARNINGS); hepatitis and liver
failure.
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Metabolic Disorders - diabetes mellitus, hypoglycemia, and hyperglycemia.
Musculoskeletal Disorders - myalgia (with or without increases in creatine kinase),
rhabdomyolysis including acute renal failure and hemodialysis, arthralgia, and
myopathy.
Ophthalmologic Disorders - Retinal depigmentation and optic neuritis (see
WARNINGS).
Pediatric Patients: In clinical trials, 743 pediatric patients between 2 weeks and
18 years of age have been treated with VIDEX. Adverse events and laboratory
abnormalities reported to occur in these patients were generally consistent with the safety
profile of didanosine in adults.
In pediatric phase 1 studies, pancreatitis occurred in 2 of 60 (3%) patients treated at
entry doses below 300 mg/m2/day and in 5 of 38 (13%) patients treated at higher doses. In
study ACTG 152, pancreatitis occurred in none of the 281 pediatric patients who received
didanosine 120 mg/m2 q12h and in <1% of the 274 pediatric patients who received
didanosine 90 mg/m2 q12h in combination with zidovudine (see Clinical Studies).
Retinal changes and optic neuritis have been reported in pediatric patients.
OVERDOSAGE
There is no known antidote for VIDEX (didanosine) overdosage. In phase 1 studies, in
which VIDEX was initially administered at doses ten times the currently recommended
dose, toxicities included: pancreatitis, peripheral neuropathy, diarrhea, hyperuricemia and
hepatic dysfunction. Didanosine is not dialyzable by peritoneal dialysis, although there is
some
clearance
by
hemodialysis
(see
CLINICAL
PHARMACOLOGY:
Pharmacokinetics).
DOSAGE AND ADMINISTRATION
Dosage
All VIDEX formulations should be administered on an empty stomach, at least 30
minutes before or 2 hours after eating. For either a once-daily or twice-daily regimen,
patients must take at least two of the appropriate strength tablets at each dose to
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provide adequate buffering and prevent gastric acid degradation of didanosine.
Because of the need for adequate buffering, the 200-mg strength tablet should only be
used as a component of a once-daily regimen. To reduce the risk of gastrointestinal
side effects, patients should take no more than four tablets at each dose.
Adults: The preferred dosing frequency of VIDEX is twice daily because there is
more evidence to support the effectiveness of this dosing regimen. Once-daily dosing
should be considered only for adult patients whose management requires once-daily dosing
of VIDEX (see Clinical Studies). The daily dose in adult patients is dependent on weight
as outlined in Table 14.
Table 14:
Adult Dosing
Patient Weight
VIDEX Tabletsa
VIDEX Buffered Powderb
Preferred dosing
≥60 kg
200 mg twice daily
250 mg twice daily
< 60 kg
125 mg twice daily
167 mg twice daily
Dosing for patients whose management requires once-daily frequency
≥ 60 kg
400 mg once daily
b
< 60 kg
250 mg once daily
b
a The 200-mg strength tablet should only be used as a component of a once-
daily regimen.
b Not suitable for once-daily dosing except for patients with renal impairment.
See Table 15.
Pediatric Patients: The recommended dose of VIDEX (didanosine) in pediatric
patients between 2 weeks and 8 months of age is 100 mg/m2 twice daily, and the
recommended VIDEX dose for pediatric patients older than 8 months is 120 mg/m2 twice
daily.
Dosing recommendations for VIDEX in patients less than 2 weeks of age cannot be
made because the pharmacokinetics of didanosine in these children are too variable to
determine an appropriate dose. There are no data on once-daily dosing of VIDEX in
pediatric patients.
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Dose Adjustment
Clinical and laboratory signs suggestive of pancreatitis should prompt dose
suspension and careful evaluation of the possibility of pancreatitis. VIDEX use should
be discontinued in patients with confirmed pancreatitis (see WARNINGS).
Patients with symptoms of peripheral neuropathy may tolerate a reduced dose of
VIDEX after resolution of the symptoms of peripheral neuropathy upon drug
discontinuation. If neuropathy recurs after resumption of VIDEX, permanent
discontinuation of VIDEX should be considered.
Renal Impairment: In adult patients with impaired renal function, the dose of
VIDEX should be adjusted to compensate for the slower rate of elimination. The
recommended doses and dosing intervals of VIDEX in adult patients with renal
insufficiency are presented in Table 15.
Table 15:
Recommended Dosage of VIDEX in Renal Impairment
≥ 60 kg
< 60 kg
Creatinine Clearance
(mL/min)
Tableta
(mg)
Buffered Powderb
(mg)
Tableta
(mg)
Buffered Powderb
(mg)
≥60
200 twice dailyc
250 twice daily
125 twice dailyc
167 twice daily
30-59
200 once daily
or 100 twice daily
100 twice daily
150 once daily
or 75 twice daily
100 twice daily
10-29
150 once daily
167 once daily
100 once daily
100 once daily
<10
100 once daily
100 once daily
75 once daily
100 once daily
a VIDEX Chewable/Dispersible Buffered Tablet. Two VIDEX tablets must be taken with each dose;
different strengths of tablets may be combined to yield the recommended dose.
b VIDEX Buffered Powder for Oral Solution.
c 400 mg once daily (≥60 kg) or 250 mg once daily (<60 kg) for patients whose management requires once-
daily frequency of administration.
Urinary excretion is also a major route of elimination of didanosine in pediatric
patients; therefore, the clearance of didanosine may be altered in children with renal
impairment. Although there are insufficient data to recommend a specific dose adjustment
of VIDEX in this patient population, a reduction in the dose and/or an increase in the
interval between doses should be considered.
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Patients Requiring Continuous Ambulatory Peritoneal Dialysis (CAPD)
or Hemodialysis: For patients requiring CAPD or hemodialysis, follow dosing
recommendations for patients with creatinine clearance less than 10 mL/min, shown in
Table 15. It is not necessary to administer a supplemental dose of VIDEX following
hemodialysis.
Hepatic Impairment: See WARNINGS and PRECAUTIONS.
Method of Preparation
VIDEX Chewable/Dispersible Buffered Tablets
Adult Dosing: To provide adequate buffering, at least two of the appropriate strength
tablets, but no more than four tablets, should be thoroughly chewed or dispersed in at least
1 ounce of water prior to consumption (see PRECAUTIONS: Information for Patients).
To disperse tablets, add 2 tablets to at least 1 ounce of drinking water. Stir until a uniform
dispersion forms, and drink the entire dispersion immediately. If additional flavoring is
desired, the dispersion may be diluted with one ounce of clear apple juice. Stir the further
diluted dispersion just prior to consumption. The dispersion with clear apple juice is stable
at room temperature, 62° to 73°F (17° to 23°C), for up to one hour.
VIDEX Buffered Powder for Oral Solution
1.
Open packet carefully and pour contents into a container with approximately 4
ounces of drinking water. Do not mix with fruit juice or other acid-containing liquid.
2.
Stir until the powder completely dissolves (approximately 2 to 3 minutes).
3.
Drink the entire solution immediately.
VIDEX Pediatric Powder for Oral Solution
Prior to dispensing, the pharmacist must constitute dry powder with Purified Water, USP,
to an initial concentration of 20 mg/mL and immediately mix the resulting solution with
antacid to a final concentration of 10 mg/mL as follows:
20 mg/mL Initial Solution: Constitute the product to 20 mg/mL by adding 100
mL or 200 mL of Purified Water, USP, to the 2 g or 4 g of VIDEX powder, respectively, in
the product bottle.
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10 mg/mL Final Admixture: 1. Immediately mix one part of the 20 mg/mL
initial solution with one part of either Mylanta® Double Strength Liquid, Extra Strength
Maalox® Plus Suspension, or Maalox ® TC Suspension for a final dispensing
concentration of 10 mg VIDEX per mL. For patient home use, the admixture should be
dispensed in appropriately sized, flint-glass or plastic (HDPE, PET, or PETG) bottles with
child-resistant closures. This admixture is stable for 30 days under refrigeration, 36° to
46° F (2° to 8° C).
2. Instruct the patient to shake the admixture thoroughly prior to use and to store
the tightly closed container in the refrigerator, 36° to 46° F (2° to 8° C), up to 30 days.
HOW SUPPLIED
VIDEX® (didanosine) Chewable/Dispersible Buffered Tablets are round, off white to
light orange/yellow with a mottled appearance, orange-flavored, tablets embossed with
"VIDEX" on one side and the product strength on the other. The tablets are available in
the following strengths of VIDEX: 25, 50, 100, 150, and 200 mg. Sixty tablets are
packaged in bottles with child-resistant closures.
The tablets should be stored in tightly closed bottles at 59° to 86° F (15° to
30 °C). If dispersed in water, the dose may be held for up to 1 hour at ambient
temperature.
VIDEX (didanosine) Buffered Powder for Oral Solution is supplied in single-
dose, child-resistant foil packets in the following strengths of VIDEX: 100, 167, or 250
mg. Each product strength provides a sweetened, buffered solution of VIDEX.
The packets should be stored at 59° to 86° F (15° to 30° C). After dissolving in
water, the solution may be stored at ambient room temperature for up to 4 hours.
VIDEX (didanosine) Pediatric Powder for Oral Solution is supplied in 4- and 8-
ounce glass bottles containing 2 g or 4 g of VIDEX, respectively.
The bottles of powder should be stored at 59° to 86° F (15° to 30° C). The VIDEX
admixture may be stored up to 30 days in a refrigerator, 36° to 46° F (2° to 8° C). Discard
any unused portion after 30 days.
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The NDC numbers for the previously described VIDEX products are:
Table 16
NDC NO.
Packaging Information
Product Strength
VIDEX
Chewable/Dispersible Buffered Tablets
0087-6650-01
60 tablets/bottle
25 mg/tablet
0087-6651-01
60 tablets/bottle
50 mg/tablet
0087-6652-01
60 tablets/bottle
100 mg/tablet
0087-6653-01
60 tablets/bottle
150 mg/tablet
0087-6665-15
60 tablets/bottle
200 mg/tablet
VIDEX
Buffered Powder for Oral Solution
0087-6614-43
One single-dose foil packet*
100 mg/packet
0087-6615-43
One single-dose foil packet*
167 mg/packet
0087-6616-43
One single-dose foil packet*
250 mg/packet
VIDEX
Pediatric Powder for Oral Solution
0087-6632-41
One bottle per carton
2 g/bottle
0087-6633-41
One bottle per carton
4 g/bottle
* Packaged as 30 packets per carton.
US Patent Nos.: 4,861,759 and 5,616,566.
HANDLING AND DISPOSAL
Spill, Leak, and Disposal Procedure
Avoid generating dust during clean-up of powdered products; use wet mop or damp
sponge. Clean surface with soap and water as necessary. Containerize larger spills.
There is no single preferred method of disposal of containerized waste. Disposal
options include incineration, landfill, or sewer as dictated by specific circumstances and
relevant national, state, and local regulations.
Maalox® is a registered trademark of Novartis Consumer Health, Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
ApprovletS037.doc (clean copy 27March02)
Page 33 of 39
Bristol-Myers Squibb Virology
A Bristol-Myers Squibb Company
Princeton, NJ 08543 USA
XXXXXX
Revised _____________________
PATIENT INFORMATION
Rx only
VIDEX®
(generic name = didanosine also known as ddI)
VIDEX® (didanosine) Chewable/Dispersible Buffered Tablets
VIDEX® (didanosine) Buffered Powder for Oral Solution
VIDEX® (didanosine) Pediatric Powder for Oral Solution
What is VIDEX?
VIDEX (pronounced VY dex) is a prescription medicine used in combination with other
drugs to treat children and adults who are infected with HIV (the human
immunodeficiency virus, the virus that causes AIDS). VIDEX belongs to a class of drugs
called nucleoside analogues. By reducing the growth of HIV, VIDEX helps your body
maintain its supply of CD4 cells, which are important for fighting HIV and other
infections.
VIDEX will not cure your HIV infection. At present there is no cure for HIV infection.
Even while taking VIDEX, you may continue to have HIV-related illnesses, including
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
ApprovletS037.doc (clean copy 27March02)
Page 34 of 39
infections with other disease-producing organisms. Continue to see your doctor regularly and
report any medical problems that occur.
VIDEX does not prevent a patient infected with HIV from passing the virus to
other people. To protect others, you must continue to practice safe sex and take precautions
to prevent others from coming in contact with your blood and other body fluids.
There is limited information on the effects of long-term use of VIDEX.
Who should not take VIDEX?
Do not take VIDEX if you are allergic to any of its ingredients, including its active ingredient,
didanosine and the inactive ingredients. (See Inactive Ingredients at the end of this leaflet.)
Tell your doctor if you think you have had an allergic reaction to any of these ingredients.
How should I take VIDEX? How should I store it?
Your doctor will determine your dose based on your body weight, kidney and liver function,
and any side effects that you may have had with other medicines. Take VIDEX on an empty
stomach - that means at least 30 minutes before or 2 hours after eating. Do not take
VIDEX with food. Try not to miss a dose, but if you do, take it as soon as possible. If it is
almost time for the next dose, skip the missed dose and continue your regular dosing schedule.
Chewable/Dispersible Tablets: Each VIDEX tablet contains antacid. Each
time you take VIDEX, you must take at least two, but not more than four,
tablets. This is because VIDEX tablets contain an antacid to reduce the amount of
acid in your stomach. If you have too much acid, the medicine will break down.
However, too much antacid may cause stomach problems.
—DO NOT swallow VIDEX tablets whole. Chew the tablets well or mix them in
water. Many patients drop the tablets in at least one ounce of water and stir well
before swallowing. If you choose to mix the tablets in water, you may add one
ounce (2 tablespoons) of clear apple juice to the mixture for flavor (do not use any
other kind of juice).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
ApprovletS037.doc (clean copy 27March02)
Page 35 of 39
—Store tablets in a tightly closed container at room temperature away from heat
and out of the reach of children and pets. Do NOT store the tablets in a damp place
such as a bathroom medicine cabinet or near the kitchen sink.
Buffered Powder for Oral Solution: Pour the contents of a packet into a glass
with 4 ounces (1/2 measuring cup) of water. Stir until completely dissolved. Drink
the entire solution right away. Do not mix with fruit juice. Store packets at room
temperature before use.
Pediatric Oral Solution: Your pharmacist will prepare the oral solution. Shake
the solution well before each use. Store in the refrigerator. Throw away any
unused portion after 30 days.
If you have kidney disease: If your kidneys are not working properly, your doctor
will need to do regular tests to check how they are working while you take VIDEX.
Your doctor may also lower your dosage of VIDEX.
What should I do if someone takes an overdose of VIDEX?
If someone may have taken an overdose of VIDEX, get medical help right away. Contact
their doctor or a poison control center.
What should I avoid while taking VIDEX?
Alcohol. Do not drink alcohol while taking VIDEX since alcohol may increase your risk of
pancreatitis (pain and inflammation of the pancreas) or liver damage.
Other medicines. Other medicines, including those you can buy without a prescription,
may interfere with the actions of VIDEX. Do not take any medicine, vitamin
supplement, or other health preparation without first checking with your doctor.
Antacids. Since VIDEX contains some of the same ingredients found in antacids,
any side effects related to VIDEX’s ingredients may get worse if you also take an
antacid.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
ApprovletS037.doc (clean copy 27March02)
Page 36 of 39
Medicines at the same time you take your VIDEX dose. Some medicines should
not be taken at the same time of day that you take VIDEX. Check with your
doctor.
Pregnancy. It is not known if VIDEX can harm a human fetus. Also, pregnant women
have experienced serious side effects when taking VIDEX in combination with ZERIT
(stavudine), also known as d4T, and other HIV medicines. VIDEX should be used during
pregnancy only after discussion with your doctor. Tell your doctor if you become
pregnant or plan to become pregnant while taking VIDEX.
Nursing. Studies have shown VIDEX is in the breast milk of animals getting the drug. It
may also be in human breast milk. The Centers for Disease Control and Prevention (CDC)
recommends that HIV-infected mothers not breast-feed. This should reduce the risk of
passing HIV infection to their babies and the potential for serious adverse reactions in
nursing infants. Therefore, do not nurse a baby while taking VIDEX.
What are the possible side effects of VIDEX?
Pancreatitis. Pancreatitis is a dangerous inflammation of the pancreas that may cause
death. Tell your doctor right away if you or a child taking VIDEX develops stomach
pain, nausea, or vomiting. These can be signs of pancreatitis. Before starting VIDEX
therapy, let your doctor know if you or a child for whom it has been prescribed has ever had
pancreatitis. This condition is more likely to happen in people who have had it before. It is also
more likely in people with advanced HIV disease. However, it can occur at any stage of HIV
disease. It may be more common in patients with kidney problems, those who drink alcohol,
and those who are also treated with stavudine or hydroxyurea. If you get pancreatitis, your
doctor will tell you to stop taking VIDEX.
Lactic acidosis, severe liver enlargement, and liver failure, including deaths, have been
reported among patients taking VIDEX (including pregnant women). Symptoms that may
indicate a liver problem are:
• feeling very weak, tired, or uncomfortable,
• unusual or unexpected stomach discomfort,
• feeling cold,
• feeling dizzy or lightheaded,
• suddenly developing a slow or irregular heartbeat.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
ApprovletS037.doc (clean copy 27March02)
Page 37 of 39
Lactic acidosis is a medical emergency that must be treated in a hospital.
If you notice any of these symptoms or if your medical condition changes, stop taking
VIDEX and call your doctor right away. Women, overweight patients, and those who have
been treated for a long time with other medicines used to treat HIV infection are more likely to
develop lactic acidosis. Your doctor should check your liver function periodically while you
are taking VIDEX. You should be especially careful if you have a history of heavy alcohol use
or a liver problem.
Vision changes. VIDEX may affect the nerves in your eyes. Because of this, you should have
regular eye examinations. You should also report any changes in vision to your doctor right
away. This includes, for example, seeing colors abnormally or blurred vision.
Peripheral neuropathy. This is a problem with the nerves in your hands or feet. The nerve
problem may be serious. Tell your doctor right away if you or a child taking VIDEX has
continuing numbness, tingling, or pain in the feet or hands. A child may not recognize these
symptoms or know to tell you that his or her feet or hands are numb, burning, tingling, or
painful. Ask your child’s doctor how to find out if your child is developing peripheral
neuropathy.
Before starting VIDEX therapy, let your doctor know if you or a child for whom it has
been prescribed has ever had peripheral neuropathy. This condition is more likely to happen in
people who have had it before. It is also more likely in patients taking medicines that affect the
nerves and in people with advanced HIV disease. However, it can occur at any stage of HIV
disease. If you get peripheral neuropathy, your doctor will tell you to stop taking VIDEX.
After stopping VIDEX, the symptoms may get worse for a short time and then get better. Once
symptoms of peripheral neuropathy go away completely, you and your doctor should decide if
starting VIDEX is right for you. If so, you might be started at a lower dose.
Special note about other medicines. If you take VIDEX along with other medicines with
similar side effects, you may increase the chance of having these side effects. For example,
using VIDEX in combination with other medicines that may cause pancreatitis, peripheral
neuropathy, or liver problems (including stavudine and hydroxyurea) may increase your chance
of having these side effects.
Other side effects: The most common side effects in adults taking VIDEX are diarrhea,
neuropathy (nerve disorders), chills or fever, rash, abdominal pain, weakness, headache, and
nausea and vomiting. Children may have similar side effects as adults.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
ApprovletS037.doc (clean copy 27March02)
Page 38 of 39
Changes in body fat have been seen in some patients taking antiretroviral therapy. These
changes may include increased amount of fat in the upper back and neck (“buffalo hump”),
breast, and around the trunk. Loss of fat from the legs, arms, and face may also happen. The
cause and long-term health effects of these conditions are not known at this time.
What else should I know about VIDEX?
If you should limit sodium (salt) intake: Each single-dose packet of Buffered Powder for
Oral Solution contains 1380 mg of sodium. Each Chewable/Dispersible Tablet contains
264.5 mg of sodium.
If you have phenylketonuria: Each Chewable/Dispersible Tablet contains 36.5 mg of
phenylalanine.
Inactive Ingredients:
Chewable/Dispersible Tablets: calcium carbonate, magnesium hydroxide,
aspartame, sorbitol, mandarin orange flavor, polyplasdone, microcrystalline
cellulose, and magnesium stearate.
Buffered Powder for Oral Solution: citrate-phosphate buffer (dibasic sodium
phosphate, sodium citrate, and citric acid) and sucrose.
Pediatric Oral Solution: Mylanta Double Strength Liquid, Extra Strength
Maalox Plus or Maalox TC Suspension.
This medicine was prescribed for your particular condition. Do not use VIDEX for another condition or give
it to others. Keep VIDEX and all medicines out of the reach of children. Throw away VIDEX when it is
outdated or no longer needed by flushing it down the toilet or pouring it down the sink.
This summary does not include everything there is to know about VIDEX. Medicines are sometimes
prescribed for purposes other than those listed in a Patient Information Leaflet. If you have questions or concerns, or
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
ApprovletS037.doc (clean copy 27March02)
Page 39 of 39
want more information about VIDEX, your physician and pharmacist have the complete prescribing information
upon which this leaflet is based. You may want to read it and discuss it with your doctor or other healthcare
professional. Remember, no written summary can replace careful discussion with your doctor.
Mylanta® is a registered trademark of Johnson & Johnson-Merck Consumer Pharmaceuticals Company.
Maalox® is a registered trademark of Novartis Consumer Health, Inc.
Bristol-Myers Squibb Virology
A Bristol-Myers Squibb Company
Princeton, NJ 08543 USA
This Patient Information Leaflet has been approved by the U.S. Food and Drug Administration.
xxxxxxxx
Revised __________________
Based on xxxxx (xx/02)
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
---------------------------------------------------------------------------------------------------------------------
This is a representation of an electronic record that was signed electronically and
this page is the manifestation of the electronic signature.
---------------------------------------------------------------------------------------------------------------------
/s/
---------------------
Jeffrey Murray
4/1/02 04:27:10 PM
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:46:54.704094
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2002/20154s37lbl.pdf', 'application_number': 20156, 'submission_type': 'SUPPL ', 'submission_number': 29}
|
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Page 4 of 39
Rx only
VIDEX
(didanosine)
VIDEX (didanosine) Chewable/Dispersible Buffered Tablets
VIDEX (didanosine) Buffered Powder for Oral Solution
VIDEX (didanosine) Pediatric Powder for Oral Solution
(Patient Information Leaflet Included)
WARNING
FATAL AND NONFATAL PANCREATITIS HAVE OCCURRED DURING THERAPY
WITH VIDEX USED ALONE OR IN COMBINATION REGIMENS IN BOTH
TREATMENT-NAIVE
AND
TREATMENT-EXPERIENCED
PATIENTS,
REGARDLESS OF DEGREE OF IMMUNOSUPPRESSION. VIDEX SHOULD BE
SUSPENDED IN PATIENTS WITH SUSPECTED PANCREATITIS AND
DISCONTINUED IN PATIENTS WITH CONFIRMED PANCREATITIS (SEE
WARNINGS).
LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS,
INCLUDING FATAL CASES, HAVE BEEN REPORTED WITH THE USE OF
NUCLEOSIDE ANALOGUES ALONE OR IN COMBINATION, INCLUDING
DIDANOSINE AND OTHER ANTIRETROVIRALS. FATAL LACTIC ACIDOSIS
HAS BEEN REPORTED IN PREGNANT WOMEN WHO RECEIVED THE
COMBINATION
OF
DIDANOSINE
AND
STAVUDINE
WITH
OTHER
ANTIRETROVIRAL AGENTS. THE COMBINATION OF DIDANOSINE AND
STAVUDINE SHOULD BE USED WITH CAUTION DURING PREGNANCY AND IS
RECOMMENDED ONLY IF THE POTENTIAL BENEFIT CLEARLY OUTWEIGHS
THE POTENTIAL RISK. (SEE WARNINGS AND PRECAUTIONS: PREGNANCY.)
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 5 of 39
DESCRIPTION
VIDEX (didanosine) is a brand name for didanosine (ddI), a synthetic purine nucleoside
analogue active against the Human Immunodeficiency Virus (HIV). VIDEX
Chewable/Dispersible Buffered Tablets are available for oral administration in strengths of 25,
50, 100, 150, and 200 mg of didanosine. Each tablet is buffered with calcium carbonate and
magnesium hydroxide. VIDEX tablets also contain aspartame, sorbitol, microcrystalline
cellulose, polyplasdone, mandarin-orange flavor, and magnesium stearate.
VIDEX Buffered Powder for Oral Solution is supplied for oral administration in single-
dose packets containing 100, 167, or 250 mg of didanosine. Packets of each product strength
also contain a citrate-phosphate buffer (composed of dibasic sodium phosphate, sodium citrate,
and citric acid) and sucrose.
VIDEX Pediatric Powder for Oral Solution is supplied for oral administration in 4- or
8-ounce glass bottles containing 2 or 4 grams of didanosine, respectively.
Didanosine is also available as an enteric-coated formulation (VIDEX® EC Delayed-
Release Capsules). Please consult the prescribing information for VIDEX EC (didanosine).
The chemical name for didanosine is 2',3'-dideoxyinosine. The structural formula is:
Didanosine is a white crystalline powder with the molecular formula C10H12N4O3 and a
molecular weight of 236.2. The aqueous solubility of didanosine at 25° C and pH of
approximately 6 is 27.3 mg/mL. Didanosine is unstable in acidic solutions. For example, at
pH <3 and 37° C, 10% of didanosine decomposes to hypoxanthine in less than 2 minutes.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 6 of 39
MICROBIOLOGY
Mechanism of Action
Didanosine is a synthetic nucleoside analogue of the naturally occurring nucleoside
deoxyadenosine in which the 3'-hydroxyl group is replaced by hydrogen. Intracellularly,
didanosine is converted by cellular enzymes to the active metabolite, dideoxyadenosine
5'-triphosphate. Dideoxyadenosine 5'-triphosphate inhibits the activity of HIV-1 reverse
transcriptase both by competing with the natural substrate, deoxyadenosine 5'-triphosphate,
and by its incorporation into viral DNA causing termination of viral DNA chain elongation.
In Vitro HIV Susceptibility
The in vitro anti-HIV-1 activity of didanosine was evaluated in a variety of HIV-1 infected
lymphoblastic cell lines and monocyte/macrophage cell cultures. The concentration of drug
necessary to inhibit viral replication by 50% (IC50) ranged from 2.5 to 10 µM (1 µM =
0.24 µg/mL) in lymphoblastic cell lines and 0.01 to 0.1 µM in monocyte/macrophage cell
cultures. The relationship between in vitro susceptibility of HIV to didanosine and the
inhibition of HIV replication in humans has not been established.
Drug Resistance
HIV-1 isolates with reduced sensitivity to didanosine have been selected in vitro and were also
obtained from patients treated with didanosine. Genetic analysis of isolates from didanosine-
treated patients showed mutations in the reverse transcriptase gene that resulted in the amino
acid substitutions K65R, L74V, and M184V. The L74V mutation was most frequently
observed in clinical isolates. Phenotypic analysis of HIV-1 isolates from 60 patients (some
with prior zidovudine treatment) receiving 6 to 24 months of didanosine monotherapy showed
that isolates from 10 of 60 patients exhibited an average of a 10-fold decrease in susceptibility
to didanosine in vitro compared to baseline isolates. Clinical isolates that exhibited a decrease
in didanosine susceptibility harbored one or more didanosine-associated mutations. The
clinical relevance of genotypic and phenotypic changes associated with didanosine therapy has
not been established.
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Page 7 of 39
Cross-resistance
HIV-1 isolates from 2 of 39 patients receiving combination therapy for up to 2 years with
zidovudine and didanosine exhibited decreased susceptibility to zidovudine, didanosine,
zalcitabine, stavudine, and lamivudine in vitro. These isolates harbored five mutations (A62V,
V75I, F77L, F116Y, and Q151M) in the reverse transcriptase gene. The clinical relevance of
these observations has not been established.
CLINICAL PHARMACOLOGY
Animal Toxicology
Evidence of a dose-limiting skeletal muscle toxicity has been observed in mice and rats (but
not in dogs) following long-term (greater than 90 days) dosing with didanosine at doses that
were approximately 1.2 to 12 times the estimated human exposure. The relationship of this
finding to the potential of VIDEX (didanosine) to cause myopathy in humans is unclear.
However, human myopathy has been associated with administration of VIDEX and other
nucleoside analogues.
Pharmacokinetics
The pharmacokinetic parameters of didanosine are summarized in Table 1. Didanosine is
rapidly absorbed, with peak plasma concentrations generally observed from 0.25 to 1.50 hours
following oral dosing. Increases in plasma didanosine concentrations were dose proportional
over the range of 50 to 400 mg. Steady-state pharmacokinetic parameters did not differ
significantly from values obtained after a single dose. Binding of didanosine to plasma
proteins in vitro was low (<5%). Based on data from in vitro and animal studies, it is presumed
that the metabolism of didanosine in man occurs by the same pathways responsible for the
elimination of endogenous purines.
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Page 8 of 39
Table 1:
Mean ± SD Pharmacokinetic Parameters for Didanosine in
Adult and Pediatric Patients
Pediatric Patientsb
Parameter
Adult Patientsa
n
8 months to 19 years
n
2 weeks to 4 months
n
Oral bioavailability (%)
42 ± 12
6
25 ± 20
46
ND
Apparent volume of
distributionc (L/m2)
43.70 ± 8.90
6
28 ± 15
49
ND
CSF-plasma ratiod
21 ± 0.03%e
5
46%
(range 12-85%)
7
ND
Systemic clearancec
(mL/min/m2)
526 ± 64.7
6
516 ± 184
49
ND
Renal clearancef
(mL/min/m2)
223 ± 85.0
6
240 ± 90
15
ND
Apparent oral clearanceg
(mL/min/m2)
1252 ± 154
6
2064 ± 736
48
1353 ± 759
41
Elimination half-lifef (h)
1.5 ± 0.4
6
0.8 ± 0.3
60
1.2 ± 0.3
21
Urinary recovery of
didanosinef (%)
18 ± 8
6
18 ± 10
15
ND
CSF = cerebrospinal fluid, ND = not determined.
a Parameter units for adults were converted to the same units in pediatric patients to facilitate comparisons
among populations: mean adult body weight = 70 kg and mean adult body surface area = 1.73 m2.
b In 1-day old infants (n=10), the mean ± SD apparent oral clearance was 1523 ± 1176 mL/min/m2 and
half-life was 2.0 ± 0.7 h.
c Following IV administration.
d Following IV administration in adults and IV or oral administration in pediatric patients.
e
Mean ± SE.
f
Following oral administration.
g Apparent oral clearance estimate was determined as the ratio of the mean systemic clearance and the
mean oral bioavailability estimate.
Effect of Food on Absorption of Didanosine: Didanosine peak plasma
concentrations (CMAX) and area under the plasma concentration time curve (AUC) were
decreased by approximately 55% when VIDEX tablets were administered up to 2 hours after a
meal. Administration of VIDEX tablets up to 30 minutes before a meal did not result in any
significant changes in bioavailability. VIDEX should be taken on an empty stomach, at least
30 minutes before or 2 hours after eating. (See DOSAGE AND ADMINISTRATION.)
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 9 of 39
Special Populations
Renal Insufficiency: It is recommended that the VIDEX (didanosine) dose be modified in
patients with reduced creatinine clearance and in patients receiving maintenance hemodialysis
(see DOSAGE AND ADMINISTRATION). Data from two studies in adults indicated that
the apparent oral clearance of didanosine decreased and the terminal elimination half-life
increased as creatinine clearance decreased (see Table 2). Following oral administration,
didanosine was not detectable in peritoneal dialysate fluid (n=6); recovery in hemodialysate
(n=5) ranged from 0.6% to 7.4% of the dose over a 3-4 hour dialysis period. The absolute
bioavailability of didanosine was not affected in patients requiring dialysis.
Table 2:
Mean ± SD Pharmacokinetic Parameters for Didanosine
Following a Single Oral Dose
Creatinine Clearance (mL/min)
Parameter
≥ 90 (n=12)
60-90 (n=6)
30-59 (n=6)
10-29 (n=3)
Dialysis Patients
(n=11)
CLcr (mL/min)
112 ± 22
68 ± 8
46 ± 8
13 ± 5
NDa
CL/F (mL/min)
2164 ± 638
1566 ± 833
1023 ± 378
628 ± 104
543 ± 174
CLR (mL/min)
458 ± 164
247 ± 153
100 ± 44
20 ± 8
<10
T½ (h)
1.42 ± 0.33
1.59 ± 0.13
1.75 ± 0.43
2.0 ± 0.3
4.1 ± 1.2
a ND = not determined due to anuria.
CLcr = creatinine clearance.
CL/F = apparent oral clearance.
CLR = renal clearance.
Pediatric Patients: The pharmacokinetics of didanosine have been evaluated in
HIV-exposed and -infected pediatric patients from birth to 19 years of age (see Table 1).
Overall, the pharmacokinetics of didanosine in pediatric patients are similar to those of
didanosine in adults. Didanosine plasma concentrations appear to increase in proportion to oral
doses ranging from 25 to 120 mg/m2 in pediatric patients less than 5 months old and from 80
to 180 mg/m2 in children above 8 months old. For information on controlled clinical studies in
pediatric patients, see INDICATIONS AND USAGE: Clinical Studies and
PRECAUTIONS: Pediatric Use.
Geriatric Patients: Didanosine pharmacokinetics have not been studied in patients
over 65 years of age.
Gender: The effects of gender on didanosine pharmacokinetics have not been studied.
This label may not be the latest approved by FDA.
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Page 10 of 39
Drug Interactions: Tables 3 and 4 summarize the effects on AUC and CMAX, with a
90% or 95% confidence interval (CI) when available, following coadministration of VIDEX
with a variety of drugs. For most of the listed drugs, no clinically significant pharmacokinetic
interactions were observed. Clinical recommendations based on drug interaction studies for
drugs in bold font are included in PRECAUTIONS: Drug Interactions.
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Page 11 of 39
Table 3:
Results of Drug Interaction Studies: Effects of Coadministered Drug on
Didanosine Plasma AUC and CMAX Values
Drugs With Clinical Recommendations Regarding Coadministration (see PRECAUTIONS: Drug Interactions)
Drug
Didanosine Dosage
n
AUC of
Didanosine
(95% CI)
CMAX of Didanosine
(95% CI)
allopurinol
renally impaired, 300 mg/day
200 mg single dose
2
↑312%
↑232%
healthy volunteer, 300 mg/day for
7 days
400 mg single dose
14
↑113%
↑69%
ciprofloxacin, 750 mg q12h for 3
days, 2 h before didanosine
200 mg q12h for 3 days
8a
↓16%
↓28%
ganciclovir, 1000 mg q8h, 2 h
after didanosine
200 mg q12h
12
↑111%
NA
indinavir, 800 mg single dose
simultaneous
1 h before didanosine
200 mg single dose
200 mg single dose
16
16
↔
↓17% (-27, - 7%)b
↔
↓13% (-28, 5%)b
ketoconazole, 200 mg/day for 4
days, 2 h before didanosine
375 mg q12h for 4 days
12a
↔
↓12%
methadone, chronic maintenance
dose
200 mg single dose
16,10c
↓57%
↓66%
tenofovir,d,e 300 mg once daily
1 h after didanosine
250f or 400 mg once
daily for 7 days
14
↑44%
(31, 59%)b
↑28%
(11, 48%)b
No Clinically Significant Interaction Observed
Drug
Didanosine Dosage
n
AUC of
Didanosine
(95% CI)
CMAX of Didanosine
(95% CI)
loperamide, 4 mg q6h for 1 day
300 mg single dose
12a
↔
↓23%
metoclopramide, 10 mg single dose
300 mg single dose
12a
↔
↑13%
ranitidine, 150 mg single dose, 2 h
before didanosine
375 mg single dose
12a
↑14%
↑13%
rifabutin, 300 or 600 mg/day for 12
days
167 or 250 mg q12h for
12 days
11
↑13% (-1, 27%)
↑17% (-4, 38%)
ritonavir, 600 mg q12h for 4 days
200 mg q12h for 4 days
12
↓13% (0, 23%)
↓16% (5, 26%)
stavudine, 40 mg q12h for 4 days
100 mg q12h for 4 days
10
↔
↔
sulfamethoxazole, 1000 mg single
dose
200 mg single dose
8a
↔
↔
trimethoprim, 200 mg single dose
200 mg single dose
8a
↔
↑17% (-23, 77%)
zidovudine, 200 mg q8h for 3 days
200 mg q12h for 3 days
6a
↔
↔
↑ indicates increase.
↓ indicates decrease.
↔ indicates no change, or mean increase or decrease of <10%.
a
HIV-infected patients.
b
90% CI.
c Parallel-group design; entries are subjects receiving combination and control regimens, respectively.
d tenofovir disoproxil fumarate.
e
In a drug interaction study with the enteric-coated formulation of didanosine (VIDEX EC) and tenofovir, the AUC and
CMAX of didanosine each increased 48% when VIDEX EC was administered in the fasting state 2 hours before
tenofovir with a light meal. The AUC and CMAX of didanosine increased 60% and 64%, respectively, when
VIDEX EC was administered together with tenofovir and a light meal.
f
patients less than 60 kg.
NA Not available.
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Table 4:
Results of Drug Interaction Studies: Effects of Didanosine on
Coadministered Drug Plasma AUC and CMAX Values
Drugs With Clinical Recommendations Regarding Coadministration (see PRECAUTIONS: Drug Interactions)
Drug
Didanosine Dosage
n
AUC of
Coadministered
Drug (95% CI)
CMAX of
Coadministered
Drug (95% CI)
ciprofloxacin
750 mg q12h for 3 days, 2 h
before didanosine
750 mg single dose
200 mg q12h for 3 days
buffered placebo tablet
8a
12
↓26%
↓98%
↓16%
↓93%
delavirdine, 400 mg single dose
simultaneous
1 h before didanosine
125 or 200 mg q12h
125 or 200 mg q12h
12a
12a
↓32%
↑20%
↓53%
↑18%
ganciclovir, 1000 mg q8h, 2 h
after didanosine
200 mg q12h
12a
↓21%
NA
indinavir, 800 mg single dose
simultaneous
1 h before didanosine
200 mg single dose
200 mg single dose
16
16
↓84%
↓11%
↓82%
↓4%
ketoconazole, 200 mg/day for 4
days, 2 h before didanosine
375 mg q12h for 4 days
12a
↓14%
↓20%
nelfinavir, 750 mg single dose,
1 h after didanosine
200 mg single dose
10a
↑12%
↔
No Clinically Significant Interaction Observed
Drug
Didanosine Dosage
n
AUC of
Coadministered
Drug (95% CI)
CMAX of
Coadministered
Drug (95% CI)
dapsone, 100 mg single dose
200 mg q12h for 14 days
6a
↔
↔
ranitidine, 150 mg single dose, 2 h
before didanosine
375 mg single dose
12a
↓16%
↔
ritonavir, 600 mg q12h for 4 days
200 mg q12h for 4 days
12
↔
↔
stavudine, 40 mg q12h for 4 days
100 mg q12h for 4 days
10a
↔
↑17%
sulfamethoxazole, 1000 mg single
dose
200 mg single dose
8a
↓11% (-17, -4%)
↓12% (-28, 8%)
tenofovir,b 300 mg once daily 1 h
after didanosine
250c or 400 mg once
daily for 7 days
14
↔
↔
trimethoprim, 200 mg single dose
200 mg single dose
8a
↑10% (-9, 34%)
↓22% (-59, 49%)
zidovudine, 200 mg q8h for 3
days
200 mg q12h for 3 days
6a
↓10% (-27, 11%)
↓16.5% (-53, 47%)
↑ indicates increase.
↓ indicates decrease.
↔ indicates no change, or mean increase or decrease of <10%.
a
HIV-infected patients.
b
tenofovir disoproxil fumarate.
c
patients less than 60 kg.
NA Not available.
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INDICATIONS AND USAGE
VIDEX in combination with other antiretroviral agents is indicated for the treatment of
HIV-1 infection (see Clinical Studies).
Clinical Studies
Combination Therapy
START 2 was a multicenter, randomized, open-label study comparing VIDEX (200 mg twice
daily)/stavudine/indinavir to zidovudine/lamivudine/indinavir in 205 treatment-naive patients.
Both regimens resulted in a similar magnitude of suppression of HIV RNA levels and
increases in CD4 cell counts through 48 weeks.
Study A1454-148 was a randomized, open-label, multicenter study comparing
treatment with VIDEX (400 mg once daily) plus stavudine (40 mg twice daily) and nelfinavir
(750 mg three times daily) versus zidovudine (300 mg twice daily) plus lamivudine (150 mg
twice daily) and nelfinavir (750 mg three times daily) in 756 treatment-naive patients, with a
median CD4 cell count of 340 cells/mm3 (range 80 to 1568 cells/mm3) and a median plasma
HIV-1 RNA of 4.69 log10 copies/mL (range 2.6 to 5.9 log10 copies/mL) at baseline. Median
CD4 cell count increases at 48 weeks were 188 cells/mm3 in both treatment groups. Treatment
response and outcomes through 48 weeks are shown in Figure 1 and Table 5.
Figure 1:
Treatment Response Through Week 48*, AI454-148
* Percent of patients at each time point who have HIV RNA <400 or <50 copies/mL, are on
their original study medication (except stavudine-zidovudine switches), and have not
experienced an AIDS-defining event.
0
20
40
60
80
100
0
8
16
24
32
40
48
Study Week
Percent of patients
] < 400 c/mL
] < 50 c/mL
VIDEX+stavudine+nelfinavir (n=503)
zidovudine+lamivudine+nelfinavir (n=253)
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Table 5:
Outcomes of Randomized Treatment through Week 48,
AI454-148
Percent of Patients with HIV RNA <400 copies/mL (<50 copies/mL)
VIDEX/stavudine/nelfinavir
lamivudine/zidovudine/nelfinavir
Week 48 Status
n=503
n=253
Responder a
50* (34*)
59 (47)
Virologic failureb
36 (57)
32 (48)
Death or disease progression
<1 (<1)
1 (<1)
Discontinued due to adverse events
4 (2)
2 (<1)
Discontinued due to other reasonsc
6 (3)
4 (2)
Never initiated treatment
4 (4)
2 (2)
* p <0.05 for the differences between treatment groups, by Cochran-Mantel-Haenszel test.
a Patients achieved virologic response [two consecutive viral loads <400 (<50) copies/mL] and maintained
it to Week 48.
b Includes viral rebound and failing to achieve confirmed <400 (<50) copies/mL by Week 48.
c Includes lost to follow-up, noncompliance, withdrawal, and pregnancy.
Monotherapy
The efficacy of VIDEX was demonstrated in two randomized, double-blind studies comparing
VIDEX, given on a twice-daily schedule, to zidovudine, given three times daily, in 617
(ACTG 116A, conducted 1989-1992) and 913 (ACTG116B/117, conducted 1989-1991)
patients with symptomatic HIV infection or AIDS who were treated for more than one year. In
treatment-naive patients (ACTG 116A), the rate of HIV disease progression or death was
similar between the treatment groups; mortality rates were 26% for patients receiving VIDEX
and 21% for patients receiving zidovudine. Of the patients who had received previous
zidovudine treatment (ACTG 116B/117), those treated with VIDEX had a lower rate of HIV
disease progression or death (32%) compared to those treated with zidovudine (41%);
however, survival rates were similar between the treatment groups.
Efficacy in pediatric patients was demonstrated in a randomized, double-blind,
controlled study (ACTG 152, conducted 1991-1995) involving 831 patients 3 months to 18
years of age treated for more than 1.5 years with zidovudine (180 mg/m2 q6h), VIDEX (120
mg/m2 q12h), or zidovudine (120 mg/m2 q6h) plus VIDEX (90 mg/m2 q12h). Patients treated
with VIDEX or VIDEX plus zidovudine had lower rates of HIV disease progression or death
compared with those treated with zidovudine alone.
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Studies have demonstrated that the clinical benefit of monotherapy with antiretrovirals,
including VIDEX, was time limited.
CONTRAINDICATION
VIDEX (didanosine) is contraindicated in patients with previously demonstrated clinically
significant hypersensitivity to any of the components of the formulations.
WARNINGS
1.
Pancreatitis
FATAL AND NONFATAL PANCREATITIS HAVE OCCURRED DURING
THERAPY WITH VIDEX USED ALONE OR IN COMBINATION REGIMENS IN
BOTH TREATMENT-NAIVE AND TREATMENT-EXPERIENCED PATIENTS,
REGARDLESS OF DEGREE OF IMMUNOSUPPRESSION. VIDEX SHOULD BE
SUSPENDED IN PATIENTS WITH SIGNS OR SYMPTOMS OF PANCREATITIS
AND DISCONTINUED IN PATIENTS WITH CONFIRMED PANCREATITIS.
PATIENTS TREATED WITH VIDEX IN COMBINATION WITH STAVUDINE,
WITH OR WITHOUT HYDROXYUREA, MAY BE AT INCREASED RISK FOR
PANCREATITIS.
When treatment with life-sustaining drugs known to cause pancreatic toxicity is
required, suspension of VIDEX (didanosine) therapy is recommended. In patients with risk
factors for pancreatitis, VIDEX should be used with extreme caution and only if clearly
indicated. Patients with advanced HIV infection, especially the elderly, are at increased risk of
pancreatitis and should be followed closely. Patients with renal impairment may be at greater
risk for pancreatitis if treated without dose adjustment.
The frequency of pancreatitis is dose related. In phase 3 studies, incidence ranged from
1% to 10% with doses higher than are currently recommended and 1% to 7% with
recommended dose.
In pediatric phase 1 studies, pancreatitis occurred in 3% (2/60) of patients treated at
entry doses below 300 mg/m2/day and in 13% (5/38) of patients treated at higher doses. In
study ACTG 152, pancreatitis occurred in none of the 281 pediatric patients who received
didanosine 120 mg/m2 q12h and in <1% of the 274 pediatric patients who received didanosine
90 mg/m2 q12h in combination with zidovudine. VIDEX use should be suspended in pediatric
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patients with signs or symptoms of pancreatitis and discontinued in pediatric patients with
confirmed pancreatitis.
2.
Lactic Acidosis/Severe Hepatomegaly with Steatosis
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have
been reported with the use of nucleoside analogues alone or in combination, including
didanosine and other antiretrovirals. A majority of these cases have been in women.
Obesity and prolonged nucleoside exposure may be risk factors. Fatal lactic acidosis has been
reported in pregnant women who received the combination of didanosine and stavudine with
other antiretroviral agents. The combination of didanosine and stavudine should be used with
caution during pregnancy and is recommended only if the potential benefit clearly outweighs
the potential risk (see PRECAUTIONS: Pregnancy). Particular caution should be exercised
when administering VIDEX to any patient with known risk factors for liver disease; however,
cases have also been reported in patients with no known risk factors. Treatment with VIDEX
should be suspended in any patient who develops clinical or laboratory findings suggestive of
symptomatic hyperlactatemia, lactic acidosis, or pronounced hepatotoxicity (which may
include hepatomegaly and steatosis even in the absence of marked transaminase elevations).
3.
Retinal Changes and Optic Neuritis
Retinal changes and optic neuritis have been reported in adult and pediatric patients.
Periodic retinal examinations should be considered for patients receiving VIDEX. (See
ADVERSE REACTIONS.)
PRECAUTIONS
Frequency of Dosing
The preferred dosing frequency of VIDEX is twice daily because there is more evidence to
support the effectiveness of this dosing frequency. Once-daily dosing should be considered
only for adult patients whose management requires once-daily dosing of VIDEX (see
INDICATIONS AND USAGE: Clinical Studies).
VIDEX should be taken on an empty stomach, at least 30 minutes before or 2
hours after eating.
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Peripheral Neuropathy
Peripheral neuropathy, manifested by numbness, tingling, or pain in the hands or feet, has been
reported in patients receiving VIDEX therapy. Peripheral neuropathy has occurred more
frequently in patients with advanced HIV disease, in patients with a history of neuropathy, or
in patients being treated with neurotoxic drug therapy, including stavudine (see ADVERSE
REACTIONS).
Fat Redistribution
Redistribution/accumulation of body fat including central obesity, dorsocervical fat
enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and
“cushingoid appearance” have been observed in patients receiving antiretroviral therapy. The
mechanism and long-term consequences of these events are currently unknown. A causal
relationship has not been established.
General
Patients with Phenylketonuria: VIDEX Chewable/Dispersible Buffered Tablets contain
the following quantities of phenylalanine:
Table 6
All Strengths
Phenylalanine per 2-tablet dose
73 mg
Phenylalanine per tablet
36.5 mg
Patients on Sodium-Restricted Diets: VIDEX Buffered Powder for Oral
Solution: Each single-dose packet of VIDEX Buffered Powder for Oral Solution contains 1380
mg sodium.
Patients with Renal Impairment: Patients with renal impairment (creatinine
clearance <60 mL/min) may be at greater risk of toxicity from VIDEX due to decreased drug
clearance (see CLINICAL PHARMACOLOGY). A dose reduction is recommended in these
patients (see DOSAGE AND ADMINISTRATION). The magnesium content of each
buffered tablet of VIDEX is 8.6 mEq. This may present an excessive load of magnesium to
patients with significant renal impairment, particularly after prolonged dosing.
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Patients with Hepatic Impairment: It is unknown if hepatic impairment
significantly affects didanosine pharmacokinetics. Therefore, these patients should be
monitored closely for evidence of didanosine toxicity.
Hyperuricemia: VIDEX has been associated with asymptomatic hyperuricemia;
treatment suspension may be necessary if clinical measures aimed at reducing uric acid levels
fail.
Information for Patients (See Patient Information Leaflet.)
Patients should be informed that a serious toxicity of VIDEX used alone and in combination
regimens, is pancreatitis, which may be fatal.
Patients should be informed that the preferred dosing frequency of VIDEX is twice
daily because there is more evidence to support the effectiveness of this dosing frequency.
Once-daily dosing should be considered only for adult patients whose management requires
once-daily dosing of VIDEX.
Patients should also be aware that peripheral neuropathy, manifested by numbness,
tingling, or pain in hands or feet, may develop during therapy with VIDEX. Patients should be
counseled that peripheral neuropathy occurs with greatest frequency in patients with advanced
HIV disease or a history of peripheral neuropathy, and that dose modification and/or
discontinuation of VIDEX may be required if toxicity develops.
Patients should be informed that when VIDEX is used in combination with other
agents with similar toxicities, the incidence of adverse events may be higher than when
VIDEX is used alone. These patients should be followed closely.
Patients should be cautioned about the use of medications or other substances,
including alcohol, that may exacerbate VIDEX toxicities.
Patients should be advised that to ensure proper acid neutralization in the stomach they
must take at least two of the appropriate strength VIDEX tablets at each dose. To reduce the
risk of gastrointestinal side effects from excess antacid, patients should take no more than four
VIDEX tablets at each dose.
VIDEX (didanosine) is not a cure for HIV infection, and patients may continue to
develop HIV-associated illnesses, including opportunistic infection. Therefore, patients should
remain under the care of a physician when using VIDEX. Patients should be advised that
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VIDEX therapy has not been shown to reduce the risk of transmission of HIV to others
through sexual contact or blood contamination. Patients should be informed that the long-term
effects of VIDEX are unknown at this time.
Patients should be informed that redistribution or accumulation of body fat may occur
in patients receiving antiretroviral therapy and that the cause and long-term health effects of
these conditions are not known at this time.
Drug Interactions (see also CLINICAL PHARMACOLOGY: Drug
Interactions)
Drug interactions that have been established based on drug interaction studies are listed with
the pharmacokinetic results in CLINICAL PHARMACOLOGY: Drug Interactions (Tables
3 and 4). The clinical recommendations based on the results of these studies are listed in Table
7.
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Table 7:
Established Drug Interactions with VIDEX
Coadministration Not Recommended Based on Drug Interaction Studies (see CLINICAL
PHARMACOLOGY: Drug Interactions for Magnitude of Interaction)
Drug
Effect
Clinical Comment
allopurinol
↑ didanosine concentration
Coadministration not recommended.
Alteration in Dose or Regimen Recommended Based on Drug Interaction Studies (see CLINICAL
PHARMACOLOGY: Drug Interactions for Magnitude of Interaction)
Drug
Effect
Clinical Comment
ciprofloxacin
↓ ciprofloxacin concentration
Administer VIDEX at least 2 hours after or
6 hours before ciprofloxacin.
delavirdine
↓ delavirdine concentration
Administer VIDEX 1 hour after delavirdine.
ganciclovir
↑ didanosine concentration
Appropriate doses for this combination,
with respect to efficacy and safety, have not
been established.
indinavir
↓ indinavir concentration
Administer VIDEX 1 hour after indinavir.
methadone
↓ didanosine concentration
Appropriate doses for this combination,
with respect to efficacy and safety, have not
been established.
nelfinavir
No interaction 1 hour after didanosine
Administer nelfinavir 1 hour after VIDEX.
tenofovir
disoproxil fumarate
↑ didanosine concentration
Appropriate doses for this combination,
with respect to efficacy and safety, have not
been established. Use with caution and
monitor closely for didanosine-associated
toxicities (see below).
↑ indicates increase.
↓ indicates decrease.
Coadministration of VIDEX with drugs that are known to cause pancreatitis may
increase the risk of this toxicity (see WARNINGS: Pancreatitis). Because VIDEX
formulations either contain buffers or are mixed with antacids before administration,
interactions may be anticipated with drugs whose absorption can be affected by the level of
acidity in the stomach and with drugs that have been demonstrated to interact with antacids
containing magnesium, calcium, or aluminum. Predicted drug interactions with VIDEX are
listed in Table 8.
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Table 8:
Predicted Drug Interactions with VIDEX
Use with Caution, Risk of Adverse Reactions May Be Increased
Drug or Drug Class
Effect
Clinical Comment
Drugs that may cause
pancreatic toxicity
↑ risk of pancreatitis
Use only with extreme caution.a
Neurotoxic drugs
↑ risk of neuropathy
Use with caution.b
Antacids containing
magnesium or aluminum
↑ side effects associated with
antacid components
Use caution with VIDEX
Chewable/Dispersible Buffered Tablets
and Pediatric Powder for Oral Solution.
Ribavirin
↑ risk of toxicity
Ribavirin has been shown in vitro to
increase intracellular triphosphate levels of
didanosine. Use with caution and monitor
closely for didanosine-associated toxicities
(see below).
Use with Caution, Plasma Concentrations May Be Decreased by Coadministration with VIDEX
Drug Class
Effect
Clinical Comment
Azole antifungals
↓ ketoconazole or itraconazole
concentration
Administer drugs such as ketoconazole or
itraconazole at least 2 hours before
VIDEX.
Quinolone antibiotics (see
also ciprofloxacin in
Table 7)
↓ quinolone concentration
Consult package insert of the quinolone.
Tetracycline antibiotics
↓ antibiotic concentration
Consult package insert of the tetracycline.
↑ indicates increase.
↓ indicates decrease.
a Only if other drugs are not available and if clearly indicated. If treatment with life-sustaining drugs that
cause pancreatic toxicity is required, suspension of VIDEX is recommended (see WARNINGS:
Pancreatitis).
b See PRECAUTIONS: Peripheral Neuropathy.
Tenofovir disoproxil fumarate or ribavirin. Exposure to didanosine or its active metabolite
(dideoxyadenosine 5’-triphosphate) is increased when didanosine is coadministered with either
tenofovir (see Tables 3 and 7) or ribavirin (see Table 8). Increased exposure may cause or
worsen didanosine-related clinical toxicities, including pancreatitis, symptomatic
hyperlactatemia/lactic acidosis, and peripheral neuropathy. Coadministration of
tenofovir or ribavirin with VIDEX should be undertaken with caution, and patients
should be monitored closely for didanosine-related toxicities. VIDEX should be
suspended if signs or symptoms of pancreatitis, symptomatic hyperlactatemia, or lactic
acidosis develop (see WARNINGS).
Carcinogenesis and Mutagenesis
Lifetime carcinogenicity studies were conducted in mice and rats for 22 and 24 months,
respectively. In the mouse study, initial doses of 120, 800, and 1200 mg/kg/day for each sex
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were lowered after 8 months to 120, 210, and 210 mg/kg/day for females and 120, 300, and
600 mg/kg/day for males. The two higher doses exceeded the maximally tolerated dose in
females and the high dose exceeded the maximally tolerated dose in males. The low dose in
females represented 0.68-fold maximum human exposure and the intermediate dose in males
represented 1.7-fold maximum human exposure based on relative AUC comparisons. In the
rat study, initial doses were 100, 250, and 1000 mg/kg/day, and the high dose was lowered to
500 mg/kg/day after 18 months. The upper dose in male and female rats represented 3-fold
maximum human exposure.
Didanosine induced no significant increase in neoplastic lesions in mice or rats at
maximally tolerated doses.
Didanosine was positive in the following genetic toxicology assays: 1) the Escherichia
coli tester strain WP2 uvrA bacterial mutagenicity assay; 2) the L5178Y/TK+/- mouse
lymphoma mammalian cell gene mutation assay; 3) the in vitro chromosomal aberrations assay
in cultured human peripheral lymphocytes; 4) the in vitro chromosomal aberrations assay in
Chinese Hamster Lung cells; and 5) the BALB/c 3T3 in vitro transformation assay. No
evidence of mutagenicity was observed in an Ames Salmonella bacterial mutagenicity assay or
in rat and mouse in vivo micronucleus assays.
Pregnancy, Reproduction, and Fertility
Pregnancy Category B. Reproduction studies have been performed in rats and rabbits at doses
up to 12 and 14.2 times the estimated human exposure (based upon plasma levels),
respectively, and have revealed no evidence of impaired fertility or harm to the fetus due to
didanosine. At approximately 12 times the estimated human exposure, didanosine was slightly
toxic to female rats and their pups during mid and late lactation. These rats showed reduced
food intake and body weight gains but the physical and functional development of the
offspring was not impaired and there were no major changes in the F2 generation. A study in
rats showed that didanosine and/or its metabolites are transferred to the fetus through the
placenta. Animal reproduction studies are not always predictive of human response.
There are no adequate and well-controlled studies of didanosine in pregnant women.
Didanosine should be used during pregnancy only if the potential benefit justifies the potential
risk.
Fatal lactic acidosis has been reported in pregnant women who received the
combination of didanosine and stavudine with other antiretroviral agents. It is unclear if
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pregnancy augments the risk of lactic acidosis/hepatic steatosis syndrome reported in
nonpregnant individuals receiving nucleoside analogues (see WARNINGS: Lactic
Acidosis/Severe Hepatomegaly with Steatosis). The combination of didanosine and
stavudine should be used with caution during pregnancy and is recommended only if the
potential benefit clearly outweighs the potential risk. Health care providers caring for HIV-
infected pregnant women receiving didanosine should be alert for early diagnosis of lactic
acidosis/hepatic steatosis syndrome.
Antiretroviral Pregnancy Registry: To monitor maternal-fetal outcomes of
pregnant women exposed to didanosine and other antiretroviral agents, an Antiretroviral
Pregnancy Registry has been established. Physicians are encouraged to register patients by
calling 1-800-258-4263.
Nursing Mothers
The Centers for Disease Control and Prevention recommend that HIV-infected mothers
not breast-feed their infants to avoid risking postnatal transmission of HIV. A study in
rats showed that following oral administration, didanosine and/or its metabolites were excreted
into the milk of lactating rats. It is not known if didanosine is excreted in human milk.
Because of both the potential for HIV transmission and the potential for serious adverse
reactions in nursing infants, mothers should be instructed not to breast-feed if they are
receiving VIDEX.
Pediatric Use
Use of VIDEX in pediatric patients from 2 weeks of age through adolescence is supported by
evidence from adequate and well-controlled studies of VIDEX in adults and pediatric patients
(see INDICATIONS AND USAGE: Clinical Studies, CLINICAL PHARMACOLOGY,
ADVERSE REACTIONS, and DOSAGE AND ADMINISTRATION).
Dosing recommendations for VIDEX in patients less than 2 weeks of age cannot be
made because the pharmacokinetics of didanosine in these children are too variable to
determine an appropriate dose.
Geriatric Use
In an Expanded Access Program for patients with advanced HIV infection, patients aged 65
years and older had a higher frequency of pancreatitis (10%) than younger patients (5%) (see
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WARNINGS). Clinical studies of didanosine did not include sufficient numbers of subjects
aged 65 years and over to determine whether they respond differently than younger subjects.
Didanosine is known to be substantially excreted by the kidney, and the risk of toxic reactions
to this drug may be greater in patients with impaired renal function. Because elderly patients
are more likely to have decreased renal function, care should be taken in dose selection. In
addition, renal function should be monitored and dosage adjustments should be made
accordingly (see DOSAGE AND ADMINISTRATION: Dose Adjustment).
ADVERSE REACTIONS
A SERIOUS TOXICITY OF VIDEX (didanosine) IS PANCREATITIS, WHICH MAY BE
FATAL (see WARNINGS). OTHER IMPORTANT TOXICITIES INCLUDE LACTIC
ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS; RETINAL CHANGES AND
OPTIC NEURITIS; AND PERIPHERAL NEUROPATHY (see WARNINGS and
PRECAUTIONS).
When VIDEX is used in combination with other agents with similar toxicities, the
incidence of these toxicities may be higher than when VIDEX is used alone. Thus,
patients treated with VIDEX in combination with stavudine, with or without
hydroxyurea, may be at increased risk for pancreatitis, which may be fatal, and
hepatotoxicity (see WARNINGS). Patients treated with VIDEX in combination with
stavudine may also be at increased risk for peripheral neuropathy (see
PRECAUTIONS).
Adults: Selected clinical adverse events that occurred in adult patients in clinical
studies with VIDEX are provided in Tables 9 and 10.
Table 9:
Selected Clinical Adverse Events from Monotherapy
Studies
Percent of Patients
ACTG 116A
ACTG 116B/117
Adverse Events
VIDEX
n=197
zidovudine
n=212
VIDEX
n=298
zidovudine
n=304
Diarrhea
19
15
28
21
Peripheral Neurologic
Symptoms/Neuropathy
17
14
20
12
Rash/Pruritus
7
8
9
5
Abdominal Pain
13
8
7
8
Pancreatitis
7
3
6
2
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Table 10:
Selected Clinical Adverse Events from Combination
Studies
Percent of Patientsa
AI454-148b
START 2b
Adverse Events
VIDEX +
stavudine +
nelfinavir
n=482
zidovudine +
lamivudine +
nelfinavir
n=248
VIDEX +
stavudine +
indinavir
n=102
zidovudine +
lamivudine +
indinavir
n=103
Diarrhea
70
60
45
39
Nausea
28
40
53
67
Headache
21
30
46
37
Peripheral Neurologic
Symptoms/Neuropathy
26
6
21
10
Rash
13
16
30
18
Vomiting
12
14
30
35
Pancreatitis (see below)
1
*
<1
*
a Percentages based on treated subjects.
b Median duration of treatment 48 weeks.
* This event was not observed in this study arm.
Pancreatitis resulting in death was observed in one patient who received VIDEX
(didanosine) plus stavudine plus nelfinavir in Study Al454-148 and in one patient who
received VIDEX plus stavudine plus indinavir in the START 2 study. In addition,
pancreatitis resulting in death was observed in 2 of 68 patients who received VIDEX plus
stavudine plus indinavir plus hydroxyurea in an ACTG clinical trial (see WARNINGS).
The frequency of pancreatitis is dose related. In phase 3 studies, incidence ranged from
1% to 10% with doses higher than are currently recommended and from 1% to 7% with
recommended dose.
Selected laboratory abnormalities in clinical studies with VIDEX are shown in
Tables 11-13.
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Table 11:
Selected Laboratory Abnormalities from Monotherapy Studies
Percent of Patients
ACTG 116A
ACTG 116B/117
VIDEX
zidovudine
VIDEX
zidovudine
Parameter
n=197
n=212
n=298
n=304
SGOT (AST) (>5 x ULN)
9
4
7
6
SGPT (ALT) (>5 x ULN)
9
6
6
6
Alkaline phosphatase (>5 x ULN)
4
1
1
1
Amylase (≥1.4 x ULN)
17
12
15
5
Uric acid (>12 mg/dL)
3
1
2
1
ULN = upper limit of normal.
Table 12:
Selected Laboratory Abnormalities from Combination Studies
(Grades 3-4)
Percent of Patientsa
AI454-148b
START 2b
VIDEX +
stavudine +
nelfinavir
zidovudine +
lamivudine +
nelfinavir
VIDEX +
stavudine +
indinavir
zidovudine +
lamivudine +
indinavir
Parameter
n=482
n=248
n=102
n=103
Bilirubin (>2.6 x ULN)
<1
<1
16
8
SGOT (AST) (>5 x ULN)
3
2
7
7
SGPT (ALT) (>5 x ULN)
3
3
8
5
GGT (>5 x ULN)
NC
NC
5
2
Lipase (>2 x ULN)
7
2
5
5
Amylase (>2 x ULN)
NC
NC
8
2
ULN = upper limit of normal.
NC=Not Collected.
a Percentages based on treated subjects.
b Median duration of treatment 48 weeks.
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Table 13:
Selected Laboratory Abnormalities from Combination
Studies (All Grades)
Percent of Patientsa
I454-148b
START 2b
Parameter
VIDEX +
stavudine +
nelfinavir
n=482
zidovudine +
lamivudine +
nelfinavir
n=248
VIDEX +
stavudine +
indinavir
n=102
zidovudine +
lamivudine +
indinavir
n=103
Bilirubin
7
3
68
55
SGOT (AST)
42
23
53
20
SGPT (ALT)
37
24
50
18
GGT
NC
NC
28
12
Lipase
17
11
26
19
Amylase
NC
NC
31
17
NC = Not Collected.
a Percentages based on treated subjects.
b Median duration of treatment 48 weeks.
Observed during Clinical Practice: The following events have been identified
during postapproval use of VIDEX (didanosine). Because they are reported voluntarily from a
population of unknown size, estimates of frequency cannot be made. These events have been
chosen for inclusion due to their seriousness, frequency of reporting, causal connection to
VIDEX, or a combination of these factors.
Body as a Whole - alopecia, anaphylactoid reaction, asthenia, chills/fever, pain, and
redistribution/accumulation of body fat (see PRECAUTIONS: Fat Redistribution).
Digestive Disorders- anorexia, dyspepsia, and flatulence.
Exocrine Gland Disorders – pancreatitis (including fatal cases) (see WARNINGS),
sialoadenitis, parotid gland enlargement, dry mouth, and dry eyes.
Hematologic Disorders - anemia, leukopenia, and thrombocytopenia.
Liver - symptomatic hyperlactatemia/lactic acidosis and hepatic steatosis (see
WARNINGS); hepatitis and liver failure.
Metabolic Disorders - diabetes mellitus, hypoglycemia, and hyperglycemia.
Musculoskeletal Disorders - myalgia (with or without increases in creatine kinase),
rhabdomyolysis including acute renal failure and hemodialysis, arthralgia, and
myopathy.
Ophthalmologic Disorders - Retinal depigmentation and optic neuritis (see
WARNINGS).
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Pediatric Patients: In clinical trials, 743 pediatric patients between 2 weeks and 18
years of age have been treated with VIDEX. Adverse events and laboratory abnormalities
reported to occur in these patients were generally consistent with the safety profile of
didanosine in adults.
In pediatric phase 1 studies, pancreatitis occurred in 2 of 60 (3%) patients treated at
entry doses below 300 mg/m2/day and in 5 of 38 (13%) patients treated at higher doses. In
study ACTG 152, pancreatitis occurred in none of the 281 pediatric patients who received
didanosine 120 mg/m2 q12h and in <1% of the 274 pediatric patients who received didanosine
90 mg/m2 q12h in combination with zidovudine (see INDICATIONS AND USAGE:
Clinical Studies).
Retinal changes and optic neuritis have been reported in pediatric patients.
OVERDOSAGE
There is no known antidote for VIDEX (didanosine) overdosage. In phase 1 studies, in which
VIDEX was initially administered at doses ten times the currently recommended dose,
toxicities included: pancreatitis, peripheral neuropathy, diarrhea, hyperuricemia and hepatic
dysfunction. Didanosine is not dialyzable by peritoneal dialysis, although there is some
clearance by hemodialysis (see CLINICAL PHARMACOLOGY: Pharmacokinetics).
DOSAGE AND ADMINISTRATION
Dosage
All VIDEX formulations should be administered on an empty stomach, at least 30
minutes before or 2 hours after eating. For either a once-daily or twice-daily regimen,
patients must take at least two of the appropriate strength tablets at each dose to provide
adequate buffering and prevent gastric acid degradation of didanosine. Because of the
need for adequate buffering, the 200-mg strength tablet should only be used as a
component of a once-daily regimen. To reduce the risk of gastrointestinal side effects,
patients should take no more than four tablets at each dose.
Adults: The preferred dosing frequency of VIDEX is twice daily because there is
more evidence to support the effectiveness of this dosing regimen. Once-daily dosing should
be considered only for adult patients whose management requires once-daily dosing of VIDEX
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(see INDICATIONS AND USAGE: Clinical Studies). The daily dose in adult patients is
dependent on weight as outlined in Table 14.
Table 14:
Adult Dosing
Patient Weight
VIDEX Tabletsa
VIDEX Buffered Powderb
Preferred dosing
≥60 kg
200 mg twice daily
250 mg twice daily
< 60 kg
125 mg twice daily
167 mg twice daily
Dosing for patients whose management requires once-daily frequency
≥ 60 kg
400 mg once daily
b
< 60 kg
250 mg once daily
b
a The 200-mg strength tablet should only be used as a component of a once-daily
regimen.
b Not suitable for once-daily dosing except for patients with renal impairment.
See Table 15.
Pediatric Patients: The recommended dose of VIDEX (didanosine) in pediatric
patients between 2 weeks and 8 months of age is 100 mg/m2 twice daily, and the
recommended VIDEX dose for pediatric patients older than 8 months is 120 mg/m2 twice
daily.
Dosing recommendations for VIDEX in patients less than 2 weeks of age cannot be
made because the pharmacokinetics of didanosine in these children are too variable to
determine an appropriate dose. There are no data on once-daily dosing of VIDEX in pediatric
patients.
Dose Adjustment
Clinical and laboratory signs suggestive of pancreatitis should prompt dose suspension
and careful evaluation of the possibility of pancreatitis. VIDEX use should be
discontinued in patients with confirmed pancreatitis (see WARNINGS and
PRECAUTIONS: Drug Interactions).
Patients with symptoms of peripheral neuropathy may tolerate a reduced dose of
VIDEX after resolution of the symptoms of peripheral neuropathy upon drug discontinuation.
If neuropathy recurs after resumption of VIDEX, permanent discontinuation of VIDEX should
be considered.
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Renal Impairment: In adult patients with impaired renal function, the dose of
VIDEX should be adjusted to compensate for the slower rate of elimination. The
recommended doses and dosing intervals of VIDEX in adult patients with renal insufficiency
are presented in Table 15.
Table 15:
Recommended Dosage of VIDEX in Renal Impairment
≥ 60 kg
< 60 kg
Creatinine Clearance
(mL/min)
Tableta
(mg)
Buffered Powderb
(mg)
Tableta
(mg)
Buffered Powderb
(mg)
≥60
200 twice dailyc
250 twice daily
125 twice dailyc
167 twice daily
30-59
200 once daily
or 100 twice daily
100 twice daily
150 once daily
or 75 twice daily
100 twice daily
10-29
150 once daily
167 once daily
100 once daily
100 once daily
<10
100 once daily
100 once daily
75 once daily
100 once daily
a VIDEX Chewable/Dispersible Buffered Tablet. Two VIDEX tablets must be taken with each dose;
different strengths of tablets may be combined to yield the recommended dose.
b VIDEX Buffered Powder for Oral Solution.
c 400 mg once daily (≥60 kg) or 250 mg once daily (<60 kg) for patients whose management requires once-
daily frequency of administration.
Urinary excretion is also a major route of elimination of didanosine in pediatric
patients; therefore, the clearance of didanosine may be altered in children with renal
impairment. Although there are insufficient data to recommend a specific dose adjustment of
VIDEX in this patient population, a reduction in the dose and/or an increase in the interval
between doses should be considered.
Patients Requiring Continuous Ambulatory Peritoneal Dialysis (CAPD) or
Hemodialysis: For patients requiring CAPD or hemodialysis, follow dosing
recommendations for patients with creatinine clearance less than 10 mL/min, shown in Table
15. It is not necessary to administer a supplemental dose of VIDEX following hemodialysis.
Hepatic Impairment: See WARNINGS and PRECAUTIONS.
Method of Preparation
VIDEX Chewable/Dispersible Buffered Tablets
Adult Dosing: To provide adequate buffering, at least two of the appropriate strength tablets,
but no more than four tablets, should be thoroughly chewed or dispersed in at least 1 ounce of
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water prior to consumption (see PRECAUTIONS: Information for Patients). To disperse
tablets, add 2 tablets to at least 1 ounce of drinking water. Stir until a uniform dispersion
forms, and drink the entire dispersion immediately. If additional flavoring is desired, the
dispersion may be diluted with one ounce of clear apple juice. Stir the further diluted
dispersion just prior to consumption. The dispersion with clear apple juice is stable at room
temperature, 62° to 73°F (17° to 23°C), for up to one hour.
VIDEX Buffered Powder for Oral Solution
1.
Open packet carefully and pour contents into a container with approximately 4 ounces
of drinking water. Do not mix with fruit juice or other acid-containing liquid.
2.
Stir until the powder completely dissolves (approximately 2 to 3 minutes).
3.
Drink the entire solution immediately.
VIDEX Pediatric Powder for Oral Solution
Prior to dispensing, the pharmacist must constitute dry powder with Purified Water, USP, to an
initial concentration of 20 mg/mL and immediately mix the resulting solution with antacid to a
final concentration of 10 mg/mL as follows:
20 mg/mL Initial Solution: Constitute the product to 20 mg/mL by adding 100 mL or
200 mL of Purified Water, USP, to the 2 g or 4 g of VIDEX powder, respectively, in the
product bottle.
10 mg/mL Final Admixture: 1. Immediately mix one part of the 20 mg/mL initial
solution with one part of either Mylanta® Double Strength Liquid, Extra Strength Maalox®
Plus Suspension, or Maalox ® TC Suspension for a final dispensing concentration of 10 mg
VIDEX per mL. For patient home use, the admixture should be dispensed in appropriately
sized, flint-glass or plastic (HDPE, PET, or PETG) bottles with child-resistant closures. This
admixture is stable for 30 days under refrigeration, 36° to 46° F (2° to 8° C).
2. Instruct the patient to shake the admixture thoroughly prior to use and to store the
tightly closed container in the refrigerator, 36° to 46° F (2° to 8° C), up to 30 days.
Mylanta® is a registered trademark of Johnson & Johnson-Merck Consumer Pharmaceuticals Company.
Maalox® is a registered trademark of Novartis Consumer Health, Inc.
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HOW SUPPLIED
VIDEX® (didanosine) Chewable/Dispersible Buffered Tablets are round, off white to light
orange/yellow with a mottled appearance, orange-flavored, tablets embossed with "VIDEX" on
one side and the product strength on the other. The tablets are available in the following
strengths of VIDEX: 25, 50, 100, 150, and 200 mg. Sixty tablets are packaged in bottles with
child-resistant closures.
The tablets should be stored in tightly closed bottles at 59° to 86° F (15° to 30 °C).
If dispersed in water, the dose may be held for up to 1 hour at ambient temperature.
VIDEX (didanosine) Buffered Powder for Oral Solution is supplied in single-dose,
child-resistant foil packets in the following strengths of VIDEX: 100, 167, or 250 mg. Each
product strength provides a sweetened, buffered solution of VIDEX.
The packets should be stored at 59° to 86° F (15° to 30° C). After dissolving in water,
the solution may be stored at ambient room temperature for up to 4 hours.
VIDEX (didanosine) Pediatric Powder for Oral Solution is supplied in 4- and 8-
ounce glass bottles containing 2 g or 4 g of VIDEX, respectively.
The bottles of powder should be stored at 59° to 86° F (15° to 30° C). The VIDEX
admixture may be stored up to 30 days in a refrigerator, 36° to 46° F (2° to 8° C). Discard any
unused portion after 30 days.
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The NDC numbers for the previously described VIDEX products are:
Table 16
NDC NO.
Packaging Information
Product Strength
VIDEX
Chewable/Dispersible Buffered Tablets
0087-6650-01
60 tablets/bottle
25 mg/tablet
0087-6651-01
60 tablets/bottle
50 mg/tablet
0087-6652-01
60 tablets/bottle
100 mg/tablet
0087-6653-01
60 tablets/bottle
150 mg/tablet
0087-6665-15
60 tablets/bottle
200 mg/tablet
VIDEX
Buffered Powder for Oral Solution
0087-6614-43
One single-dose foil packet*
100 mg/packet
0087-6615-43
One single-dose foil packet*
167 mg/packet
0087-6616-43
One single-dose foil packet*
250 mg/packet
VIDEX
Pediatric Powder for Oral Solution
0087-6632-41
One bottle per carton
2 g/bottle
0087-6633-41
One bottle per carton
4 g/bottle
* Packaged as 30 packets per carton.
US Patent Nos.: 4,861,759 and 5,616,566.
HANDLING AND DISPOSAL
Spill, Leak, and Disposal Procedure
Avoid generating dust during clean-up of powdered products; use wet mop or damp sponge.
Clean surface with soap and water as necessary. Containerize larger spills.
There is no single preferred method of disposal of containerized waste. Disposal
options include incineration, landfill, or sewer as dictated by specific circumstances and
relevant national, state, and local regulations.
Bristol-Myers Squibb Virology
Bristol-Myers Squibb Company
Princeton, NJ 08543 USA
XXXXXX
Revised _____________________
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PATIENT INFORMATION
Rx only
VIDEX®
(generic name = didanosine also known as ddI)
VIDEX® (didanosine) Chewable/Dispersible Buffered Tablets
VIDEX® (didanosine) Buffered Powder for Oral Solution
VIDEX® (didanosine) Pediatric Powder for Oral Solution
What is VIDEX?
VIDEX (pronounced VY dex) is a prescription medicine used in combination with other drugs
to treat children and adults who are infected with HIV (the human immunodeficiency virus, the
virus that causes AIDS). VIDEX belongs to a class of drugs called nucleoside analogues. By
reducing the growth of HIV, VIDEX helps your body maintain its supply of CD4 cells, which
are important for fighting HIV and other infections.
VIDEX will not cure your HIV infection. At present there is no cure for HIV infection.
Even while taking VIDEX, you may continue to have HIV-related illnesses, including infections
with other disease-producing organisms. Continue to see your doctor regularly and report any
medical problems that occur.
VIDEX does not prevent a patient infected with HIV from passing the virus to other
people. To protect others, you must continue to practice safe sex and take precautions to
prevent others from coming in contact with your blood and other body fluids.
There is limited information on the effects of long-term use of VIDEX.
Who should not take VIDEX?
Do not take VIDEX if you are allergic to any of its ingredients, including its active ingredient,
didanosine and the inactive ingredients. (See Inactive Ingredients at the end of this leaflet.) Tell
your doctor if you think you have had an allergic reaction to any of these ingredients.
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How should I take VIDEX? How should I store it?
Your doctor will determine your dose based on your body weight, kidney and liver function, other
medicines you are taking, and any side effects that you may have had with VIDEX or other
medicines. Take VIDEX on an empty stomach - that means at least 30 minutes before or 2
hours after eating. Do not take VIDEX with food. Try not to miss a dose, but if you do, take it as
soon as possible. If it is almost time for the next dose, skip the missed dose and continue your
regular dosing schedule.
Chewable/Dispersible Tablets: Each VIDEX tablet contains antacid. Each time
you take VIDEX, you must take at least two, but not more than four, tablets. This
is because VIDEX tablets contain an antacid to reduce the amount of acid in your
stomach. If you have too much acid, the medicine will break down. However, too
much antacid may cause stomach problems.
—DO NOT swallow VIDEX tablets whole. Chew the tablets well or mix them in
water. Many patients drop the tablets in at least one ounce of water and stir well
before swallowing. If you choose to mix the tablets in water, you may add one ounce
(2 tablespoons) of clear apple juice to the mixture for flavor (do not use any other kind
of juice).
—Store tablets in a tightly closed container at room temperature away from heat and
out of the reach of children and pets. Do NOT store the tablets in a damp place such as
a bathroom medicine cabinet or near the kitchen sink.
Buffered Powder for Oral Solution: Pour the contents of a packet into a glass with 4
ounces (1/2 measuring cup) of water. Stir until completely dissolved. Drink the entire
solution right away. Do not mix with fruit juice. Store packets at room temperature
before use.
Pediatric Oral Solution: Your pharmacist will prepare the oral solution. Shake
the solution well before each use. Store in the refrigerator. Throw away any unused
portion after 30 days.
If you have kidney disease: If your kidneys are not working properly, your doctor will
need to do regular tests to check how they are working while you take VIDEX. Your
doctor may also lower your dosage of VIDEX.
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What should I do if someone takes an overdose of VIDEX?
If someone may have taken an overdose of VIDEX, get medical help right away. Contact their
doctor or a poison control center.
What should I avoid while taking VIDEX?
Alcohol. Do not drink alcohol while taking VIDEX since alcohol may increase your risk of
pancreatitis (pain and inflammation of the pancreas) or liver damage.
Other medicines. Other medicines, including those you can buy without a prescription, may
interfere with the actions of VIDEX. Do not take any medicine, vitamin supplement, or
other health preparation without first checking with your doctor.
Antacids. Since VIDEX contains some of the same ingredients found in antacids, any
side effects related to VIDEX’s ingredients may get worse if you also take an antacid.
Medicines at the same time you take your VIDEX dose. Some medicines should not
be taken at the same time of day that you take VIDEX. Check with your doctor.
Pregnancy. It is not known if VIDEX can harm a human fetus. Also, pregnant women have
experienced serious side effects when taking VIDEX in combination with ZERIT (stavudine),
also known as d4T, and other HIV medicines. VIDEX should be used during pregnancy only
after discussion with your doctor. Tell your doctor if you become pregnant or plan to
become pregnant while taking VIDEX.
Nursing. Studies have shown VIDEX is in the breast milk of animals getting the drug. It may
also be in human breast milk. The Centers for Disease Control and Prevention (CDC)
recommends that HIV-infected mothers not breast-feed. This should reduce the risk of
passing HIV infection to their babies and the potential for serious adverse reactions in nursing
infants. Therefore, do not nurse a baby while taking VIDEX.
What are the possible side effects of VIDEX?
Pancreatitis. Pancreatitis is a dangerous inflammation of the pancreas that may cause death.
Tell your doctor right away if you or a child taking VIDEX develops stomach pain, nausea,
or vomiting. These can be signs of pancreatitis. Before starting VIDEX therapy, let your
doctor know if you or a child for whom it has been prescribed has ever had pancreatitis. This
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condition is more likely to happen in people who have had it before. It is also more likely in people
with advanced HIV disease. However, it can occur at any stage of HIV disease. It may be more
common in patients with kidney problems, those who drink alcohol, and those who are also treated
with stavudine or hydroxyurea. If you get pancreatitis, your doctor will tell you to stop taking
VIDEX.
Lactic acidosis, severe liver enlargement, and liver failure, including deaths, have been
reported among patients taking VIDEX (including pregnant women). Symptoms that may
indicate a liver problem are:
• feeling very weak, tired, or uncomfortable,
• unusual or unexpected stomach discomfort,
• feeling cold,
• feeling dizzy or lightheaded,
• suddenly developing a slow or irregular heartbeat.
Lactic acidosis is a medical emergency that must be treated in a hospital.
If you notice any of these symptoms or if your medical condition changes, stop taking
VIDEX and call your doctor right away. Women, overweight patients, and those who have been
treated for a long time with other medicines used to treat HIV infection are more likely to develop
lactic acidosis. Your doctor should check your liver function periodically while you are taking
VIDEX. You should be especially careful if you have a history of heavy alcohol use or a liver
problem.
Vision changes. VIDEX may affect the nerves in your eyes. Because of this, you should have
regular eye examinations. You should also report any changes in vision to your doctor right away.
This includes, for example, seeing colors abnormally or blurred vision.
Peripheral neuropathy. This is a problem with the nerves in your hands or feet. The nerve
problem may be serious. Tell your doctor right away if you or a child taking VIDEX has
continuing numbness, tingling, or pain in the feet or hands. A child may not recognize these
symptoms or know to tell you that his or her feet or hands are numb, burning, tingling, or painful.
Ask your child’s doctor how to find out if your child is developing peripheral neuropathy.
Before starting VIDEX therapy, let your doctor know if you or a child for whom it has been
prescribed has ever had peripheral neuropathy. This condition is more likely to happen in people
who have had it before. It is also more likely in patients taking medicines that affect the nerves and
in people with advanced HIV disease. However, it can occur at any stage of HIV disease. If you
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get peripheral neuropathy, your doctor will tell you to stop taking VIDEX. After stopping VIDEX,
the symptoms may get worse for a short time and then get better. Once symptoms of peripheral
neuropathy go away completely, you and your doctor should decide if starting VIDEX is right for
you. If so, you might be started at a lower dose.
Special note about other medicines. If you take VIDEX along with other medicines with similar
side effects, you may increase the chance of having these side effects. For example, using VIDEX
in combination with other medicines that may cause pancreatitis, peripheral neuropathy, or liver
problems (including stavudine and hydroxyurea) may increase your chance of having these side
effects.
Other side effects: The most common side effects in adults taking VIDEX are diarrhea, neuropathy
(nerve disorders), chills or fever, rash, abdominal pain, weakness, headache, and nausea and
vomiting. Children may have similar side effects as adults.
Changes in body fat have been seen in some patients taking antiretroviral therapy. These
changes may include increased amount of fat in the upper back and neck (“buffalo hump”), breast,
and around the trunk. Loss of fat from the legs, arms, and face may also happen. The cause and
long-term health effects of these conditions are not known at this time.
What else should I know about VIDEX?
If you should limit sodium (salt) intake: Each single-dose packet of Buffered Powder for
Oral Solution contains 1380 mg of sodium. Each Chewable/Dispersible Tablet contains 264.5
mg of sodium.
If you have phenylketonuria: Each Chewable/Dispersible Tablet contains 36.5 mg of
phenylalanine.
Inactive Ingredients:
Chewable/Dispersible Tablets: calcium carbonate, magnesium hydroxide, aspartame,
sorbitol, mandarin orange flavor, polyplasdone, microcrystalline cellulose, and
magnesium stearate.
Buffered Powder for Oral Solution: citrate-phosphate buffer (dibasic sodium
phosphate, sodium citrate, and citric acid) and sucrose.
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Pediatric Oral Solution: Mylanta Double Strength Liquid, Extra Strength
Maalox Plus or Maalox TC Suspension.
This medicine was prescribed for your particular condition. Do not use VIDEX for another condition or give it to
others. Keep VIDEX and all medicines out of the reach of children. Throw away VIDEX when it is outdated or
no longer needed by flushing it down the toilet or pouring it down the sink.
This summary does not include everything there is to know about VIDEX. Medicines are sometimes prescribed
for purposes other than those listed in a Patient Information Leaflet. If you have questions or concerns, or want more
information about VIDEX, your physician and pharmacist have the complete prescribing information upon which this
leaflet is based. You may want to read it and discuss it with your doctor or other healthcare professional. Remember, no
written summary can replace careful discussion with your doctor.
Mylanta® is a registered trademark of Johnson & Johnson-Merck Consumer Pharmaceuticals Company.
Maalox® is a registered trademark of Novartis Consumer Health, Inc.
Bristol-Myers Squibb Virology
Bristol-Myers Squibb Company
Princeton, NJ 08543 USA
This Patient Information Leaflet has been approved by the U.S. Food and Drug Administration.
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Revised __________________
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9/25/02 04:03:13 PM
NDA 20-156 NDA 20-155, NDA 20-154
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ApprovletS035.doc (clean copy 1/10/01)
Page 4 of 33
Rx only
VIDEX
(didanosine)
VIDEX (didanosine) Chewable/Dispersible Buffered Tablets
VIDEX (didanosine) Buffered Powder for Oral Solution
VIDEX (didanosine) Pediatric Powder for Oral Solution
(Patient Information Leaflet Included)
WARNING
FATAL AND NONFATAL PANCREATITIS HAVE OCCURRED DURING THERAPY WITH
VIDEX USED ALONE OR IN COMBINATION REGIMENS IN BOTH TREATMENT-NAIVE
AND
TREATMENT-EXPERIENCED
PATIENTS,
REGARDLESS
OF
DEGREE
OF
IMMUNOSUPPRESSION.
VIDEX
SHOULD
BE
SUSPENDED
IN
PATIENTS
WITH
SUSPECTED PANCREATITIS AND DISCONTINUED IN PATIENTS WITH CONFIRMED
PANCREATITIS (SEE WARNINGS).
LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS, INCLUDING
FATAL CASES, HAVE BEEN REPORTED WITH THE USE OF NUCLEOSIDE ANALOGUES
ALONE
OR
IN
COMBINATION,
INCLUDING
DIDANOSINE
AND
OTHER
ANTIRETROVIRALS. FATAL LACTIC ACIDOSIS HAS BEEN REPORTED IN PREGNANT
WOMEN WHO RECEIVED THE COMBINATION OF DIDANOSINE AND STAVUDINE WITH
OTHER ANTIRETROVIRAL AGENTS. THE COMBINATION OF DIDANOSINE AND
STAVUDINE SHOULD BE USED WITH CAUTION DURING PREGNANCY AND IS
RECOMMENDED ONLY IF THE POTENTIAL BENEFIT CLEARLY OUTWEIGHS THE
POTENTIAL RISK. (SEE WARNINGS AND PRECAUTIONS: PREGNANCY.)
DESCRIPTION
VIDEX is a brand name for didanosine (ddI), a synthetic purine nucleoside analogue active against the
Human Immunodeficiency Virus (HIV). VIDEX Chewable/Dispersible Buffered Tablets are available for
oral administration in strengths of 25, 50, 100, 150, and 200 mg of didanosine. Each tablet is buffered with
calcium carbonate and magnesium hydroxide. VIDEX tablets also contain aspartame, sorbitol,
microcrystalline cellulose, polyplasdone, mandarin-orange flavor, and magnesium stearate.
VIDEX Buffered Powder for Oral Solution is supplied for oral administration in
single-dose packets containing 100, 167, or 250 mg of didanosine. Packets of each product
strength also contain a citrate-phosphate buffer (composed of dibasic sodium phosphate,
sodium citrate, and citric acid) and sucrose.
VIDEX Pediatric Powder for Oral Solution is supplied for oral administration in 4- or
8-ounce glass bottles containing 2 or 4 grams of didanosine, respectively.
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Page 5 of 33
Didanosine is also available as an enteric-coated formulation (VIDEX® EC Delayed-
Release Capsules). Please consult the prescribing information for VIDEX EC (didanosine).
The chemical name for didanosine is 2',3'-dideoxyinosine. The structural formula is:
Didanosine is a white crystalline powder with the molecular formula C10H12N4O3 and a molecular weight
of 236.2. The aqueous solubility of didanosine at 25°C and pH of approximately 6 is 27.3 mg/mL.
Didanosine is unstable in acidic solutions. For example, at pH <3 and 37°C, 10% of didanosine decomposes
to hypoxanthine in less than 2 minutes.
MICROBIOLOGY
Mechanism of Action
Didanosine is a synthetic nucleoside analogue of the naturally occurring nucleoside
deoxyadenosine in which the 3'-hydroxyl group is replaced by hydrogen. Intracellularly,
didanosine is converted by cellular enzymes to the active metabolite, dideoxyadenosine
5'-triphosphate. Dideoxyadenosine 5'-triphosphate inhibits the activity of HIV-1 reverse
transcriptase both by competing with the natural substrate, deoxyadenosine 5'-triphosphate,
and by its incorporation into viral DNA causing termination of viral DNA chain
elongation.
In Vitro HIV Susceptibility
The in vitro anti-HIV-1 activity of didanosine was evaluated in a variety of HIV-1 infected lymphoblastic
cell lines and monocyte/macrophage cell cultures. The concentration of drug necessary to inhibit viral
replication by 50% (IC50) ranged from 2.5 to 10 µM (1 µM = 0.24 µg/mL) in lymphoblastic cell lines and
0.01 to 0.1 µM in monocyte/macrophage cell cultures. The relationship between in vitro susceptibility of
HIV to didanosine and the inhibition of HIV replication in humans has not been established.
Drug Resistance
HIV-1 isolates with reduced sensitivity to didanosine have been selected in vitro and were also obtained from
patients treated with didanosine. Genetic analysis of isolates from didanosine-treated patients showed
mutations in the reverse transcriptase gene that resulted in the amino acid substitutions K65R, L74V, and
M184V. The L74V mutation was most frequently observed in clinical isolates. Phenotypic analysis of HIV-1
isolates from 60 patients (some with prior zidovudine treatment) receiving 6 to 24 months of didanosine
monotherapy showed that isolates from 10 of 60 patients exhibited an average of a 10-fold decrease in
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Page 6 of 33
susceptibility to didanosine in vitro compared to baseline isolates. Clinical isolates that exhibited a decrease
in didanosine susceptibility harbored one or more didanosine-associated mutations. The clinical relevance of
genotypic and phenotypic changes associated with didanosine therapy has not been established.
Cross-resistance
HIV-1 isolates from 2 of 39 patients receiving combination therapy for up to 2 years with zidovudine and
didanosine exhibited decreased susceptibility to zidovudine, didanosine, zalcitabine, stavudine, and
lamivudine in vitro. These isolates harbored five mutations (A62V, V75I, F77L, F116Y, and Q151M) in the
reverse transcriptase gene. The clinical relevance of these observations has not been established.
CLINICAL PHARMACOLOGY
Animal Toxicology
Evidence of a dose-limiting skeletal muscle toxicity has been observed in mice and rats
(but not in dogs) following long-term (greater than 90 days) dosing with didanosine at
doses that were approximately 1.2 to 12 times the estimated human exposure. The
relationship of this finding to the potential of VIDEX (didanosine) to cause myopathy in
humans is unclear. However, human myopathy has been associated with administration of
VIDEX and other nucleoside analogues.
Pharmacokinetics
The pharmacokinetic parameters of didanosine are summarized in Table 1. Didanosine is rapidly absorbed,
with peak plasma concentrations generally observed from 0.25 to 1.50 hours following oral dosing.
Increases in plasma didanosine concentrations were dose proportional over the range of 50 to 400 mg.
Steady-state pharmacokinetic parameters did not differ significantly from values obtained after a single dose.
Binding of didanosine to plasma proteins in vitro was low (<5%). Based on data from in vitro and animal
studies, it is presumed that the metabolism of didanosine in man occurs by the same pathways responsible for
the elimination of endogenous purines.
Table 1
Mean ± SD Pharmacokinetic Parameters for Didanosine in Adult and Pediatric Patients
Parameter
Adult
Patients
n
Pediatric
Patients
n
Oral bioavailability
42 ± 12%
6
25 ± 20%
46
Apparent volume
of distributiona
1.08 ± 0.22 L/kg
6
28 ± 15 L/m2
49
CSF-plasma ratiob
21 ± 0.03%c
5
46%
(range 12-85%)
7
Systemic clearancea
13.0 ± 1.6
mL/min/kg
6
516 ± 184
mL/min/m2
49
Renal clearanced
5.5 ± 2.1
mL/min/kg
6
240 ± 90
mL/min/m2
15
Elimination half-lifed
1.5 ± 0.4 h
6
0.8 ± 0.3 h
60
Urinary recovery of didanosined
18 ± 8%
6
18 ± 10%
15
CSF = cerebrospinal fluid
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Page 7 of 33
a following IV administration
b following IV administration in adults and IV or oral administration in pediatric patients
c mean ± SE
d following oral administration
Effect of Food on Absorption of Didanosine: Didanosine peak plasma concentrations (CMAX) and
area under the plasma concentration time curve (AUC) were decreased by approximately 55% when VIDEX
tablets were administered up to 2 hours after a meal. Administration of VIDEX tablets up to 30 minutes
before a meal did not result in any significant changes in bioavailability. VIDEX should be taken on an
empty stomach, at least 30 minutes before or 2 hours after eating. (See DOSAGE AND
ADMINISTRATION.)
Special Populations
Renal Insufficiency: It is recommended that the VIDEX (didanosine) dose be modified in patients with
reduced creatinine clearance and in patients receiving maintenance hemodialysis (see DOSAGE AND
ADMINISTRATION). Data from two studies indicated that the apparent oral clearance of didanosine
decreased and the terminal elimination half-life increased as creatinine clearance decreased (see Table 2).
Following oral administration, didanosine was not detectable in peritoneal dialysate fluid (n=6); recovery in
hemodialysate (n=5) ranged from 0.6% to 7.4% of the dose over a 3-4 hour dialysis period. The absolute
bioavailability of didanosine was not affected in patients requiring dialysis.
Table 2
Mean ± SD Pharmacokinetic Parameters for Didanosine Following a Single Oral Dose
Creatinine Clearance (mL/min)
Parameter
≥ 90
(n=12)
60-90
(n=6)
30-59
(n=6)
10-29
(n=3)
Dialysis
Patients
(n=11)
CLcr (mL/min)
112 ± 22
68 ± 8
46 ± 8
13 ± 5
NDa
CL/F (mL/min)
2164 ± 638
1566 ± 833
1023 ± 378
628 ± 104
543 ± 174
CLR (mL/min)
458 ± 164
247 ± 153
100 ± 44
20 ± 8
<10
T½ (h)
1.42 ± 0.33
1.59 ± 0.13
1.75 ± 0.43
2.0 ± 0.3
4.1 ± 1.2
a ND = not determined due to anuria
CLcr = creatinine clearance
CL/F = apparent oral clearance
CLR = renal clearance
Pediatric Patients: The pharmacokinetics of didanosine have been evaluated in HIV-infected
pediatric patients from 0.7 to 18.9 years of age (see Table 1). Overall, the pharmacokinetics of didanosine in
pediatric patients greater than 0.7 years of age are similar to those of didanosine in adults. Didanosine plasma
concentrations increased in proportion to oral doses ranging from 80 to 180 mg/m2. For information on
controlled clinical studies in pediatric patients, see PRECAUTIONS, Pediatric Use and Clinical Studies.
Geriatric Patients: Didanosine pharmacokinetics have not been studied in patients over 65 years of
age.
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Page 8 of 33
Gender: The effects of gender on didanosine pharmacokinetics have not been studied.
Drug Interactions: Tables 3 and 4 summarize the effects on AUC and CMAX, with a 90% or 95%
confidence interval (CI) when available, following coadministration of VIDEX with a variety of drugs. For
most of the listed drugs, no clinically significant pharmacokinetic interactions were observed. Clinical
recommendations based on drug interaction studies for drugs in bold font are included in PRECAUTIONS:
Drug Interactions.
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Table 3
Results of Drug Interaction Studies: Effects of Coadministered Drug on Didanosine Plasma AUC and
CMAX Values
Drugs With Clinical Recommendations Regarding Coadministration (see PRECAUTIONS: Drug
Interactions)
Drug
Didanosine Dosage
n
AUC of
Didanosine
(95% CI)
CMAX of
Didanosine
(95% CI)
allopurinol
renally impaired, 300 mg/day
200 mg single dose
2
↑312%
↑232%
healthy volunteer, 300
mg/day for 7 days
400 mg single dose
14
↑113%
↑69%
ciprofloxacin, 750 mg q12h for
3 days, 2 h before didanosine
200 mg q12h for 3
days
8a
↓16%
↓28%
ganciclovir, 1000 mg q8h, 2 h
after didanosine
200 mg q12h
12
↑111%
NA
indinavir, 800 mg single dose
simultaneous
200 mg single dose
16
↔
↔
1 h before didanosine
200 mg single dose
16
↓17% (-27, -7%)b
↓13% (-28, 5%)b
ketoconazole, 200 mg/day for 4
days, 2 h before didanosine
375 mg q12h for 4
days
12a
↔
↓12%
methadone, chronic
maintenance dose
200 mg single dose
16,10c
↓57%
↓66%
No Clinically Significant Interaction Observed
Drug
Didanosine Dosage
n
AUC of
Didanosine
(95% CI)
CMAX of
Didanosine
(95% CI)
loperamide, 4 mg q6h for 1 day
300 mg single dose
12a
↔
↓23%
metoclopramide, 10 mg single
dose
300 mg single dose
12a
↔
↑13%
ranitidine, 150 mg single dose,
2 h before didanosine
375 mg single dose
12a
↑14%
↑13%
rifabutin, 300 or 600 mg/day for
12 days
167 or 250 mg q12h
for 12 days
11
↑13% (-1, 27%)
↑17% (-4, 38%)
ritonavir, 600 mg q12h for 4
days
200 mg q12h for 4
days
12
↓13% (0, 23%)
↓16% (5, 26%)
stavudine, 40 mg q12h for 4
days
100 mg q12h for 4
days
10
↔
↔
sulfamethoxazole, 1000 mg
single dose
200 mg single dose
8a
↔
↔
trimethoprim, 200 mg single
dose
200 mg single dose
8a
↔
↑17% (-23, 77%)
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Table 3
Results of Drug Interaction Studies: Effects of Coadministered Drug on Didanosine Plasma AUC and
CMAX Values
No Clinically Significant Interaction Observed (continued)
Drug
Didanosine Dosage
n
AUC of
Didanosine
(95% CI)
CMAX of
Didanosine
(95% CI)
zidovudine, 200 mg q8h for 3
days
200 mg q12h for 3
days
6a
↔
↔
↑ indicates increase.
↓ indicates decrease.
↔indicates no change, or mean increase or decrease of <10%.
aHIV-infected patients.
b90% CI.
c Parallel-group design; entries are subjects receiving combination and control regimens, respectively.
NA Not available.
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Table 4
Results of Drug Interaction Studies: Effects of Didanosine on Coadministered Drug Plasma AUC and
CMAX Values
Drugs With Clinical Recommendations Regarding Coadministration (see PRECAUTIONS: Drug
Interactions)
Drug
Didanosine Dosage
n
AUC of
Coadministered
Drug (95% CI)
CMAX of
Coadministered
Drug (95% CI)
ciprofloxacin
750 mg q12h for 3 days, 2 h
before didanosine
200 mg q12h for 3
days
8a
↓26%
↓16%
750 mg single dose
buffered placebo
tablet
12
↓98%
↓93%
delavirdine, 400 mg single
dose
simultaneous
125 or 200 mg q12h
12a
↓32%
↓53%
1 h before didanosine
125 or 200 mg q12h
12a
↑20%
↑18%
ganciclovir, 1000 mg q8h, 2 h
after didanosine
200 mg q12h
12a
↓21%
NA
indinavir, 800 mg single dose
simultaneous
200 mg single dose
16
↓84%
↓82%
1 h before didanosine
200 mg single dose
16
↓11%
↓4%
ketoconazole, 200 mg/day for 4
days, 2 h before didanosine
375 mg q12h for 4
days
12a
↓14%
↓20%
nelfinavir, 750 mg single dose,
1 h after didanosine
200 mg single dose
10a
↑12%
↔
No Clinically Significant Interaction Observed
Drug
Didanosine Dosage
n
AUC of
Coadministered
Drug (95% CI)
AUC of
Coadministered
Drug (95% CI)
dapsone, 100 mg single dose
200 mg q12h for 14
days
6a
↔
↔
ranitidine, 150 mg single dose,
2 h before didanosine
375 mg single dose
12a
↓16%
↔
ritonavir, 600 mg q12h for 4
days
200 mg q12h for 4
days
12
↔
↔
stavudine, 40 mg q12h for 4
days
100 mg q12h for 4
days
10a
↔
↑17%
sulfamethoxazole, 1000 mg
single dose
200 mg single dose
8a
↓11% (-17, -4%)
↓12% (-28, 8%)
trimethoprim, 200 mg single
dose
200 mg single dose
8a
↑10% (-9, 34%)
↓22% (-59, 49%)
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Table 4
Results of Drug Interaction Studies: Effects of Didanosine on Coadministered Drug Plasma AUC and
CMAX Values
No Clinically Significant Interaction Observed (continued)
Drug
Didanosine Dosage
n
AUC of
Coadministered
Drug (95% CI)
AUC of
Coadministered
Drug (95% CI)
zidovudine, 200 mg q8h for 3
days
200 mg q12h for 3
days
6a
↓10% (-27, 11%)
↓16.5% (-53,
47%)
↑ indicates increase.
↓ indicates decrease.
↔ indicates no change, or a mean increase or decrease of <10%.
a HIV-infected patients.
NA Not available.
INDICATIONS AND USAGE
VIDEX in combination with other antiretroviral agents is indicated for the treatment of HIV-1
infection (see Clinical Studies).
Clinical Studies
Combination Therapy
START 2 was a multicenter, randomized, open-label study comparing VIDEX (200 mg twice
daily)/stavudine/indinavir to zidovudine/lamivudine/indinavir in 205 treatment-naive patients. Both regimens
resulted in a similar magnitude of suppression of HIV RNA levels and increases in CD4 cell counts through
48 weeks.
Study A1454-148 was a randomized, open-label, multicenter study comparing treatment with VIDEX
(400 mg once daily) plus stavudine (40 mg twice daily) and nelfinavir (750 mg three times daily) versus
zidovudine (300 mg twice daily) plus lamivudine (150 mg twice daily) and nelfinavir (750 mg three times
daily) in 756 treatment-naive patients, with a median CD4 cell count of 340 cells/mm3 (range 80 to 1568
cells/mm3) and a median plasma HIV-1 RNA of 4.69 log10 copies/mL (range 2.6 to 5.9 log10 copies/mL) at
baseline. Median CD4 cell count increases at 48 weeks were 188 cells/mm3 in both treatment groups.
Treatment response and outcomes through 48 weeks are shown in Figure 1 and Table 5.
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Figure 1
Treatment Response Through Week 48*, AI454-148
0
20
40
60
80
100
0
8
16
24
32
40
48
Study Week
Percent of patients
] < 400 c/mL
] < 50 c/mL
VIDEX+stavudine+nelfinavir (n=503)
zidovudine+lamivudine+nelfinavir (n=253)
*Percent of patients at each time point who have HIV RNA <400 or <50
copies/mL, are on their original study medication (except stavudine-
zidovudine switches), and have not experienced an AIDS-defining event.
Table 5
Outcomes of Randomized Treatment through Week 48, AI454-148
Percent of Patients with HIV RNA <400 copies/mL (<50 copies/mL)
VIDEX/stavudine/
nelfinavir
lamivudine/zidovudine/
nelfinavir
Week 48 Status
n=503
n=253
Responder a
50* (34*)
59 (47)
Virologic failureb
36 (57)
32 (48)
Death or disease progression
<1 (<1)
1 (<1)
Discontinued due to adverse
events
4 (2)
2 (<1)
Discontinued due to other
reasonsc
6 (3)
4 (2)
Never initiated treatment
4 (4)
2 (2)
* p < 0.05 for the differences between treatment groups, by Cochran-Mantel-Haenszel test.
a Patients achieved virologic response [two consecutive viral load <400 (<50) copies/mL] and maintained it
to Week 48.
b Includes viral rebound and failing to achieve confirmed <400 (<50) copies/mL by Week 48.
c Includes lost to follow-up, noncompliance, withdrawal, and pregnancy.
Monotherapy
The efficacy of VIDEX was demonstrated in two randomized, double-blind studies comparing VIDEX, given
on a twice-daily schedule, to zidovudine, given three times daily, in 617 (ACTG 116A, conducted 1989-
1992) and 913 (ACTG116B/117, conducted 1989-1991) patients with symptomatic HIV infection or AIDS
who were treated for more than one year. In treatment-naive patients (ACTG 116A), the rate of HIV disease
progression or death was similar between the treatment groups; mortality rates were 26% for patients
receiving VIDEX and 21% for patients receiving zidovudine. Of the patients who had received previous
zidovudine treatment (ACTG 116B/117), those treated with VIDEX had a lower rate of HIV disease
progression or death (32%) compared to those treated with zidovudine (41%); however, survival rates were
similar between the treatment groups.
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Efficacy in pediatric patients was demonstrated in a randomized, double-blind, controlled study (ACTG
152, conducted 1991-1995) involving 831 patients treated for more than 1.5 years with zidovudine (180
mg/m2 q6h), VIDEX (120 mg/m2 q12h), or zidovudine (120 mg/m2 q6h) plus VIDEX (90 mg/m2 q12h).
Patients treated with VIDEX or VIDEX plus zidovudine had lower rates of HIV disease progression or death
compared with those treated with zidovudine alone.
Studies have demonstrated that the clinical benefit of monotherapy with antiretrovirals, including
VIDEX, was time limited.
CONTRAINDICATION
VIDEX (didanosine) is contraindicated in patients with previously demonstrated clinically significant
hypersensitivity to any of the components of the formulations.
WARNINGS
1. Pancreatitis
FATAL AND NONFATAL PANCREATITIS HAVE OCCURRED DURING THERAPY WITH
VIDEX USED ALONE OR IN COMBINATION REGIMENS IN BOTH TREATMENT-NAIVE AND
TREATMENT-EXPERIENCED
PATIENTS,
REGARDLESS
OF
DEGREE
OF
IMMUNOSUPPRESSION. VIDEX SHOULD BE SUSPENDED IN PATIENTS WITH SIGNS OR
SYMPTOMS OF PANCREATITIS AND DISCONTINUED IN PATIENTS WITH CONFIRMED
PANCREATITIS. PATIENTS TREATED WITH VIDEX IN COMBINATION WITH STAVUDINE,
WITH OR WITHOUT HYDROXYUREA, MAY BE AT INCREASED RISK FOR PANCREATITIS.
When treatment with life-sustaining drugs known to cause pancreatic toxicity is
required, suspension of VIDEX (didanosine) therapy is recommended. In patients with risk
factors for pancreatitis, VIDEX should be used with extreme caution and only if clearly
indicated. Patients with advanced HIV infection, especially the elderly, are at increased
risk of pancreatitis and should be followed closely. Patients with renal impairment may be
at greater risk for pancreatitis if treated without dose adjustment.
The frequency of pancreatitis is dose related. In phase 3 studies, incidence ranged from 1% to 10% with
doses higher than are currently recommended and 1% to 7% with recommended dose.
In pediatric studies, pancreatitis occurred in 3% (2/60) of patients treated at entry doses below 300
mg/m2/day and in 13% (5/38) of patients treated at higher doses. VIDEX use should be suspended in
pediatric patients with signs or symptoms of pancreatitis and discontinued in pediatric patients with
confirmed pancreatitis.
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2. Lactic Acidosis/Severe Hepatomegaly with Steatosis
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported
with the use of nucleoside analogues alone or in combination, including didanosine and other
antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure
may be risk factors. Fatal lactic acidosis has been reported in pregnant women who received the combination
of didanosine and stavudine with other antiretroviral agents. The combination of didanosine and stavudine
should be used with caution during pregnancy and is recommended only if the potential benefit clearly
outweighs the potential risk (see PRECAUTIONS: Pregnancy). Particular caution should be exercised
when administering VIDEX to any patient with known risk factors for liver disease; however, cases have also
been reported in patients with no known risk factors. Treatment with VIDEX should be suspended in any
patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced
hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase
elevations).
3. Retinal Changes and Optic Neuritis
Retinal changes and optic neuritis have been reported in adult and pediatric patients. Periodic retinal
examinations should be considered for patients receiving VIDEX. (See ADVERSE REACTIONS.)
PRECAUTIONS
Frequency of Dosing
The preferred dosing frequency of VIDEX is twice daily because there is more evidence to support the
effectiveness of this dosing frequency. Once-daily dosing should be considered only for adult patients whose
management requires once-daily dosing of VIDEX (see Clinical Studies).
VIDEX should be taken on an empty stomach, at least 30 minutes before or 2 hours after eating.
Peripheral Neuropathy
Peripheral neuropathy, manifested by numbness, tingling, or pain in the hands or feet, has been reported in
patients receiving VIDEX therapy. Peripheral neuropathy has occurred more frequently in patients with
advanced HIV disease, in patients with a history of neuropathy, or in patients being treated with neurotoxic
drug therapy, including stavudine (see ADVERSE REACTIONS).
General
Patients with Phenylketonuria: VIDEX Chewable/Dispersible Buffered Tablets contain the
following quantities of phenylalanine:
Table 6
All Strengths
Phenylalanine per 2-tablet dose
73 mg
Phenylalanine per tablet
36.5 mg
Patients on Sodium-Restricted Diets: VIDEX Buffered Powder for Oral Solution: Each single-
dose packet of VIDEX Buffered Powder for Oral Solution contains 1380 mg sodium.
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Patients with Renal Impairment: Patients with renal impairment (creatinine clearance <60 mL/min)
may be at greater risk of toxicity from VIDEX due to decreased drug clearance (see CLINICAL
PHARMACOLOGY). A dose reduction is recommended in these patients (see DOSAGE AND
ADMINISTRATION). The magnesium content of each buffered tablet of VIDEX is 8.6 mEq. This may
present an excessive load of magnesium to patients with significant renal impairment, particularly after
prolonged dosing.
Patients with Hepatic Impairment: It is unknown if hepatic impairment significantly affects
didanosine pharmacokinetics. Therefore, these patients should be monitored closely for evidence of
didanosine toxicity.
Hyperuricemia: VIDEX has been associated with asymptomatic hyperuricemia; treatment suspension
may be necessary if clinical measures aimed at reducing uric acid levels fail.
Information for Patients (see Patient Information Leaflet)
Patients should be informed that a serious toxicity of VIDEX used alone and in combination regimens, is
pancreatitis, which may be fatal.
Patients should be informed that the preferred dosing frequency of VIDEX is twice daily because there is
more evidence to support the effectiveness of this dosing frequency. Once-daily dosing should be considered
only for adult patients whose management requires once-daily dosing of VIDEX.
Patients should also be aware that peripheral neuropathy, manifested by numbness, tingling, or pain in
hands or feet, may develop during therapy with VIDEX. Patients should be counseled that peripheral
neuropathy occurs with greatest frequency in patients with advanced HIV disease or a history of peripheral
neuropathy, and that dose modification and/or discontinuation of VIDEX may be required if toxicity
develops.
Patients should be informed that when VIDEX is used in combination with other agents with similar
toxicities, the incidence of adverse events may be higher than when VIDEX is used alone. These patients
should be followed closely.
Patients should be cautioned about the use of medications or other substances, including alcohol, that
may exacerbate VIDEX toxicities.
Patients should be advised that to ensure proper acid neutralization in the stomach they must take at least
two of the appropriate strength VIDEX tablets at each dose. To reduce the risk of gastrointestinal side effects
from excess antacid, patients should take no more than four VIDEX tablets at each dose.
VIDEX (didanosine) is not a cure for HIV infection, and patients may continue to develop HIV-
associated illnesses, including opportunistic infection. Therefore, patients should remain under the care of a
physician when using VIDEX. Patients should be advised that VIDEX therapy has not been shown to reduce
the risk of transmission of HIV to others through sexual contact or blood contamination. Patients should be
informed that the long-term effects of VIDEX are unknown at this time.
Drug Interactions (see also CLINICAL PHARMACOLOGY: Drug Interactions)
Drug interactions that have been established based on drug interaction studies are listed with the
pharmacokinetic results in CLINICAL PHARMACOLOGY: Drug Interactions (Tables 3 and 4). The
clinical recommendations based on the results of these studies are listed in Table 7.
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Table 7
Established Drug Interactions with VIDEX
Coadministration Not Recommended Based on Drug Interaction Studies (see CLINICAL
PHARMACOLOGY: Drug Interactions for Magnitude of Interaction)
Drug
Effect
Clinical Comment
allopurinol
↑ didanosine concentration
Coadministration not recommended.
Alteration in Dose or Regimen Recommended Based on Drug Interaction Studies (see CLINICAL
PHARMACOLOGY: Drug Interactions for Magnitude of Interaction)
Drug
Effect
Clinical Comment
ciprofloxacin
↓ ciprofloxacin concentration
Administer VIDEX at least 2 hours after or
6 hours before ciprofloxacin.
delavirdine
↓ delavirdine concentration
Administer VIDEX 1 hour after
delavirdine.
ganciclovir
↑ didanosine concentration
Appropriate doses for this combination,
with respect to efficacy and safety, have not
been established.
indinavir
↓ indinavir concentration
Administer VIDEX 1 hour after indinavir.
methadone
↓ didanosine concentration
Appropriate doses for this combination,
with respect to efficacy and safety, have not
been established.
nelfinavir
No interaction 1 hour after didanosine
Administer nelfinavir 1 hour after VIDEX.
↑ indicates increase.
↓ indicates decrease.
Coadministration of VIDEX with drugs that are known to cause pancreatitis may increase the risk
of this toxicity (see WARNINGS: Pancreatitis). Because VIDEX formulations either contain buffers or are
mixed with antacids before administration, interactions may be anticipated with drugs whose absorption can
be affected by the level of acidity in the stomach and with drugs that have been demonstrated to interact with
antacids containing magnesium, calcium, or aluminum. Predicted drug interactions with VIDEX are listed in
Table 8.
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Table 8
Predicted Drug Interactions with VIDEX
Use with Caution, Risk of Adverse Reactions May Be Increased
Drug Class
Effect
Clinical Comment
Drugs that may cause
pancreatic toxicity
↑ risk of pancreatitis
Use only with extreme caution.a
Neurotoxic drugs
↑ risk of neuropathy
Use with caution.b
Antacids containing
magnesium or aluminum
↑ side effects associated with
antacid components
Use caution with VIDEX
Chewable/Dispersible Buffered Tablets and
Pediatric Powder for Oral Solution.
Use with Caution, Plasma Concentrations May Be Decreased by Coadministration with VIDEX
Drug Class
Effect
Clinical Comment
Azole antifungals
↓ ketoconazole or itraconazole
concentration
Administer drugs such as ketoconazole or
itraconazole at least 2 hours before VIDEX.
Quinolone
antibiotics (see also
ciprofloxacin in
Table 7)
↓ quinolone concentration
Consult package insert of the quinolone.
Tetracycline
antibiotics
↓ antibiotic concentration
Consult package insert of the tetracycline.
↑ indicates increase.
↓ indicates decrease.
a Only if other drugs are not available and if clearly indicated. If treatment with life-sustaining drugs that
cause pancreatic toxicity is required, suspension of VIDEX is recommended (see WARNINGS:
Pancreatitis).
b See PRECAUTIONS: Peripheral Neuropathy.
Carcinogenesis and Mutagenesis
Lifetime carcinogenicity studies were conducted in mice and rats for 22 and 24 months, respectively. In the
mouse study, initial doses of 120, 800, and 1200 mg/kg/day for each sex were lowered after 8 months to 120,
210, and 210 mg/kg/day for females and 120, 300, and 600 mg/kg/day for males. The two higher doses
exceeded the maximally tolerated dose in females and the high dose exceeded the maximally tolerated dose
in males. The low dose in females represented 0.68-fold maximum human exposure and the intermediate
dose in males represented 1.7-fold maximum human exposure based on relative AUC comparisons. In the
rat study, initial doses were 100, 250, and 1000 mg/kg/day, and the high dose was lowered to 500 mg/kg/day
after 18 months. The upper dose in male and female rats represented 3-fold maximum human exposure.
Didanosine induced no significant increase in neoplastic lesions in mice or rats at maximally tolerated
doses.
Didanosine was positive in the following genetic toxicology assays: 1) the Escherichia coli tester strain
WP2 uvrA bacterial mutagenicity assay; 2) the L5178Y/TK+/- mouse lymphoma mammalian cell gene
mutation assay; 3) the in vitro chromosomal aberrations assay in cultured human peripheral lymphocytes; 4)
the in vitro chromosomal aberrations assay in Chinese Hamster Lung cells; and 5) the BALB/c 3T3 in vitro
transformation assay. No evidence of mutagenicity was observed in an Ames Salmonella bacterial
mutagenicity assay or in rat and mouse in vivo micronucleus assays.
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Pregnancy, Reproduction, and Fertility
Pregnancy Category B. Reproduction studies have been performed in rats and rabbits at
doses up to 12 and 14.2 times the estimated human exposure (based upon plasma levels),
respectively, and have revealed no evidence of impaired fertility or harm to the fetus due to
didanosine. At approximately 12 times the estimated human exposure, didanosine was
slightly toxic to female rats and their pups during mid and late lactation. These rats
showed reduced food intake and body weight gains but the physical and functional
development of the offspring was not impaired and there were no major changes in the F2
generation. A study in rats showed that didanosine and/or its metabolites are transferred to
the fetus through the placenta. Animal reproduction studies are not always predictive of
human response.
There are no adequate and well-controlled studies of didanosine in pregnant women. Didanosine should
be used during pregnancy only if the potential benefit justifies the potential risk.
Fatal lactic acidosis has been reported in pregnant women who received the combination of didanosine
and stavudine with other antiretroviral agents. It is unclear if pregnancy augments the risk of lactic
acidosis/hepatic steatosis syndrome reported in nonpregnant individuals receiving nucleoside analogues (see
WARNINGS: Lactic Acidosis/Severe Hepatomegaly with Steatosis). The combination of didanosine
and stavudine should be used with caution during pregnancy and is recommended only if the potential
benefit clearly outweighs the potential risk. Health care providers caring for HIV-infected pregnant
women receiving didanosine should be alert for early diagnosis of lactic acidosis/hepatic steatosis syndrome.
Antiretroviral Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant women exposed
to didanosine and other antiretroviral agents, an Antiretroviral Pregnancy Registry has been established.
Physicians are encouraged to register patients by calling 1-800-258-4263.
Nursing Mothers
The Centers for Disease Control and Prevention recommend that HIV-infected
mothers not breast-feed their infants to avoid risking postnatal transmission of HIV.
A study in rats showed that following oral administration, didanosine and/or its metabolites
were excreted into the milk of lactating rats. It is not known if didanosine is excreted in
human milk. Because of both the potential for HIV transmission and the potential for
serious adverse reactions in nursing infants, mothers should be instructed not to breast-
feed if they are receiving VIDEX.
Pediatric Use
Use of VIDEX in pediatric patients is supported by evidence from adequate and well-
controlled studies of VIDEX in adults and pediatric patients (see Clinical Studies,
CLINICAL PHARMACOLOGY, ADVERSE REACTIONS, and DOSAGE AND
ADMINISTRATION).
Geriatric Use
In an Expanded Access Program for patients with advanced HIV infection, patients aged 65 years and older
had a higher frequency of pancreatitis (10%) than younger patients (5%) (see WARNINGS). Clinical studies
of didanosine did not include sufficient numbers of subjects aged 65 years and over to determine whether
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they respond differently than younger subjects. Didanosine is known to be substantially excreted by the
kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function.
Because elderly patients are more likely to have decreased renal function, care should be taken in dose
selection. In addition, renal function should be monitored and dosage adjustments should be made
accordingly (see DOSAGE AND ADMINISTRATION: Dose Adjustment).
ADVERSE REACTIONS
A SERIOUS TOXICITY OF VIDEX (didanosine) IS PANCREATITIS, WHICH MAY BE FATAL (see
WARNINGS).
OTHER
IMPORTANT
TOXICITIES
INCLUDE
LACTIC
ACIDOSIS/SEVERE
HEPATOMEGALY WITH STEATOSIS; RETINAL CHANGES AND OPTIC NEURITIS; AND
PERIPHERAL NEUROPATHY (see WARNINGS and PRECAUTIONS).
When VIDEX is used in combination with other agents with similar toxicities, the incidence of
these toxicities may be higher than when VIDEX is used alone. Thus, patients treated with VIDEX in
combination with stavudine, with or without hydroxyurea, may be at increased risk for pancreatitis,
which may be fatal, and hepatotoxicity (see WARNINGS). Patients treated with VIDEX in
combination with stavudine may also be at increased risk for peripheral neuropathy (see
PRECAUTIONS).
Adults: Selected clinical adverse events that occurred in adult patients in clinical studies with VIDEX
are provided in Tables 9 and 10.
Table 9
Selected Clinical Adverse Events from Monotherapy Studies
Percent of Patients
ACTG 116A ACTG 116B/117
VIDEX
zidovudine
VIDEX
zidovudine
Adverse Events
n=197
n=212
n=298
n=304
Diarrhea
19
15
28
21
Peripheral Neurologic
Symptoms/Neuropathy
17
14
20
12
Rash/Pruritus
7
8
9
5
Abdominal Pain
13
8
7
8
Pancreatitis
7
3
6
2
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Table 10
Selected Clinical Adverse Events from Combination Studies
Percent of Patientsa
AI454-148b START 2b
VIDEX +
stavudine +
nelfinavir
zidovudine +
lamivudine +
nelfinavir
VIDEX +
stavudine +
indinavir
zidovudine +
lamivudine +
indinavir
Adverse Events
n=482
n=248
n=102
n=103
Diarrhea
70
60
45
39
Nausea
28
40
53
67
Headache
21
30
46
37
Peripheral Neurologic
Symptoms/Neuropathy
26
6
21
10
Rash
13
16
30
18
Vomiting
12
14
30
35
Pancreatitis (see below)
1
*
<1
*
a Percentages based on treated subjects.
b Median duration of treatment 48 weeks.
* This event was not observed in this study arm.
Pancreatitis resulting in death was observed in one patient who received VIDEX plus stavudine
plus nelfinavir in Study Al454-148 and in one patient who received VIDEX plus stavudine plus
indinavir in the START 2 study. In addition, pancreatitis resulting in death was observed in 2 of 68
patients who received VIDEX plus stavudine plus indinavir plus hydroxyurea in an ACTG clinical
trial (see WARNINGS).
The frequency of pancreatitis is dose related. In phase 3 studies, incidence ranged from 1% to 10% with
doses higher than are currently recommended and from 1% to 7% with recommended dose.
Selected laboratory abnormalities in clinical studies with VIDEX are shown in Tables 11-13.
Table 11
Selected Laboratory Abnormalities from Monotherapy Studies
Percent of Patients
ACTG 116A
ACTG 116B/117
VIDEX
zidovudine
VIDEX
zidovudine
Parameter
n=197
n=212
n=298
n=304
SGOT (AST) (>5 x ULN)
9
4
7
6
SGPT (ALT) (>5 x ULN)
9
6
6
6
Alkaline phosphatase
(>5 x ULN)
4
1
1
1
Amylase (≥1.4 x ULN)
17
12
15
5
Uric acid (>12 mg/dL)
3
1
2
1
ULN = upper limit of normal.
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Table 12
Selected Laboratory Abnormalities from Combination Studies (Grades 3-4)
Percent of Patientsa
AI454-148b START 2b
VIDEX +
stavudine +
nelfinavir
zidovudine +
lamivudine +
nelfinavir
VIDEX +
stavudine +
indinavir
zidovudine +
lamivudine +
indinavir
Parameter
n=482
n=248
n=102
n=103
Bilirubin (>2.6 x ULN)
<1
<1
16
8
SGOT (AST) (>5 x ULN)
3
2
7
7
SGPT (ALT) (>5 x ULN)
3
3
8
5
GGT (>5 x ULN)
NC
NC
5
2
Lipase (>2 x ULN)
7
2
5
5
Amylase (>2 x ULN)
NC
NC
8
2
ULN = upper limit of normal.
NC=Not Collected
a Percentages based on treated subjects.
b Median duration of treatment 48 weeks.
Table 13
Selected Laboratory Abnormalities from Combination Studies (All Grades)
Percent of Patientsa
AI454-148b START 2b
VIDEX +
stavudine +
nelfinavir
zidovudine +
lamivudine +
nelfinavir
VIDEX +
stavudine +
indinavir
zidovudine +
lamivudine +
indinavir
Parameter
n=482
n=248
n=102
n=103
Bilirubin
7
3
68
55
SGOT (AST)
42
23
53
20
SGPT (ALT)
37
24
50
18
GGT
NC
NC
28
12
Lipase
17
11
26
19
Amylase
NC
NC
31
17
NC = Not Collected
a Percentages based on treated subjects.
b Median duration of treatment 48 weeks.
Observed during Clinical Practice: The following events have been identified during postapproval
use of VIDEX (didanosine). Because they are reported voluntarily from a population of unknown size,
estimates of frequency cannot be made. These events have been chosen for inclusion due to their
seriousness, frequency of reporting, causal connection to VIDEX, or a combination of these factors.
Body as a Whole - alopecia, anaphylactoid reaction, asthenia, chills/fever, and pain.
Digestive Disorders- anorexia, dyspepsia, and flatulence.
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Exocrine Gland Disorders – pancreatitis (including fatal cases) (see WARNINGS), sialoadenitis,
parotid gland enlargement, dry mouth, and dry eyes.
Hematologic Disorders - anemia, leukopenia, and thrombocytopenia.
Liver - lactic acidosis and hepatic steatosis (see WARNINGS); hepatitis and liver failure.
Metabolic Disorders - diabetes mellitus, hypoglycemia, and hyperglycemia.
Musculoskeletal Disorders - myalgia (with or without increases in creatine kinase), rhabdomyolysis
including acute renal failure and hemodialysis, arthralgia, and myopathy.
Ophthalmologic Disorders - Retinal depigmentation and optic neuritis (see WARNINGS).
Pediatric Patients: Adverse events and laboratory abnormalities reported to occur in the pediatric
patients in ACTG 152 were generally similar to adverse events and laboratory abnormalities reported in adult
patients.
In pediatric phase 1 studies, pancreatitis occurred in 2 of 60 (3%) patients treated at entry doses below
300 mg/m2/day and in 5 of 38 (13%) patients treated at higher doses.
Retinal changes and optic neuritis have been reported in pediatric patients.
OVERDOSAGE
There is no known antidote for VIDEX (didanosine) overdosage. In phase 1 studies, in which VIDEX was
initially administered at doses ten times the currently recommended dose, toxicities included: pancreatitis,
peripheral neuropathy, diarrhea, hyperuricemia and hepatic dysfunction. Didanosine is not dialyzable by
peritoneal
dialysis,
although
there
is
some
clearance
by
hemodialysis
(see
CLINICAL
PHARMACOLOGY: Pharmacokinetics).
DOSAGE AND ADMINISTRATION
Dosage
All VIDEX formulations should be administered on an empty stomach, at least 30
minutes before or 2 hours after eating. For either a once-daily or twice-daily regimen,
patients must take at least two of the appropriate strength tablets at each dose to
provide adequate buffering and prevent gastric acid degradation of didanosine.
Because of the need for adequate buffering, the 200-mg strength tablet should only be
used as a component of a once-daily regimen. To reduce the risk of gastrointestinal
side effects, patients should take no more than four tablets at each dose.
Adults: The preferred dosing frequency of VIDEX is twice daily because there is more evidence to
support the effectiveness of this dosing regimen. Once-daily dosing should be considered only for adult
patients whose management requires once-daily dosing of VIDEX (see Clinical Studies). The daily dose in
adult patients is dependent on weight as outlined in Table 14.
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Table 14
Adult Dosing
Patient Weight
VIDEX Tabletsa
VIDEX Buffered
Powderb
Preferred dosing
≥60 kg
200 mg twice daily
250 mg twice daily
< 60 kg
125 mg twice daily
167 mg twice daily
Dosing for patients whose management requires once-daily frequency
≥ 60 kg
400 mg once daily
B
< 60 kg
250 mg once daily
B
a The 200-mg strength tablet should only be used as a component of a once-
daily regimen.
b Not suitable for once-daily dosing except for patients with renal
impairment. See Table 15.
Pediatric Patients: The recommended dose of VIDEX (didanosine) in pediatric patients is 120 mg/m2
twice daily. There are no data on once-daily dosing of VIDEX in pediatric patients.
Dose Adjustment
Clinical and laboratory signs suggestive of pancreatitis should prompt dose suspension and careful
evaluation of the possibility of pancreatitis. VIDEX use should be discontinued in patients with
confirmed pancreatitis (see WARNINGS).
Patients with symptoms of peripheral neuropathy may tolerate a reduced dose of VIDEX after resolution
of the symptoms of peripheral neuropathy upon drug discontinuation. If neuropathy recurs after resumption
of VIDEX, permanent discontinuation of VIDEX should be considered.
Renal Impairment: In adult patients with impaired renal function, the dose of VIDEX should be
adjusted to compensate for the slower rate of elimination. The recommended doses and dosing intervals of
VIDEX in adult patients with renal insufficiency are presented in Table 15.
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Table 15
Recommended Dosage of VIDEX in Renal Impairment
≥ 60 kg
< 60 kg
Creatinine
Clearance
(mL/min)
Tableta
(mg)
Buffered
Powderb
(mg)
Tableta
(mg)
Buffered
Powderb
(mg)
≥60
200 twice dailyc
250 twice daily
125 twice dailyc
167 twice
daily
30-59
200 once daily
or 100 twice daily
100 twice daily
150 once daily
or 75 twice daily
100 twice
daily
10-29
150 once daily
167 once daily
100 once daily
100 once daily
<10
100 once daily
100 once daily
75 once daily
100 once daily
a VIDEX Chewable/Dispersible Buffered Tablet. Two VIDEX tablets must be taken with
each dose; different strengths of tablets may be combined to yield the recommended dose.
b VIDEX Buffered Powder for Oral Solution
c 400 mg once daily (≥60 kg) or 250 mg once daily (<60 kg) for patients whose management
requires once-daily frequency of administration.
Urinary excretion is also a major route of elimination of didanosine in pediatric patients; therefore, the
clearance of didanosine may be altered in children with renal impairment. Although there are insufficient
data to recommend a specific dose adjustment of VIDEX in this patient population, a reduction in the dose
and/or an increase in the interval between doses should be considered.
Patients Requiring Continuous Ambulatory Peritoneal Dialysis (CAPD) or Hemodialysis:
For patients requiring CAPD or hemodialysis, follow dosing recommendations for patients with creatinine
clearance less than 10 mL/min, shown in Table 15. It is not necessary to administer a supplemental dose of
VIDEX following hemodialysis.
Hepatic Impairment: See WARNINGS and PRECAUTIONS.
Method of Preparation
VIDEX Chewable/Dispersible Buffered Tablets
Adult Dosing: To provide adequate buffering, at least two of the appropriate strength tablets, but no more
than four tablets, should be thoroughly chewed or dispersed in at least 1 ounce of water prior to consumption
(see PRECAUTIONS: Information for Patients). To disperse tablets, add 2 tablets to at least 1 ounce of
drinking water. Stir until a uniform dispersion forms, and drink the entire dispersion immediately. If
additional flavoring is desired, the dispersion may be diluted with one ounce of clear apple juice. Stir the
further diluted dispersion just prior to consumption. The dispersion with clear apple juice is stable at room
temperature, 62° to 73°F (17° to 23°C), for up to one hour.
VIDEX Buffered Powder for Oral Solution
1.
Open packet carefully and pour contents into a container with approximately 4 ounces of drinking water.
Do not mix with fruit juice or other acid-containing liquid.
2.
Stir until the powder completely dissolves (approximately 2 to 3 minutes).
3.
Drink the entire solution immediately.
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VIDEX Pediatric Powder for Oral Solution
Prior to dispensing, the pharmacist must constitute dry powder with Purified Water, USP, to an initial
concentration of 20 mg/mL and immediately mix the resulting solution with antacid to a final concentration
of 10 mg/mL as follows:
20 mg/mL Initial Solution: Constitute the product to 20 mg/mL by adding 100 mL or 200 mL of
Purified Water, USP, to the 2 g or 4 g of VIDEX powder, respectively, in the product bottle.
10 mg/mL Final Admixture: 1. Immediately mix one part of the 20 mg/mL initial solution with one
part of either Mylanta Double Strength Liquid, Extra Strength Maalox Plus Suspension, or Maalox TC
Suspension for a final dispensing concentration of 10 mg VIDEX per mL. For patient home use, the
admixture should be dispensed in appropriately sized, flint-glass or plastic (HDPE, PET, or PETG) bottles
with child-resistant closures. This admixture is stable for 30 days under refrigeration, 36° to 46° F (2° to 8°
C).
2. Instruct the patient to shake the admixture thoroughly prior to use and to store the tightly closed
container in the refrigerator, 36° to 46° F (2° to 8° C), up to 30 days.
HOW SUPPLIED
VIDEX
(didanosine) Chewable/Dispersible Buffered Tablets are round, off white to light orange/yellow
with a mottled appearance, orange-flavored, tablets embossed with "VIDEX" on one side and the product
strength on the other. The tablets are available in the following strengths of VIDEX: 25, 50, 100, 150, and
200 mg. Sixty tablets are packaged in bottles with child-resistant closures.
The tablets should be stored in tightly closed bottles at 59° to 86° F (15° to 30° C). If dispersed in
water, the dose may be held for up to 1 hour at ambient temperature.
VIDEX (didanosine) Buffered Powder for Oral Solution is supplied in single-dose, child-resistant foil
packets in the following strengths of VIDEX: 100, 167, or 250 mg. Each product strength provides a
sweetened, buffered solution of VIDEX.
The packets should be stored at 59° to 86° F (15° to 30° C). After dissolving in water, the solution may
be stored at ambient room temperature for up to 4 hours.
VIDEX (didanosine) Pediatric Powder for Oral Solution is supplied in 4- and 8-ounce glass bottles
containing 2 g or 4 g of VIDEX, respectively.
The bottles of powder should be stored at 59° to 86° F (15° to 30° C). The VIDEX admixture may be
stored up to 30 days in a refrigerator, 36° to 46° F (2° to 8° C). Discard any unused portion after 30 days.
Mylanta® is a registered trademark of Johnson & Johnson-Merck Consumer Pharmaceuticals Company.
Maalox® is a registered trademark of Novartis Consumer Health, Inc.
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The NDC numbers for the previously described VIDEX products are:
Table 16
NDC NO.
Packaging Information
Product Strength
VIDEX
Chewable/Dispersible Buffered Tablets
0087-6650-01
60 tablets/bottle
25 mg/tablet
0087-6651-01
60 tablets/bottle
50 mg/tablet
0087-6652-01
60 tablets/bottle
100 mg/tablet
0087-6653-01
60 tablets/bottle
150 mg/tablet
0087-6665-15
60 tablets/bottle
200 mg/tablet
VIDEX
Buffered Powder for Oral Solution
0087-6614-43
One single-dose foil packet*
100 mg/packet
0087-6615-43
One single-dose foil packet*
167 mg/packet
0087-6616-43
One single-dose foil packet*
250 mg/packet
VIDEX
Pediatric Powder for Oral Solution
0087-6632-41
One bottle per carton
2 g/bottle
0087-6633-41
One bottle per carton
4 g/bottle
*Packaged as 30 packets per carton.
US Patent Nos.: 4,861,759 and 5,616,566.
HANDLING AND DISPOSAL
Spill, Leak, and Disposal Procedure
Avoid generating dust during clean-up of powdered products; use wet mop or damp sponge. Clean surface
with soap and water as necessary. Containerize larger spills.
There is no single preferred method of disposal of containerized waste. Disposal options include
incineration, landfill, or sewer as dictated by specific circumstances and relevant national, state, and local
regulations.
A Bristol-Myers Squibb Company
Princeton, NJ 08543 USA
Revised _______________
Patient Information
Rx only
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
ApprovletS035.doc (clean copy 1/10/01)
Page 28 of 33
VIDEX®
(generic name = didanosine also known as ddI)
VIDEX® (didanosine) Chewable/Dispersible Buffered Tablets
VIDEX® (didanosine) Buffered Powder for Oral Solution
VIDEX® (didanosine) Pediatric Powder for Oral Solution
What is VIDEX?
VIDEX (pronounced VY dex) is a prescription medicine used in combination with other drugs to treat
children and adults who are infected with HIV (the human immunodeficiency virus, the virus that causes
AIDS). VIDEX belongs to a class of drugs called nucleoside analogues. By reducing the growth of HIV,
VIDEX helps your body maintain its supply of CD4 cells, which are important for fighting HIV and other
infections.
VIDEX will not cure your HIV infection. At present there is no cure for HIV infection. Even while taking
VIDEX, you may continue to have HIV-related illnesses, including infections with other disease-producing
organisms. Continue to see your doctor regularly and report any medical problems that occur.
VIDEX does not prevent a patient infected with HIV from passing the virus to other people. To protect
others, you must continue to practice safe sex and take precautions to prevent others from coming in contact
with your blood and other body fluids.
There is limited information on the effects of long-term use of VIDEX.
Who should not take VIDEX?
Do not take VIDEX if you are allergic to any of its ingredients, including its active ingredient, didanosine and the
inactive ingredients. (See Inactive Ingredients at the end of this leaflet.) Tell your doctor if you think you have had
an allergic reaction to any of these ingredients.
How should I take VIDEX? How should I store it?
Your doctor will determine your dose based on your body weight, kidney and liver function, and any side effects
that you may have had with other medicines. Take VIDEX on an empty stomach - that means at least 30 minutes
before or 2 hours after eating. Do not take VIDEX with food. Try not to miss a dose, but if you do, take it as
soon as possible. If it is almost time for the next dose, skip the missed dose and continue your regular dosing
schedule.
Chewable/Dispersible Tablets: Each VIDEX tablet contains antacid. Each time you take
VIDEX, you must take at least two, but not more than four, tablets. This is because VIDEX
tablets contain an antacid to reduce the amount of acid in your stomach. If you have too much acid,
the medicine will break down. However, too much antacid may cause stomach problems.
--DO NOT swallow VIDEX tablets whole. Chew the tablets well or mix them in water. Many
patients drop the tablets in at least one ounce of water and stir well before swallowing. If you choose
to mix the tablets in water, you may add one ounce (2 tablespoons) of clear apple juice to the mixture
for flavor (do not use any other kind of juice).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
ApprovletS035.doc (clean copy 1/10/01)
Page 29 of 33
--Store tablets in a tightly closed container at room temperature away from heat and out of the reach
of children and pets. Do NOT store the tablets in a damp place such as a bathroom medicine cabinet
or near the kitchen sink.
Buffered Powder for Oral Solution: Pour the contents of a packet into a glass with 4 ounces (1/2
measuring cup) of water. Stir until completely dissolved. Drink the entire solution right away. Do not
mix with fruit juice. Store packets at room temperature before use.
Pediatric Oral Solution: Your pharmacist will prepare the oral solution. Shake the solution
well before each use. Store in the refrigerator. Throw away any unused portion after 30 days.
If you have kidney disease: If your kidneys are not working properly, your doctor will need to do
regular tests to check how they are working while you take VIDEX. Your doctor may also lower
your dosage of VIDEX.
What should I do if someone takes an overdose of VIDEX?
If someone may have taken an overdose of VIDEX, get medical help right away.
Contact their doctor or a poison control center.
What should I avoid while taking VIDEX?
Alcohol. Do not drink alcohol while taking VIDEX since alcohol may increase your risk of pancreatitis (pain
and inflammation of the pancreas) or liver damage.
Other medicines. Other medicines, including those you can buy without a prescription, may interfere with
the actions of VIDEX. Do not take any medicine, vitamin supplement, or other health preparation
without first checking with your doctor.
Antacids. Since VIDEX contains some of the same ingredients found in antacids, any side effects related
to VIDEX’s ingredients may get worse if you also take an antacid.
Medicines at the same time you take your VIDEX dose. Some medicines should not be taken at the
same time of day that you take VIDEX. Check with your doctor.
Pregnancy. It is not known if VIDEX can harm a human fetus. Also, pregnant women have experienced
serious side effects when taking VIDEX in combination with ZERIT (stavudine), also known as d4T, and
other HIV medicines. VIDEX should be used during pregnancy only after discussion with your doctor. Tell
your doctor if you become pregnant or plan to become pregnant while taking VIDEX.
Nursing. Studies have shown VIDEX is in the breast milk of animals getting the drug. It may also be in
human breast milk. The Centers for Disease Control and Prevention (CDC) recommends that HIV-infected
mothers not breast-feed. This should reduce the risk of passing HIV infection to their babies and the
potential for serious adverse reactions in nursing infants. Therefore, do not nurse a baby while taking
VIDEX.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
ApprovletS035.doc (clean copy 1/10/01)
Page 30 of 33
What are the possible side effects of VIDEX?
Pancreatitis. Pancreatitis is a dangerous inflammation of the pancreas that may cause death. Tell your
doctor right away if you or a child taking VIDEX develops stomach pain, nausea, or vomiting. These can
be signs of pancreatitis. Before starting VIDEX therapy, let your doctor know if you or a child for whom it has
been prescribed has ever had pancreatitis. This condition is more likely to happen in people who have had it before.
It is also more likely in people with advanced HIV disease. However, it can occur at any stage of HIV disease. It
may be more common in patients with kidney problems, those who drink alcohol, and those who are also treated
with stavudine or hydroxyurea. If you get pancreatitis, your doctor will tell you to stop taking VIDEX.
Lactic acidosis, severe liver enlargement, and liver failure, including deaths, have been reported among
patients taking VIDEX (including pregnant women). Symptoms that may indicate a liver problem are:
•
feeling very weak, tired, or uncomfortable,
•
unusual or unexpected stomach discomfort,
•
feeling cold,
•
feeling dizzy or lightheaded,
•
suddenly developing a slow or irregular heartbeat.
Lactic acidosis is a medical emergency that must be treated in a hospital.
If you notice any of these symptoms or if your medical condition changes, stop taking VIDEX and call your
doctor right away. Women, overweight patients, and those who have been treated for a long time with other
medicines used to treat HIV infection are more likely to develop lactic acidosis. Your doctor should check your
liver function periodically while you are taking VIDEX. You should be especially careful if you have a history of
heavy alcohol use or a liver problem.
Vision changes. VIDEX may affect the nerves in your eyes. Because of this, you should have regular eye
examinations. You should also report any changes in vision to your doctor right away. This includes, for example,
seeing colors abnormally or blurred vision.
Peripheral neuropathy. This is a problem with the nerves in your hands or feet. The nerve problem may be
serious. Tell your doctor right away if you or a child taking VIDEX has continuing numbness, tingling, or pain
in the feet or hands. A child may not recognize these symptoms or know to tell you that his or her feet or hands are
numb, burning, tingling, or painful. Ask your child’s doctor how to find out if your child is developing peripheral
neuropathy.
Before starting VIDEX therapy, let your doctor know if you or a child for whom it has been prescribed has ever
had peripheral neuropathy. This condition is more likely to happen in people who have had it before. It is also more
likely in patients taking medicines that affect the nerves and in people with advanced HIV disease. However, it can
occur at any stage of HIV disease. If you get peripheral neuropathy, your doctor will tell you to stop taking VIDEX.
After stopping VIDEX, the symptoms may get worse for a short time and then get better. Once symptoms of
peripheral neuropathy go away completely, you and your doctor should decide if starting VIDEX is right for you. If
so, you might be started at a lower dose.
Special note about other medicines. If you take VIDEX along with other medicines with similar side effects, you
may increase the chance of having these side effects. For example, using VIDEX in combination with other
medicines that may cause pancreatitis, peripheral neuropathy, or liver problems (including stavudine and
hydroxyurea) may increase your chance of having these side effects.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
ApprovletS035.doc (clean copy 1/10/01)
Page 31 of 33
Other side effects: The most common side effects in adults taking VIDEX are diarrhea, neuropathy (nerve
disorders), chills or fever, rash, abdominal pain, weakness, headache, and nausea and vomiting. Children may have
similar side effects as adults.
What else should I know about VIDEX?
If you should limit sodium (salt) intake: Each single-dose packet of Buffered Powder for Oral Solution
contains 1380 mg of sodium. Each Chewable/Dispersible Tablet contains 264.5 mg of sodium.
If you have phenylketonuria: Each Chewable/Dispersible Tablet contains 36.5 mg of phenylalanine.
Inactive Ingredients:
Chewable/Dispersible Tablets: calcium carbonate, magnesium hydroxide, aspartame, sorbitol,
mandarin orange flavor, polyplasdone, microcrystalline cellulose, and magnesium stearate.
Buffered Powder for Oral Solution: citrate-phosphate buffer (dibasic sodium phosphate, sodium
citrate, and citric acid) and sucrose.
Pediatric Oral Solution: Mylanta Double Strength Liquid, Extra Strength Maalox Plus or
Maalox TC Suspension.
This medicine was prescribed for your particular condition. Do not use VIDEX for another condition or give
it to others. Keep VIDEX and all medicines out of the reach of children. Throw away VIDEX when it is
outdated or no longer needed by flushing it down the toilet or pouring it down the sink.
This summary does not include everything there is to know about VIDEX. Medicines are sometimes prescribed
for purposes other than those listed in a Patient Information Leaflet. If you have questions or concerns, or want more
information about VIDEX, your physician and pharmacist have the complete prescribing information upon which
this leaflet is based. You may want to read it and discuss it with your doctor or other healthcare professional.
Remember, no written summary can replace careful discussion with your doctor.
Mylanta® is a registered trademark of Johnson & Johnson-Merck Consumer Pharmaceuticals Company.
Maalox® is a registered trademark of Novartis Consumer Health, Inc.
A Bristol-Myers Squibb Company
Princeton, NJ 08543 USA
This Patient Information Leaflet has been approved by the U.S. Food and Drug Administration.
Revised December 2000
Based on _____ (xx/00)
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
--------------------------------------------------------------------------------------------------------
This is a representation of an electronic record that was signed electronically and
this page is the manifestation of the electronic signature.
--------------------------------------------------------------------------------------------------------
/s/
---------------------
Debra Birnkrant
9/10/01 11:18:39 AM
NDA 20-156 SLR 027, NDA 20-155 SLR 026, NDA 20-154 SLR 035
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:46:55.023694
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2001/20156s27lbl.pdf', 'application_number': 20156, 'submission_type': 'SUPPL ', 'submission_number': 27}
|
12,276
|
Page 4 of 39
Rx only
VIDEX
(didanosine)
VIDEX (didanosine) Chewable/Dispersible Buffered Tablets
VIDEX (didanosine) Buffered Powder for Oral Solution
VIDEX (didanosine) Pediatric Powder for Oral Solution
(Patient Information Leaflet Included)
WARNING
FATAL AND NONFATAL PANCREATITIS HAVE OCCURRED DURING THERAPY
WITH VIDEX USED ALONE OR IN COMBINATION REGIMENS IN BOTH
TREATMENT-NAIVE
AND
TREATMENT-EXPERIENCED
PATIENTS,
REGARDLESS OF DEGREE OF IMMUNOSUPPRESSION. VIDEX SHOULD BE
SUSPENDED IN PATIENTS WITH SUSPECTED PANCREATITIS AND
DISCONTINUED IN PATIENTS WITH CONFIRMED PANCREATITIS (SEE
WARNINGS).
LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS,
INCLUDING FATAL CASES, HAVE BEEN REPORTED WITH THE USE OF
NUCLEOSIDE ANALOGUES ALONE OR IN COMBINATION, INCLUDING
DIDANOSINE AND OTHER ANTIRETROVIRALS. FATAL LACTIC ACIDOSIS
HAS BEEN REPORTED IN PREGNANT WOMEN WHO RECEIVED THE
COMBINATION
OF
DIDANOSINE
AND
STAVUDINE
WITH
OTHER
ANTIRETROVIRAL AGENTS. THE COMBINATION OF DIDANOSINE AND
STAVUDINE SHOULD BE USED WITH CAUTION DURING PREGNANCY AND IS
RECOMMENDED ONLY IF THE POTENTIAL BENEFIT CLEARLY OUTWEIGHS
THE POTENTIAL RISK. (SEE WARNINGS AND PRECAUTIONS: PREGNANCY.)
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 5 of 39
DESCRIPTION
VIDEX (didanosine) is a brand name for didanosine (ddI), a synthetic purine nucleoside
analogue active against the Human Immunodeficiency Virus (HIV). VIDEX
Chewable/Dispersible Buffered Tablets are available for oral administration in strengths of 25,
50, 100, 150, and 200 mg of didanosine. Each tablet is buffered with calcium carbonate and
magnesium hydroxide. VIDEX tablets also contain aspartame, sorbitol, microcrystalline
cellulose, polyplasdone, mandarin-orange flavor, and magnesium stearate.
VIDEX Buffered Powder for Oral Solution is supplied for oral administration in single-
dose packets containing 100, 167, or 250 mg of didanosine. Packets of each product strength
also contain a citrate-phosphate buffer (composed of dibasic sodium phosphate, sodium citrate,
and citric acid) and sucrose.
VIDEX Pediatric Powder for Oral Solution is supplied for oral administration in 4- or
8-ounce glass bottles containing 2 or 4 grams of didanosine, respectively.
Didanosine is also available as an enteric-coated formulation (VIDEX® EC Delayed-
Release Capsules). Please consult the prescribing information for VIDEX EC (didanosine).
The chemical name for didanosine is 2',3'-dideoxyinosine. The structural formula is:
Didanosine is a white crystalline powder with the molecular formula C10H12N4O3 and a
molecular weight of 236.2. The aqueous solubility of didanosine at 25° C and pH of
approximately 6 is 27.3 mg/mL. Didanosine is unstable in acidic solutions. For example, at
pH <3 and 37° C, 10% of didanosine decomposes to hypoxanthine in less than 2 minutes.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 6 of 39
MICROBIOLOGY
Mechanism of Action
Didanosine is a synthetic nucleoside analogue of the naturally occurring nucleoside
deoxyadenosine in which the 3'-hydroxyl group is replaced by hydrogen. Intracellularly,
didanosine is converted by cellular enzymes to the active metabolite, dideoxyadenosine
5'-triphosphate. Dideoxyadenosine 5'-triphosphate inhibits the activity of HIV-1 reverse
transcriptase both by competing with the natural substrate, deoxyadenosine 5'-triphosphate,
and by its incorporation into viral DNA causing termination of viral DNA chain elongation.
In Vitro HIV Susceptibility
The in vitro anti-HIV-1 activity of didanosine was evaluated in a variety of HIV-1 infected
lymphoblastic cell lines and monocyte/macrophage cell cultures. The concentration of drug
necessary to inhibit viral replication by 50% (IC50) ranged from 2.5 to 10 µM (1 µM =
0.24 µg/mL) in lymphoblastic cell lines and 0.01 to 0.1 µM in monocyte/macrophage cell
cultures. The relationship between in vitro susceptibility of HIV to didanosine and the
inhibition of HIV replication in humans has not been established.
Drug Resistance
HIV-1 isolates with reduced sensitivity to didanosine have been selected in vitro and were also
obtained from patients treated with didanosine. Genetic analysis of isolates from didanosine-
treated patients showed mutations in the reverse transcriptase gene that resulted in the amino
acid substitutions K65R, L74V, and M184V. The L74V mutation was most frequently
observed in clinical isolates. Phenotypic analysis of HIV-1 isolates from 60 patients (some
with prior zidovudine treatment) receiving 6 to 24 months of didanosine monotherapy showed
that isolates from 10 of 60 patients exhibited an average of a 10-fold decrease in susceptibility
to didanosine in vitro compared to baseline isolates. Clinical isolates that exhibited a decrease
in didanosine susceptibility harbored one or more didanosine-associated mutations. The
clinical relevance of genotypic and phenotypic changes associated with didanosine therapy has
not been established.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 7 of 39
Cross-resistance
HIV-1 isolates from 2 of 39 patients receiving combination therapy for up to 2 years with
zidovudine and didanosine exhibited decreased susceptibility to zidovudine, didanosine,
zalcitabine, stavudine, and lamivudine in vitro. These isolates harbored five mutations (A62V,
V75I, F77L, F116Y, and Q151M) in the reverse transcriptase gene. The clinical relevance of
these observations has not been established.
CLINICAL PHARMACOLOGY
Animal Toxicology
Evidence of a dose-limiting skeletal muscle toxicity has been observed in mice and rats (but
not in dogs) following long-term (greater than 90 days) dosing with didanosine at doses that
were approximately 1.2 to 12 times the estimated human exposure. The relationship of this
finding to the potential of VIDEX (didanosine) to cause myopathy in humans is unclear.
However, human myopathy has been associated with administration of VIDEX and other
nucleoside analogues.
Pharmacokinetics
The pharmacokinetic parameters of didanosine are summarized in Table 1. Didanosine is
rapidly absorbed, with peak plasma concentrations generally observed from 0.25 to 1.50 hours
following oral dosing. Increases in plasma didanosine concentrations were dose proportional
over the range of 50 to 400 mg. Steady-state pharmacokinetic parameters did not differ
significantly from values obtained after a single dose. Binding of didanosine to plasma
proteins in vitro was low (<5%). Based on data from in vitro and animal studies, it is presumed
that the metabolism of didanosine in man occurs by the same pathways responsible for the
elimination of endogenous purines.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 8 of 39
Table 1:
Mean ± SD Pharmacokinetic Parameters for Didanosine in
Adult and Pediatric Patients
Pediatric Patientsb
Parameter
Adult Patientsa
n
8 months to 19 years
n
2 weeks to 4 months
n
Oral bioavailability (%)
42 ± 12
6
25 ± 20
46
ND
Apparent volume of
distributionc (L/m2)
43.70 ± 8.90
6
28 ± 15
49
ND
CSF-plasma ratiod
21 ± 0.03%e
5
46%
(range 12-85%)
7
ND
Systemic clearancec
(mL/min/m2)
526 ± 64.7
6
516 ± 184
49
ND
Renal clearancef
(mL/min/m2)
223 ± 85.0
6
240 ± 90
15
ND
Apparent oral clearanceg
(mL/min/m2)
1252 ± 154
6
2064 ± 736
48
1353 ± 759
41
Elimination half-lifef (h)
1.5 ± 0.4
6
0.8 ± 0.3
60
1.2 ± 0.3
21
Urinary recovery of
didanosinef (%)
18 ± 8
6
18 ± 10
15
ND
CSF = cerebrospinal fluid, ND = not determined.
a Parameter units for adults were converted to the same units in pediatric patients to facilitate comparisons
among populations: mean adult body weight = 70 kg and mean adult body surface area = 1.73 m2.
b In 1-day old infants (n=10), the mean ± SD apparent oral clearance was 1523 ± 1176 mL/min/m2 and
half-life was 2.0 ± 0.7 h.
c Following IV administration.
d Following IV administration in adults and IV or oral administration in pediatric patients.
e
Mean ± SE.
f
Following oral administration.
g Apparent oral clearance estimate was determined as the ratio of the mean systemic clearance and the
mean oral bioavailability estimate.
Effect of Food on Absorption of Didanosine: Didanosine peak plasma
concentrations (CMAX) and area under the plasma concentration time curve (AUC) were
decreased by approximately 55% when VIDEX tablets were administered up to 2 hours after a
meal. Administration of VIDEX tablets up to 30 minutes before a meal did not result in any
significant changes in bioavailability. VIDEX should be taken on an empty stomach, at least
30 minutes before or 2 hours after eating. (See DOSAGE AND ADMINISTRATION.)
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 9 of 39
Special Populations
Renal Insufficiency: It is recommended that the VIDEX (didanosine) dose be modified in
patients with reduced creatinine clearance and in patients receiving maintenance hemodialysis
(see DOSAGE AND ADMINISTRATION). Data from two studies in adults indicated that
the apparent oral clearance of didanosine decreased and the terminal elimination half-life
increased as creatinine clearance decreased (see Table 2). Following oral administration,
didanosine was not detectable in peritoneal dialysate fluid (n=6); recovery in hemodialysate
(n=5) ranged from 0.6% to 7.4% of the dose over a 3-4 hour dialysis period. The absolute
bioavailability of didanosine was not affected in patients requiring dialysis.
Table 2:
Mean ± SD Pharmacokinetic Parameters for Didanosine
Following a Single Oral Dose
Creatinine Clearance (mL/min)
Parameter
≥ 90 (n=12)
60-90 (n=6)
30-59 (n=6)
10-29 (n=3)
Dialysis Patients
(n=11)
CLcr (mL/min)
112 ± 22
68 ± 8
46 ± 8
13 ± 5
NDa
CL/F (mL/min)
2164 ± 638
1566 ± 833
1023 ± 378
628 ± 104
543 ± 174
CLR (mL/min)
458 ± 164
247 ± 153
100 ± 44
20 ± 8
<10
T½ (h)
1.42 ± 0.33
1.59 ± 0.13
1.75 ± 0.43
2.0 ± 0.3
4.1 ± 1.2
a ND = not determined due to anuria.
CLcr = creatinine clearance.
CL/F = apparent oral clearance.
CLR = renal clearance.
Pediatric Patients: The pharmacokinetics of didanosine have been evaluated in
HIV-exposed and -infected pediatric patients from birth to 19 years of age (see Table 1).
Overall, the pharmacokinetics of didanosine in pediatric patients are similar to those of
didanosine in adults. Didanosine plasma concentrations appear to increase in proportion to oral
doses ranging from 25 to 120 mg/m2 in pediatric patients less than 5 months old and from 80
to 180 mg/m2 in children above 8 months old. For information on controlled clinical studies in
pediatric patients, see INDICATIONS AND USAGE: Clinical Studies and
PRECAUTIONS: Pediatric Use.
Geriatric Patients: Didanosine pharmacokinetics have not been studied in patients
over 65 years of age.
Gender: The effects of gender on didanosine pharmacokinetics have not been studied.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 10 of 39
Drug Interactions: Tables 3 and 4 summarize the effects on AUC and CMAX, with a
90% or 95% confidence interval (CI) when available, following coadministration of VIDEX
with a variety of drugs. For most of the listed drugs, no clinically significant pharmacokinetic
interactions were observed. Clinical recommendations based on drug interaction studies for
drugs in bold font are included in PRECAUTIONS: Drug Interactions.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 11 of 39
Table 3:
Results of Drug Interaction Studies: Effects of Coadministered Drug on
Didanosine Plasma AUC and CMAX Values
Drugs With Clinical Recommendations Regarding Coadministration (see PRECAUTIONS: Drug Interactions)
Drug
Didanosine Dosage
n
AUC of
Didanosine
(95% CI)
CMAX of Didanosine
(95% CI)
allopurinol
renally impaired, 300 mg/day
200 mg single dose
2
↑312%
↑232%
healthy volunteer, 300 mg/day for
7 days
400 mg single dose
14
↑113%
↑69%
ciprofloxacin, 750 mg q12h for 3
days, 2 h before didanosine
200 mg q12h for 3 days
8a
↓16%
↓28%
ganciclovir, 1000 mg q8h, 2 h
after didanosine
200 mg q12h
12
↑111%
NA
indinavir, 800 mg single dose
simultaneous
1 h before didanosine
200 mg single dose
200 mg single dose
16
16
↔
↓17% (-27, - 7%)b
↔
↓13% (-28, 5%)b
ketoconazole, 200 mg/day for 4
days, 2 h before didanosine
375 mg q12h for 4 days
12a
↔
↓12%
methadone, chronic maintenance
dose
200 mg single dose
16,10c
↓57%
↓66%
tenofovir,d,e 300 mg once daily
1 h after didanosine
250f or 400 mg once
daily for 7 days
14
↑44%
(31, 59%)b
↑28%
(11, 48%)b
No Clinically Significant Interaction Observed
Drug
Didanosine Dosage
n
AUC of
Didanosine
(95% CI)
CMAX of Didanosine
(95% CI)
loperamide, 4 mg q6h for 1 day
300 mg single dose
12a
↔
↓23%
metoclopramide, 10 mg single dose
300 mg single dose
12a
↔
↑13%
ranitidine, 150 mg single dose, 2 h
before didanosine
375 mg single dose
12a
↑14%
↑13%
rifabutin, 300 or 600 mg/day for 12
days
167 or 250 mg q12h for
12 days
11
↑13% (-1, 27%)
↑17% (-4, 38%)
ritonavir, 600 mg q12h for 4 days
200 mg q12h for 4 days
12
↓13% (0, 23%)
↓16% (5, 26%)
stavudine, 40 mg q12h for 4 days
100 mg q12h for 4 days
10
↔
↔
sulfamethoxazole, 1000 mg single
dose
200 mg single dose
8a
↔
↔
trimethoprim, 200 mg single dose
200 mg single dose
8a
↔
↑17% (-23, 77%)
zidovudine, 200 mg q8h for 3 days
200 mg q12h for 3 days
6a
↔
↔
↑ indicates increase.
↓ indicates decrease.
↔ indicates no change, or mean increase or decrease of <10%.
a
HIV-infected patients.
b
90% CI.
c Parallel-group design; entries are subjects receiving combination and control regimens, respectively.
d tenofovir disoproxil fumarate.
e
In a drug interaction study with the enteric-coated formulation of didanosine (VIDEX EC) and tenofovir, the AUC and
CMAX of didanosine each increased 48% when VIDEX EC was administered in the fasting state 2 hours before
tenofovir with a light meal. The AUC and CMAX of didanosine increased 60% and 64%, respectively, when
VIDEX EC was administered together with tenofovir and a light meal.
f
patients less than 60 kg.
NA Not available.
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Page 12 of 39
Table 4:
Results of Drug Interaction Studies: Effects of Didanosine on
Coadministered Drug Plasma AUC and CMAX Values
Drugs With Clinical Recommendations Regarding Coadministration (see PRECAUTIONS: Drug Interactions)
Drug
Didanosine Dosage
n
AUC of
Coadministered
Drug (95% CI)
CMAX of
Coadministered
Drug (95% CI)
ciprofloxacin
750 mg q12h for 3 days, 2 h
before didanosine
750 mg single dose
200 mg q12h for 3 days
buffered placebo tablet
8a
12
↓26%
↓98%
↓16%
↓93%
delavirdine, 400 mg single dose
simultaneous
1 h before didanosine
125 or 200 mg q12h
125 or 200 mg q12h
12a
12a
↓32%
↑20%
↓53%
↑18%
ganciclovir, 1000 mg q8h, 2 h
after didanosine
200 mg q12h
12a
↓21%
NA
indinavir, 800 mg single dose
simultaneous
1 h before didanosine
200 mg single dose
200 mg single dose
16
16
↓84%
↓11%
↓82%
↓4%
ketoconazole, 200 mg/day for 4
days, 2 h before didanosine
375 mg q12h for 4 days
12a
↓14%
↓20%
nelfinavir, 750 mg single dose,
1 h after didanosine
200 mg single dose
10a
↑12%
↔
No Clinically Significant Interaction Observed
Drug
Didanosine Dosage
n
AUC of
Coadministered
Drug (95% CI)
CMAX of
Coadministered
Drug (95% CI)
dapsone, 100 mg single dose
200 mg q12h for 14 days
6a
↔
↔
ranitidine, 150 mg single dose, 2 h
before didanosine
375 mg single dose
12a
↓16%
↔
ritonavir, 600 mg q12h for 4 days
200 mg q12h for 4 days
12
↔
↔
stavudine, 40 mg q12h for 4 days
100 mg q12h for 4 days
10a
↔
↑17%
sulfamethoxazole, 1000 mg single
dose
200 mg single dose
8a
↓11% (-17, -4%)
↓12% (-28, 8%)
tenofovir,b 300 mg once daily 1 h
after didanosine
250c or 400 mg once
daily for 7 days
14
↔
↔
trimethoprim, 200 mg single dose
200 mg single dose
8a
↑10% (-9, 34%)
↓22% (-59, 49%)
zidovudine, 200 mg q8h for 3
days
200 mg q12h for 3 days
6a
↓10% (-27, 11%)
↓16.5% (-53, 47%)
↑ indicates increase.
↓ indicates decrease.
↔ indicates no change, or mean increase or decrease of <10%.
a
HIV-infected patients.
b
tenofovir disoproxil fumarate.
c
patients less than 60 kg.
NA Not available.
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INDICATIONS AND USAGE
VIDEX in combination with other antiretroviral agents is indicated for the treatment of
HIV-1 infection (see Clinical Studies).
Clinical Studies
Combination Therapy
START 2 was a multicenter, randomized, open-label study comparing VIDEX (200 mg twice
daily)/stavudine/indinavir to zidovudine/lamivudine/indinavir in 205 treatment-naive patients.
Both regimens resulted in a similar magnitude of suppression of HIV RNA levels and
increases in CD4 cell counts through 48 weeks.
Study A1454-148 was a randomized, open-label, multicenter study comparing
treatment with VIDEX (400 mg once daily) plus stavudine (40 mg twice daily) and nelfinavir
(750 mg three times daily) versus zidovudine (300 mg twice daily) plus lamivudine (150 mg
twice daily) and nelfinavir (750 mg three times daily) in 756 treatment-naive patients, with a
median CD4 cell count of 340 cells/mm3 (range 80 to 1568 cells/mm3) and a median plasma
HIV-1 RNA of 4.69 log10 copies/mL (range 2.6 to 5.9 log10 copies/mL) at baseline. Median
CD4 cell count increases at 48 weeks were 188 cells/mm3 in both treatment groups. Treatment
response and outcomes through 48 weeks are shown in Figure 1 and Table 5.
Figure 1:
Treatment Response Through Week 48*, AI454-148
* Percent of patients at each time point who have HIV RNA <400 or <50 copies/mL, are on
their original study medication (except stavudine-zidovudine switches), and have not
experienced an AIDS-defining event.
0
20
40
60
80
100
0
8
16
24
32
40
48
Study Week
Percent of patients
] < 400 c/mL
] < 50 c/mL
VIDEX+stavudine+nelfinavir (n=503)
zidovudine+lamivudine+nelfinavir (n=253)
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Table 5:
Outcomes of Randomized Treatment through Week 48,
AI454-148
Percent of Patients with HIV RNA <400 copies/mL (<50 copies/mL)
VIDEX/stavudine/nelfinavir
lamivudine/zidovudine/nelfinavir
Week 48 Status
n=503
n=253
Responder a
50* (34*)
59 (47)
Virologic failureb
36 (57)
32 (48)
Death or disease progression
<1 (<1)
1 (<1)
Discontinued due to adverse events
4 (2)
2 (<1)
Discontinued due to other reasonsc
6 (3)
4 (2)
Never initiated treatment
4 (4)
2 (2)
* p <0.05 for the differences between treatment groups, by Cochran-Mantel-Haenszel test.
a Patients achieved virologic response [two consecutive viral loads <400 (<50) copies/mL] and maintained
it to Week 48.
b Includes viral rebound and failing to achieve confirmed <400 (<50) copies/mL by Week 48.
c Includes lost to follow-up, noncompliance, withdrawal, and pregnancy.
Monotherapy
The efficacy of VIDEX was demonstrated in two randomized, double-blind studies comparing
VIDEX, given on a twice-daily schedule, to zidovudine, given three times daily, in 617
(ACTG 116A, conducted 1989-1992) and 913 (ACTG116B/117, conducted 1989-1991)
patients with symptomatic HIV infection or AIDS who were treated for more than one year. In
treatment-naive patients (ACTG 116A), the rate of HIV disease progression or death was
similar between the treatment groups; mortality rates were 26% for patients receiving VIDEX
and 21% for patients receiving zidovudine. Of the patients who had received previous
zidovudine treatment (ACTG 116B/117), those treated with VIDEX had a lower rate of HIV
disease progression or death (32%) compared to those treated with zidovudine (41%);
however, survival rates were similar between the treatment groups.
Efficacy in pediatric patients was demonstrated in a randomized, double-blind,
controlled study (ACTG 152, conducted 1991-1995) involving 831 patients 3 months to 18
years of age treated for more than 1.5 years with zidovudine (180 mg/m2 q6h), VIDEX (120
mg/m2 q12h), or zidovudine (120 mg/m2 q6h) plus VIDEX (90 mg/m2 q12h). Patients treated
with VIDEX or VIDEX plus zidovudine had lower rates of HIV disease progression or death
compared with those treated with zidovudine alone.
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Studies have demonstrated that the clinical benefit of monotherapy with antiretrovirals,
including VIDEX, was time limited.
CONTRAINDICATION
VIDEX (didanosine) is contraindicated in patients with previously demonstrated clinically
significant hypersensitivity to any of the components of the formulations.
WARNINGS
1.
Pancreatitis
FATAL AND NONFATAL PANCREATITIS HAVE OCCURRED DURING
THERAPY WITH VIDEX USED ALONE OR IN COMBINATION REGIMENS IN
BOTH TREATMENT-NAIVE AND TREATMENT-EXPERIENCED PATIENTS,
REGARDLESS OF DEGREE OF IMMUNOSUPPRESSION. VIDEX SHOULD BE
SUSPENDED IN PATIENTS WITH SIGNS OR SYMPTOMS OF PANCREATITIS
AND DISCONTINUED IN PATIENTS WITH CONFIRMED PANCREATITIS.
PATIENTS TREATED WITH VIDEX IN COMBINATION WITH STAVUDINE,
WITH OR WITHOUT HYDROXYUREA, MAY BE AT INCREASED RISK FOR
PANCREATITIS.
When treatment with life-sustaining drugs known to cause pancreatic toxicity is
required, suspension of VIDEX (didanosine) therapy is recommended. In patients with risk
factors for pancreatitis, VIDEX should be used with extreme caution and only if clearly
indicated. Patients with advanced HIV infection, especially the elderly, are at increased risk of
pancreatitis and should be followed closely. Patients with renal impairment may be at greater
risk for pancreatitis if treated without dose adjustment.
The frequency of pancreatitis is dose related. In phase 3 studies, incidence ranged from
1% to 10% with doses higher than are currently recommended and 1% to 7% with
recommended dose.
In pediatric phase 1 studies, pancreatitis occurred in 3% (2/60) of patients treated at
entry doses below 300 mg/m2/day and in 13% (5/38) of patients treated at higher doses. In
study ACTG 152, pancreatitis occurred in none of the 281 pediatric patients who received
didanosine 120 mg/m2 q12h and in <1% of the 274 pediatric patients who received didanosine
90 mg/m2 q12h in combination with zidovudine. VIDEX use should be suspended in pediatric
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patients with signs or symptoms of pancreatitis and discontinued in pediatric patients with
confirmed pancreatitis.
2.
Lactic Acidosis/Severe Hepatomegaly with Steatosis
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have
been reported with the use of nucleoside analogues alone or in combination, including
didanosine and other antiretrovirals. A majority of these cases have been in women.
Obesity and prolonged nucleoside exposure may be risk factors. Fatal lactic acidosis has been
reported in pregnant women who received the combination of didanosine and stavudine with
other antiretroviral agents. The combination of didanosine and stavudine should be used with
caution during pregnancy and is recommended only if the potential benefit clearly outweighs
the potential risk (see PRECAUTIONS: Pregnancy). Particular caution should be exercised
when administering VIDEX to any patient with known risk factors for liver disease; however,
cases have also been reported in patients with no known risk factors. Treatment with VIDEX
should be suspended in any patient who develops clinical or laboratory findings suggestive of
symptomatic hyperlactatemia, lactic acidosis, or pronounced hepatotoxicity (which may
include hepatomegaly and steatosis even in the absence of marked transaminase elevations).
3.
Retinal Changes and Optic Neuritis
Retinal changes and optic neuritis have been reported in adult and pediatric patients.
Periodic retinal examinations should be considered for patients receiving VIDEX. (See
ADVERSE REACTIONS.)
PRECAUTIONS
Frequency of Dosing
The preferred dosing frequency of VIDEX is twice daily because there is more evidence to
support the effectiveness of this dosing frequency. Once-daily dosing should be considered
only for adult patients whose management requires once-daily dosing of VIDEX (see
INDICATIONS AND USAGE: Clinical Studies).
VIDEX should be taken on an empty stomach, at least 30 minutes before or 2
hours after eating.
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Peripheral Neuropathy
Peripheral neuropathy, manifested by numbness, tingling, or pain in the hands or feet, has been
reported in patients receiving VIDEX therapy. Peripheral neuropathy has occurred more
frequently in patients with advanced HIV disease, in patients with a history of neuropathy, or
in patients being treated with neurotoxic drug therapy, including stavudine (see ADVERSE
REACTIONS).
Fat Redistribution
Redistribution/accumulation of body fat including central obesity, dorsocervical fat
enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and
“cushingoid appearance” have been observed in patients receiving antiretroviral therapy. The
mechanism and long-term consequences of these events are currently unknown. A causal
relationship has not been established.
General
Patients with Phenylketonuria: VIDEX Chewable/Dispersible Buffered Tablets contain
the following quantities of phenylalanine:
Table 6
All Strengths
Phenylalanine per 2-tablet dose
73 mg
Phenylalanine per tablet
36.5 mg
Patients on Sodium-Restricted Diets: VIDEX Buffered Powder for Oral
Solution: Each single-dose packet of VIDEX Buffered Powder for Oral Solution contains 1380
mg sodium.
Patients with Renal Impairment: Patients with renal impairment (creatinine
clearance <60 mL/min) may be at greater risk of toxicity from VIDEX due to decreased drug
clearance (see CLINICAL PHARMACOLOGY). A dose reduction is recommended in these
patients (see DOSAGE AND ADMINISTRATION). The magnesium content of each
buffered tablet of VIDEX is 8.6 mEq. This may present an excessive load of magnesium to
patients with significant renal impairment, particularly after prolonged dosing.
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Patients with Hepatic Impairment: It is unknown if hepatic impairment
significantly affects didanosine pharmacokinetics. Therefore, these patients should be
monitored closely for evidence of didanosine toxicity.
Hyperuricemia: VIDEX has been associated with asymptomatic hyperuricemia;
treatment suspension may be necessary if clinical measures aimed at reducing uric acid levels
fail.
Information for Patients (See Patient Information Leaflet.)
Patients should be informed that a serious toxicity of VIDEX used alone and in combination
regimens, is pancreatitis, which may be fatal.
Patients should be informed that the preferred dosing frequency of VIDEX is twice
daily because there is more evidence to support the effectiveness of this dosing frequency.
Once-daily dosing should be considered only for adult patients whose management requires
once-daily dosing of VIDEX.
Patients should also be aware that peripheral neuropathy, manifested by numbness,
tingling, or pain in hands or feet, may develop during therapy with VIDEX. Patients should be
counseled that peripheral neuropathy occurs with greatest frequency in patients with advanced
HIV disease or a history of peripheral neuropathy, and that dose modification and/or
discontinuation of VIDEX may be required if toxicity develops.
Patients should be informed that when VIDEX is used in combination with other
agents with similar toxicities, the incidence of adverse events may be higher than when
VIDEX is used alone. These patients should be followed closely.
Patients should be cautioned about the use of medications or other substances,
including alcohol, that may exacerbate VIDEX toxicities.
Patients should be advised that to ensure proper acid neutralization in the stomach they
must take at least two of the appropriate strength VIDEX tablets at each dose. To reduce the
risk of gastrointestinal side effects from excess antacid, patients should take no more than four
VIDEX tablets at each dose.
VIDEX (didanosine) is not a cure for HIV infection, and patients may continue to
develop HIV-associated illnesses, including opportunistic infection. Therefore, patients should
remain under the care of a physician when using VIDEX. Patients should be advised that
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VIDEX therapy has not been shown to reduce the risk of transmission of HIV to others
through sexual contact or blood contamination. Patients should be informed that the long-term
effects of VIDEX are unknown at this time.
Patients should be informed that redistribution or accumulation of body fat may occur
in patients receiving antiretroviral therapy and that the cause and long-term health effects of
these conditions are not known at this time.
Drug Interactions (see also CLINICAL PHARMACOLOGY: Drug
Interactions)
Drug interactions that have been established based on drug interaction studies are listed with
the pharmacokinetic results in CLINICAL PHARMACOLOGY: Drug Interactions (Tables
3 and 4). The clinical recommendations based on the results of these studies are listed in Table
7.
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Table 7:
Established Drug Interactions with VIDEX
Coadministration Not Recommended Based on Drug Interaction Studies (see CLINICAL
PHARMACOLOGY: Drug Interactions for Magnitude of Interaction)
Drug
Effect
Clinical Comment
allopurinol
↑ didanosine concentration
Coadministration not recommended.
Alteration in Dose or Regimen Recommended Based on Drug Interaction Studies (see CLINICAL
PHARMACOLOGY: Drug Interactions for Magnitude of Interaction)
Drug
Effect
Clinical Comment
ciprofloxacin
↓ ciprofloxacin concentration
Administer VIDEX at least 2 hours after or
6 hours before ciprofloxacin.
delavirdine
↓ delavirdine concentration
Administer VIDEX 1 hour after delavirdine.
ganciclovir
↑ didanosine concentration
Appropriate doses for this combination,
with respect to efficacy and safety, have not
been established.
indinavir
↓ indinavir concentration
Administer VIDEX 1 hour after indinavir.
methadone
↓ didanosine concentration
Appropriate doses for this combination,
with respect to efficacy and safety, have not
been established.
nelfinavir
No interaction 1 hour after didanosine
Administer nelfinavir 1 hour after VIDEX.
tenofovir
disoproxil fumarate
↑ didanosine concentration
Appropriate doses for this combination,
with respect to efficacy and safety, have not
been established. Use with caution and
monitor closely for didanosine-associated
toxicities (see below).
↑ indicates increase.
↓ indicates decrease.
Coadministration of VIDEX with drugs that are known to cause pancreatitis may
increase the risk of this toxicity (see WARNINGS: Pancreatitis). Because VIDEX
formulations either contain buffers or are mixed with antacids before administration,
interactions may be anticipated with drugs whose absorption can be affected by the level of
acidity in the stomach and with drugs that have been demonstrated to interact with antacids
containing magnesium, calcium, or aluminum. Predicted drug interactions with VIDEX are
listed in Table 8.
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Table 8:
Predicted Drug Interactions with VIDEX
Use with Caution, Risk of Adverse Reactions May Be Increased
Drug or Drug Class
Effect
Clinical Comment
Drugs that may cause
pancreatic toxicity
↑ risk of pancreatitis
Use only with extreme caution.a
Neurotoxic drugs
↑ risk of neuropathy
Use with caution.b
Antacids containing
magnesium or aluminum
↑ side effects associated with
antacid components
Use caution with VIDEX
Chewable/Dispersible Buffered Tablets
and Pediatric Powder for Oral Solution.
Ribavirin
↑ risk of toxicity
Ribavirin has been shown in vitro to
increase intracellular triphosphate levels of
didanosine. Use with caution and monitor
closely for didanosine-associated toxicities
(see below).
Use with Caution, Plasma Concentrations May Be Decreased by Coadministration with VIDEX
Drug Class
Effect
Clinical Comment
Azole antifungals
↓ ketoconazole or itraconazole
concentration
Administer drugs such as ketoconazole or
itraconazole at least 2 hours before
VIDEX.
Quinolone antibiotics (see
also ciprofloxacin in
Table 7)
↓ quinolone concentration
Consult package insert of the quinolone.
Tetracycline antibiotics
↓ antibiotic concentration
Consult package insert of the tetracycline.
↑ indicates increase.
↓ indicates decrease.
a Only if other drugs are not available and if clearly indicated. If treatment with life-sustaining drugs that
cause pancreatic toxicity is required, suspension of VIDEX is recommended (see WARNINGS:
Pancreatitis).
b See PRECAUTIONS: Peripheral Neuropathy.
Tenofovir disoproxil fumarate or ribavirin. Exposure to didanosine or its active metabolite
(dideoxyadenosine 5’-triphosphate) is increased when didanosine is coadministered with either
tenofovir (see Tables 3 and 7) or ribavirin (see Table 8). Increased exposure may cause or
worsen didanosine-related clinical toxicities, including pancreatitis, symptomatic
hyperlactatemia/lactic acidosis, and peripheral neuropathy. Coadministration of
tenofovir or ribavirin with VIDEX should be undertaken with caution, and patients
should be monitored closely for didanosine-related toxicities. VIDEX should be
suspended if signs or symptoms of pancreatitis, symptomatic hyperlactatemia, or lactic
acidosis develop (see WARNINGS).
Carcinogenesis and Mutagenesis
Lifetime carcinogenicity studies were conducted in mice and rats for 22 and 24 months,
respectively. In the mouse study, initial doses of 120, 800, and 1200 mg/kg/day for each sex
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Page 22 of 39
were lowered after 8 months to 120, 210, and 210 mg/kg/day for females and 120, 300, and
600 mg/kg/day for males. The two higher doses exceeded the maximally tolerated dose in
females and the high dose exceeded the maximally tolerated dose in males. The low dose in
females represented 0.68-fold maximum human exposure and the intermediate dose in males
represented 1.7-fold maximum human exposure based on relative AUC comparisons. In the
rat study, initial doses were 100, 250, and 1000 mg/kg/day, and the high dose was lowered to
500 mg/kg/day after 18 months. The upper dose in male and female rats represented 3-fold
maximum human exposure.
Didanosine induced no significant increase in neoplastic lesions in mice or rats at
maximally tolerated doses.
Didanosine was positive in the following genetic toxicology assays: 1) the Escherichia
coli tester strain WP2 uvrA bacterial mutagenicity assay; 2) the L5178Y/TK+/- mouse
lymphoma mammalian cell gene mutation assay; 3) the in vitro chromosomal aberrations assay
in cultured human peripheral lymphocytes; 4) the in vitro chromosomal aberrations assay in
Chinese Hamster Lung cells; and 5) the BALB/c 3T3 in vitro transformation assay. No
evidence of mutagenicity was observed in an Ames Salmonella bacterial mutagenicity assay or
in rat and mouse in vivo micronucleus assays.
Pregnancy, Reproduction, and Fertility
Pregnancy Category B. Reproduction studies have been performed in rats and rabbits at doses
up to 12 and 14.2 times the estimated human exposure (based upon plasma levels),
respectively, and have revealed no evidence of impaired fertility or harm to the fetus due to
didanosine. At approximately 12 times the estimated human exposure, didanosine was slightly
toxic to female rats and their pups during mid and late lactation. These rats showed reduced
food intake and body weight gains but the physical and functional development of the
offspring was not impaired and there were no major changes in the F2 generation. A study in
rats showed that didanosine and/or its metabolites are transferred to the fetus through the
placenta. Animal reproduction studies are not always predictive of human response.
There are no adequate and well-controlled studies of didanosine in pregnant women.
Didanosine should be used during pregnancy only if the potential benefit justifies the potential
risk.
Fatal lactic acidosis has been reported in pregnant women who received the
combination of didanosine and stavudine with other antiretroviral agents. It is unclear if
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pregnancy augments the risk of lactic acidosis/hepatic steatosis syndrome reported in
nonpregnant individuals receiving nucleoside analogues (see WARNINGS: Lactic
Acidosis/Severe Hepatomegaly with Steatosis). The combination of didanosine and
stavudine should be used with caution during pregnancy and is recommended only if the
potential benefit clearly outweighs the potential risk. Health care providers caring for HIV-
infected pregnant women receiving didanosine should be alert for early diagnosis of lactic
acidosis/hepatic steatosis syndrome.
Antiretroviral Pregnancy Registry: To monitor maternal-fetal outcomes of
pregnant women exposed to didanosine and other antiretroviral agents, an Antiretroviral
Pregnancy Registry has been established. Physicians are encouraged to register patients by
calling 1-800-258-4263.
Nursing Mothers
The Centers for Disease Control and Prevention recommend that HIV-infected mothers
not breast-feed their infants to avoid risking postnatal transmission of HIV. A study in
rats showed that following oral administration, didanosine and/or its metabolites were excreted
into the milk of lactating rats. It is not known if didanosine is excreted in human milk.
Because of both the potential for HIV transmission and the potential for serious adverse
reactions in nursing infants, mothers should be instructed not to breast-feed if they are
receiving VIDEX.
Pediatric Use
Use of VIDEX in pediatric patients from 2 weeks of age through adolescence is supported by
evidence from adequate and well-controlled studies of VIDEX in adults and pediatric patients
(see INDICATIONS AND USAGE: Clinical Studies, CLINICAL PHARMACOLOGY,
ADVERSE REACTIONS, and DOSAGE AND ADMINISTRATION).
Dosing recommendations for VIDEX in patients less than 2 weeks of age cannot be
made because the pharmacokinetics of didanosine in these children are too variable to
determine an appropriate dose.
Geriatric Use
In an Expanded Access Program for patients with advanced HIV infection, patients aged 65
years and older had a higher frequency of pancreatitis (10%) than younger patients (5%) (see
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WARNINGS). Clinical studies of didanosine did not include sufficient numbers of subjects
aged 65 years and over to determine whether they respond differently than younger subjects.
Didanosine is known to be substantially excreted by the kidney, and the risk of toxic reactions
to this drug may be greater in patients with impaired renal function. Because elderly patients
are more likely to have decreased renal function, care should be taken in dose selection. In
addition, renal function should be monitored and dosage adjustments should be made
accordingly (see DOSAGE AND ADMINISTRATION: Dose Adjustment).
ADVERSE REACTIONS
A SERIOUS TOXICITY OF VIDEX (didanosine) IS PANCREATITIS, WHICH MAY BE
FATAL (see WARNINGS). OTHER IMPORTANT TOXICITIES INCLUDE LACTIC
ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS; RETINAL CHANGES AND
OPTIC NEURITIS; AND PERIPHERAL NEUROPATHY (see WARNINGS and
PRECAUTIONS).
When VIDEX is used in combination with other agents with similar toxicities, the
incidence of these toxicities may be higher than when VIDEX is used alone. Thus,
patients treated with VIDEX in combination with stavudine, with or without
hydroxyurea, may be at increased risk for pancreatitis, which may be fatal, and
hepatotoxicity (see WARNINGS). Patients treated with VIDEX in combination with
stavudine may also be at increased risk for peripheral neuropathy (see
PRECAUTIONS).
Adults: Selected clinical adverse events that occurred in adult patients in clinical
studies with VIDEX are provided in Tables 9 and 10.
Table 9:
Selected Clinical Adverse Events from Monotherapy
Studies
Percent of Patients
ACTG 116A
ACTG 116B/117
Adverse Events
VIDEX
n=197
zidovudine
n=212
VIDEX
n=298
zidovudine
n=304
Diarrhea
19
15
28
21
Peripheral Neurologic
Symptoms/Neuropathy
17
14
20
12
Rash/Pruritus
7
8
9
5
Abdominal Pain
13
8
7
8
Pancreatitis
7
3
6
2
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Table 10:
Selected Clinical Adverse Events from Combination
Studies
Percent of Patientsa
AI454-148b
START 2b
Adverse Events
VIDEX +
stavudine +
nelfinavir
n=482
zidovudine +
lamivudine +
nelfinavir
n=248
VIDEX +
stavudine +
indinavir
n=102
zidovudine +
lamivudine +
indinavir
n=103
Diarrhea
70
60
45
39
Nausea
28
40
53
67
Headache
21
30
46
37
Peripheral Neurologic
Symptoms/Neuropathy
26
6
21
10
Rash
13
16
30
18
Vomiting
12
14
30
35
Pancreatitis (see below)
1
*
<1
*
a Percentages based on treated subjects.
b Median duration of treatment 48 weeks.
* This event was not observed in this study arm.
Pancreatitis resulting in death was observed in one patient who received VIDEX
(didanosine) plus stavudine plus nelfinavir in Study Al454-148 and in one patient who
received VIDEX plus stavudine plus indinavir in the START 2 study. In addition,
pancreatitis resulting in death was observed in 2 of 68 patients who received VIDEX plus
stavudine plus indinavir plus hydroxyurea in an ACTG clinical trial (see WARNINGS).
The frequency of pancreatitis is dose related. In phase 3 studies, incidence ranged from
1% to 10% with doses higher than are currently recommended and from 1% to 7% with
recommended dose.
Selected laboratory abnormalities in clinical studies with VIDEX are shown in
Tables 11-13.
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Page 26 of 39
Table 11:
Selected Laboratory Abnormalities from Monotherapy Studies
Percent of Patients
ACTG 116A
ACTG 116B/117
VIDEX
zidovudine
VIDEX
zidovudine
Parameter
n=197
n=212
n=298
n=304
SGOT (AST) (>5 x ULN)
9
4
7
6
SGPT (ALT) (>5 x ULN)
9
6
6
6
Alkaline phosphatase (>5 x ULN)
4
1
1
1
Amylase (≥1.4 x ULN)
17
12
15
5
Uric acid (>12 mg/dL)
3
1
2
1
ULN = upper limit of normal.
Table 12:
Selected Laboratory Abnormalities from Combination Studies
(Grades 3-4)
Percent of Patientsa
AI454-148b
START 2b
VIDEX +
stavudine +
nelfinavir
zidovudine +
lamivudine +
nelfinavir
VIDEX +
stavudine +
indinavir
zidovudine +
lamivudine +
indinavir
Parameter
n=482
n=248
n=102
n=103
Bilirubin (>2.6 x ULN)
<1
<1
16
8
SGOT (AST) (>5 x ULN)
3
2
7
7
SGPT (ALT) (>5 x ULN)
3
3
8
5
GGT (>5 x ULN)
NC
NC
5
2
Lipase (>2 x ULN)
7
2
5
5
Amylase (>2 x ULN)
NC
NC
8
2
ULN = upper limit of normal.
NC=Not Collected.
a Percentages based on treated subjects.
b Median duration of treatment 48 weeks.
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Table 13:
Selected Laboratory Abnormalities from Combination
Studies (All Grades)
Percent of Patientsa
I454-148b
START 2b
Parameter
VIDEX +
stavudine +
nelfinavir
n=482
zidovudine +
lamivudine +
nelfinavir
n=248
VIDEX +
stavudine +
indinavir
n=102
zidovudine +
lamivudine +
indinavir
n=103
Bilirubin
7
3
68
55
SGOT (AST)
42
23
53
20
SGPT (ALT)
37
24
50
18
GGT
NC
NC
28
12
Lipase
17
11
26
19
Amylase
NC
NC
31
17
NC = Not Collected.
a Percentages based on treated subjects.
b Median duration of treatment 48 weeks.
Observed during Clinical Practice: The following events have been identified
during postapproval use of VIDEX (didanosine). Because they are reported voluntarily from a
population of unknown size, estimates of frequency cannot be made. These events have been
chosen for inclusion due to their seriousness, frequency of reporting, causal connection to
VIDEX, or a combination of these factors.
Body as a Whole - alopecia, anaphylactoid reaction, asthenia, chills/fever, pain, and
redistribution/accumulation of body fat (see PRECAUTIONS: Fat Redistribution).
Digestive Disorders- anorexia, dyspepsia, and flatulence.
Exocrine Gland Disorders – pancreatitis (including fatal cases) (see WARNINGS),
sialoadenitis, parotid gland enlargement, dry mouth, and dry eyes.
Hematologic Disorders - anemia, leukopenia, and thrombocytopenia.
Liver - symptomatic hyperlactatemia/lactic acidosis and hepatic steatosis (see
WARNINGS); hepatitis and liver failure.
Metabolic Disorders - diabetes mellitus, hypoglycemia, and hyperglycemia.
Musculoskeletal Disorders - myalgia (with or without increases in creatine kinase),
rhabdomyolysis including acute renal failure and hemodialysis, arthralgia, and
myopathy.
Ophthalmologic Disorders - Retinal depigmentation and optic neuritis (see
WARNINGS).
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Pediatric Patients: In clinical trials, 743 pediatric patients between 2 weeks and 18
years of age have been treated with VIDEX. Adverse events and laboratory abnormalities
reported to occur in these patients were generally consistent with the safety profile of
didanosine in adults.
In pediatric phase 1 studies, pancreatitis occurred in 2 of 60 (3%) patients treated at
entry doses below 300 mg/m2/day and in 5 of 38 (13%) patients treated at higher doses. In
study ACTG 152, pancreatitis occurred in none of the 281 pediatric patients who received
didanosine 120 mg/m2 q12h and in <1% of the 274 pediatric patients who received didanosine
90 mg/m2 q12h in combination with zidovudine (see INDICATIONS AND USAGE:
Clinical Studies).
Retinal changes and optic neuritis have been reported in pediatric patients.
OVERDOSAGE
There is no known antidote for VIDEX (didanosine) overdosage. In phase 1 studies, in which
VIDEX was initially administered at doses ten times the currently recommended dose,
toxicities included: pancreatitis, peripheral neuropathy, diarrhea, hyperuricemia and hepatic
dysfunction. Didanosine is not dialyzable by peritoneal dialysis, although there is some
clearance by hemodialysis (see CLINICAL PHARMACOLOGY: Pharmacokinetics).
DOSAGE AND ADMINISTRATION
Dosage
All VIDEX formulations should be administered on an empty stomach, at least 30
minutes before or 2 hours after eating. For either a once-daily or twice-daily regimen,
patients must take at least two of the appropriate strength tablets at each dose to provide
adequate buffering and prevent gastric acid degradation of didanosine. Because of the
need for adequate buffering, the 200-mg strength tablet should only be used as a
component of a once-daily regimen. To reduce the risk of gastrointestinal side effects,
patients should take no more than four tablets at each dose.
Adults: The preferred dosing frequency of VIDEX is twice daily because there is
more evidence to support the effectiveness of this dosing regimen. Once-daily dosing should
be considered only for adult patients whose management requires once-daily dosing of VIDEX
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(see INDICATIONS AND USAGE: Clinical Studies). The daily dose in adult patients is
dependent on weight as outlined in Table 14.
Table 14:
Adult Dosing
Patient Weight
VIDEX Tabletsa
VIDEX Buffered Powderb
Preferred dosing
≥60 kg
200 mg twice daily
250 mg twice daily
< 60 kg
125 mg twice daily
167 mg twice daily
Dosing for patients whose management requires once-daily frequency
≥ 60 kg
400 mg once daily
b
< 60 kg
250 mg once daily
b
a The 200-mg strength tablet should only be used as a component of a once-daily
regimen.
b Not suitable for once-daily dosing except for patients with renal impairment.
See Table 15.
Pediatric Patients: The recommended dose of VIDEX (didanosine) in pediatric
patients between 2 weeks and 8 months of age is 100 mg/m2 twice daily, and the
recommended VIDEX dose for pediatric patients older than 8 months is 120 mg/m2 twice
daily.
Dosing recommendations for VIDEX in patients less than 2 weeks of age cannot be
made because the pharmacokinetics of didanosine in these children are too variable to
determine an appropriate dose. There are no data on once-daily dosing of VIDEX in pediatric
patients.
Dose Adjustment
Clinical and laboratory signs suggestive of pancreatitis should prompt dose suspension
and careful evaluation of the possibility of pancreatitis. VIDEX use should be
discontinued in patients with confirmed pancreatitis (see WARNINGS and
PRECAUTIONS: Drug Interactions).
Patients with symptoms of peripheral neuropathy may tolerate a reduced dose of
VIDEX after resolution of the symptoms of peripheral neuropathy upon drug discontinuation.
If neuropathy recurs after resumption of VIDEX, permanent discontinuation of VIDEX should
be considered.
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Renal Impairment: In adult patients with impaired renal function, the dose of
VIDEX should be adjusted to compensate for the slower rate of elimination. The
recommended doses and dosing intervals of VIDEX in adult patients with renal insufficiency
are presented in Table 15.
Table 15:
Recommended Dosage of VIDEX in Renal Impairment
≥ 60 kg
< 60 kg
Creatinine Clearance
(mL/min)
Tableta
(mg)
Buffered Powderb
(mg)
Tableta
(mg)
Buffered Powderb
(mg)
≥60
200 twice dailyc
250 twice daily
125 twice dailyc
167 twice daily
30-59
200 once daily
or 100 twice daily
100 twice daily
150 once daily
or 75 twice daily
100 twice daily
10-29
150 once daily
167 once daily
100 once daily
100 once daily
<10
100 once daily
100 once daily
75 once daily
100 once daily
a VIDEX Chewable/Dispersible Buffered Tablet. Two VIDEX tablets must be taken with each dose;
different strengths of tablets may be combined to yield the recommended dose.
b VIDEX Buffered Powder for Oral Solution.
c 400 mg once daily (≥60 kg) or 250 mg once daily (<60 kg) for patients whose management requires once-
daily frequency of administration.
Urinary excretion is also a major route of elimination of didanosine in pediatric
patients; therefore, the clearance of didanosine may be altered in children with renal
impairment. Although there are insufficient data to recommend a specific dose adjustment of
VIDEX in this patient population, a reduction in the dose and/or an increase in the interval
between doses should be considered.
Patients Requiring Continuous Ambulatory Peritoneal Dialysis (CAPD) or
Hemodialysis: For patients requiring CAPD or hemodialysis, follow dosing
recommendations for patients with creatinine clearance less than 10 mL/min, shown in Table
15. It is not necessary to administer a supplemental dose of VIDEX following hemodialysis.
Hepatic Impairment: See WARNINGS and PRECAUTIONS.
Method of Preparation
VIDEX Chewable/Dispersible Buffered Tablets
Adult Dosing: To provide adequate buffering, at least two of the appropriate strength tablets,
but no more than four tablets, should be thoroughly chewed or dispersed in at least 1 ounce of
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Page 31 of 39
water prior to consumption (see PRECAUTIONS: Information for Patients). To disperse
tablets, add 2 tablets to at least 1 ounce of drinking water. Stir until a uniform dispersion
forms, and drink the entire dispersion immediately. If additional flavoring is desired, the
dispersion may be diluted with one ounce of clear apple juice. Stir the further diluted
dispersion just prior to consumption. The dispersion with clear apple juice is stable at room
temperature, 62° to 73°F (17° to 23°C), for up to one hour.
VIDEX Buffered Powder for Oral Solution
1.
Open packet carefully and pour contents into a container with approximately 4 ounces
of drinking water. Do not mix with fruit juice or other acid-containing liquid.
2.
Stir until the powder completely dissolves (approximately 2 to 3 minutes).
3.
Drink the entire solution immediately.
VIDEX Pediatric Powder for Oral Solution
Prior to dispensing, the pharmacist must constitute dry powder with Purified Water, USP, to an
initial concentration of 20 mg/mL and immediately mix the resulting solution with antacid to a
final concentration of 10 mg/mL as follows:
20 mg/mL Initial Solution: Constitute the product to 20 mg/mL by adding 100 mL or
200 mL of Purified Water, USP, to the 2 g or 4 g of VIDEX powder, respectively, in the
product bottle.
10 mg/mL Final Admixture: 1. Immediately mix one part of the 20 mg/mL initial
solution with one part of either Mylanta® Double Strength Liquid, Extra Strength Maalox®
Plus Suspension, or Maalox ® TC Suspension for a final dispensing concentration of 10 mg
VIDEX per mL. For patient home use, the admixture should be dispensed in appropriately
sized, flint-glass or plastic (HDPE, PET, or PETG) bottles with child-resistant closures. This
admixture is stable for 30 days under refrigeration, 36° to 46° F (2° to 8° C).
2. Instruct the patient to shake the admixture thoroughly prior to use and to store the
tightly closed container in the refrigerator, 36° to 46° F (2° to 8° C), up to 30 days.
Mylanta® is a registered trademark of Johnson & Johnson-Merck Consumer Pharmaceuticals Company.
Maalox® is a registered trademark of Novartis Consumer Health, Inc.
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HOW SUPPLIED
VIDEX® (didanosine) Chewable/Dispersible Buffered Tablets are round, off white to light
orange/yellow with a mottled appearance, orange-flavored, tablets embossed with "VIDEX" on
one side and the product strength on the other. The tablets are available in the following
strengths of VIDEX: 25, 50, 100, 150, and 200 mg. Sixty tablets are packaged in bottles with
child-resistant closures.
The tablets should be stored in tightly closed bottles at 59° to 86° F (15° to 30 °C).
If dispersed in water, the dose may be held for up to 1 hour at ambient temperature.
VIDEX (didanosine) Buffered Powder for Oral Solution is supplied in single-dose,
child-resistant foil packets in the following strengths of VIDEX: 100, 167, or 250 mg. Each
product strength provides a sweetened, buffered solution of VIDEX.
The packets should be stored at 59° to 86° F (15° to 30° C). After dissolving in water,
the solution may be stored at ambient room temperature for up to 4 hours.
VIDEX (didanosine) Pediatric Powder for Oral Solution is supplied in 4- and 8-
ounce glass bottles containing 2 g or 4 g of VIDEX, respectively.
The bottles of powder should be stored at 59° to 86° F (15° to 30° C). The VIDEX
admixture may be stored up to 30 days in a refrigerator, 36° to 46° F (2° to 8° C). Discard any
unused portion after 30 days.
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The NDC numbers for the previously described VIDEX products are:
Table 16
NDC NO.
Packaging Information
Product Strength
VIDEX
Chewable/Dispersible Buffered Tablets
0087-6650-01
60 tablets/bottle
25 mg/tablet
0087-6651-01
60 tablets/bottle
50 mg/tablet
0087-6652-01
60 tablets/bottle
100 mg/tablet
0087-6653-01
60 tablets/bottle
150 mg/tablet
0087-6665-15
60 tablets/bottle
200 mg/tablet
VIDEX
Buffered Powder for Oral Solution
0087-6614-43
One single-dose foil packet*
100 mg/packet
0087-6615-43
One single-dose foil packet*
167 mg/packet
0087-6616-43
One single-dose foil packet*
250 mg/packet
VIDEX
Pediatric Powder for Oral Solution
0087-6632-41
One bottle per carton
2 g/bottle
0087-6633-41
One bottle per carton
4 g/bottle
* Packaged as 30 packets per carton.
US Patent Nos.: 4,861,759 and 5,616,566.
HANDLING AND DISPOSAL
Spill, Leak, and Disposal Procedure
Avoid generating dust during clean-up of powdered products; use wet mop or damp sponge.
Clean surface with soap and water as necessary. Containerize larger spills.
There is no single preferred method of disposal of containerized waste. Disposal
options include incineration, landfill, or sewer as dictated by specific circumstances and
relevant national, state, and local regulations.
Bristol-Myers Squibb Virology
Bristol-Myers Squibb Company
Princeton, NJ 08543 USA
XXXXXX
Revised _____________________
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 34 of 39
PATIENT INFORMATION
Rx only
VIDEX®
(generic name = didanosine also known as ddI)
VIDEX® (didanosine) Chewable/Dispersible Buffered Tablets
VIDEX® (didanosine) Buffered Powder for Oral Solution
VIDEX® (didanosine) Pediatric Powder for Oral Solution
What is VIDEX?
VIDEX (pronounced VY dex) is a prescription medicine used in combination with other drugs
to treat children and adults who are infected with HIV (the human immunodeficiency virus, the
virus that causes AIDS). VIDEX belongs to a class of drugs called nucleoside analogues. By
reducing the growth of HIV, VIDEX helps your body maintain its supply of CD4 cells, which
are important for fighting HIV and other infections.
VIDEX will not cure your HIV infection. At present there is no cure for HIV infection.
Even while taking VIDEX, you may continue to have HIV-related illnesses, including infections
with other disease-producing organisms. Continue to see your doctor regularly and report any
medical problems that occur.
VIDEX does not prevent a patient infected with HIV from passing the virus to other
people. To protect others, you must continue to practice safe sex and take precautions to
prevent others from coming in contact with your blood and other body fluids.
There is limited information on the effects of long-term use of VIDEX.
Who should not take VIDEX?
Do not take VIDEX if you are allergic to any of its ingredients, including its active ingredient,
didanosine and the inactive ingredients. (See Inactive Ingredients at the end of this leaflet.) Tell
your doctor if you think you have had an allergic reaction to any of these ingredients.
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How should I take VIDEX? How should I store it?
Your doctor will determine your dose based on your body weight, kidney and liver function, other
medicines you are taking, and any side effects that you may have had with VIDEX or other
medicines. Take VIDEX on an empty stomach - that means at least 30 minutes before or 2
hours after eating. Do not take VIDEX with food. Try not to miss a dose, but if you do, take it as
soon as possible. If it is almost time for the next dose, skip the missed dose and continue your
regular dosing schedule.
Chewable/Dispersible Tablets: Each VIDEX tablet contains antacid. Each time
you take VIDEX, you must take at least two, but not more than four, tablets. This
is because VIDEX tablets contain an antacid to reduce the amount of acid in your
stomach. If you have too much acid, the medicine will break down. However, too
much antacid may cause stomach problems.
—DO NOT swallow VIDEX tablets whole. Chew the tablets well or mix them in
water. Many patients drop the tablets in at least one ounce of water and stir well
before swallowing. If you choose to mix the tablets in water, you may add one ounce
(2 tablespoons) of clear apple juice to the mixture for flavor (do not use any other kind
of juice).
—Store tablets in a tightly closed container at room temperature away from heat and
out of the reach of children and pets. Do NOT store the tablets in a damp place such as
a bathroom medicine cabinet or near the kitchen sink.
Buffered Powder for Oral Solution: Pour the contents of a packet into a glass with 4
ounces (1/2 measuring cup) of water. Stir until completely dissolved. Drink the entire
solution right away. Do not mix with fruit juice. Store packets at room temperature
before use.
Pediatric Oral Solution: Your pharmacist will prepare the oral solution. Shake
the solution well before each use. Store in the refrigerator. Throw away any unused
portion after 30 days.
If you have kidney disease: If your kidneys are not working properly, your doctor will
need to do regular tests to check how they are working while you take VIDEX. Your
doctor may also lower your dosage of VIDEX.
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What should I do if someone takes an overdose of VIDEX?
If someone may have taken an overdose of VIDEX, get medical help right away. Contact their
doctor or a poison control center.
What should I avoid while taking VIDEX?
Alcohol. Do not drink alcohol while taking VIDEX since alcohol may increase your risk of
pancreatitis (pain and inflammation of the pancreas) or liver damage.
Other medicines. Other medicines, including those you can buy without a prescription, may
interfere with the actions of VIDEX. Do not take any medicine, vitamin supplement, or
other health preparation without first checking with your doctor.
Antacids. Since VIDEX contains some of the same ingredients found in antacids, any
side effects related to VIDEX’s ingredients may get worse if you also take an antacid.
Medicines at the same time you take your VIDEX dose. Some medicines should not
be taken at the same time of day that you take VIDEX. Check with your doctor.
Pregnancy. It is not known if VIDEX can harm a human fetus. Also, pregnant women have
experienced serious side effects when taking VIDEX in combination with ZERIT (stavudine),
also known as d4T, and other HIV medicines. VIDEX should be used during pregnancy only
after discussion with your doctor. Tell your doctor if you become pregnant or plan to
become pregnant while taking VIDEX.
Nursing. Studies have shown VIDEX is in the breast milk of animals getting the drug. It may
also be in human breast milk. The Centers for Disease Control and Prevention (CDC)
recommends that HIV-infected mothers not breast-feed. This should reduce the risk of
passing HIV infection to their babies and the potential for serious adverse reactions in nursing
infants. Therefore, do not nurse a baby while taking VIDEX.
What are the possible side effects of VIDEX?
Pancreatitis. Pancreatitis is a dangerous inflammation of the pancreas that may cause death.
Tell your doctor right away if you or a child taking VIDEX develops stomach pain, nausea,
or vomiting. These can be signs of pancreatitis. Before starting VIDEX therapy, let your
doctor know if you or a child for whom it has been prescribed has ever had pancreatitis. This
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Page 37 of 39
condition is more likely to happen in people who have had it before. It is also more likely in people
with advanced HIV disease. However, it can occur at any stage of HIV disease. It may be more
common in patients with kidney problems, those who drink alcohol, and those who are also treated
with stavudine or hydroxyurea. If you get pancreatitis, your doctor will tell you to stop taking
VIDEX.
Lactic acidosis, severe liver enlargement, and liver failure, including deaths, have been
reported among patients taking VIDEX (including pregnant women). Symptoms that may
indicate a liver problem are:
• feeling very weak, tired, or uncomfortable,
• unusual or unexpected stomach discomfort,
• feeling cold,
• feeling dizzy or lightheaded,
• suddenly developing a slow or irregular heartbeat.
Lactic acidosis is a medical emergency that must be treated in a hospital.
If you notice any of these symptoms or if your medical condition changes, stop taking
VIDEX and call your doctor right away. Women, overweight patients, and those who have been
treated for a long time with other medicines used to treat HIV infection are more likely to develop
lactic acidosis. Your doctor should check your liver function periodically while you are taking
VIDEX. You should be especially careful if you have a history of heavy alcohol use or a liver
problem.
Vision changes. VIDEX may affect the nerves in your eyes. Because of this, you should have
regular eye examinations. You should also report any changes in vision to your doctor right away.
This includes, for example, seeing colors abnormally or blurred vision.
Peripheral neuropathy. This is a problem with the nerves in your hands or feet. The nerve
problem may be serious. Tell your doctor right away if you or a child taking VIDEX has
continuing numbness, tingling, or pain in the feet or hands. A child may not recognize these
symptoms or know to tell you that his or her feet or hands are numb, burning, tingling, or painful.
Ask your child’s doctor how to find out if your child is developing peripheral neuropathy.
Before starting VIDEX therapy, let your doctor know if you or a child for whom it has been
prescribed has ever had peripheral neuropathy. This condition is more likely to happen in people
who have had it before. It is also more likely in patients taking medicines that affect the nerves and
in people with advanced HIV disease. However, it can occur at any stage of HIV disease. If you
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Page 38 of 39
get peripheral neuropathy, your doctor will tell you to stop taking VIDEX. After stopping VIDEX,
the symptoms may get worse for a short time and then get better. Once symptoms of peripheral
neuropathy go away completely, you and your doctor should decide if starting VIDEX is right for
you. If so, you might be started at a lower dose.
Special note about other medicines. If you take VIDEX along with other medicines with similar
side effects, you may increase the chance of having these side effects. For example, using VIDEX
in combination with other medicines that may cause pancreatitis, peripheral neuropathy, or liver
problems (including stavudine and hydroxyurea) may increase your chance of having these side
effects.
Other side effects: The most common side effects in adults taking VIDEX are diarrhea, neuropathy
(nerve disorders), chills or fever, rash, abdominal pain, weakness, headache, and nausea and
vomiting. Children may have similar side effects as adults.
Changes in body fat have been seen in some patients taking antiretroviral therapy. These
changes may include increased amount of fat in the upper back and neck (“buffalo hump”), breast,
and around the trunk. Loss of fat from the legs, arms, and face may also happen. The cause and
long-term health effects of these conditions are not known at this time.
What else should I know about VIDEX?
If you should limit sodium (salt) intake: Each single-dose packet of Buffered Powder for
Oral Solution contains 1380 mg of sodium. Each Chewable/Dispersible Tablet contains 264.5
mg of sodium.
If you have phenylketonuria: Each Chewable/Dispersible Tablet contains 36.5 mg of
phenylalanine.
Inactive Ingredients:
Chewable/Dispersible Tablets: calcium carbonate, magnesium hydroxide, aspartame,
sorbitol, mandarin orange flavor, polyplasdone, microcrystalline cellulose, and
magnesium stearate.
Buffered Powder for Oral Solution: citrate-phosphate buffer (dibasic sodium
phosphate, sodium citrate, and citric acid) and sucrose.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 39 of 39
Pediatric Oral Solution: Mylanta Double Strength Liquid, Extra Strength
Maalox Plus or Maalox TC Suspension.
This medicine was prescribed for your particular condition. Do not use VIDEX for another condition or give it to
others. Keep VIDEX and all medicines out of the reach of children. Throw away VIDEX when it is outdated or
no longer needed by flushing it down the toilet or pouring it down the sink.
This summary does not include everything there is to know about VIDEX. Medicines are sometimes prescribed
for purposes other than those listed in a Patient Information Leaflet. If you have questions or concerns, or want more
information about VIDEX, your physician and pharmacist have the complete prescribing information upon which this
leaflet is based. You may want to read it and discuss it with your doctor or other healthcare professional. Remember, no
written summary can replace careful discussion with your doctor.
Mylanta® is a registered trademark of Johnson & Johnson-Merck Consumer Pharmaceuticals Company.
Maalox® is a registered trademark of Novartis Consumer Health, Inc.
Bristol-Myers Squibb Virology
Bristol-Myers Squibb Company
Princeton, NJ 08543 USA
This Patient Information Leaflet has been approved by the U.S. Food and Drug Administration.
xxxxxxxx
Revised __________________
Based on xxxxx (xx/02)
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
---------------------------------------------------------------------------------------------------------------------
This is a representation of an electronic record that was signed electronically and
this page is the manifestation of the electronic signature.
---------------------------------------------------------------------------------------------------------------------
/s/
---------------------
Debra Birnkrant
9/25/02 04:03:13 PM
NDA 20-156 NDA 20-155, NDA 20-154
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
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NDA 20-154/S-050
NDA 20-155/S-039
NDA 20-156/S-040
NDA 21-183/S-016
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Rx only
VIDEX® (didanosine)
VIDEX® (didanosine) Pediatric Powder for Oral Solution
(Patient Information Leaflet Included)
WARNING
FATAL AND NONFATAL PANCREATITIS HAVE OCCURRED DURING
THERAPY WITH VIDEX USED ALONE OR IN COMBINATION REGIMENS IN
BOTH TREATMENT-NAIVE AND TREATMENT-EXPERIENCED PATIENTS,
REGARDLESS OF DEGREE OF IMMUNOSUPPRESSION. VIDEX SHOULD BE
SUSPENDED IN PATIENTS WITH SUSPECTED PANCREATITIS AND
DISCONTINUED IN PATIENTS WITH CONFIRMED PANCREATITIS (SEE
WARNINGS).
LACTIC
ACIDOSIS
AND
SEVERE
HEPATOMEGALY
WITH
STEATOSIS, INCLUDING FATAL CASES, HAVE BEEN REPORTED WITH
THE USE OF NUCLEOSIDE ANALOGUES ALONE OR IN COMBINATION,
INCLUDING DIDANOSINE AND OTHER ANTIRETROVIRALS. FATAL
LACTIC ACIDOSIS HAS BEEN REPORTED IN PREGNANT WOMEN WHO
RECEIVED THE COMBINATION OF DIDANOSINE AND STAVUDINE WITH
OTHER ANTIRETROVIRAL AGENTS. THE COMBINATION OF DIDANOSINE
AND STAVUDINE SHOULD BE USED WITH CAUTION DURING PREGNANCY
AND IS RECOMMENDED ONLY IF THE POTENTIAL BENEFIT CLEARLY
OUTWEIGHS THE POTENTIAL RISK (SEE WARNINGS AND PRECAUTIONS:
PREGNANCY, REPRODUCTION, AND FERTILITY).
DESCRIPTION
VIDEX® (didanosine) is a brand name for didanosine (ddI), a synthetic purine nucleoside
analogue active against the Human Immunodeficiency Virus (HIV).
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VIDEX Pediatric Powder for Oral Solution is supplied for oral administration in 4-
or 8-ounce glass bottles containing 2 or 4 grams of didanosine, respectively.
Didanosine is also available as an enteric-coated formulation (VIDEX® EC
Delayed-Release Capsules). Please consult the prescribing information for VIDEX EC
(didanosine).
The chemical name for didanosine is 2',3'-dideoxyinosine. The structural formula is:
Didanosine is a white crystalline powder with the molecular formula C10H12N4O3
and a molecular weight of 236.2. The aqueous solubility of didanosine at 25° C and pH of
approximately 6 is 27.3 mg/mL. Didanosine is unstable in acidic solutions. For example,
at pH <3 and 37° C, 10% of didanosine decomposes to hypoxanthine in less than 2
minutes.
MICROBIOLOGY
Mechanism of Action
Didanosine is a synthetic nucleoside analogue of the naturally occurring nucleoside
deoxyadenosine in which the 3'-hydroxyl group is replaced by hydrogen. Intracellularly,
didanosine is converted by cellular enzymes to the active metabolite, dideoxyadenosine
5'-triphosphate. Dideoxyadenosine 5'-triphosphate inhibits the activity of HIV-1 reverse
transcriptase both by competing with the natural substrate, deoxyadenosine 5'-triphosphate,
and by its incorporation into viral DNA causing termination of viral DNA chain
elongation.
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In Vitro HIV Susceptibility
The in vitro anti-HIV-1 activity of didanosine was evaluated in a variety of HIV-1 infected
lymphoblastic cell lines and monocyte/macrophage cell cultures. The concentration of drug
necessary to inhibit viral replication by 50% (IC50) ranged from 2.5 to 10 µM (1 µM =
0.24 µg/mL) in lymphoblastic cell lines and 0.01 to 0.1 µM in monocyte/macrophage cell
cultures. The relationship between in vitro susceptibility of HIV to didanosine and the
inhibition of HIV replication in humans has not been established.
Drug Resistance
HIV-1 isolates with reduced sensitivity to didanosine have been selected in vitro and were
also obtained from patients treated with didanosine. Genetic analysis of isolates from
didanosine-treated patients showed mutations in the reverse transcriptase gene that resulted
in the amino acid substitutions K65R, L74V, and M184V. The L74V mutation was most
frequently observed in clinical isolates. Phenotypic analysis of HIV-1 isolates from 60
patients (some with prior zidovudine treatment) receiving 6 to 24 months of didanosine
monotherapy showed that isolates from 10 of 60 patients exhibited an average of a 10-fold
decrease in susceptibility to didanosine in vitro compared to baseline isolates. Clinical
isolates that exhibited a decrease in didanosine susceptibility harbored one or more
didanosine-associated mutations. The clinical relevance of genotypic and phenotypic
changes associated with didanosine therapy has not been established.
Cross-resistance
HIV-1 isolates from 2 of 39 patients receiving combination therapy for up to 2 years with
zidovudine and didanosine exhibited decreased susceptibility to zidovudine, didanosine,
zalcitabine, stavudine, and lamivudine in vitro. These isolates harbored five mutations
(A62V, V75I, F77L, F116Y, and Q151M) in the reverse transcriptase gene. In data from
clinical studies, the presence of thymidine analogue mutations (M41L, D67N, L210W,
T215Y, K219Q) has been shown to decrease the response to didanosine.
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CLINICAL PHARMACOLOGY
Animal Toxicology
Evidence of a dose-limiting skeletal muscle toxicity has been observed in mice and rats
(but not in dogs) following long-term (greater than 90 days) dosing with didanosine at
doses that were approximately 1.2 to 12 times the estimated human exposure. The
relationship of this finding to the potential of VIDEX (didanosine) to cause myopathy in
humans is unclear. However, human myopathy has been associated with administration of
VIDEX and other nucleoside analogues.
Pharmacokinetics
The pharmacokinetic parameters of didanosine are summarized in Table 1. Didanosine is
rapidly absorbed, with peak plasma concentrations generally observed from 0.25 to 1.50
hours following oral dosing. Increases in plasma didanosine concentrations were dose
proportional over the range of 50 to 400 mg. Steady-state pharmacokinetic parameters did
not differ significantly from values obtained after a single dose. Binding of didanosine to
plasma proteins in vitro was low (<5%). Based on data from in vitro and animal studies, it
is presumed that the metabolism of didanosine in man occurs by the same pathways
responsible for the elimination of endogenous purines.
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Table 1:
Mean ± SD Pharmacokinetic Parameters for Didanosine in
Adult and Pediatric Patients
Pediatric Patientsb
Parameter
Adult Patientsa
n
8 months to 19 years
n
2 weeks to 4 months
n
Oral bioavailability (%)
42 ± 12
6
25 ± 20
46
ND
Apparent volume of
distributionc (L/m2)
43.70 ± 8.90
6
28 ± 15
49
ND
CSF-plasma ratiod
21 ± 0.03%e
5
46%
(range 12-85%)
7
ND
Systemic clearancec
(mL/min/m2)
526 ± 64.7
6
516 ± 184
49
ND
Renal clearancef
(mL/min/m2)
223 ± 85.0
6
240 ± 90
15
ND
Apparent oral clearanceg
(mL/min/m2)
1252 ± 154
6
2064 ± 736
48
1353 ± 759
41
Elimination half-lifef (h)
1.5 ± 0.4
6
0.8 ± 0.3
60
1.2 ± 0.3
21
Urinary recovery of
didanosinef (%)
18 ± 8
6
18 ± 10
15
ND
CSF = cerebrospinal fluid, ND = not determined.
a Parameter units for adults were converted to the same units in pediatric patients to facilitate comparisons
among populations: mean adult body weight = 70 kg and mean adult body surface area = 1.73 m2.
b In 1-day old infants (n=10), the mean ± SD apparent oral clearance was 1523 ± 1176 mL/min/m2 and
half-life was 2.0 ± 0.7 h.
c Following IV administration.
d Following IV administration in adults and IV or oral administration in pediatric patients.
e
Mean ± SE.
f
Following oral administration.
g Apparent oral clearance estimate was determined as the ratio of the mean systemic clearance and the
mean oral bioavailability estimate.
Effect of Food on Absorption of Didanosine: Didanosine peak plasma
concentrations (CMAX) and area under the plasma concentration time curve (AUC) were
decreased by approximately 55% when VIDEX tablets were administered up to 2 hours
after a meal. Administration of VIDEX tablets up to 30 minutes before a meal did not
result in any significant changes in bioavailability. VIDEX should be taken on an empty
stomach, at least 30 minutes before or 2 hours after eating. (See DOSAGE AND
ADMINISTRATION.)
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Special Populations
Renal Insufficiency: It is recommended that the VIDEX (didanosine) dose be modified
in patients with reduced creatinine clearance and in patients receiving maintenance
hemodialysis (see DOSAGE AND ADMINISTRATION). Data from two studies in
adults indicated that the apparent oral clearance of didanosine decreased and the terminal
elimination half-life increased as creatinine clearance decreased (see Table 2). Following
oral administration, didanosine was not detectable in peritoneal dialysate fluid (n=6);
recovery in hemodialysate (n=5) ranged from 0.6% to 7.4% of the dose over a 3-4 hour
dialysis period. The absolute bioavailability of didanosine was not affected in patients
requiring dialysis.
Table 2:
Mean ± SD Pharmacokinetic Parameters for Didanosine
Following a Single Oral Dose
Creatinine Clearance (mL/min)
Parameter
≥ 90
(n=12)
60-90
(n=6)
30-59
(n=6)
10-29
(n=3)
Dialysis Patients
(n=11)
CLcr (mL/min)
112 ± 22
68 ± 8
46 ± 8
13 ± 5
ND
CL/F (mL/min)
2164 ± 638
1566 ± 833
1023 ± 378
628 ± 104
543 ± 174
CLR (mL/min)
458 ± 164
247 ± 153
100 ± 44
20 ± 8
<10
T½ (h)
1.42 ± 0.33
1.59 ± 0.13
1.75 ± 0.43
2.0 ± 0.3
4.1 ± 1.2
ND = not determined due to anuria.
CLcr = creatinine clearance.
CL/F = apparent oral clearance.
CLR = renal clearance.
Pediatric Patients: The pharmacokinetics of didanosine have been evaluated in
HIV-exposed and -infected pediatric patients from birth to 19 years of age (see Table 1).
Overall, the pharmacokinetics of didanosine in pediatric patients are similar to those of
didanosine in adults. Didanosine plasma concentrations appear to increase in proportion to
oral doses ranging from 25 to 120 mg/m2 in pediatric patients less than 5 months old and
from 80 to 180 mg/m2 in children above 8 months old. For information on controlled
clinical studies in pediatric patients, see INDICATIONS AND USAGE: Clinical Studies
and PRECAUTIONS: Pediatric Use.
Geriatric Patients: Didanosine pharmacokinetics have not been studied in
patients over 65 years of age.
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Gender: The effects of gender on didanosine pharmacokinetics have not been
studied.
Drug Interactions: Ribavirin has been shown in vitro to increase intracellular
triphosphate levels of didanosine, which could cause or worsen clinical toxicities (see
PRECAUTIONS: Drug Interactions).
Tables 3 and 4 summarize the effects on AUC and CMAX, with a 90% or 95%
confidence interval (CI) when available, following coadministration of VIDEX with a
variety of drugs. For most of the listed drugs, no clinically significant pharmacokinetic
interactions were observed. Clinical recommendations based on drug interaction studies for
drugs in bold font are included in PRECAUTIONS: Drug Interactions and DOSAGE
AND ADMINISTRATION (for tenofovir).
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Table 3:
Results of Drug Interaction Studies with VIDEX: Effects of Coadministered
Drug on Didanosine Plasma AUC and CMAX Values
Drugs With Clinical Recommendations Regarding Coadministration (see PRECAUTIONS: Drug Interactions)
Drug
Didanosine Dosage
n
AUC of
Didanosine
(95% CI)
CMAX of Didanosine
(95% CI)
allopurinol
renally impaired, 300 mg/day
200 mg single dose
2
↑ 312%
↑ 232%
healthy volunteer, 300 mg/day for
7 days
400 mg single dose
14
↑ 113%
↑ 69%
ciprofloxacin, 750 mg q12h for 3
days, 2 h before didanosine
200 mg q12h for 3 days
8a
↓ 16%
↓ 28%
ganciclovir, 1000 mg q8h, 2 h
after didanosine
200 mg q12h
12
↑ 111%
NA
indinavir, 800 mg single dose
simultaneous
1 h before didanosine
200 mg single dose
200 mg single dose
16
16
↔
↓ 17% (-27, - 7%)b
↔
↓ 13% (-28, 5%)b
ketoconazole, 200 mg/day for 4
days, 2 h before didanosine
375 mg q12h for 4 days
12a
↔
↓ 12%
methadone, chronic maintenance
dose
200 mg single dose
16, 10c
↓ 57%
↓ 66%
tenofovir,d,e 300 mg once daily
1 h after didanosine
250f or 400 mg once
daily for 7 days
14
↑ 44%
(31, 59%)b
↑ 28%
(11, 48%)b
No Clinically Significant Interaction Observed
Drug
Didanosine Dosage
n
AUC of
Didanosine
(95% CI)
CMAX of Didanosine
(95% CI)
loperamide, 4 mg q6h for 1 day
300 mg single dose
12a
↔
↓ 23%
metoclopramide, 10 mg single dose
300 mg single dose
12a
↔
↑ 13%
ranitidine, 150 mg single dose, 2 h
before didanosine
375 mg single dose
12a
↑ 14%
↑ 13%
rifabutin, 300 or 600 mg/day for 12
days
167 or 250 mg q12h for
12 days
11
↑ 13% (-1, 27%)
↑ 17% (-4, 38%)
ritonavir, 600 mg q12h for 4 days
200 mg q12h for 4 days
12
↓ 13% (0, 23%)
↓ 16% (5, 26%)
stavudine, 40 mg q12h for 4 days
100 mg q12h for 4 days
10
↔
↔
sulfamethoxazole, 1000 mg single
dose
200 mg single dose
8a
↔
↔
trimethoprim, 200 mg single dose
200 mg single dose
8a
↔
↑ 17% (-23, 77%)
zidovudine, 200 mg q8h for 3 days
200 mg q12h for 3 days
6a
↔
↔
↑ indicates increase.
↓ indicates decrease.
↔ indicates no change, or mean increase or decrease of <10%.
a
HIV-infected patients.
b
90% CI.
c Parallel-group design; entries are subjects receiving combination and control regimens, respectively.
d tenofovir disoproxil fumarate.
e
For results of drug interaction studies between the enteric-coated formulation of didanosine (VIDEX EC) and
tenofovir, see the complete prescribing information for VIDEX EC.
f
patients <60 kg with creatinine clearance ≥60 mL/min.
NA Not available.
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Table 4:
Results of Drug Interaction Studies with VIDEX: Effects of
Didanosine on Coadministered Drug Plasma AUC and CMAX
Values
Drugs With Clinical Recommendations Regarding Coadministration (see PRECAUTIONS: Drug Interactions)
Drug
Didanosine Dosage
n
AUC of
Coadministered
Drug (95% CI)
CMAX of
Coadministered
Drug (95% CI)
ciprofloxacin
750 mg q12h for 3 days, 2 h
before didanosine
750 mg single dose
200 mg q12h for 3 days
buffered placebo tablet
8a
12
↓ 26%
↓ 98%
↓ 16%
↓ 93%
delavirdine, 400 mg single dose
simultaneous
1 h before didanosine
125 or 200 mg q12h
125 or 200 mg q12h
12a
12a
↓ 32%
↑ 20%
↓ 53%
↑ 18%
ganciclovir, 1000 mg q8h, 2 h
after didanosine
200 mg q12h
12a
↓ 21%
NA
indinavir, 800 mg single dose
simultaneous
1 h before didanosine
200 mg single dose
200 mg single dose
16
16
↓ 84%
↓ 11%
↓ 82%
↓ 4%
ketoconazole, 200 mg/day for 4
days, 2 h before didanosine
375 mg q12h for 4 days
12a
↓ 14%
↓ 20%
nelfinavir, 750 mg single dose,
1 h after didanosine
200 mg single dose
10a
↑ 12%
↔
No Clinically Significant Interaction Observed
Drug
Didanosine Dosage
n
AUC of
Coadministered
Drug (95% CI)
CMAX of
Coadministered
Drug (95% CI)
dapsone, 100 mg single dose
200 mg q12h for 14 days
6a
↔
↔
ranitidine, 150 mg single dose, 2 h
before didanosine
375 mg single dose
12a
↓ 16%
↔
ritonavir, 600 mg q12h for 4 days
200 mg q12h for 4 days
12
↔
↔
stavudine, 40 mg q12h for 4 days
100 mg q12h for 4 days
10a
↔
↑ 17%
sulfamethoxazole, 1000 mg single
dose
200 mg single dose
8a
↓ 11% (-17, -4%)
↓ 12% (-28, 8%)
tenofovir,b 300 mg once daily 1 h
after didanosine
250c or 400 mg once
daily for 7 days
14
↔
↔
trimethoprim, 200 mg single dose
200 mg single dose
8a
↑ 10% (-9, 34%)
↓ 22% (-59, 49%)
zidovudine, 200 mg q8h for 3
days
200 mg q12h for 3 days
6a
↓ 10% (-27, 11%)
↓ 16.5% (-53, 47%)
↑ indicates increase.
↓ indicates decrease.
↔ indicates no change, or mean increase or decrease of <10%.
a
HIV-infected patients.
b
tenofovir disoproxil fumarate.
c
patients <60 kg with creatinine clearance ≥60 mL/min.
NA Not available.
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INDICATIONS AND USAGE
VIDEX (didanosine) in combination with other antiretroviral agents is indicated for
the treatment of HIV-1 infection (see Clinical Studies).
Clinical Studies
Combination Therapy
START 2 was a multicenter, randomized, open-label study comparing VIDEX (200 mg
twice daily)/stavudine/indinavir to zidovudine/lamivudine/indinavir in 205 treatment-naive
patients. Both regimens resulted in a similar magnitude of suppression of HIV RNA levels
and increases in CD4 cell counts through 48 weeks.
Study A1454-148 was a randomized, open-label, multicenter study comparing
treatment with VIDEX (400 mg once daily) plus stavudine (40 mg twice daily) and
nelfinavir (750 mg three times daily) versus zidovudine (300 mg twice daily) plus
lamivudine (150 mg twice daily) and nelfinavir (750 mg three times daily) in 756
treatment-naive patients, with a median CD4 cell count of 340 cells/mm3 (range 80 to 1568
cells/mm3) and a median plasma HIV-1 RNA of 4.69 log10 copies/mL (range 2.6 to 5.9
log10 copies/mL) at baseline. Median CD4 cell count increases at 48 weeks were 188
cells/mm3 in both treatment groups. Treatment response and outcomes through 48 weeks
are shown in Figure 1 and Table 5.
Figure 1:
Treatment Response Through Week 48*, AI454-148
* Percent of patients at each time point who have HIV RNA <400 or <50 copies/mL, are on
their original study medication (except stavudine-zidovudine switches), and have not
experienced an AIDS-defining event.
0
20
40
60
80
100
0
8
16
24
32
40
48
Study Week
Percent of patients
] < 400 c/mL
] < 50 c/mL
VIDEX+stavudine+nelfinavir (n=503)
zidovudine+lamivudine+nelfinavir (n=253)
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Table 5:
Outcomes of Randomized Treatment through Week 48,
AI454-148
Percent of Patients with HIV RNA <400 copies/mL (<50 copies/mL)
VIDEX/stavudine/nelfinavir
lamivudine/zidovudine/nelfinavir
Week 48 Status
n=503
n=253
Responder a
50* (34*)
59 (47)
Virologic failureb
36 (57)
32 (48)
Death or disease progression
<1 (<1)
1 (<1)
Discontinued due to adverse events
4 (2)
2 (<1)
Discontinued due to other reasonsc
6 (3)
4 (2)
Never initiated treatment
4 (4)
2 (2)
* p <0.05 for the differences between treatment groups, by Cochran-Mantel-Haenszel test.
a Patients achieved virologic response [two consecutive viral loads <400 (<50) copies/mL] and maintained
it to Week 48.
b Includes viral rebound and failing to achieve confirmed <400 (<50) copies/mL by Week 48.
c Includes lost to follow-up, noncompliance, withdrawal, and pregnancy.
Monotherapy
The efficacy of VIDEX was demonstrated in two randomized, double-blind studies
comparing VIDEX, given on a twice-daily schedule, to zidovudine, given three times daily,
in 617 (ACTG 116A, conducted 1989-1992) and 913 (ACTG 116B/117, conducted 1989-
1991) patients with symptomatic HIV infection or AIDS who were treated for more than
one year. In treatment-naive patients (ACTG 116A), the rate of HIV disease progression or
death was similar between the treatment groups; mortality rates were 26% for patients
receiving VIDEX and 21% for patients receiving zidovudine. Of the patients who had
received previous zidovudine treatment (ACTG 116B/117), those treated with VIDEX had
a lower rate of HIV disease progression or death (32%) compared to those treated with
zidovudine (41%); however, survival rates were similar between the treatment groups.
Efficacy in pediatric patients was demonstrated in a randomized, double-blind,
controlled study (ACTG 152, conducted 1991-1995) involving 831 patients 3 months to 18
years of age treated for more than 1.5 years with zidovudine (180 mg/m2 q6h), VIDEX
(120 mg/m2 q12h), or zidovudine (120 mg/m2q6h) plus VIDEX (90 mg/m2 q12h). Patients
treated with VIDEX or VIDEX plus zidovudine had lower rates of HIV disease progression
or death compared with those treated with zidovudine alone.
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Studies have demonstrated that the clinical benefit of monotherapy with
antiretrovirals, including VIDEX, was time limited.
CONTRAINDICATION
VIDEX (didanosine) is contraindicated in patients with previously demonstrated clinically
significant hypersensitivity to any of the components of the formulations.
WARNINGS
1.
Pancreatitis
FATAL AND NONFATAL PANCREATITIS HAVE OCCURRED DURING
THERAPY WITH VIDEX USED ALONE OR IN COMBINATION REGIMENS IN
BOTH TREATMENT-NAIVE AND TREATMENT-EXPERIENCED PATIENTS,
REGARDLESS OF DEGREE OF IMMUNOSUPPRESSION. VIDEX SHOULD BE
SUSPENDED IN PATIENTS WITH SIGNS OR SYMPTOMS OF PANCREATITIS
AND DISCONTINUED IN PATIENTS WITH CONFIRMED PANCREATITIS.
PATIENTS TREATED WITH VIDEX IN COMBINATION WITH STAVUDINE,
WITH OR WITHOUT HYDROXYUREA, MAY BE AT INCREASED RISK FOR
PANCREATITIS.
When treatment with life-sustaining drugs known to cause pancreatic toxicity is
required, suspension of VIDEX (didanosine) therapy is recommended. In patients with risk
factors for pancreatitis, VIDEX should be used with extreme caution and only if clearly
indicated. Patients with advanced HIV infection, especially the elderly, are at increased risk
of pancreatitis and should be followed closely. Patients with renal impairment may be at
greater risk for pancreatitis if treated without dose adjustment.
The frequency of pancreatitis is dose related. In phase 3 studies, incidence ranged
from 1% to 10% with doses higher than are currently recommended and 1% to 7% with
recommended dose.
In pediatric phase 1 studies, pancreatitis occurred in 3% (2/60) of patients treated at
entry doses below 300 mg/m2/day and in 13% (5/38) of patients treated at higher doses. In
study ACTG 152, pancreatitis occurred in none of the 281 pediatric patients who received
didanosine 120 mg/m2 q12h and in <1% of the 274 pediatric patients who received
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didanosine 90 mg/m2 q12h in combination with zidovudine. VIDEX (didanosine) use
should be suspended in pediatric patients with signs or symptoms of pancreatitis and
discontinued in pediatric patients with confirmed pancreatitis.
2.
Lactic Acidosis/Severe Hepatomegaly with Steatosis
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases,
have been reported with the use of nucleoside analogues alone or in combination,
including didanosine and other antiretrovirals. A majority of these cases have been in
women. Obesity and prolonged nucleoside exposure may be risk factors. Fatal lactic
acidosis has been reported in pregnant women who received the combination of didanosine
and stavudine with other antiretroviral agents. The combination of didanosine and
stavudine should be used with caution during pregnancy and is recommended only if the
potential benefit clearly outweighs the potential risk (see PRECAUTIONS: Pregnancy,
Reproduction, and Fertility). Particular caution should be exercised when administering
VIDEX to any patient with known risk factors for liver disease; however, cases have also
been reported in patients with no known risk factors. Treatment with VIDEX should be
suspended in any patient who develops clinical or laboratory findings suggestive of
symptomatic hyperlactatemia, lactic acidosis, or pronounced hepatotoxicity (which may
include hepatomegaly and steatosis even in the absence of marked transaminase
elevations).
3.
Retinal Changes and Optic Neuritis
Retinal changes and optic neuritis have been reported in adult and pediatric
patients. Periodic retinal examinations should be considered for patients receiving VIDEX.
(See ADVERSE REACTIONS.)
4.
Hepatic Impairment and Toxicity
It
is
unknown
if
hepatic
impairment
significantly
affects
didanosine
pharmacokinetics. Therefore, these patients should be monitored closely for evidence of
didanosine toxicity. The safety and efficacy of VIDEX have not been established in HIV-
infected patients with significant underlying liver disease. During combination
antiretroviral therapy, patients with preexisting liver dysfunction, including chronic active
hepatitis, have an increased frequency of liver function abnormalities, including severe and
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potentially fatal hepatic adverse events, and should be monitored according to standard
practice. If there is evidence of worsening liver disease in such patients, interruption or
discontinuation of treatment must be considered.
Hepatotoxicity and hepatic failure resulting in death were reported during
postmarketing surveillance in HIV-infected patients treated with hydroxyurea and other
antiretroviral agents. Fatal hepatic events were reported most often in patients treated with
the combination of hydroxyurea, didanosine, and stavudine. This combination should be
avoided.
PRECAUTIONS
Frequency of Dosing
The preferred dosing frequency of VIDEX is twice daily because there is more evidence to
support the effectiveness of this dosing frequency. Once-daily dosing should be considered
only for adult patients whose management requires once-daily dosing of VIDEX (see
INDICATIONS AND USAGE: Clinical Studies).
VIDEX should be taken on an empty stomach, at least 30 minutes before or 2
hours after eating.
Peripheral Neuropathy
Peripheral neuropathy, manifested by numbness, tingling, or pain in the hands or feet, has
been reported in patients receiving VIDEX therapy. Peripheral neuropathy has occurred
more frequently in patients with advanced HIV disease, in patients with a history of
neuropathy, or in patients being treated with neurotoxic drug therapy, including stavudine.
Peripheral neuropathy, which was severe in some cases, has been reported in HIV-infected
patients receiving hydroxyurea in combination with antiretroviral agents, including
didanosine, with or without stavudine (see ADVERSE REACTIONS).
Fat Redistribution
Redistribution/accumulation of body fat including central obesity, dorsocervical fat
enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and
“cushingoid appearance” have been observed in patients receiving antiretroviral therapy.
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The mechanism and long-term consequences of these events are currently unknown. A
causal relationship has not been established.
Immune Reconstitution Syndrome
Immune reconstitution syndrome has been reported in patients treated with combination
antiretroviral therapy, including VIDEX. During the initial phase of combination
antiretroviral treatment, patients whose immune system responds may develop an
inflammatory response to indolent or residual opportunistic infections (such as
Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia
[PCP], or tuberculosis), which may necessitate further evaluation and treatment.
General
Patients with Renal Impairment: Patients with renal impairment (creatinine clearance
<60 mL/min) may be at greater risk of toxicity from VIDEX due to decreased drug
clearance (see CLINICAL PHARMACOLOGY). A dose reduction is recommended in
these patients (see DOSAGE AND ADMINISTRATION).
Hyperuricemia: VIDEX has been associated with asymptomatic hyperuricemia;
treatment suspension may be necessary if clinical measures aimed at reducing uric acid
levels fail.
Information for Patients (see Patient Information Leaflet)
Patients should be informed that a serious toxicity of VIDEX used alone and in
combination regimens is pancreatitis, which may be fatal.
Patients should be informed that the preferred dosing frequency of VIDEX is twice
daily because there is more evidence to support the effectiveness of this dosing frequency.
Once-daily dosing should be considered only for adult patients whose management
requires once-daily dosing of VIDEX.
Patients should also be aware that peripheral neuropathy, manifested by numbness,
tingling, or pain in hands or feet, may develop during therapy with VIDEX. Patients
should be counseled that peripheral neuropathy occurs with greatest frequency in patients
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with advanced HIV disease or a history of peripheral neuropathy, and that dose
modification and/or discontinuation of VIDEX may be required if toxicity develops.
Patients should be informed that when VIDEX is used in combination with other
agents with similar toxicities, the incidence of adverse events may be higher than when
VIDEX is used alone. These patients should be followed closely.
Patients should be cautioned about the use of medications or other substances,
including alcohol, that may exacerbate VIDEX toxicities.
VIDEX (didanosine) is not a cure for HIV infection, and patients may continue to
develop HIV-associated illnesses, including opportunistic infection. Therefore, patients
should remain under the care of a physician when using VIDEX. Patients should be
advised that VIDEX therapy has not been shown to reduce the risk of transmission of HIV
to others through sexual contact or blood contamination. Patients should be informed that
the long-term effects of VIDEX are unknown at this time.
Patients should be informed that redistribution or accumulation of body fat may
occur in patients receiving antiretroviral therapy and that the cause and long-term health
effects of these conditions are not known at this time.
Drug Interactions (see also CLINICAL PHARMACOLOGY: Drug
Interactions)
Drug interactions that have been established based on drug interaction studies are listed
with the pharmacokinetic results in CLINICAL PHARMACOLOGY: Drug
Interactions (Tables 3 and 4). The clinical recommendations based on the results of these
studies are listed in Table 6.
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Table 6:
Established Drug Interactions with VIDEX
Coadministration Not Recommended Based on Drug Interaction Studies (see CLINICAL
PHARMACOLOGY: Drug Interactions for Magnitude of Interaction)
Drug
Effect
Clinical Comment
allopurinol
↑ didanosine concentration
Coadministration not recommended.
Alteration in Dose or Regimen Recommended Based on Drug Interaction Studies (see CLINICAL
PHARMACOLOGY: Drug Interactions for Magnitude of Interaction)
Drug
Effect
Clinical Comment
ciprofloxacin
↓ ciprofloxacin concentration
Administer VIDEX at least 2 hours after or
6 hours before ciprofloxacin.
delavirdine
↓ delavirdine concentration
Administer VIDEX 1 hour after delavirdine.
ganciclovir
↑ didanosine concentration
Appropriate doses for this combination,
with respect to efficacy and safety, have not
been established.
indinavir
↓ indinavir concentration
Administer VIDEX 1 hour after indinavir.
methadone
↓ didanosine concentration
Appropriate doses for this combination,
with respect to efficacy and safety, have not
been established.
nelfinavir
No interaction 1 hour after didanosine
Administer nelfinavir 1 hour after VIDEX.
tenofovir
disoproxil fumarate
↑ didanosine concentration
A dose reduction of VIDEX to 250 mg
(adults weighing ≥60 kg with creatinine
clearance ≥60 mL/min) or 200 mg (adults
weighing <60 kg with creatinine clearance ≥60
mL/min) once daily is recommended. VIDEX
and tenofovir may be taken together in the fasted
state. Alternatively, if tenofovir is taken with
food, VIDEX should be taken on an empty
stomach (at least 30 minutes before food or 2
hours after food). Patients should be monitored
for didanosine-associated toxicities and
clinical response (see below).
↑ indicates increase.
↓ indicates decrease.
Coadministration of VIDEX with drugs that are known to cause pancreatitis
may increase the risk of this toxicity (see WARNINGS: Pancreatitis). Because VIDEX
is mixed with an antacid before administration, interactions may be anticipated with drugs
whose absorption can be affected by the level of acidity in the stomach and with drugs that
have been demonstrated to interact with antacids containing magnesium, calcium, or
aluminum. Predicted drug interactions with VIDEX are listed in Table 7.
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Table 7:
Predicted Drug Interactions with VIDEX
Use with Caution or Not Recommended, Risk of Adverse Reactions May Be Increased
Drug or Drug Class
Effect
Clinical Comment
Drugs that may cause
pancreatic toxicity
↑ risk of pancreatitis
Use only with extreme caution.a
Neurotoxic drugs
↑ risk of neuropathy
Use with caution.b
Antacids containing
magnesium or aluminum
↑ side effects associated with
antacid components
Use caution with VIDEX Pediatric Powder
for Oral Solution.
Ribavirin
↑ risk of toxicity
Ribavirin has been shown in vitro to
increase intracellular triphosphate levels of
didanosine. Coadministration is not
recommended (see below).
Use with Caution, Plasma Concentrations May Be Decreased by Coadministration with VIDEX
Drug Class
Effect
Clinical Comment
Azole antifungals
↓ ketoconazole or itraconazole
concentration
Administer drugs such as ketoconazole or
itraconazole at least 2 hours before
VIDEX.
Quinolone antibiotics (see
also ciprofloxacin in
Table 6)
↓ quinolone concentration
Consult package insert of the quinolone.
Tetracycline antibiotics
↓ antibiotic concentration
Consult package insert of the tetracycline.
↑ indicates increase.
↓ indicates decrease.
a Only if other drugs are not available and if clearly indicated. If treatment with life-sustaining drugs that
cause pancreatic toxicity is required, suspension of VIDEX is recommended (see WARNINGS:
Pancreatitis).
b See PRECAUTIONS: Peripheral Neuropathy.
Nucleoside/nucleotide analogues
Tenofovir disoproxil fumarate. Exposure to didanosine is increased when coadministered
with tenofovir (see Table 3). Increased exposure may cause or worsen didanosine-
related clinical toxicities, including pancreatitis, symptomatic hyperlactatemia/lactic
acidosis, and peripheral neuropathy. Coadministration of tenofovir with VIDEX
should be undertaken with caution, and patients should be monitored closely for
didanosine-related toxicities and clinical response. VIDEX should be suspended if
signs or symptoms of pancreatitis, symptomatic hyperlactatemia, or lactic acidosis
develop (see WARNINGS). A dose reduction of VIDEX to 250 mg (adults weighing ≥60
kg with creatinine clearance ≥60 mL/min) or 200 mg (adults weighing <60 kg with
creatinine clearance ≥60 mL/min) once daily is recommended. VIDEX and tenofovir may
be taken together in the fasted state. Alternatively, if tenofovir is taken with food, VIDEX
should be taken on an empty stomach, at least 30 minutes before food or 2 hours after food
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(see DOSAGE AND ADMINISTRATION). (The dosing recommendation for
coadministration of VIDEX EC and tenofovir disoproxil fumarate with respect to meal
consumption differs from that of VIDEX. See the complete prescribing information for
VIDEX EC.)
Ribavirin. Exposure to the active metabolite of didanosine (dideoxyadenosine 5’-
triphosphate) is increased when didanosine is coadministered with ribavirin (see Table 7).
Fatal hepatic failure, as well as peripheral neuropathy, pancreatitis, and symptomatic
hyperlactatemia/lactic acidosis have been reported in patients receiving both didanosine
and ribavirin. Coadministration of didanosine and ribavirin is not recommended.
Carcinogenesis and Mutagenesis
Lifetime carcinogenicity studies were conducted in mice and rats for 22 and 24 months,
respectively. In the mouse study, initial doses of 120, 800, and 1200 mg/kg/day for each
sex were lowered after 8 months to 120, 210, and 210 mg/kg/day for females and 120, 300,
and 600 mg/kg/day for males. The two higher doses exceeded the maximally tolerated
dose in females and the high dose exceeded the maximally tolerated dose in males. The
low dose in females represented 0.68-fold maximum human exposure and the intermediate
dose in males represented 1.7-fold maximum human exposure based on relative AUC
comparisons. In the rat study, initial doses were 100, 250, and 1000 mg/kg/day, and the
high dose was lowered to 500 mg/kg/day after 18 months. The upper dose in male and
female rats represented 3-fold maximum human exposure.
Didanosine induced no significant increase in neoplastic lesions in mice or rats at
maximally tolerated doses.
Didanosine was positive in the following genetic toxicology assays: 1) the
Escherichia coli tester strain WP2 uvrA bacterial mutagenicity assay; 2) the
L5178Y/TK+/-mouse lymphoma mammalian cell gene mutation assay; 3) the in vitro
chromosomal aberrations assay in cultured human peripheral lymphocytes; 4) the in vitro
chromosomal aberrations assay in Chinese Hamster Lung cells; and 5) the BALB/c 3T3 in
vitro transformation assay. No evidence of mutagenicity was observed in an Ames
Salmonella bacterial mutagenicity assay or in rat and mouse in vivo micronucleus assays.
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Pregnancy, Reproduction, and Fertility
Pregnancy Category B. Reproduction studies have been performed in rats and rabbits at
doses up to 12 and 14.2 times the estimated human exposure (based upon plasma levels),
respectively, and have revealed no evidence of impaired fertility or harm to the fetus due to
didanosine. At approximately 12 times the estimated human exposure, didanosine was
slightly toxic to female rats and their pups during mid and late lactation. These rats
showed reduced food intake and body weight gains but the physical and functional
development of the offspring was not impaired and there were no major changes in the F2
generation. A study in rats showed that didanosine and/or its metabolites are transferred to
the fetus through the placenta. Animal reproduction studies are not always predictive of
human response.
There are no adequate and well-controlled studies of didanosine in pregnant
women. Didanosine should be used during pregnancy only if the potential benefit justifies
the potential risk.
Fatal lactic acidosis has been reported in pregnant women who received the
combination of didanosine and stavudine with other antiretroviral agents. It is unclear if
pregnancy augments the risk of lactic acidosis/hepatic steatosis syndrome reported in
nonpregnant individuals receiving nucleoside analogues (see WARNINGS: Lactic
Acidosis/Severe Hepatomegaly with Steatosis). The combination of didanosine and
stavudine should be used with caution during pregnancy and is recommended only if
the potential benefit clearly outweighs the potential risk. Health care providers caring
for HIV-infected pregnant women receiving didanosine should be alert for early diagnosis
of lactic acidosis/hepatic steatosis syndrome.
Antiretroviral Pregnancy Registry: To monitor maternal-fetal outcomes of
pregnant women exposed to didanosine and other antiretroviral agents, an Antiretroviral
Pregnancy Registry has been established. Physicians are encouraged to register patients by
calling 1-800-258-4263.
Nursing Mothers
The Centers for Disease Control and Prevention recommend that HIV-infected
mothers not breast-feed their infants to avoid risking postnatal transmission of HIV.
A study in rats showed that following oral administration, didanosine and/or its metabolites
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were excreted into the milk of lactating rats. It is not known if didanosine is excreted in
human milk. Because of both the potential for HIV transmission and the potential for
serious adverse reactions in nursing infants, mothers should be instructed not to breast-
feed if they are receiving VIDEX.
Pediatric Use
Use of VIDEX in pediatric patients from 2 weeks of age through adolescence is supported
by evidence from adequate and well-controlled studies of VIDEX in adults and pediatric
patients
(see
INDICATIONS
AND
USAGE:
Clinical
Studies,
CLINICAL
PHARMACOLOGY,
ADVERSE
REACTIONS,
and
DOSAGE
AND
ADMINISTRATION).
Dosing recommendations for VIDEX in patients less than 2 weeks of age cannot be
made because the pharmacokinetics of didanosine in these children are too variable to
determine an appropriate dose.
Geriatric Use
In an Expanded Access Program for patients with advanced HIV infection, patients aged 65
years and older had a higher frequency of pancreatitis (10%) than younger patients (5%)
(see WARNINGS). Clinical studies of didanosine did not include sufficient numbers of
subjects aged 65 years and over to determine whether they respond differently than younger
subjects. Didanosine is known to be substantially excreted by the kidney, and the risk of
toxic reactions to this drug may be greater in patients with impaired renal function.
Because elderly patients are more likely to have decreased renal function, care should be
taken in dose selection. In addition, renal function should be monitored and dosage
adjustments should be made accordingly (see DOSAGE AND ADMINISTRATION:
Dose Adjustment).
ADVERSE REACTIONS
A SERIOUS TOXICITY OF VIDEX (didanosine) IS PANCREATITIS, WHICH MAY BE
FATAL (see WARNINGS). OTHER IMPORTANT TOXICITIES INCLUDE LACTIC
ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS; RETINAL CHANGES
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AND OPTIC NEURITIS; AND PERIPHERAL NEUROPATHY (see WARNINGS and
PRECAUTIONS).
When VIDEX is used in combination with other agents with similar toxicities,
the incidence of these toxicities may be higher than when VIDEX is used alone. Thus,
patients treated with VIDEX in combination with stavudine, with or without
hydroxyurea, may be at increased risk for pancreatitis and hepatotoxicity, which may
be fatal, and severe peripheral neuropathy (see WARNINGS and PRECAUTIONS).
Adults: Selected clinical adverse events that occurred in adult patients in clinical
studies with VIDEX are provided in Tables 8 and 9.
Table 8:
Selected Clinical Adverse Events from Monotherapy
Studies
Percent of Patients
ACTG 116A
ACTG 116B/117
Adverse Events
VIDEX
n=197
zidovudine
n=212
VIDEX
n=298
zidovudine
n=304
Diarrhea
19
15
28
21
Peripheral Neurologic
Symptoms/Neuropathy
17
14
20
12
Rash/Pruritus
7
8
9
5
Abdominal Pain
13
8
7
8
Pancreatitis
7
3
6
2
Table 9:
Selected Clinical Adverse Events from Combination
Studies
Percent of Patientsa
AI454-148b
START 2b
Adverse Events
VIDEX +
stavudine +
nelfinavir
n=482
zidovudine +
lamivudine +
nelfinavir
n=248
VIDEX +
stavudine +
indinavir
n=102
zidovudine +
lamivudine +
indinavir
n=103
Diarrhea
70
60
45
39
Nausea
28
40
53
67
Headache
21
30
46
37
Peripheral Neurologic
Symptoms/Neuropathy
26
6
21
10
Rash
13
16
30
18
Vomiting
12
14
30
35
Pancreatitis (see below)
1
*
<1
*
a Percentages based on treated subjects.
b Median duration of treatment 48 weeks.
* This event was not observed in this study arm.
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Pancreatitis resulting in death was observed in one patient who received
VIDEX (didanosine) plus stavudine plus nelfinavir in Study Al454-148 and in one
patient who received VIDEX plus stavudine plus indinavir in the START 2 study. In
addition, pancreatitis resulting in death was observed in 2 of 68 patients who received
VIDEX plus stavudine plus indinavir plus hydroxyurea in an ACTG clinical trial (see
WARNINGS).
The frequency of pancreatitis is dose related. In phase 3 studies, incidence ranged
from 1% to 10% with doses higher than are currently recommended and from 1% to 7%
with recommended dose.
Selected laboratory abnormalities in clinical studies with VIDEX are shown in
Tables 10-12.
Table 10:
Selected Laboratory Abnormalities from Monotherapy Studies
Percent of Patients
ACTG 116A
ACTG 116B/117
VIDEX
zidovudine
VIDEX
zidovudine
Parameter
n=197
n=212
n=298
n=304
SGOT (AST) (>5 x ULN)
9
4
7
6
SGPT (ALT) (>5 x ULN)
9
6
6
6
Alkaline phosphatase (>5 x ULN)
4
1
1
1
Amylase (≥1.4 x ULN)
17
12
15
5
Uric acid (>12 mg/dL)
3
1
2
1
ULN = upper limit of normal.
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Table 11:
Selected Laboratory Abnormalities from Combination Studies
(Grades 3-4)
Percent of Patientsa
AI454-148b
START 2b
VIDEX +
stavudine +
nelfinavir
zidovudine +
lamivudine +
nelfinavir
VIDEX +
stavudine +
indinavir
zidovudine +
lamivudine +
indinavir
Parameter
n=482
n=248
n=102
n=103
Bilirubin (>2.6 x ULN)
<1
<1
16
8
SGOT (AST) (>5 x ULN)
3
2
7
7
SGPT (ALT) (>5 x ULN)
3
3
8
5
GGT (>5 x ULN)
NC
NC
5
2
Lipase (>2 x ULN)
7
2
5
5
Amylase (>2 x ULN)
NC
NC
8
2
ULN = upper limit of normal.
NC = Not Collected.
a Percentages based on treated subjects.
b Median duration of treatment 48 weeks.
Table 12:
Selected Laboratory Abnormalities from Combination
Studies (All Grades)
Percent of Patientsa
AI454-148b
START 2b
Parameter
VIDEX +
stavudine +
nelfinavir
n=482
zidovudine +
lamivudine +
nelfinavir
n=248
VIDEX +
stavudine +
indinavir
n=102
zidovudine +
lamivudine +
indinavir
n=103
Bilirubin
7
3
68
55
SGOT (AST)
42
23
53
20
SGPT (ALT)
37
24
50
18
GGT
NC
NC
28
12
Lipase
17
11
26
19
Amylase
NC
NC
31
17
NC = Not Collected.
a Percentages based on treated subjects.
b Median duration of treatment 48 weeks.
Observed during Clinical Practice: The following events have been identified
during postapproval use of VIDEX (didanosine). Because they are reported voluntarily
from a population of unknown size, estimates of frequency cannot be made. These events
have been chosen for inclusion due to their seriousness, frequency of reporting, causal
connection to VIDEX, or a combination of these factors.
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Body as a Whole – alopecia, anaphylactoid reaction, asthenia, chills/fever, pain, and
redistribution/accumulation
of
body
fat
(see
PRECAUTIONS:
Fat
Redistribution).
Digestive Disorders – anorexia, dyspepsia, and flatulence.
Exocrine Gland Disorders – pancreatitis (including fatal cases) (see WARNINGS),
sialoadenitis, parotid gland enlargement, dry mouth, and dry eyes.
Hematologic Disorders – anemia, leukopenia, and thrombocytopenia.
Liver – symptomatic hyperlactatemia/lactic acidosis and hepatic steatosis (see
WARNINGS); hepatitis and liver failure.
Metabolic Disorders – diabetes mellitus, hypoglycemia, and hyperglycemia.
Musculoskeletal Disorders – myalgia (with or without increases in creatine kinase),
rhabdomyolysis including acute renal failure and hemodialysis, arthralgia, and
myopathy.
Ophthalmologic Disorders – Retinal depigmentation and optic neuritis (see
WARNINGS).
Pediatric Patients: In clinical trials, 743 pediatric patients between 2 weeks and
18 years of age have been treated with VIDEX. Adverse events and laboratory
abnormalities reported to occur in these patients were generally consistent with the safety
profile of didanosine in adults.
In pediatric phase 1 studies, pancreatitis occurred in 2 of 60 (3%) patients treated at
entry doses below 300 mg/m2/day and in 5 of 38 (13%) patients treated at higher doses. In
study ACTG 152, pancreatitis occurred in none of the 281 pediatric patients who received
didanosine 120 mg/m2 q12h and in <1% of the 274 pediatric patients who received
didanosine 90 mg/m2 q12h in combination with zidovudine (see INDICATIONS AND
USAGE: Clinical Studies).
Retinal changes and optic neuritis have been reported in pediatric patients.
OVERDOSAGE
There is no known antidote for VIDEX (didanosine) overdosage. In phase 1 studies, in
which VIDEX was initially administered at doses ten times the currently recommended
dose, toxicities included: pancreatitis, peripheral neuropathy, diarrhea, hyperuricemia, and
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hepatic dysfunction. Didanosine is not dialyzable by peritoneal dialysis, although there is
some
clearance
by
hemodialysis
(see
CLINICAL
PHARMACOLOGY:
Pharmacokinetics).
DOSAGE AND ADMINISTRATION
Dosage
VIDEX should be administered on an empty stomach, at least 30 minutes before or 2
hours after eating.
Adults: The preferred dosing frequency of VIDEX is twice daily because there is
more evidence to support the effectiveness of this dosing regimen. Once-daily dosing
should be considered only for adult patients whose management requires once-daily dosing
of VIDEX (see INDICATIONS AND USAGE: Clinical Studies). The daily dose in adult
patients is dependent on weight as outlined in Table 13.
Table 13:
Adult Dosing
Recommended VIDEX Dose by Patient Weight
≥60 kg
<60 kg
Preferred dosing
200 mg twice daily
125 mg twice daily
Dosing for patients whose
management requires once-daily
frequency
400 mg once daily
250 mg once daily
Pediatric Patients: The recommended dose of VIDEX (didanosine) in pediatric
patients between 2 weeks and 8 months of age is 100 mg/m2 twice daily, and the
recommended VIDEX dose for pediatric patients older than 8 months is 120 mg/m2 twice
daily.
Dosing recommendations for VIDEX in patients less than 2 weeks of age cannot be
made because the pharmacokinetics of didanosine in these children are too variable to
determine an appropriate dose. There are no data on once-daily dosing of VIDEX in
pediatric patients.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-154/S-050
NDA 20-155/S-039
NDA 20-156/S-040
NDA 21-183/S-016
Page 31 of 72
Dose Adjustment
Clinical and laboratory signs suggestive of pancreatitis should prompt dose
suspension and careful evaluation of the possibility of pancreatitis. VIDEX use should
be discontinued in patients with confirmed pancreatitis (see WARNINGS and
PRECAUTIONS: Drug Interactions).
Patients with symptoms of peripheral neuropathy may tolerate a reduced dose of
VIDEX after resolution of the symptoms of peripheral neuropathy upon drug
discontinuation. If neuropathy recurs after resumption of VIDEX, permanent
discontinuation of VIDEX should be considered.
Concomitant Therapy: Tenofovir disoproxil fumarate. A dose reduction of
VIDEX to 250 mg (adults weighing ≥60 kg with creatinine clearance ≥60 mL/min) or 200
mg (adults weighing <60 kg with creatinine clearance ≥60 mL/min) once daily is
recommended. VIDEX and tenofovir may be taken together in the fasted state.
Alternatively, if tenofovir is taken with food, VIDEX should be taken on an empty stomach
(at least 30 minutes before food or 2 hours after food). The appropriate dose of VIDEX
coadministered with tenofovir in patients with creatinine clearance <60 mL/min has
not been established. [See CLINICAL PHARMACOLOGY: Drug Interactions and
PRECAUTIONS: Drug Interactions; see the complete prescribing information for
VIDEX EC (enteric-coated formulation of didanosine) for results of drug interaction
studies of tenofovir with reduced doses of the enteric-coated formulation of didanosine.]
Renal Impairment: In adult patients with impaired renal function, the dose of
VIDEX should be adjusted to compensate for the slower rate of elimination. The
recommended doses and dosing intervals of VIDEX in adult patients with renal
insufficiency are presented in Table 14.
Table 14:
Recommended Dosage of VIDEX in Renal Impairment
Recommended VIDEX Dose by Patient Weight
Creatinine Clearance
(mL/min)
≥60 kg
<60 kg
≥60
200 mg twice dailya
125 twice dailya
30-59
200 mg once daily
or 100 mg twice daily
150 mg once daily
or 75 mg twice daily
10-29
150 mg once daily
100 mg once daily
<10
100 mg once daily
75 mg once daily
a 400 mg once daily (≥60 kg) or 250 mg once daily (<60 kg) for patients whose management requires once-
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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NDA 20-156/S-040
NDA 21-183/S-016
Page 32 of 72
Table 14:
Recommended Dosage of VIDEX in Renal Impairment
daily frequency of administration.
Urinary excretion is also a major route of elimination of didanosine in pediatric
patients; therefore, the clearance of didanosine may be altered in children with renal
impairment. Although there are insufficient data to recommend a specific dose adjustment
of VIDEX in this patient population, a reduction in the dose and/or an increase in the
interval between doses should be considered.
Patients Requiring Continuous Ambulatory Peritoneal Dialysis (CAPD) or
Hemodialysis:
For
patients
requiring
CAPD
or
hemodialysis,
follow
dosing
recommendations for patients with creatinine clearance less than 10 mL/min, shown in Table
14. It is not necessary to administer a supplemental dose of VIDEX following hemodialysis.
Hepatic Impairment and Toxicity: See WARNINGS.
Method of Preparation
VIDEX Pediatric Powder for Oral Solution
Prior to dispensing, the pharmacist must constitute dry powder with Purified Water, USP,
to an initial concentration of 20 mg/mL and immediately mix the resulting solution with
antacid to a final concentration of 10 mg/mL as follows:
20 mg/mL Initial Solution: Constitute the product to 20 mg/mL by adding 100
mL or 200 mL of Purified Water, USP, to the 2 g or 4 g of VIDEX powder, respectively, in
the product bottle.
10 mg/mL Final Admixture: 1. Immediately mix one part of the 20 mg/mL initial
solution with one part of Maximum Strength Mylanta® Liquid for a final dispensing
concentration of 10 mg VIDEX per mL. For patient home use, the admixture should be
dispensed in appropriately sized, flint-glass or plastic (HDPE, PET, or PETG) bottles with
child-resistant closures. This admixture is stable for 30 days under refrigeration, 36° to 46°
F (2° to 8° C).
2. Instruct the patient to shake the admixture thoroughly prior to use and to store
the tightly closed container in the refrigerator, 36° to 46° F (2° to 8° C), up to 30 days.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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Page 33 of 72
HOW SUPPLIED
VIDEX (didanosine) Pediatric Powder for Oral Solution is supplied in 4- and 8-ounce
glass bottles containing 2 g or 4 g of VIDEX, respectively.
The bottles of powder should be stored at 59° to 86° F (15° to 30° C). The VIDEX
admixture may be stored up to 30 days in a refrigerator, 36° to 46° F (2° to 8° C). Discard
any unused portion after 30 days.
The NDC numbers for the previously described VIDEX products are:
Table 15
NDC NO.
Packaging Information
Product Strength
VIDEX® Pediatric Powder for Oral Solution
0087-6632-41
One bottle per carton
2 g/bottle
0087-6633-41
One bottle per carton
4 g/bottle
US Patent Nos.: 4,861,759, 5,254,539, 5,616,566 and 5,880,106.
HANDLING AND DISPOSAL
Spill, Leak, and Disposal Procedure
Avoid generating dust during clean-up of powdered products; use wet mop or damp
sponge. Clean surface with soap and water as necessary. Containerize larger spills.
There is no single preferred method of disposal of containerized waste. Disposal
options include incineration, landfill, or sewer as dictated by specific circumstances and
relevant national, state, and local regulations.
Mylanta® is a registered trademark of Johnson & Johnson-Merck Consumer Pharmaceuticals Company.
Bristol-Myers Squibb Company
Princeton, NJ 08543 USA
1196181A3
Revised August 2006
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-154/S-050
NDA 20-155/S-039
NDA 20-156/S-040
NDA 21-183/S-016
Page 34 of 72
Patient Information
Rx only
VIDEX®
(generic name = didanosine also known as ddI)
VIDEX® (didanosine) Pediatric Powder for Oral Solution
What is VIDEX?
VIDEX (pronounced VY dex) is a prescription medicine used in combination with other
drugs to treat children and adults who are infected with HIV (the human immunodeficiency
virus, the virus that causes AIDS). VIDEX belongs to a class of drugs called nucleoside
analogues. By reducing the growth of HIV, VIDEX helps your body maintain its supply of
CD4 cells, which are important for fighting HIV and other infections.
VIDEX will not cure your HIV infection. At present there is no cure for HIV infection.
Even while taking VIDEX, you may continue to have HIV-related illnesses, including
infections with other disease-producing organisms. Continue to see your doctor regularly and
report any medical problems that occur.
VIDEX does not prevent a patient infected with HIV from passing the virus to other
people. To protect others, you must continue to practice safe sex and take precautions to
prevent others from coming in contact with your blood and other body fluids.
There is limited information on the effects of long-term use of VIDEX.
Who should not take VIDEX?
Do not take VIDEX if you are allergic to any of its ingredients, including its active ingredient,
didanosine and the inactive ingredients. (See Inactive Ingredients at the end of this leaflet.)
Tell your doctor if you think you have had an allergic reaction to any of these ingredients.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-154/S-050
NDA 20-155/S-039
NDA 20-156/S-040
NDA 21-183/S-016
Page 35 of 72
How should I take VIDEX? How should I store it?
Your doctor will determine your dose based on your body weight, kidney and liver function,
other medicines you are taking, and any side effects that you may have had with VIDEX or
other medicines. Take VIDEX on an empty stomach - that means at least 30 minutes before
or 2 hours after eating. Do not take VIDEX with food. Try not to miss a dose, but if you do,
take it as soon as possible. If it is almost time for the next dose, skip the missed dose and
continue your regular dosing schedule.
Your pharmacist will prepare the oral solution. Shake the solution well before
each use. Store in the refrigerator. Throw away any unused portion after 30
days.
If you have kidney disease: If your kidneys are not working properly, your doctor will
need to do regular tests to check how they are working while you take VIDEX. Your
doctor may also lower your dosage of VIDEX.
What should I do if someone takes an overdose of VIDEX?
If someone may have taken an overdose of VIDEX, get medical help right away. Contact
their doctor or a poison control center.
What should I avoid while taking VIDEX?
Alcohol. Do not drink alcohol while taking VIDEX since alcohol may increase your risk of
pancreatitis (pain and inflammation of the pancreas) or liver damage.
Other medicines. Other medicines, including those you can buy without a prescription,
may interfere with the actions of VIDEX or may increase the possibility or severity of side
effects. Do not take any medicine, vitamin supplement, or other health preparation
without first checking with your doctor.
Antacids. Since VIDEX is mixed with an antacid, any side effects related to
VIDEX’s ingredients may get worse if you also take an antacid.
Medicines at the same time you take your VIDEX dose. Some medicines should
not be taken at the same time of day that you take VIDEX. Check with your doctor.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-154/S-050
NDA 20-155/S-039
NDA 20-156/S-040
NDA 21-183/S-016
Page 36 of 72
Pregnancy. It is not known if VIDEX can harm a human fetus. Also, pregnant women
have experienced serious side effects when taking VIDEX in combination with ZERIT
(stavudine), also known as d4T, and other HIV medicines. VIDEX should be used during
pregnancy only after discussion with your doctor. Tell your doctor if you become
pregnant or plan to become pregnant while taking VIDEX.
Nursing. Studies have shown VIDEX is in the breast milk of animals getting the drug. It
may also be in human breast milk. The Centers for Disease Control and Prevention (CDC)
recommends that HIV-infected mothers not breast-feed. This should reduce the risk of
passing HIV infection to their babies and the potential for serious adverse reactions in
nursing infants. Therefore, do not nurse a baby while taking VIDEX.
What are the possible side effects of VIDEX?
Pancreatitis. Pancreatitis is a dangerous inflammation of the pancreas that may cause
death. Tell your doctor right away if you or a child taking VIDEX develops stomach
pain, nausea, or vomiting. These can be signs of pancreatitis. Before starting VIDEX
therapy, let your doctor know if you or a child for whom it has been prescribed has ever had
pancreatitis. This condition is more likely to happen in people who have had it before. It is also
more likely in people with advanced HIV disease. However, it can occur at any stage of HIV
disease. It may be more common in patients with kidney problems, those who drink alcohol,
and those who are also treated with stavudine or hydroxyurea. If you get pancreatitis, your
doctor will tell you to stop taking VIDEX.
Lactic acidosis, severe liver enlargement, and liver failure, including deaths, have been
reported among patients taking VIDEX (including pregnant women). Symptoms that may
indicate a liver problem are:
• feeling very weak, tired, or uncomfortable,
• unusual or unexpected stomach discomfort,
• feeling cold,
• feeling dizzy or lightheaded,
• suddenly developing a slow or irregular heartbeat.
Lactic acidosis is a medical emergency that must be treated in a hospital.
If you notice any of these symptoms or if your medical condition changes, stop taking
VIDEX and call your doctor right away. Women, overweight patients, and those who have
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-154/S-050
NDA 20-155/S-039
NDA 20-156/S-040
NDA 21-183/S-016
Page 37 of 72
been treated for a long time with other medicines used to treat HIV infection are more likely to
develop lactic acidosis. Your doctor should check your liver function periodically while you are
taking VIDEX. You should be especially careful if you have a history of heavy alcohol use or a
liver problem.
Vision changes. VIDEX may affect the nerves in your eyes. Because of this, you should have
regular eye examinations. You should also report any changes in vision to your doctor right
away. This includes, for example, seeing colors abnormally or blurred vision.
Peripheral neuropathy. This is a problem with the nerves in your hands or feet. The nerve
problem may be serious. Tell your doctor right away if you or a child taking VIDEX has
continuing numbness, tingling, or pain in the feet or hands. A child may not recognize these
symptoms or know to tell you that his or her feet or hands are numb, burning, tingling, or
painful. Ask your child’s doctor how to find out if your child is developing peripheral
neuropathy.
Before starting VIDEX therapy, let your doctor know if you or a child for whom it has
been prescribed has ever had peripheral neuropathy. This condition is more likely to happen in
people who have had it before. It is also more likely in patients taking medicines that affect the
nerves and in people with advanced HIV disease. However, it can occur at any stage of HIV
disease. If you get peripheral neuropathy, your doctor will tell you to stop taking VIDEX. After
stopping VIDEX, the symptoms may get worse for a short time and then get better. Once
symptoms of peripheral neuropathy go away completely, you and your doctor should decide if
starting VIDEX is right for you. If so, you might be started at a lower dose.
Special note about other medicines. If you take VIDEX along with other medicines with
similar side effects, you may increase the chance of having these side effects. For example,
using VIDEX in combination with other medicines that may cause pancreatitis, peripheral
neuropathy, or liver problems (including stavudine and hydroxyurea) may increase your chance
of having these side effects.
Other side effects: The most common side effects in adults taking VIDEX are diarrhea,
neuropathy (nerve disorders), chills or fever, rash, abdominal pain, weakness, headache, and
nausea and vomiting. Children may have similar side effects as adults.
Changes in body fat have been seen in some patients taking antiretroviral therapy. These
changes may include increased amount of fat in the upper back and neck (“buffalo hump”),
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For current labeling information, please visit https://www.fda.gov/drugsatfda
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Page 38 of 72
breast, and around the trunk. Loss of fat from the legs, arms, and face may also happen. The
cause and long-term health effects of these conditions are not known at this time.
Inactive Ingredients:
Pediatric Oral Solution: Maximum Strength Mylanta® Liquid.
This medicine was prescribed for your particular condition. Do not use VIDEX for another condition or give
it to others. Keep VIDEX and all medicines out of the reach of children. Throw away VIDEX when it is
outdated or no longer needed by flushing it down the toilet or pouring it down the sink.
This summary does not include everything there is to know about VIDEX. Medicines are sometimes
prescribed for purposes other than those listed in a Patient Information Leaflet. If you have questions or concerns, or
want more information about VIDEX, your physician and pharmacist have the complete prescribing information
upon which this leaflet is based. You may want to read it and discuss it with your doctor or other healthcare
professional. Remember, no written summary can replace careful discussion with your doctor.
Mylanta® is a registered trademark of Johnson & Johnson-Merck Consumer Pharmaceuticals Company.
Bristol-Myers Squibb Company
Princeton, NJ 08543 USA
This Patient Information Leaflet has been approved by the U.S. Food and Drug Administration.
1196181A3
Revised August 2006
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-154/S-050
NDA 20-155/S-039
NDA 20-156/S-040
NDA 21-183/S-016
Page 39 of 72
Rx only
VIDEX® EC (didanosine)
VIDEX® EC (didanosine) Delayed-Release Capsules
Enteric-Coated Beadlets
(Patient Information Leaflet Included)
WARNING
FATAL AND NONFATAL PANCREATITIS HAVE OCCURRED DURING
THERAPY WITH DIDANOSINE USED ALONE OR IN COMBINATION
REGIMENS
IN
BOTH
TREATMENT-NAIVE
AND
TREATMENT-
EXPERIENCED
PATIENTS,
REGARDLESS
OF
DEGREE
OF
IMMUNOSUPPRESSION. VIDEX EC SHOULD BE SUSPENDED IN PATIENTS
WITH SUSPECTED PANCREATITIS AND DISCONTINUED IN PATIENTS
WITH CONFIRMED PANCREATITIS (SEE WARNINGS).
LACTIC
ACIDOSIS
AND
SEVERE
HEPATOMEGALY
WITH
STEATOSIS, INCLUDING FATAL CASES, HAVE BEEN REPORTED WITH
THE USE OF NUCLEOSIDE ANALOGUES ALONE OR IN COMBINATION,
INCLUDING DIDANOSINE AND OTHER ANTIRETROVIRALS. FATAL
LACTIC ACIDOSIS HAS BEEN REPORTED IN PREGNANT WOMEN WHO
RECEIVED THE COMBINATION OF DIDANOSINE AND STAVUDINE WITH
OTHER
ANTIRETROVIRAL
AGENTS.
THE
COMBINATION
OF
DIDANOSINE AND STAVUDINE SHOULD BE USED WITH CAUTION
DURING PREGNANCY AND IS RECOMMENDED ONLY IF THE POTENTIAL
BENEFIT CLEARLY OUTWEIGHS THE POTENTIAL RISK (SEE WARNINGS
AND PRECAUTIONS: PREGNANCY, REPRODUCTION, AND FERTILITY).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-154/S-050
NDA 20-155/S-039
NDA 20-156/S-040
NDA 21-183/S-016
Page 40 of 72
DESCRIPTION
VIDEX® EC is the brand name for an enteric-coated formulation of didanosine (ddI), a
synthetic purine nucleoside analogue active against the Human Immunodeficiency Virus
(HIV). VIDEX EC (didanosine) Delayed-Release Capsules, containing enteric-coated
beadlets, are available for oral administration in strengths of 125, 200, 250, and 400 mg of
didanosine. The inactive ingredients in the beadlets include carboxymethylcellulose
sodium 12, diethyl phthalate, methacrylic acid copolymer, sodium hydroxide, sodium
starch glycolate, and talc. The capsule shells contain colloidal silicon dioxide, gelatin,
sodium lauryl sulfate, and titanium dioxide. The capsules are imprinted with edible inks.
Didanosine is also available in a powder formulation. Please consult the prescribing
information for VIDEX (didanosine) Pediatric Powder for Oral Solution for additional
information.
The chemical name for didanosine is 2',3'-dideoxyinosine. The structural formula
is:
Didanosine is a white crystalline powder with the molecular formula C10H12N4O3
and a molecular weight of 236.2. The aqueous solubility of didanosine at 25° C and pH of
approximately 6 is 27.3 mg/mL. Didanosine is unstable in acidic solutions. For example, at
pH <3 and 37° C, 10% of didanosine decomposes to hypoxanthine in less than 2 minutes.
In VIDEX EC, an enteric coating is used to protect didanosine from degradation by
stomach acid.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-154/S-050
NDA 20-155/S-039
NDA 20-156/S-040
NDA 21-183/S-016
Page 41 of 72
MICROBIOLOGY
Mechanism of Action
Didanosine is a synthetic nucleoside analogue of the naturally occurring nucleoside
deoxyadenosine in which the 3'-hydroxyl group is replaced by hydrogen. Intracellularly,
didanosine is converted by cellular enzymes to the active metabolite, dideoxyadenosine
5'-triphosphate. Dideoxyadenosine 5'-triphosphate inhibits the activity of HIV-1 reverse
transcriptase both by competing with the natural substrate, deoxyadenosine 5'-triphosphate,
and by its incorporation into viral DNA causing termination of viral DNA chain
elongation.
In Vitro HIV Susceptibility
The in vitro anti-HIV-1 activity of didanosine was evaluated in a variety of HIV-1 infected
lymphoblastic cell lines and monocyte/macrophage cell cultures. The concentration of drug
necessary to inhibit viral replication by 50% (IC50) ranged from 2.5 to 10 µM (1 µM = 0.24
µg/mL) in lymphoblastic cell lines and 0.01 to 0.1 µM in monocyte/macrophage cell
cultures. The relationship between in vitro susceptibility of HIV to didanosine and the
inhibition of HIV replication in humans has not been established.
Drug Resistance
HIV-1 isolates with reduced sensitivity to didanosine have been selected in vitro and were
also obtained from patients treated with didanosine. Genetic analysis of isolates from
didanosine-treated patients showed mutations in the reverse transcriptase gene that resulted
in the amino acid substitutions K65R, L74V, and M184V. The L74V mutation was most
frequently observed in clinical isolates. Phenotypic analysis of HIV-1 isolates from 60
patients (some with prior zidovudine treatment) receiving 6 to 24 months of didanosine
monotherapy showed that isolates from 10 of 60 patients exhibited an average of a 10-fold
decrease in susceptibility to didanosine in vitro compared to baseline isolates. Clinical
isolates that exhibited a decrease in didanosine susceptibility harbored one or more
didanosine-associated mutations. The clinical relevance of genotypic and phenotypic
changes associated with didanosine therapy has not been established.
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Cross-resistance
HIV-1 isolates from 2 of 39 patients receiving combination therapy for up to 2 years with
zidovudine and didanosine exhibited decreased susceptibility to zidovudine, didanosine,
zalcitabine, stavudine, and lamivudine in vitro. These isolates harbored five mutations
(A62V, V75I, F77L, F116Y, and Q151M) in the reverse transcriptase gene. In data from
clinical studies, the presence of thymidine analogue mutations (M41L, D67N, L210W,
T215Y, K219Q) has been shown to decrease the response to didanosine.
CLINICAL PHARMACOLOGY
Animal Toxicology
Evidence of a dose-limiting skeletal muscle toxicity has been observed in mice and rats
(but not in dogs) following long-term (greater than 90 days) dosing with didanosine at
doses that were approximately 1.2 to 12 times the estimated human exposure. The
relationship of this finding to the potential of didanosine to cause myopathy in humans is
unclear. However, human myopathy has been associated with administration of didanosine
and other nucleoside analogues.
Pharmacokinetics
The pharmacokinetic parameters of didanosine are summarized in Table 1. Didanosine is
rapidly absorbed, with peak plasma concentrations generally observed from 0.25 to 1.50
hours following oral dosing with a buffered formulation. Increases in plasma didanosine
concentrations were dose proportional over the range of 50 to 400 mg. Steady-state
pharmacokinetic parameters did not differ significantly from values obtained after a single
dose. Binding of didanosine to plasma proteins in vitro was low (<5%). Based on data
from in vitro and animal studies, it is presumed that the metabolism of didanosine in man
occurs by the same pathways responsible for the elimination of endogenous purines.
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Page 43 of 72
Table 1:
Pharmacokinetic Parameters for Didanosine in Adults
Parameter
Mean ± SD
n
Oral bioavailabilitya
42 ± 12%
6
Apparent volume of distributionb
1.08 ± 0.22 L/kg
6
CSF-plasma ratiob
21 ± 0.03%c
5
Systemic clearanceb
13.0 ± 1.6 mL/min/kg
6
Renal clearancea
5.5 ± 2.1 mL/min/kg
6
Elimination half-lifea
1.5 ± 0.4 h
6
Urinary recovery of didanosinea
18 ± 8%
6
CSF = cerebrospinal fluid.
a following oral administration of a buffered formulation.
b following IV administration.
c mean ± SE.
Comparison of Didanosine Formulations
In VIDEX EC, the active ingredient, didanosine, is protected against degradation by
stomach acid by the use of an enteric coating on the beadlets in the capsule. The enteric
coating dissolves when the beadlets empty into the small intestine, the site of drug
absorption. With buffered formulations of didanosine, administration with antacid provides
protection from degradation by stomach acid.
In healthy volunteers, as well as subjects infected with HIV, the area under the
plasma concentration time curve (AUC) is equivalent for didanosine administered as the
VIDEX EC formulation relative to a buffered tablet formulation. The peak plasma
concentration (CMAX) of didanosine, administered as VIDEX EC, is reduced approximately
40% relative to didanosine buffered tablets. The time to the peak concentration (TMAX)
increases from approximately 0.67 hours for didanosine buffered tablets to 2.0 hours for
VIDEX EC.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
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NDA 20-156/S-040
NDA 21-183/S-016
Page 44 of 72
Effect of Food on Absorption of Didanosine
In the presence of food, the CMAX and AUC for VIDEX EC were reduced by approximately
46% and 19%, respectively, compared to the fasting state. VIDEX EC should be taken on
an empty stomach.
Special Populations
Renal Insufficiency
It is recommended that the VIDEX EC (didanosine) dose be modified in patients with
reduced creatinine clearance and in patients receiving maintenance hemodialysis (see
DOSAGE AND ADMINISTRATION). Data from two studies using a buffered
formulation of didanosine indicated that the apparent oral clearance of didanosine
decreased and the terminal elimination half-life increased as creatinine clearance decreased
(see Table 2). Following oral administration, didanosine was not detectable in peritoneal
dialysate fluid (n=6); recovery in hemodialysate (n=5) ranged from 0.6% to 7.4% of the
dose over a 3-4 hour dialysis period. The absolute bioavailability of didanosine was not
affected in patients requiring dialysis.
Table 2:
Mean ± SD Pharmacokinetic Parameters for Didanosine
Following a Single Oral Dose of a Buffered Formulation
Creatinine Clearance (mL/min)
Parameter
≥ 90
(n=12)
60-90
(n=6)
30-59
(n=6)
10-29
(n=3)
Dialysis
Patients
(n=11)
CLcr (mL/min)
112 ± 22
68 ± 8
46 ± 8
13 ± 5
ND
CL/F (mL/min)
2164 ± 638
1566 ± 833
1023 ± 378
628 ± 104
543 ± 174
CLR (mL/min)
458 ± 164
247 ± 153
100 ± 44
20 ± 8
<10
T½ (h)
1.42 ± 0.33
1.59 ± 0.13
1.75 ± 0.43
2.0 ± 0.3
4.1 ± 1.2
ND = not determined due to anuria.
CLcr = creatinine clearance.
CL/F = apparent oral clearance.
CLR = renal clearance.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
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Pediatric Patients
The pharmacokinetics of didanosine administered as VIDEX EC have not been studied in
pediatric patients.
Geriatric Patients
Didanosine pharmacokinetics have not been studied in patients over 65 years of age (see
PRECAUTIONS: Geriatric Use).
Gender
The effects of gender on didanosine pharmacokinetics have not been studied.
Drug Interactions (See also PRECAUTIONS: Drug Interactions.)
Ribavirin has been shown in vitro to increase intracellular triphosphate levels of
didanosine, which could cause or worsen clinical toxicities (see PRECAUTIONS: Drug
Interactions).
VIDEX EC
Tables 3 and 4 summarize the effects on AUC and CMAX, with a 90% confidence interval
(CI) when available, following coadministration of VIDEX EC with a variety of drugs.
Clinical recommendations based on drug interaction studies for drugs in bold font are
included
in
PRECAUTIONS:
Drug
Interactions
and
DOSAGE
AND
ADMINISTRATION.
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Table 3:
Results of Drug Interaction Studies with VIDEX EC: Effects of
Coadministered Drug on Didanosine Plasma AUC and CMAX
Valuesa
Drug
Didanosine Dosage
n
AUC of Didanosine
(90% CI)
CMAX of Didanosine
(90% CI)
tenofovir,b 300 mg
once daily with a
light mealc
400 mg single dose
fasting 2 h before
tenofovir
26
↑ 48% (31, 67%)
↑ 48% (25, 76%)
tenofovir,b 300 mg
once daily with a
light mealc
400 mg single dose
with tenofovir and
a light meal
25
↑ 60% (44, 79%)
↑ 64% (41, 89%)
tenofovir,b 300 mg
once daily with a
light mealc
200 mg single dose
with tenofovir and
a light meal
33
↑ 16% (6, 27%)d
↓ 12% (−25, 3%)d
250 mg single dose
with tenofovir and
a light meal
33
↔ (−13, 5%)e
↓ 20% (−32, −7%)e
325 mg single dose
with tenofovir and
a light meal
33
↑ 13% (3, 24%)e
↓ 11% (−24, 4%)e
↑ indicates increase.
↓ indicates decrease.
↔ indicates no change, or mean increase or decrease of <10%.
a All studies conducted in healthy volunteers ≥60 kg with creatinine clearance ≥60 mL/min.
b tenofovir disoproxil fumarate.
c 373 kcalories, 8.2 grams fat.
d Compared with VIDEX EC 250 mg administered alone under fasting conditions.
e Compared with VIDEX EC 400 mg administered alone under fasting conditions.
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Table 4:
Results of Drug Interaction Studies with VIDEX EC: Effects of
Didanosine on Coadministered Drug Plasma AUC and CMAX
Valuesa
Drug
Didanosine Dosage
n
AUC of
Coadministered Drug
CMAX of Coadministered
Drug
ciprofloxacin, 750 mg
single dose
400 mg single dose
16
↔
↔
indinavir, 800 mg
single dose
400 mg single dose
23
↔
↔
ketoconazole, 200 mg
single dose
400 mg single dose
21
↔
↔
tenofovir,b 300 mg
once daily with a
light mealc
400 mg single dose
fasting 2 h before
tenofovir
25
↔
↔
tenofovir,b 300 mg
once daily with a
light mealc
400 mg single dose
with tenofovir and
a light meal
25
↔
↔
↔ indicates no change, or mean increase or decrease of <10%.
a All studies conducted in healthy volunteers ≥60 kg with creatinine clearance ≥60 mL/min.
b tenofovir disoproxil fumarate.
c 373 kcalories, 8.2 grams fat.
Didanosine Buffered Formulations
Tables 5 and 6 summarize the effects on AUC and CMAX, with a 90% or 95% CI when
available, following coadministration of buffered formulations of didanosine with a variety
of drugs. Except as noted in table footnotes, the results of these studies may be expected to
apply to VIDEX EC. For most of the listed drugs, no clinically significant
pharmacokinetic interactions were noted. Clinical recommendations based on drug
interaction studies for drugs in bold font are included in PRECAUTIONS: Drug
Interactions and DOSAGE AND ADMINISTRATION (for tenofovir).
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Table 5:
Results of Drug Interaction Studies with Buffered
Formulations of Didanosine: Effects of Coadministered Drug
on Didanosine Plasma AUC and CMAX Values
Drugs With Clinical Recommendations Regarding Coadministration (see PRECAUTIONS: Drug
Interactions)
Drug
Didanosine Dosage
n
AUC of Didanosine
(95% CI)
CMAX of Didanosine
(95% CI)
allopurinol
renally impaired, 300 mg/day
200 mg single dose
2
↑ 312%
↑ 232%
healthy volunteer, 300 mg/day for
7 days
400 mg single dose
14
↑ 113%
↑ 69%
ganciclovir, 1000 mg q8h,
2 h after didanosine
200 mg q12h
12
↑ 111%
NA
methadone, chronic maintenance
dose
200 mg single dose
16,
10a
↓ 57%
↓ 66%
tenofovir,b 300 mg once daily 1 h
after didanosine
250c or 400 mg once
daily for 7 days
14
↑ 44%
(31, 59%)d
↑ 28%
(11, 48%)d
No Clinically Significant Interaction Observed
Drug
Didanosine Dosage
n
AUC of Didanosine
(95% CI)
CMAX of Didanosine
(95% CI)
ciprofloxacin, 750 mg q12h for 3
days, 2 h before didanosine
200 mg q12h for 3 days
8e
↓ 16%
↓ 28%
indinavir, 800 mg single dose
simultaneous
200 mg single dose
16
↔
↔
1 h before didanosine
200 mg single dose
16
↓ 17% (-27, -7%)d
↓ 13% (-28, 5%)d
ketoconazole, 200 mg/day for 4
days, 2 h before didanosine
375 mg q12h for 4 days
12e
↔
↓12%
loperamide, 4 mg q6h for 1 day
300 mg single dose
12e
↔
↓23%
metoclopramide, 10 mg single dose
300 mg single dose
12e
↔
↑13%
ranitidine, 150 mg single dose, 2 h
before didanosine
375 mg single dose
12e
↑14%
↑13%
rifabutin, 300 or 600 mg/day for 12
days
167 or 250 mg q12h for
12 days
11
↑ 13% (-1, 27%)
↑ 17% (-4, 38%)
ritonavir, 600 mg q12h for 4 days
200 mg q12h for 4 days
12
↓ 13% (0, 23%)
↓ 16% (5, 26%)
stavudine, 40 mg q12h for 4 days
100 mg q12h for 4 days
10
↔
↔
sulfamethoxazole, 1000 mg single
dose
200 mg single dose
8e
↔
↔
trimethoprim, 200 mg single dose
200 mg single dose
8e
↔
↑ 17% (-23, 77%)
zidovudine, 200 mg q8h for 3 days
200 mg q12h for 3 days
6e
↔
↔
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Table 5:
Results of Drug Interaction Studies with Buffered
Formulations of Didanosine: Effects of Coadministered Drug
on Didanosine Plasma AUC and CMAX Values
↑
indicates increase.
↓
indicates decrease.
↔ indicates no change, or mean increase or decrease of <10%.
a
Parallel-group design; entries are subjects receiving combination and control regimens, respectively.
b
tenofovir disoproxil fumarate.
c
patients <60 kg with creatinine clearance ≥60 mL/min.
d
90% Cl.
e
HIV-infected patients.
NA Not available.
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Table 6:
Results of Drug Interaction Studies with Buffered
Formulations of Didanosine: Effects of Didanosine on
Coadministered Drug Plasma AUC and CMAX Values
No Clinically Significant Interaction Observed
Drug
Didanosine Dosage
n
AUC of
Coadministered Drug
(95% CI)
CMAX of
Coadministered Drug
(95% CI)
dapsone, 100 mg single dose
200 mg q12h for 14 days
6a
↔
↔
delavirdine, 400 mg single
dose
simultaneous
1 h before didanosine
125 or 200 mg q12h
125 or 200 mg q12h
12a
12a
↓ 32%b
↑ 20%
↓ 53%b
↑ 18%
ganciclovir, 1000 mg q8h,
2 h after didanosine
200 mg q12h
12a
↓21%
NA
nelfinavir, 750 mg single
dose, 1 h after didanosine
200 mg single dose
10a
↑12%
↔
ranitidine, 150 mg single
dose, 2 h before didanosine
375 mg single dose
12a
↓16%
↔
ritonavir, 600 mg q12h for
4 days
200 mg q12h for 4 days
12
↔
↔
stavudine, 40 mg q12h for
4 days
100 mg q12h for 4 days
10a
↔
↑17%
sulfamethoxazole, 1000 mg
single dose
200 mg single dose
8a
↓ 11% (-17, -4%)
↓ 12% (-28, 8%)
tenofovir,c 300 mg once daily
1 h after didanosine
250d or 400 mg once daily
for 7 days
14
↔
↔
trimethoprim, 200 mg single
dose
200 mg single dose
8a
↑ 10% (-9, 34%)
↓ 22% (-59, 49%)
zidovudine, 200 mg q8h for
3 days
200 mg q12h for 3 days
6a
↓ 10% (-27, 11%)
↓ 16.5% (-53, 47%)
↑
indicates increase.
↓
indicates decrease.
↔ indicates no change, or mean increase or decrease of <10%.
a
HIV-infected patients.
b
This result is probably related to the buffer and is not expected to occur with VIDEX EC.
c
tenofovir disoproxil fumarate.
d
patients <60 kg with creatinine clearance ≥60 mL/min.
NA Not available.
INDICATIONS AND USAGE
VIDEX EC (didanosine) in combination with other antiretroviral agents is indicated
for the treatment of HIV-1 infection in adults. (See Clinical Studies.)
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Clinical Studies
Study Al454-152 was a 48-week, randomized, open-label study comparing VIDEX EC
(400 mg once daily) plus stavudine (40 mg twice daily) plus nelfinavir (750 mg three times
daily) to zidovudine (300 mg) plus lamivudine (150 mg) combination tablets twice daily
plus nelfinavir (750 mg three times daily) in 511 treatment-naive patients, with a mean
CD4 cell count of 411 cells/mm3 (range 39 to 1105 cells/mm3) and a mean plasma HIV-1
RNA of 4.71 log10 copies/mL (range 2.8 to 5.9 log10 copies/mL) at baseline. Patients were
primarily males (72%) and Caucasian (53%) with a mean age of 35 years (range 18 to 73
years). The percentages of patients with HIV RNA <400 and <50 copies/mL and outcomes
of patients through 48 weeks are summarized in Figure 1 and Table 7, respectively.
Figure 1
Treatment Response Through Week 48*, AI454-152
*Percent of patients at each time point who have HIV RNA <400 or
<50 copies/mL and do not meet any criteria for treatment failure (eg,
virologic failure or discontinuation for any reason).
0
20
40
60
80
100
0
12
24
36
48
Study Week
Percent of Patients
] < 400 c/mL
] < 50 c/mL
VIDEX EC+stavudine+nelfinavir, n=258
zidovudine/lamivudine+nelfinavir, n=253
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Table 7:
Outcomes of Randomized Treatment Through Week 48, AI454-152
Percent of Patients with HIV RNA <400 copies/mL (<50 copies/mL)
VIDEX EC + stavudine +
zidovudine/lamivudinea +
nelfinavir
nelfinavir
Outcome
n=258
n=253
Responderb,c
55% (33%)
56% (33%)
Virologic failured
22% (45%)
21% (43%)
Death or discontinued due to
disease progression
1% (1%)
2% (2%)
Discontinued due to adverse event
6% (6%)
7% (7%)
Discontinued due to other reasonse
16% (16%)
15% (16%)
a Zidovudine/lamivudine combination tablet.
b Corresponds to rates at Week 48 in Figure 1.
c Subjects achieved and maintained confirmed HIV RNA <400 copies/mL (<50 copies/mL) through
Week 48.
d Includes viral rebound at or before Week 48 and failure to achieve confirmed HIV RNA <400 copies/mL
(<50 copies/mL) through Week 48.
e Includes lost to follow-up, subject’s withdrawal, discontinuation due to physician’s decision, never treated,
and other reasons.
CONTRAINDICATION
VIDEX EC (didanosine) is contraindicated in patients with previously demonstrated
clinically significant hypersensitivity to any component of the formulation.
WARNINGS
1. Pancreatitis
FATAL AND NONFATAL PANCREATITIS HAVE OCCURRED DURING
THERAPY WITH DIDANOSINE USED ALONE OR IN COMBINATION
REGIMENS
IN
BOTH
TREATMENT-NAIVE
AND
TREATMENT-
EXPERIENCED
PATIENTS,
REGARDLESS
OF
DEGREE
OF
IMMUNOSUPPRESSION. VIDEX EC SHOULD BE SUSPENDED IN PATIENTS
WITH SIGNS OR SYMPTOMS OF PANCREATITIS AND DISCONTINUED IN
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PATIENTS WITH CONFIRMED PANCREATITIS. PATIENTS TREATED WITH
VIDEX EC IN COMBINATION WITH STAVUDINE, WITH OR WITHOUT
HYDROXYUREA, MAY BE AT INCREASED RISK FOR PANCREATITIS.
When treatment with life-sustaining drugs known to cause pancreatic toxicity is
required, suspension of VIDEX EC therapy is recommended. In patients with risk factors
for pancreatitis, VIDEX EC should be used with extreme caution and only if clearly
indicated. Patients with advanced HIV infection, especially the elderly, are at increased risk
of pancreatitis and should be followed closely. Patients with renal impairment may be at
greater risk for pancreatitis if treated without dose adjustment.
The frequency of pancreatitis is dose related. In phase 3 studies with buffered
formulations of didanosine, incidence ranged from 1% to 10% with doses higher than are
currently recommended and 1% to 7% with recommended dose.
2. Lactic Acidosis/Severe Hepatomegaly with Steatosis
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases,
have been reported with the use of nucleoside analogues alone or in combination,
including didanosine and other antiretrovirals. A majority of these cases have been in
women. Obesity and prolonged nucleoside exposure may be risk factors. Fatal lactic
acidosis has been reported in pregnant women who received the combination of didanosine
and stavudine with other antiretroviral agents. The combination of didanosine and
stavudine should be used with caution during pregnancy and is recommended only if the
potential benefit clearly outweighs the potential risk (see PRECAUTIONS: Pregnancy,
Reproduction, and Fertility). Particular caution should be exercised when administering
VIDEX EC to any patient with known risk factors for liver disease; however, cases have
also been reported in patients with no known risk factors. Treatment with VIDEX EC
should be suspended in any patient who develops clinical or laboratory findings suggestive
of symptomatic hyperlactatemia, lactic acidosis, or pronounced hepatotoxicity (which may
include hepatomegaly and steatosis even in the absence of marked transaminase
elevations).
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3. Retinal Changes and Optic Neuritis
Retinal changes and optic neuritis have been reported in patients taking didanosine.
Periodic retinal examinations should be considered for patients receiving VIDEX EC. (See
ADVERSE REACTIONS.)
4. Hepatic Impairment and Toxicity
It is unknown if hepatic impairment significantly affects didanosine pharmaco-
kinetics. Therefore, these patients should be monitored closely for evidence of didanosine
toxicity. The safety and efficacy of VIDEX EC have not been established in HIV-infected
patients with significant underlying liver disease. During combination antiretroviral
therapy, patients with preexisting liver dysfunction, including chronic active hepatitis, have
an increased frequency of liver function abnormalities, including severe and potentially
fatal hepatic adverse events, and should be monitored according to standard practice. If
there is evidence of worsening liver disease in such patients, interruption or discontinuation
of treatment must be considered.
Hepatotoxicity and hepatic failure resulting in death were reported during
postmarketing surveillance in HIV-infected patients treated with hydroxyurea and other
antiretroviral agents. Fatal hepatic events were reported most often in patients treated with
the combination of hydroxyurea, didanosine, and stavudine. This combination should be
avoided.
PRECAUTIONS
Dosing
VIDEX EC should be administered once daily on an empty stomach.
Peripheral Neuropathy
Peripheral neuropathy, manifested by numbness, tingling, or pain in the hands or feet, has
been reported in patients receiving didanosine therapy. Peripheral neuropathy has occurred
more frequently in patients with advanced HIV disease, in patients with a history of
neuropathy, or in patients being treated with neurotoxic drug therapy, including stavudine.
Peripheral neuropathy, which was severe in some cases, has been reported in HIV-infected
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patients receiving hydroxyurea in combination with antiretroviral agents, including
didanosine, with or without stavudine (see ADVERSE REACTIONS).
Fat Redistribution
Redistribution/accumulation of body fat including central obesity, dorsocervical fat
enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and
“cushingoid appearance” have been observed in patients receiving antiretroviral therapy.
The mechanism and long-term consequences of these events are currently unknown. A
causal relationship has not been established.
Immune Reconstitution Syndrome
Immune reconstitution syndrome has been reported in patients treated with combination
antiretroviral therapy, including VIDEX EC. During the initial phase of combination
antiretroviral treatment, patients whose immune system responds may develop an
inflammatory response to indolent or residual opportunistic infections (such as
Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia
[PCP], or tuberculosis), which may necessitate further evaluation and treatment.
General
Patients with Renal Impairment
Patients with renal impairment (creatinine clearance <60 mL/min) may be at greater risk of
toxicity from didanosine due to decreased drug clearance (see CLINICAL
PHARMACOLOGY). A dose reduction is recommended in these patients (see DOSAGE
AND ADMINISTRATION).
Hyperuricemia
Didanosine has been associated with asymptomatic hyperuricemia; treatment suspension
may be necessary if clinical measures aimed at reducing uric acid levels fail.
Information for Patients (See Patient Information Leaflet)
Patients should be informed that a serious toxicity of didanosine, used alone and in
combination regimens, is pancreatitis, which may be fatal.
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Patients should also be aware that peripheral neuropathy, manifested by numbness,
tingling, or pain in hands or feet, may develop during therapy with VIDEX EC
(didanosine). Patients should be counseled that peripheral neuropathy occurs with greatest
frequency in patients with advanced HIV disease or a history of peripheral neuropathy, and
that dose modification and/or discontinuation of VIDEX EC may be required if toxicity
develops.
Patients should be informed that when didanosine is used in combination with other
agents with similar toxicities, the incidence of adverse events may be higher than when
didanosine is used alone. These patients should be followed closely.
Patients should be cautioned about the use of medications or other substances,
including alcohol, that may exacerbate VIDEX EC toxicities.
VIDEX EC is not a cure for HIV infection, and patients may continue to develop
HIV-associated illnesses, including opportunistic infection. Therefore, patients should
remain under the care of a physician when using VIDEX EC. Patients should be advised
that VIDEX EC therapy has not been shown to reduce the risk of transmission of HIV to
others through sexual contact or blood contamination. Patients should be informed that the
long-term effects of VIDEX EC are unknown at this time.
Patients should be informed that redistribution or accumulation of body fat may
occur in patients receiving antiretroviral therapy and that the cause and long-term health
effects of these conditions are not known at this time.
Drug Interactions (see also CLINICAL PHARMACOLOGY: Drug
Interactions)
Drug interactions that have been established based on drug interaction studies are listed
with the pharmacokinetic results in CLINICAL PHARMACOLOGY: Drug
Interactions (Tables 3-6). The clinical recommendations based on the results of these
studies are listed in Table 8.
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Table 8:
Established Drug Interactions Based on Studies with
VIDEX EC or Studies with Buffered Formulations of
Didanosine and Expected to Occur with VIDEX EC
Coadministration Not Recommended Based on Drug Interaction Studies (see CLINICAL
PHARMACOLOGY: Drug Interactions for Magnitude of Interaction)
Drug
Effect
Clinical Comment
allopurinol
↑ didanosine concentration
Coadministration not recommended.
Alteration in Dose or Regimen Recommended Based on Drug Interaction Studies (see CLINICAL
PHARMACOLOGY: Drug Interactions for Magnitude of Interaction)
Drug
Effect
Clinical Comment
ganciclovir
↑ didanosine concentration
Appropriate doses for this combination, with
respect to efficacy and safety, have not been
established.
methadone
↓ didanosine concentration
Appropriate doses for this combination, with
respect to efficacy and safety, have not been
established.
tenofovir disoproxil
fumarate
↑ didanosine concentration
A dose reduction of VIDEX EC to 250 mg
(adults weighing ≥60 kg with creatinine
clearance ≥60 mL/min) or 200 mg (adults
weighing <60 kg with creatinine clearance
≥60 mL/min) once daily taken together with
tenofovir and a light meal (≤400 kcalories and
≤20% fat) or in the fasted state is
recommended. Patients should be monitored
for didanosine-associated toxicities and
clinical response (see below).
↑ indicates increase.
↓ indicates decrease.
Coadministration of VIDEX EC with drugs that are known to cause
pancreatitis may increase the risk of this toxicity (see WARNINGS: Pancreatitis).
Predicted drug interactions with VIDEX EC are listed in Table 9.
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Table 9:
Predicted Drug Interactions with VIDEX EC
Drug or Drug Class
Effect
Clinical Comment
Drugs that may cause
pancreatic toxicity
↑ risk of pancreatitis
Use only with extreme caution.a
Neurotoxic drugs
↑ risk of neuropathy
Use with caution.b
Ribavirin
↑ risk of toxicity
Ribavirin has been shown in vitro to increase
intracellular triphosphate levels of didanosine.
Coadministration is not recommended (see
below).
↑ indicates increase.
a Only if other drugs are not available and if clearly indicated. If treatment with life-sustaining drugs that
cause pancreatic toxicity is required, suspension of VIDEX EC is recommended (see WARNINGS:
Pancreatitis).
b See PRECAUTIONS: Peripheral Neuropathy.
Nucleoside/nucleotide analogues
Tenofovir disoproxil fumarate. Exposure to didanosine is increased when coadministered
with tenofovir (see Tables 3, 5, and 8). Increased exposure may cause or worsen
didanosine-related
clinical
toxicities,
including
pancreatitis,
symptomatic
hyperlactatemia/lactic acidosis, and peripheral neuropathy. Coadministration of
tenofovir with VIDEX EC should be undertaken with caution, and patients should be
monitored closely for didanosine-related toxicities and clinical response. VIDEX EC
should be suspended if signs or symptoms of pancreatitis, symptomatic
hyperlactatemia, or lactic acidosis develop (see WARNINGS). Administration of
reduced doses of VIDEX EC with tenofovir and a light meal resulted in didanosine
exposures (AUC) similar to the recommended doses of VIDEX EC given alone in the
fasted state (see Table 3). Therefore, when administered with tenofovir, a dose reduction
of VIDEX EC to 250 mg (adults weighing ≥60 kg with creatinine clearance ≥60 mL/min)
or 200 mg (adults weighing <60 kg with creatinine clearance ≥60 mL/min) once daily is
recommended, and both drugs may be taken together with a light meal (≤400 kcalories,
≤20% fat) or in the fasted state (see DOSAGE AND ADMINISTRATION).
Coadministration of didanosine with food decreases didanosine concentrations. Thus,
although not studied, it is possible that coadministration with heavier meals could reduce
didanosine concentrations further.
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Ribavirin. Exposure to the active metabolite of didanosine (dideoxyadenosine 5'-
triphosphate) is increased when didanosine is coadministered with ribavirin (see Table 9).
Fatal hepatic failure, as well as peripheral neuropathy, pancreatitis, and symptomatic
hyperlactatemia/lactic acidosis have been reported in patients receiving both didanosine
and ribavirin. Coadministration of didanosine and ribavirin is not recommended.
Carcinogenesis and Mutagenesis
Lifetime carcinogenicity studies were conducted in mice and rats for 22 and 24 months,
respectively. In the mouse study, initial doses of 120, 800, and 1200 mg/kg/day for each
sex were lowered after 8 months to 120, 210, and 210 mg/kg/day for females and 120, 300,
and 600 mg/kg/day for males. The two higher doses exceeded the maximally tolerated
dose in females and the high dose exceeded the maximally tolerated dose in males. The
low dose in females represented 0.68-fold maximum human exposure and the intermediate
dose in males represented 1.7-fold maximum human exposure based on relative AUC
comparisons. In the rat study, initial doses were 100, 250, and 1000 mg/kg/day, and the
high dose was lowered to 500 mg/kg/day after 18 months. The upper dose in male and
female rats represented 3-fold maximum human exposure.
Didanosine induced no significant increase in neoplastic lesions in mice or rats at
maximally tolerated doses.
Didanosine was positive in the following genetic toxicology assays: 1) the
Escherichia coli tester strain WP2 uvrA bacterial mutagenicity assay; 2) the
L5178Y/TK+/- mouse lymphoma mammalian cell gene mutation assay; 3) the in vitro
chromosomal aberrations assay in cultured human peripheral lymphocytes; 4) the in vitro
chromosomal aberrations assay in Chinese Hamster Lung cells; and 5) the BALB/c 3T3 in
vitro transformation assay. No evidence of mutagenicity was observed in an Ames
Salmonella bacterial mutagenicity assay or in rat and mouse in vivo micronucleus assays.
Pregnancy, Reproduction, and Fertility
Pregnancy Category B. Reproduction studies have been performed in rats and rabbits at
doses up to 12 and 14.2 times the estimated human exposure (based upon plasma levels),
respectively, and have revealed no evidence of impaired fertility or harm to the fetus due to
didanosine. At approximately 12 times the estimated human exposure, didanosine was
slightly toxic to female rats and their pups during mid and late lactation. These rats showed
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-154/S-050
NDA 20-155/S-039
NDA 20-156/S-040
NDA 21-183/S-016
Page 60 of 72
reduced food intake and body weight gains but the physical and functional development of
the offspring was not impaired and there were no major changes in the F2 generation. A
study in rats showed that didanosine and/or its metabolites are transferred to the fetus
through the placenta. Animal reproduction studies are not always predictive of human
response.
There are no adequate and well-controlled studies of didanosine in pregnant
women. Didanosine should be used during pregnancy only if the potential benefit justifies
the potential risk.
Fatal lactic acidosis has been reported in pregnant women who received the
combination of didanosine and stavudine with other antiretroviral agents. It is unclear if
pregnancy augments the risk of lactic acidosis/hepatic steatosis syndrome reported in
nonpregnant individuals receiving nucleoside analogues (see WARNINGS: Lactic
Acidosis/Severe Hepatomegaly with Steatosis). The combination of didanosine and
stavudine should be used with caution during pregnancy and is recommended only if
the potential benefit clearly outweighs the potential risk. Health care providers caring
for HIV-infected pregnant women receiving didanosine should be alert for early diagnosis
of lactic acidosis/hepatic steatosis syndrome.
Antiretroviral Pregnancy Registry: To monitor maternal-fetal outcomes of
pregnant women exposed to didanosine and other antiretroviral agents, an Antiretroviral
Pregnancy Registry has been established. Physicians are encouraged to register patients by
calling 1-800-258-4263.
Nursing Mothers
The Centers for Disease Control and Prevention recommend that HIV-infected
mothers not breast-feed their infants to avoid risking postnatal transmission of HIV.
A study in rats showed that following oral administration, didanosine and/or its metabolites
were excreted into the milk of lactating rats. It is not known if didanosine is excreted in
human milk. Because of both the potential for HIV transmission and the potential for
serious adverse reactions in nursing infants, mothers should be instructed not to breast-
feed if they are receiving VIDEX EC (didanosine).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-154/S-050
NDA 20-155/S-039
NDA 20-156/S-040
NDA 21-183/S-016
Page 61 of 72
Pediatric Use
The safety and efficacy of VIDEX EC in pediatric patients have not been established.
Please consult the complete prescribing information for VIDEX (didanosine) Pediatric
Powder for Oral Solution for dosage and administration of didanosine to pediatric patients.
Geriatric Use
In an Expanded Access Program using a buffered formulation of didanosine for the
treatment of advanced HIV infection, patients aged 65 years and older had a higher
frequency of pancreatitis (10%) than younger patients (5%) (see WARNINGS). Clinical
studies of didanosine, including those for VIDEX EC, did not include sufficient numbers
of subjects aged 65 years and over to determine whether they respond differently than
younger subjects. Didanosine is known to be substantially excreted by the kidney, and the
risk of toxic reactions to this drug may be greater in patients with impaired renal function.
Because elderly patients are more likely to have decreased renal function, care should be
taken in dose selection. In addition, renal function should be monitored and dosage
adjustments should be made accordingly (see DOSAGE AND ADMINISTRATION:
Dose Adjustment).
ADVERSE REACTIONS
A SERIOUS TOXICITY OF DIDANOSINE IS PANCREATITIS, WHICH MAY BE
FATAL (see WARNINGS). OTHER IMPORTANT TOXICITIES INCLUDE LACTIC
ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS; RETINAL CHANGES
AND OPTIC NEURITIS; AND PERIPHERAL NEUROPATHY (see WARNINGS and
PRECAUTIONS).
When didanosine is used in combination with other agents with similar
toxicities, the incidence of these toxicities may be higher than when didanosine is used
alone. Thus, patients treated with VIDEX EC in combination with stavudine, with or
without hydroxyurea, may be at increased risk for pancreatitis and hepatotoxicity,
which may be fatal, and severe peripheral neuropathy (see WARNINGS and
PRECAUTIONS).
Selected clinical adverse events that occurred in a study of VIDEX EC in
combination with other antiretroviral agents are provided in Table 10.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-154/S-050
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NDA 20-156/S-040
NDA 21-183/S-016
Page 62 of 72
Table 10:
Selected Clinical Adverse Events, Study AI454-152a
Percent of Patientsb
VIDEX EC +
stavudine +
nelfinavir
zidovudine/
lamivudinec +
nelfinavir
Adverse Events
n=258
n=253
Diarrhea
57
58
Peripheral Neurologic
Symptoms/Neuropathy
25
11
Nausea
24
36
Headache
22
17
Rash
14
12
Vomiting
14
19
Pancreatitis (see below)
<1
*
a Median duration of treatment was 62 weeks in the VIDEX EC + stavudine + nelfinavir group and
61 weeks in the zidovudine/lamivudine + nelfinavir group.
b Percentages based on treated patients.
c Zidovudine/lamivudine combination tablet.
* This event was not observed in this study arm.
In clinical trials using a buffered formulation of didanosine, pancreatitis
resulting in death was observed in one patient who received didanosine plus
stavudine plus nelfinavir, one patient who received didanosine plus stavudine plus
indinavir, and 2 of 68 patients who received didanosine plus stavudine plus indinavir
plus hydroxyurea. In an early access program, pancreatitis resulting in death was
observed in one patient who received VIDEX EC plus stavudine plus hydroxyurea
plus ritonavir plus indinavir plus efavirenz (see WARNINGS).
The frequency of pancreatitis is dose related. In phase 3 studies with buffered
formulations of didanosine, incidence ranged from 1% to 10% with doses higher than are
currently recommended and 1% to 7% with recommended dose.
Selected laboratory abnormalities that occurred in a study of VIDEX EC in
combination with other antiretroviral agents are shown in Table 11.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
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NDA 20-155/S-039
NDA 20-156/S-040
NDA 21-183/S-016
Page 63 of 72
Table 11:
Selected Laboratory Abnormalities, Study AI454-152a
Percent of Patientsb
VIDEX EC + stavudine
+ nelfinavir
n=258
zidovudine/lamivudinec
+ nelfinavir
n=253
Parameter
Grades 3-4d
All Grades
Grades 3-4d
All Grades
SGOT (AST)
5
46
5
19
SGPT (ALT)
6
44
5
22
Lipase
5
23
2
13
Bilirubin
<1
9
<1
3
a Median duration of treatment was 62 weeks in the VIDEX EC + stavudine + nelfinavir group
and 61 weeks in the zidovudine/lamivudine + nelfinavir group.
b Percentages based on treated patients.
c Zidovudine/lamivudine combination tablet.
d >5 x ULN for SGOT and SGPT, ≥2.1 x ULN for lipase, and ≥2.6 x ULN for bilirubin (ULN =
upper limit of normal).
Observed During Clinical Practice
The following events have been identified during postapproval use of didanosine buffered
formulations. Because they are reported voluntarily from a population of unknown size,
estimates of frequency cannot be made. These events have been chosen for inclusion due
to their seriousness, frequency of reporting, causal connection to didanosine, or a
combination of these factors.
Body as a Whole – abdominal pain, alopecia, anaphylactoid reaction, asthenia,
chills/fever,
pain,
and
redistribution/accumulation
of
body
fat
(see
PRECAUTIONS: Fat Redistribution).
Digestive Disorders – anorexia, dyspepsia, and flatulence.
Exocrine Gland Disorders – pancreatitis (including fatal cases) (see WARNINGS),
sialoadenitis, parotid gland enlargement, dry mouth, and dry eyes.
Hematologic Disorders – anemia, leukopenia, and thrombocytopenia.
Liver – symptomatic hyperlactatemia/lactic acidosis and hepatic steatosis (see
WARNINGS); hepatitis and liver failure.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-154/S-050
NDA 20-155/S-039
NDA 20-156/S-040
NDA 21-183/S-016
Page 64 of 72
Metabolic Disorders – diabetes mellitus, elevated serum alkaline phosphatase level,
elevated serum amylase level, elevated serum gamma-glutamyltransferase level,
elevated serum uric acid level, hypoglycemia, and hyperglycemia.
Musculoskeletal Disorders – myalgia (with or without increases in creatine kinase),
rhabdomyolysis including acute renal failure and hemodialysis, arthralgia, and
myopathy.
Ophthalmologic Disorders – Retinal depigmentation and optic neuritis (see
WARNINGS).
OVERDOSAGE
There is no known antidote for didanosine overdosage. In phase 1 studies, in which
buffered formulations of didanosine were initially administered at doses ten times the
currently recommended dose, toxicities included: pancreatitis, peripheral neuropathy,
diarrhea, hyperuricemia, and hepatic dysfunction. Didanosine is not dialyzable by
peritoneal dialysis, although there is some clearance by hemodialysis (see CLINICAL
PHARMACOLOGY: Pharmacokinetics).
DOSAGE AND ADMINISTRATION
Dosage
Adults
VIDEX EC (didanosine) should be administered on an empty stomach.
VIDEX EC Delayed-Release Capsules should be swallowed intact.
The recommended daily dose is dependent on body weight and is administered as
one capsule given on a once-daily schedule as outlined in Table 12.
Table 12:
Dosing of VIDEX EC Delayed-Release Capsules
Patient Weight
Dosage
≥60 kg
400 mg once daily
<60 kg
250 mg once daily
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-154/S-050
NDA 20-155/S-039
NDA 20-156/S-040
NDA 21-183/S-016
Page 65 of 72
Pediatric Patients
VIDEX EC has not been studied in pediatric patients. Please consult the complete
prescribing information for VIDEX (didanosine) Pediatric Powder for Oral Solution for
dosage and administration of didanosine to pediatric patients.
Dose Adjustment
Clinical and laboratory signs suggestive of pancreatitis should prompt dose
suspension and careful evaluation of the possibility of pancreatitis. VIDEX EC use
should be discontinued in patients with confirmed pancreatitis (see WARNINGS and
PRECAUTIONS: Drug Interactions).
Based on data with buffered didanosine formulations, patients with symptoms of
peripheral neuropathy may tolerate a reduced dose of VIDEX EC after resolution of the
symptoms of peripheral neuropathy upon drug interruption. If neuropathy recurs after
resumption of VIDEX EC, permanent discontinuation of VIDEX EC should be considered.
Concomitant Therapy
Tenofovir disoproxil fumarate. A dose reduction of VIDEX EC to 250 mg (adults weighing
≥60 kg with creatinine clearance ≥60 mL/min) or 200 mg (adults weighing <60 kg with
creatinine clearance ≥60 mL/min) once daily taken together with tenofovir and a light meal
(≤400 kcalories, ≤20% fat) or in the fasted state is recommended. The appropriate dose
of VIDEX EC coadministered with tenofovir in patients with creatinine clearance <60
mL/min has not been established. (See CLINICAL PHARMACOLOGY: Drug
Interactions and PRECAUTIONS: Drug Interactions.)
Renal Impairment
Dosing recommendations for VIDEX EC and VIDEX Pediatric Powder for Oral Solution
are different for patients with renal impairment. Please consult the complete prescribing
information on administration of VIDEX (didanosine) Pediatric Powder for Oral Solution
to patients with renal impairment.
In adult patients with impaired renal function, the dose of VIDEX EC should be
adjusted to compensate for the slower rate of elimination. The recommended doses and
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-154/S-050
NDA 20-155/S-039
NDA 20-156/S-040
NDA 21-183/S-016
Page 66 of 72
dosing intervals of VIDEX EC in adult patients with renal insufficiency are presented in
Table 13.
Table 13:
Recommended Dosage of VIDEX EC in Renal
Impairment by Body Weighta
Dosage
Creatinine
Clearance
(mL/min)
≥60 kg
<60 kg
≥60
400 once daily
250 once daily
30-59
200 once daily
125 once daily
10-29
125 once daily
125 once daily
<10
125 once daily
b
a Based on studies using a buffered formulation of didanosine.
b Not suitable for use in patients <60 kg with CLcr <10 mL/min. An alternate formulation of
didanosine should be used.
Patients Requiring Continuous Ambulatory Peritoneal Dialysis (CAPD) or
Hemodialysis
For patients requiring CAPD or hemodialysis, follow dosing recommendations for patients
with creatinine clearance less than 10 mL/min, shown in Table 13. It is not necessary to
administer a supplemental dose of didanosine following hemodialysis.
Hepatic Impairment and Toxicity: See WARNINGS.
HOW SUPPLIED
VIDEX® EC (didanosine) Delayed-Release Capsules are white, opaque capsules that are
packaged in bottles with child-resistant closures as described in Table 14.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-154/S-050
NDA 20-155/S-039
NDA 20-156/S-040
NDA 21-183/S-016
Page 67 of 72
Table 14:
VIDEX EC Delayed-Release Capsules
125 mg capsule imprinted with BMS 125 mg 6671 in Tan
NDC No. 0087-6671-17
30 capsules/bottle
200 mg capsule imprinted with BMS 200 mg 6672 in Green
NDC No. 0087-6672-17
30 capsules/bottle
250 mg capsule imprinted with BMS 250 mg 6673 in Blue
NDC No. 0087-6673-17
30 capsules/bottle
400 mg capsule imprinted with BMS 400 mg 6674 in Red
NDC No. 0087-6674-17
30 capsules/bottle
The capsules should be stored in tightly closed containers at 25° C (77° F).
Excursions between 15° and 30° C (59° and 86° F) are permitted [see USP Controlled
Room Temperature].
HANDLING AND DISPOSAL
Disposal options include incineration, landfill, or sewer as dictated by specific
circumstances and relevant national, state, and local regulations.
US Patent Nos: 4,861,759, 5,254,539, 5,616,566, and 5,880,106 (didanosine).
Patent also Pending (didanosine capsules).
Bristol-Myers Squibb Company
Princeton, NJ 08543 USA
1196180A3
Revised August 2006
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-154/S-050
NDA 20-155/S-039
NDA 20-156/S-040
NDA 21-183/S-016
Page 68 of 72
PATIENT INFORMATION
Rx only
VIDEX® EC
(generic name = didanosine also known as ddI)
VIDEX® EC (didanosine) Delayed-Release Capsules
Enteric-Coated Beadlets
What is VIDEX EC?
VIDEX EC (pronounced VY dex ee see) is a prescription medicine used in combination
with other drugs to treat adults who are infected with HIV (the human immunodeficiency
virus, the virus that causes AIDS). VIDEX EC belongs to a class of drugs called nucleoside
analogues. By reducing the growth of HIV, VIDEX EC helps your body maintain its supply
of CD4 cells, which are important for fighting HIV and other infections.
VIDEX EC will not cure your HIV infection. At present there is no cure for HIV
infection. Even while taking VIDEX EC, you may continue to have HIV-related illnesses,
including infections with other disease-producing organisms. Continue to see your doctor
regularly and report any medical problems that occur.
VIDEX EC does not prevent a patient infected with HIV from passing the virus to
other people. To protect others, you must continue to practice safe sex and take precautions
to prevent others from coming in contact with your blood and other body fluids.
There is limited information on the antiviral response of long-term use of
VIDEX EC.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-154/S-050
NDA 20-155/S-039
NDA 20-156/S-040
NDA 21-183/S-016
Page 69 of 72
In VIDEX EC, an enteric coating is used to protect the medicine while it is in your
stomach since stomach acids can break it down. The enteric coating dissolves when the
medicine reaches your small intestine.
Who should not take VIDEX EC?
Do not take VIDEX EC if you are allergic to any of its ingredients, including its active
ingredient, didanosine, and the inactive ingredients. (See Inactive Ingredients at the end
of this leaflet.) Tell your doctor if you think you have had an allergic reaction to any of
these ingredients.
Because it has only been studied in adults, VIDEX EC is not recommended for
children.
How should I take VIDEX EC?
How should I store it?
VIDEX EC should only be taken once daily. Your doctor will determine your dose based
on your body weight, kidney and liver function, other medicines you are taking, and any
side effects that you may have had with VIDEX EC or other medicines. Take VIDEX EC
on an empty stomach. Do not take VIDEX EC with food. Swallow the capsule whole;
do not open it. Try not to miss a dose, but if you do, take it as soon as possible. If it is
almost time for the next dose, skip the missed dose and continue your regular dosing
schedule.
Store capsules in a tightly closed container at room temperature away from heat
and out of the reach of children and pets.
If you have kidney disease: If your kidneys are not working properly, your doctor will
need to do regular tests to check how they are working while you take VIDEX EC. Your
doctor may also lower your dosage of VIDEX EC.
What should I do if someone takes an overdose of VIDEX EC?
If someone may have taken an overdose of VIDEX EC, get medical help right away.
Contact their doctor or a poison control center.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-154/S-050
NDA 20-155/S-039
NDA 20-156/S-040
NDA 21-183/S-016
Page 70 of 72
What should I avoid while taking VIDEX EC?
Alcohol. Do not drink alcohol while taking VIDEX EC since alcohol may increase your
risk of pancreatitis (pain and inflammation of the pancreas) or liver damage.
Other medicines. Other medicines, including those you can buy without a prescription,
may interfere with the actions of VIDEX EC or may increase the possibility or severity of
side effects. Do not take any medicine, vitamin supplement, or other health
preparation without first checking with your doctor.
Pregnancy. It is not known if VIDEX EC can harm a human fetus. Also, pregnant women
have experienced serious side effects when taking didanosine (the active ingredient in
VIDEX EC) in combination with ZERIT (stavudine), also known as d4T, and other HIV
medicines. VIDEX EC should be used during pregnancy only after discussion with your
doctor. Tell your doctor if you become pregnant or plan to become pregnant while
taking VIDEX EC.
Nursing. Studies have shown didanosine (the active ingredient in VIDEX EC) is in the
breast milk of animals getting the drug. It may also be in human breast milk. The Centers
for Disease Control and Prevention (CDC) recommends that HIV-infected mothers not
breast-feed. This should reduce the risk of passing HIV infection to their babies and the
potential for serious adverse reactions in nursing infants. Therefore, do not nurse a baby
while taking VIDEX EC.
What are the possible side effects of VIDEX EC?
Pancreatitis. Pancreatitis is a dangerous inflammation of the pancreas that may cause
death. Tell your doctor right away if you develop stomach pain, nausea, or vomiting.
These can be signs of pancreatitis. Before starting VIDEX EC therapy, let your doctor
know if you have ever had pancreatitis. This condition is more likely to happen in people who
have had it before. It is also more likely in people with advanced HIV disease. However, it can
occur at any stage of HIV disease. It may be more common in patients with kidney problems,
those who drink alcohol, and those who are also treated with stavudine or hydroxyurea. If you
get pancreatitis, your doctor will tell you to stop taking VIDEX EC.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-154/S-050
NDA 20-155/S-039
NDA 20-156/S-040
NDA 21-183/S-016
Page 71 of 72
Lactic acidosis, severe liver enlargement, and liver failure, including deaths, have been
reported among patients taking VIDEX EC (including pregnant women). Symptoms that
may indicate a liver problem are:
•
feeling very weak, tired, or uncomfortable,
•
unusual or unexpected stomach discomfort,
•
feeling cold,
•
feeling dizzy or lightheaded,
•
suddenly developing a slow or irregular heartbeat.
Lactic acidosis is a medical emergency that must be treated in a hospital.
If you notice any of these symptoms or if your medical condition changes, stop
taking VIDEX EC and call your doctor right away. Women, overweight patients, and
those who have been treated for a long time with other medicines used to treat HIV
infection are more likely to develop lactic acidosis. Your doctor should check your liver
function periodically while you are taking VIDEX EC. You should be especially careful if
you have a history of heavy alcohol use or a liver problem.
Vision changes. VIDEX EC may affect the nerves in your eyes. Because of this, you
should have regular eye examinations. You should also report any changes in vision to your
doctor right away. This includes, for example, seeing colors abnormally or blurred vision.
Peripheral neuropathy. This is a problem with the nerves in your hands or feet. The
nerve problem may be serious. Tell your doctor right away if you have continuing
numbness, tingling, or pain in the feet or hands.
Before starting VIDEX EC therapy, let your doctor know if you have ever had
peripheral neuropathy. This condition is more likely to happen in people who have had it
before. It is also more likely in patients taking medicines that affect the nerves and in
people with advanced HIV disease. However, it can occur at any stage of HIV disease. If
you get peripheral neuropathy, your doctor will tell you to stop taking VIDEX EC. After
stopping VIDEX EC, the symptoms may get worse for a short time and then get better.
Once symptoms of peripheral neuropathy go away completely, you and your doctor should
decide if starting VIDEX EC is right for you. If so, you might be started at a lower dose.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-154/S-050
NDA 20-155/S-039
NDA 20-156/S-040
NDA 21-183/S-016
Page 72 of 72
Special note about other medicines. If you take VIDEX EC along with other medicines
with similar side effects, you may increase the chance of having these side effects. For
example, using VIDEX EC in combination with other medicines that may cause
pancreatitis, peripheral neuropathy, or liver problems (including stavudine and
hydroxyurea) may increase your chance of having these side effects.
Other side effects: The most common side effects in adults taking VIDEX EC in
combination with other HIV drugs included diarrhea, nausea, headache, vomiting, and
rash.
Changes in body fat have been seen in some patients taking antiretroviral therapy.
These changes may include increased amount of fat in the upper back and neck (“buffalo
hump”), breast, and around the trunk. Loss of fat from the legs, arms, and face may also
happen. The cause and long-term health effects of these conditions are not known at this
time.
Inactive Ingredients:
Carboxymethylcellulose sodium 12, diethyl phthalate, methacrylic acid copolymer, sodium
hydroxide, sodium starch glycolate, talc, colloidal silicon dioxide, gelatin, sodium lauryl
sulfate, and titanium dioxide.
This medicine was prescribed for your particular condition. Do not use VIDEX EC for another condition or
give it to others. Keep VIDEX EC and all medicines out of the reach of children. Throw away VIDEX EC
when it is outdated or no longer needed by flushing it down the toilet or pouring it down the sink.
This summary does not include everything there is to know about VIDEX EC. Medicines are sometimes
prescribed for purposes other than those listed in a Patient Information Leaflet. If you have questions or concerns, or
want more information about VIDEX EC, your physician and pharmacist have the complete prescribing information
upon which this leaflet is based. You may want to read it and discuss it with your doctor or other healthcare
professional. Remember, no written summary can replace careful discussion with your doctor.
Bristol-Myers Squibb Company
Princeton, NJ 08543 USA
This Patient Information Leaflet has been approved by the U.S. Food and Drug Administration.
1196180A3
Revised August 2006
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:46:55.455540
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/020154s50,20155s39,20156s40,21183s16lbl.pdf', 'application_number': 20156, 'submission_type': 'SUPPL ', 'submission_number': 40}
|
12,278
|
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NDA 20-155/S-038
NDA 20-156/S-039
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Page 4 of 75
Rx only
VIDEX® (didanosine)
VIDEX® (didanosine) Chewable/Dispersible Buffered Tablets
VIDEX® (didanosine) Pediatric Powder for Oral Solution
(Patient Information Leaflet Included)
WARNING
FATAL AND NONFATAL PANCREATITIS HAVE OCCURRED DURING
THERAPY WITH VIDEX USED ALONE OR IN COMBINATION REGIMENS IN
BOTH TREATMENT-NAIVE AND TREATMENT-EXPERIENCED PATIENTS,
REGARDLESS OF DEGREE OF IMMUNOSUPPRESSION. VIDEX SHOULD BE
SUSPENDED IN PATIENTS WITH SUSPECTED PANCREATITIS AND
DISCONTINUED IN PATIENTS WITH CONFIRMED PANCREATITIS (SEE
WARNINGS).
LACTIC
ACIDOSIS
AND
SEVERE
HEPATOMEGALY
WITH
STEATOSIS, INCLUDING FATAL CASES, HAVE BEEN REPORTED WITH THE
USE OF NUCLEOSIDE ANALOGUES ALONE OR IN COMBINATION,
INCLUDING DIDANOSINE AND OTHER ANTIRETROVIRALS. FATAL
LACTIC ACIDOSIS HAS BEEN REPORTED IN PREGNANT WOMEN WHO
RECEIVED THE COMBINATION OF DIDANOSINE AND STAVUDINE WITH
OTHER ANTIRETROVIRAL AGENTS. THE COMBINATION OF DIDANOSINE
AND STAVUDINE SHOULD BE USED WITH CAUTION DURING PREGNANCY
AND IS RECOMMENDED ONLY IF THE POTENTIAL BENEFIT CLEARLY
OUTWEIGHS THE POTENTIAL RISK (SEE WARNINGS AND PRECAUTIONS:
PREGNANCY).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-154/S-049
NDA 20-155/S-038
NDA 20-156/S-039
NDA 21-183/S-015
Page 5 of 75
DESCRIPTION
VIDEX® (didanosine) is a brand name for didanosine (ddI), a synthetic purine nucleoside
analogue active against the Human Immunodeficiency Virus (HIV). VIDEX
Chewable/Dispersible Buffered Tablets are available for oral administration in strengths of
25, 50, 100, 150, and 200 mg of didanosine. Each tablet is buffered with calcium
carbonate and magnesium hydroxide. VIDEX tablets also contain aspartame, sorbitol,
microcrystalline cellulose, polyplasdone, mandarin-orange flavor, and magnesium stearate.
VIDEX Pediatric Powder for Oral Solution is supplied for oral administration in 4-
or 8-ounce glass bottles containing 2 or 4 grams of didanosine, respectively.
Didanosine is also available as an enteric-coated formulation (VIDEX® EC
Delayed-Release Capsules). Please consult the prescribing information for VIDEX EC
(didanosine).
The chemical name for didanosine is 2',3'-dideoxyinosine. The structural formula is:
Didanosine is a white crystalline powder with the molecular formula C10H12N4O3
and a molecular weight of 236.2. The aqueous solubility of didanosine at 25° C and pH of
approximately 6 is 27.3 mg/mL. Didanosine is unstable in acidic solutions. For example,
at pH <3 and 37° C, 10% of didanosine decomposes to hypoxanthine in less than 2
minutes.
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MICROBIOLOGY
Mechanism of Action
Didanosine is a synthetic nucleoside analogue of the naturally occurring nucleoside
deoxyadenosine in which the 3'-hydroxyl group is replaced by hydrogen. Intracellularly,
didanosine is converted by cellular enzymes to the active metabolite, dideoxyadenosine
5'-triphosphate. Dideoxyadenosine 5'-triphosphate inhibits the activity of HIV-1 reverse
transcriptase both by competing with the natural substrate, deoxyadenosine 5'-triphosphate,
and by its incorporation into viral DNA causing termination of viral DNA chain
elongation.
In Vitro HIV Susceptibility
The in vitro anti-HIV-1 activity of didanosine was evaluated in a variety of HIV-1 infected
lymphoblastic cell lines and monocyte/macrophage cell cultures. The concentration of
drug necessary to inhibit viral replication by 50% (IC50) ranged from 2.5 to 10 µM (1 µM
= 0.24 µg/mL) in lymphoblastic cell lines and 0.01 to 0.1 µM in monocyte/macrophage
cell cultures. The relationship between in vitro susceptibility of HIV to didanosine and the
inhibition of HIV replication in humans has not been established.
Drug Resistance
HIV-1 isolates with reduced sensitivity to didanosine have been selected in vitro and were
also obtained from patients treated with didanosine. Genetic analysis of isolates from
didanosine-treated patients showed mutations in the reverse transcriptase gene that resulted
in the amino acid substitutions K65R, L74V, and M184V. The L74V mutation was most
frequently observed in clinical isolates. Phenotypic analysis of HIV-1 isolates from 60
patients (some with prior zidovudine treatment) receiving 6 to 24 months of didanosine
monotherapy showed that isolates from 10 of 60 patients exhibited an average of a 10-fold
decrease in susceptibility to didanosine in vitro compared to baseline isolates. Clinical
isolates that exhibited a decrease in didanosine susceptibility harbored one or more
didanosine-associated mutations. The clinical relevance of genotypic and phenotypic
changes associated with didanosine therapy has not been established.
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Cross-resistance
HIV-1 isolates from 2 of 39 patients receiving combination therapy for up to 2 years with
zidovudine and didanosine exhibited decreased susceptibility to zidovudine, didanosine,
zalcitabine, stavudine, and lamivudine in vitro. These isolates harbored five mutations
(A62V, V75I, F77L, F116Y, and Q151M) in the reverse transcriptase gene. The clinical
relevance of these observations has not been established.
CLINICAL PHARMACOLOGY
Animal Toxicology
Evidence of a dose-limiting skeletal muscle toxicity has been observed in mice and rats
(but not in dogs) following long-term (greater than 90 days) dosing with didanosine at
doses that were approximately 1.2 to 12 times the estimated human exposure. The
relationship of this finding to the potential of VIDEX (didanosine) to cause myopathy in
humans is unclear. However, human myopathy has been associated with administration of
VIDEX and other nucleoside analogues.
Pharmacokinetics
The pharmacokinetic parameters of didanosine are summarized in Table 1. Didanosine is
rapidly absorbed, with peak plasma concentrations generally observed from 0.25 to 1.50
hours following oral dosing. Increases in plasma didanosine concentrations were dose
proportional over the range of 50 to 400 mg. Steady-state pharmacokinetic parameters did
not differ significantly from values obtained after a single dose. Binding of didanosine to
plasma proteins in vitro was low (<5%). Based on data from in vitro and animal studies, it
is presumed that the metabolism of didanosine in man occurs by the same pathways
responsible for the elimination of endogenous purines.
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Table 1:
Mean ± SD Pharmacokinetic Parameters for Didanosine in
Adult and Pediatric Patients
Pediatric Patientsb
Parameter
Adult Patientsa
n
8 months to 19 years
n
2 weeks to 4 months
n
Oral bioavailability (%)
42 ± 12
6
25 ± 20
46
ND
Apparent volume of
distributionc (L/m2)
43.70 ± 8.90
6
28 ± 15
49
ND
CSF-plasma ratiod
21 ± 0.03%e
5
46%
(range 12-85%)
7
ND
Systemic clearancec
(mL/min/m2)
526 ± 64.7
6
516 ± 184
49
ND
Renal clearancef
(mL/min/m2)
223 ± 85.0
6
240 ± 90
15
ND
Apparent oral clearanceg
(mL/min/m2)
1252 ± 154
6
2064 ± 736
48
1353 ± 759
41
Elimination half-lifef (h)
1.5 ± 0.4
6
0.8 ± 0.3
60
1.2 ± 0.3
21
Urinary recovery of
didanosinef (%)
18 ± 8
6
18 ± 10
15
ND
CSF = cerebrospinal fluid, ND = not determined.
a Parameter units for adults were converted to the same units in pediatric patients to facilitate comparisons
among populations: mean adult body weight = 70 kg and mean adult body surface area = 1.73 m2.
b In 1-day old infants (n=10), the mean ± SD apparent oral clearance was 1523 ± 1176 mL/min/m2 and
half-life was 2.0 ± 0.7 h.
c Following IV administration.
d Following IV administration in adults and IV or oral administration in pediatric patients.
e Mean ± SE.
f
Following oral administration.
g Apparent oral clearance estimate was determined as the ratio of the mean systemic clearance and the
mean oral bioavailability estimate.
Effect of Food on Absorption of Didanosine: Didanosine peak plasma
concentrations (CMAX) and area under the plasma concentration time curve (AUC) were
decreased by approximately 55% when VIDEX tablets were administered up to 2 hours
after a meal. Administration of VIDEX tablets up to 30 minutes before a meal did not
result in any significant changes in bioavailability. VIDEX should be taken on an empty
stomach, at least 30 minutes before or 2 hours after eating. (See DOSAGE AND
ADMINISTRATION.)
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Special Populations
Renal Insufficiency: It is recommended that the VIDEX (didanosine) dose be modified
in patients with reduced creatinine clearance and in patients receiving maintenance
hemodialysis (see DOSAGE AND ADMINISTRATION). Data from two studies in
adults indicated that the apparent oral clearance of didanosine decreased and the terminal
elimination half-life increased as creatinine clearance decreased (see Table 2). Following
oral administration, didanosine was not detectable in peritoneal dialysate fluid (n=6);
recovery in hemodialysate (n=5) ranged from 0.6% to 7.4% of the dose over a 3-4 hour
dialysis period. The absolute bioavailability of didanosine was not affected in patients
requiring dialysis.
Table 2:
Mean ± SD Pharmacokinetic Parameters for Didanosine
Following a Single Oral Dose
Creatinine Clearance (mL/min)
Parameter
≥ 90
(n=12)
60-90
(n=6)
30-59
(n=6)
10-29
(n=3)
Dialysis Patients
(n=11)
CLcr (mL/min)
112 ± 22
68 ± 8
46 ± 8
13 ± 5
ND
CL/F (mL/min)
2164 ± 638
1566 ± 833
1023 ± 378
628 ± 104
543 ± 174
CLR (mL/min)
458 ± 164
247 ± 153
100 ± 44
20 ± 8
<10
T½ (h)
1.42 ± 0.33
1.59 ± 0.13
1.75 ± 0.43
2.0 ± 0.3
4.1 ± 1.2
ND = not determined due to anuria.
CLcr = creatinine clearance.
CL/F = apparent oral clearance.
CLR = renal clearance.
Pediatric Patients: The pharmacokinetics of didanosine have been evaluated in
HIV-exposed and -infected pediatric patients from birth to 19 years of age (see Table 1).
Overall, the pharmacokinetics of didanosine in pediatric patients are similar to those of
didanosine in adults. Didanosine plasma concentrations appear to increase in proportion to
oral doses ranging from 25 to 120 mg/m2 in pediatric patients less than 5 months old and
from 80 to 180 mg/m2 in children above 8 months old. For information on controlled
clinical studies in pediatric patients, see INDICATIONS AND USAGE: Clinical Studies
and PRECAUTIONS: Pediatric Use.
Geriatric Patients: Didanosine pharmacokinetics have not been studied in
patients over 65 years of age.
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Gender: The effects of gender on didanosine pharmacokinetics have not been
studied.
Drug Interactions: Ribavirin has been shown in vitro to increase intracellular
triphosphate levels of didanosine, which could cause or worsen clinical toxicities (see
PRECAUTIONS: Drug Interactions).
Tables 3 and 4 summarize the effects on AUC and CMAX, with a 90% or 95%
confidence interval (CI) when available, following coadministration of VIDEX with a
variety of drugs. For most of the listed drugs, no clinically significant pharmacokinetic
interactions were observed. Clinical recommendations based on drug interaction studies
for drugs in bold font are included in PRECAUTIONS: Drug Interactions and
DOSAGE AND ADMINISTRATION (for tenofovir).
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Table 3:
Results of Drug Interaction Studies with VIDEX: Effects of Coadministered
Drug on Didanosine Plasma AUC and CMAX Values
Drugs With Clinical Recommendations Regarding Coadministration (see PRECAUTIONS: Drug Interactions)
Drug
Didanosine Dosage
n
AUC of
Didanosine
(95% CI)
CMAX of Didanosine
(95% CI)
allopurinol
renally impaired, 300 mg/day
200 mg single dose
2
↑ 312%
↑ 232%
healthy volunteer, 300 mg/day for
7 days
400 mg single dose
14
↑ 113%
↑ 69%
ciprofloxacin, 750 mg q12h for 3
days, 2 h before didanosine
200 mg q12h for 3 days
8a
↓ 16%
↓ 28%
ganciclovir, 1000 mg q8h, 2 h
after didanosine
200 mg q12h
12
↑ 111%
NA
indinavir, 800 mg single dose
simultaneous
1 h before didanosine
200 mg single dose
200 mg single dose
16
16
↔
↓ 17% (-27, - 7%)b
↔
↓ 13% (-28, 5%)b
ketoconazole, 200 mg/day for 4
days, 2 h before didanosine
375 mg q12h for 4 days
12a
↔
↓ 12%
methadone, chronic maintenance
dose
200 mg single dose
16, 10c
↓ 57%
↓ 66%
tenofovir,d,e 300 mg once daily
1 h after didanosine
250f or 400 mg once
daily for 7 days
14
↑ 44%
(31, 59%)b
↑ 28%
(11, 48%)b
No Clinically Significant Interaction Observed
Drug
Didanosine Dosage
n
AUC of
Didanosine
(95% CI)
CMAX of Didanosine
(95% CI)
loperamide, 4 mg q6h for 1 day
300 mg single dose
12a
↔
↓ 23%
metoclopramide, 10 mg single dose
300 mg single dose
12a
↔
↑ 13%
ranitidine, 150 mg single dose, 2 h
before didanosine
375 mg single dose
12a
↑ 14%
↑ 13%
rifabutin, 300 or 600 mg/day for 12
days
167 or 250 mg q12h for
12 days
11
↑ 13% (-1, 27%)
↑ 17% (-4, 38%)
ritonavir, 600 mg q12h for 4 days
200 mg q12h for 4 days
12
↓ 13% (0, 23%)
↓ 16% (5, 26%)
stavudine, 40 mg q12h for 4 days
100 mg q12h for 4 days
10
↔
↔
sulfamethoxazole, 1000 mg single
dose
200 mg single dose
8a
↔
↔
trimethoprim, 200 mg single dose
200 mg single dose
8a
↔
↑ 17% (-23, 77%)
zidovudine, 200 mg q8h for 3 days
200 mg q12h for 3 days
6a
↔
↔
↑ indicates increase.
↓ indicates decrease.
↔ indicates no change, or mean increase or decrease of <10%.
a
HIV-infected patients.
b
90% CI.
c Parallel-group design; entries are subjects receiving combination and control regimens, respectively.
d tenofovir disoproxil fumarate.
e
For results of drug interaction studies between the enteric-coated formulation of didanosine (VIDEX EC) and
tenofovir, see the complete prescribing information for VIDEX EC.
f
patients <60 kg with creatinine clearance ≥60 mL/min.
NA Not available.
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Table 4:
Results of Drug Interaction Studies with VIDEX: Effects of
Didanosine on Coadministered Drug Plasma AUC and CMAX
Values
Drugs With Clinical Recommendations Regarding Coadministration (see PRECAUTIONS: Drug Interactions)
Drug
Didanosine Dosage
n
AUC of
Coadministered
Drug (95% CI)
CMAX of
Coadministered
Drug (95% CI)
ciprofloxacin
750 mg q12h for 3 days, 2 h
before didanosine
750 mg single dose
200 mg q12h for 3 days
buffered placebo tablet
8a
12
↓ 26%
↓ 98%
↓ 16%
↓ 93%
delavirdine, 400 mg single dose
simultaneous
1 h before didanosine
125 or 200 mg q12h
125 or 200 mg q12h
12a
12a
↓ 32%
↑ 20%
↓ 53%
↑ 18%
ganciclovir, 1000 mg q8h, 2 h
after didanosine
200 mg q12h
12a
↓ 21%
NA
indinavir, 800 mg single dose
simultaneous
1 h before didanosine
200 mg single dose
200 mg single dose
16
16
↓ 84%
↓ 11%
↓ 82%
↓ 4%
ketoconazole, 200 mg/day for 4
days, 2 h before didanosine
375 mg q12h for 4 days
12a
↓ 14%
↓ 20%
nelfinavir, 750 mg single dose,
1 h after didanosine
200 mg single dose
10a
↑ 12%
↔
No Clinically Significant Interaction Observed
Drug
Didanosine Dosage
n
AUC of
Coadministered
Drug (95% CI)
CMAX of
Coadministered
Drug (95% CI)
dapsone, 100 mg single dose
200 mg q12h for 14 days
6a
↔
↔
ranitidine, 150 mg single dose, 2 h
before didanosine
375 mg single dose
12a
↓ 16%
↔
ritonavir, 600 mg q12h for 4 days
200 mg q12h for 4 days
12
↔
↔
stavudine, 40 mg q12h for 4 days
100 mg q12h for 4 days
10a
↔
↑ 17%
sulfamethoxazole, 1000 mg single
dose
200 mg single dose
8a
↓ 11% (-17, -4%)
↓ 12% (-28, 8%)
tenofovir,b 300 mg once daily 1 h
after didanosine
250c or 400 mg once
daily for 7 days
14
↔
↔
trimethoprim, 200 mg single dose
200 mg single dose
8a
↑ 10% (-9, 34%)
↓ 22% (-59, 49%)
zidovudine, 200 mg q8h for 3
days
200 mg q12h for 3 days
6a
↓ 10% (-27, 11%)
↓ 16.5% (-53, 47%)
↑ indicates increase.
↓ indicates decrease.
↔ indicates no change, or mean increase or decrease of <10%.
a
HIV-infected patients.
b
tenofovir disoproxil fumarate.
c
patients <60 kg with creatinine clearance ≥60 mL/min.
NA Not available.
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INDICATIONS AND USAGE
VIDEX (didanosine) in combination with other antiretroviral agents is indicated for
the treatment of HIV-1 infection (see Clinical Studies).
Clinical Studies
Combination Therapy
START 2 was a multicenter, randomized, open-label study comparing VIDEX (200 mg
twice daily)/stavudine/indinavir to zidovudine/lamivudine/indinavir in 205 treatment-naive
patients. Both regimens resulted in a similar magnitude of suppression of HIV RNA levels
and increases in CD4 cell counts through 48 weeks.
Study A1454-148 was a randomized, open-label, multicenter study comparing
treatment with VIDEX (400 mg once daily) plus stavudine (40 mg twice daily) and
nelfinavir (750 mg three times daily) versus zidovudine (300 mg twice daily) plus
lamivudine (150 mg twice daily) and nelfinavir (750 mg three times daily) in 756
treatment-naive patients, with a median CD4 cell count of 340 cells/mm3 (range 80 to 1568
cells/mm3) and a median plasma HIV-1 RNA of 4.69 log10 copies/mL (range 2.6 to 5.9
log10 copies/mL) at baseline. Median CD4 cell count increases at 48 weeks were 188
cells/mm3 in both treatment groups. Treatment response and outcomes through 48 weeks
are shown in Figure 1 and Table 5.
Figure 1:
Treatment Response Through Week 48*, AI454-148
0
20
40
60
80
100
0
8
16
24
32
40
48
Study Week
Percent of patients
] < 400 c/mL
] < 50 c/mL
VIDEX+stavudine+nelfinavir (n=503)
zidovudine+lamivudine+nelfinavir (n=253)
* Percent of patients at each time point who have HIV RNA <400 or <50 copies/mL, are on
their original study medication (except stavudine-zidovudine switches), and have not
experienced an AIDS-defining event.
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Table 5:
Outcomes of Randomized Treatment through Week 48,
AI454-148
Percent of Patients with HIV RNA <400 copies/mL (<50 copies/mL)
VIDEX/stavudine/nelfinavir
lamivudine/zidovudine/nelfinavir
Week 48 Status
n=503
n=253
Responder a
50* (34*)
59 (47)
Virologic failureb
36 (57)
32 (48)
Death or disease progression
<1 (<1)
1 (<1)
Discontinued due to adverse events
4 (2)
2 (<1)
Discontinued due to other reasonsc
6 (3)
4 (2)
Never initiated treatment
4 (4)
2 (2)
* p <0.05 for the differences between treatment groups, by Cochran-Mantel-Haenszel test.
a Patients achieved virologic response [two consecutive viral loads <400 (<50) copies/mL] and maintained
it to Week 48.
b Includes viral rebound and failing to achieve confirmed <400 (<50) copies/mL by Week 48.
c Includes lost to follow-up, noncompliance, withdrawal, and pregnancy.
Monotherapy
The efficacy of VIDEX was demonstrated in two randomized, double-blind studies
comparing VIDEX, given on a twice-daily schedule, to zidovudine, given three times
daily, in 617 (ACTG 116A, conducted 1989-1992) and 913 (ACTG 116B/117, conducted
1989-1991) patients with symptomatic HIV infection or AIDS who were treated for more
than one year. In treatment-naive patients (ACTG 116A), the rate of HIV disease
progression or death was similar between the treatment groups; mortality rates were 26%
for patients receiving VIDEX and 21% for patients receiving zidovudine. Of the patients
who had received previous zidovudine treatment (ACTG 116B/117), those treated with
VIDEX had a lower rate of HIV disease progression or death (32%) compared to those
treated with zidovudine (41%); however, survival rates were similar between the treatment
groups.
Efficacy in pediatric patients was demonstrated in a randomized, double-blind,
controlled study (ACTG 152, conducted 1991-1995) involving 831 patients 3 months to 18
years of age treated for more than 1.5 years with zidovudine (180 mg/m2 q6h), VIDEX
(120 mg/m2 q12h), or zidovudine (120 mg/m2q6h) plus VIDEX (90 mg/m2 q12h). Patients
treated with VIDEX or VIDEX plus zidovudine had lower rates of HIV disease
progression or death compared with those treated with zidovudine alone.
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Studies have demonstrated that the clinical benefit of monotherapy with
antiretrovirals, including VIDEX, was time limited.
CONTRAINDICATION
VIDEX (didanosine) is contraindicated in patients with previously demonstrated clinically
significant hypersensitivity to any of the components of the formulations.
WARNINGS
1.
Pancreatitis
FATAL AND NONFATAL PANCREATITIS HAVE OCCURRED DURING
THERAPY WITH VIDEX USED ALONE OR IN COMBINATION REGIMENS IN
BOTH TREATMENT-NAIVE AND TREATMENT-EXPERIENCED PATIENTS,
REGARDLESS OF DEGREE OF IMMUNOSUPPRESSION. VIDEX SHOULD BE
SUSPENDED IN PATIENTS WITH SIGNS OR SYMPTOMS OF PANCREATITIS
AND DISCONTINUED IN PATIENTS WITH CONFIRMED PANCREATITIS.
PATIENTS TREATED WITH VIDEX IN COMBINATION WITH STAVUDINE,
WITH OR WITHOUT HYDROXYUREA, MAY BE AT INCREASED RISK FOR
PANCREATITIS.
When treatment with life-sustaining drugs known to cause pancreatic toxicity is
required, suspension of VIDEX (didanosine) therapy is recommended. In patients with risk
factors for pancreatitis, VIDEX should be used with extreme caution and only if clearly
indicated. Patients with advanced HIV infection, especially the elderly, are at increased
risk of pancreatitis and should be followed closely. Patients with renal impairment may be
at greater risk for pancreatitis if treated without dose adjustment.
The frequency of pancreatitis is dose related. In phase 3 studies, incidence ranged
from 1% to 10% with doses higher than are currently recommended and 1% to 7% with
recommended dose.
In pediatric phase 1 studies, pancreatitis occurred in 3% (2/60) of patients treated at
entry doses below 300 mg/m2/day and in 13% (5/38) of patients treated at higher doses. In
study ACTG 152, pancreatitis occurred in none of the 281 pediatric patients who received
didanosine 120 mg/m2 q12h and in <1% of the 274 pediatric patients who received
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didanosine 90 mg/m2 q12h in combination with zidovudine. VIDEX (didanosine) use
should be suspended in pediatric patients with signs or symptoms of pancreatitis and
discontinued in pediatric patients with confirmed pancreatitis.
2.
Lactic Acidosis/Severe Hepatomegaly with Steatosis
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases,
have been reported with the use of nucleoside analogues alone or in combination,
including didanosine and other antiretrovirals. A majority of these cases have been in
women. Obesity and prolonged nucleoside exposure may be risk factors. Fatal lactic
acidosis has been reported in pregnant women who received the combination of didanosine
and stavudine with other antiretroviral agents. The combination of didanosine and
stavudine should be used with caution during pregnancy and is recommended only if the
potential benefit clearly outweighs the potential risk (see PRECAUTIONS: Pregnancy).
Particular caution should be exercised when administering VIDEX to any patient with
known risk factors for liver disease; however, cases have also been reported in patients
with no known risk factors. Treatment with VIDEX should be suspended in any patient
who develops clinical or laboratory findings suggestive of symptomatic hyperlactatemia,
lactic acidosis, or pronounced hepatotoxicity (which may include hepatomegaly and
steatosis even in the absence of marked transaminase elevations).
3.
Retinal Changes and Optic Neuritis
Retinal changes and optic neuritis have been reported in adult and pediatric
patients. Periodic retinal examinations should be considered for patients receiving VIDEX.
(See ADVERSE REACTIONS.)
4.
Hepatic Impairment and Toxicity
It
is
unknown
if
hepatic
impairment
significantly
affects
didanosine
pharmacokinetics. Therefore, these patients should be monitored closely for evidence of
didanosine toxicity. The safety and efficacy of VIDEX have not been established in HIV-
infected patients with significant underlying liver disease. During combination
antiretroviral therapy, patients with preexisting liver dysfunction, including chronic active
hepatitis, have an increased frequency of liver function abnormalities, including severe and
potentially fatal hepatic adverse events, and should be monitored according to standard
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practice. If there is evidence of worsening liver disease in such patients, interruption or
discontinuation of treatment must be considered.
Hepatotoxicity and hepatic failure resulting in death were reported during
postmarketing surveillance in HIV-infected patients treated with hydroxyurea and other
antiretroviral agents. Fatal hepatic events were reported most often in patients treated with
the combination of hydroxyurea, didanosine, and stavudine. This combination should be
avoided.
PRECAUTIONS
Frequency of Dosing
The preferred dosing frequency of VIDEX is twice daily because there is more evidence to
support the effectiveness of this dosing frequency. Once-daily dosing should be considered
only for adult patients whose management requires once-daily dosing of VIDEX (see
INDICATIONS AND USAGE: Clinical Studies).
VIDEX should be taken on an empty stomach, at least 30 minutes before or 2
hours after eating.
Peripheral Neuropathy
Peripheral neuropathy, manifested by numbness, tingling, or pain in the hands or feet, has
been reported in patients receiving VIDEX therapy. Peripheral neuropathy has occurred
more frequently in patients with advanced HIV disease, in patients with a history of
neuropathy, or in patients being treated with neurotoxic drug therapy, including stavudine.
Peripheral neuropathy, which was severe in some cases, has been reported in HIV-infected
patients receiving hydroxyurea in combination with antiretroviral agents, including
didanosine, with or without stavudine (see ADVERSE REACTIONS).
Fat Redistribution
Redistribution/accumulation of body fat including central obesity, dorsocervical fat
enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and
“cushingoid appearance” have been observed in patients receiving antiretroviral therapy.
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The mechanism and long-term consequences of these events are currently unknown. A
causal relationship has not been established.
Immune Reconstitution Syndrome
Immune reconstitution syndrome has been reported in patients treated with combination
antiretroviral therapy, including VIDEX. During the initial phase of combination
antiretroviral treatment, patients whose immune system responds may develop an
inflammatory response to indolent or residual opportunistic infections (such as
Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia
[PCP], or tuberculosis), which may necessitate further evaluation and treatment.
General
Patients with Phenylketonuria: VIDEX Chewable/Dispersible Buffered Tablets
contain the following quantities of phenylalanine:
Table 6
All Strengths
Phenylalanine per 2-tablet dose
73 mg
Phenylalanine per tablet
36.5 mg
Patients with Renal Impairment: Patients with renal impairment (creatinine
clearance <60 mL/min) may be at greater risk of toxicity from VIDEX due to decreased
drug clearance (see CLINICAL PHARMACOLOGY). A dose reduction is
recommended in these patients (see DOSAGE AND ADMINISTRATION). The
magnesium content of each buffered tablet of VIDEX is 8.6 mEq. This may present an
excessive load of magnesium to patients with significant renal impairment, particularly
after prolonged dosing.
Hyperuricemia: VIDEX has been associated with asymptomatic hyperuricemia;
treatment suspension may be necessary if clinical measures aimed at reducing uric acid
levels fail.
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Information for Patients (see Patient Information Leaflet)
Patients should be informed that a serious toxicity of VIDEX used alone and in
combination regimens is pancreatitis, which may be fatal.
Patients should be informed that the preferred dosing frequency of VIDEX is twice
daily because there is more evidence to support the effectiveness of this dosing frequency.
Once-daily dosing should be considered only for adult patients whose management
requires once-daily dosing of VIDEX.
Patients should also be aware that peripheral neuropathy, manifested by numbness,
tingling, or pain in hands or feet, may develop during therapy with VIDEX. Patients
should be counseled that peripheral neuropathy occurs with greatest frequency in patients
with advanced HIV disease or a history of peripheral neuropathy, and that dose
modification and/or discontinuation of VIDEX may be required if toxicity develops.
Patients should be informed that when VIDEX is used in combination with other
agents with similar toxicities, the incidence of adverse events may be higher than when
VIDEX is used alone. These patients should be followed closely.
Patients should be cautioned about the use of medications or other substances,
including alcohol, that may exacerbate VIDEX toxicities.
Patients should be advised that to ensure proper acid neutralization in the stomach
they must take at least two of the appropriate strength VIDEX tablets at each dose. To
reduce the risk of gastrointestinal side effects from excess antacid, patients should take no
more than four VIDEX tablets at each dose.
VIDEX (didanosine) is not a cure for HIV infection, and patients may continue to
develop HIV-associated illnesses, including opportunistic infection. Therefore, patients
should remain under the care of a physician when using VIDEX. Patients should be
advised that VIDEX therapy has not been shown to reduce the risk of transmission of HIV
to others through sexual contact or blood contamination. Patients should be informed that
the long-term effects of VIDEX are unknown at this time.
Patients should be informed that redistribution or accumulation of body fat may
occur in patients receiving antiretroviral therapy and that the cause and long-term health
effects of these conditions are not known at this time.
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Drug Interactions (see also CLINICAL PHARMACOLOGY: Drug
Interactions)
Drug interactions that have been established based on drug interaction studies are listed
with the pharmacokinetic results in CLINICAL PHARMACOLOGY: Drug
Interactions (Tables 3 and 4). The clinical recommendations based on the results of these
studies are listed in Table 7.
Table 7:
Established Drug Interactions with VIDEX
Coadministration Not Recommended Based on Drug Interaction Studies (see CLINICAL
PHARMACOLOGY: Drug Interactions for Magnitude of Interaction)
Drug
Effect
Clinical Comment
allopurinol
↑ didanosine concentration
Coadministration not recommended.
Alteration in Dose or Regimen Recommended Based on Drug Interaction Studies (see CLINICAL
PHARMACOLOGY: Drug Interactions for Magnitude of Interaction)
Drug
Effect
Clinical Comment
ciprofloxacin
↓ ciprofloxacin concentration
Administer VIDEX at least 2 hours after or
6 hours before ciprofloxacin.
delavirdine
↓ delavirdine concentration
Administer VIDEX 1 hour after delavirdine.
ganciclovir
↑ didanosine concentration
Appropriate doses for this combination,
with respect to efficacy and safety, have not
been established.
indinavir
↓ indinavir concentration
Administer VIDEX 1 hour after indinavir.
methadone
↓ didanosine concentration
Appropriate doses for this combination,
with respect to efficacy and safety, have not
been established.
nelfinavir
No interaction 1 hour after didanosine
Administer nelfinavir 1 hour after VIDEX.
tenofovir
disoproxil fumarate
↑ didanosine concentration
A dose reduction of VIDEX to 250 mg
(adults weighing ≥60 kg with creatinine
clearance ≥60 mL/min) or 200 mg (adults
weighing <60 kg with creatinine clearance ≥60
mL/min) once daily is recommended. VIDEX
and tenofovir may be taken together in the fasted
state. Alternatively, if tenofovir is taken with
food, VIDEX should be taken on an empty
stomach (at least 30 minutes before food or 2
hours after food). Patients should be monitored
for didanosine-associated toxicities and
clinical response (see below).
↑ indicates increase.
↓ indicates decrease.
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Coadministration of VIDEX with drugs that are known to cause pancreatitis
may increase the risk of this toxicity (see WARNINGS: Pancreatitis). Because VIDEX
formulations either contain buffers or are mixed with antacids before administration,
interactions may be anticipated with drugs whose absorption can be affected by the level of
acidity in the stomach and with drugs that have been demonstrated to interact with antacids
containing magnesium, calcium, or aluminum. Predicted drug interactions with VIDEX
are listed in Table 8.
Table 8:
Predicted Drug Interactions with VIDEX
Use with Caution or Not Recommended, Risk of Adverse Reactions May Be Increased
Drug or Drug Class
Effect
Clinical Comment
Drugs that may cause
pancreatic toxicity
↑ risk of pancreatitis
Use only with extreme caution.a
Neurotoxic drugs
↑ risk of neuropathy
Use with caution.b
Antacids containing
magnesium or aluminum
↑ side effects associated with
antacid components
Use caution with VIDEX
Chewable/Dispersible Buffered Tablets
and Pediatric Powder for Oral Solution.
Ribavirin
↑ risk of toxicity
Ribavirin has been shown in vitro to
increase intracellular triphosphate levels of
didanosine. Coadministration is not
recommended (see below).
Use with Caution, Plasma Concentrations May Be Decreased by Coadministration with VIDEX
Drug Class
Effect
Clinical Comment
Azole antifungals
↓ ketoconazole or itraconazole
concentration
Administer drugs such as ketoconazole or
itraconazole at least 2 hours before
VIDEX.
Quinolone antibiotics (see
also ciprofloxacin in
Table 7)
↓ quinolone concentration
Consult package insert of the quinolone.
Tetracycline antibiotics
↓ antibiotic concentration
Consult package insert of the tetracycline.
↑ indicates increase.
↓ indicates decrease.
a Only if other drugs are not available and if clearly indicated. If treatment with life-sustaining drugs that
cause pancreatic toxicity is required, suspension of VIDEX is recommended (see WARNINGS:
Pancreatitis).
b See PRECAUTIONS: Peripheral Neuropathy.
Nucleoside/nucleotide analogues
Tenofovir disoproxil fumarate. Exposure to didanosine is increased when coadministered
with tenofovir (see Table 3). Increased exposure may cause or worsen didanosine-
related clinical toxicities, including pancreatitis, symptomatic hyperlactatemia/lactic
acidosis, and peripheral neuropathy. Coadministration of tenofovir with VIDEX
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should be undertaken with caution, and patients should be monitored closely for
didanosine-related toxicities and clinical response. VIDEX should be suspended if
signs or symptoms of pancreatitis, symptomatic hyperlactatemia, or lactic acidosis
develop (see WARNINGS). A dose reduction of VIDEX to 250 mg (adults weighing ≥60
kg with creatinine clearance ≥60 mL/min) or 200 mg (adults weighing <60 kg with
creatinine clearance ≥60 mL/min) once daily is recommended. VIDEX and tenofovir may
be taken together in the fasted state. Alternatively, if tenofovir is taken with food, VIDEX
should be taken on an empty stomach, at least 30 minutes before food or 2 hours after food
(see DOSAGE AND ADMINISTRATION). (The dosing recommendation for
coadministration of VIDEX EC and tenofovir disoproxil fumarate with respect to meal
consumption differs from that of VIDEX. See the complete prescribing information for
VIDEX EC.)
Ribavirin. Exposure to the active metabolite of didanosine (dideoxyadenosine 5’-
triphosphate) is increased when didanosine is coadministered with ribavirin (see Table 8).
Fatal hepatic failure, as well as peripheral neuropathy, pancreatitis, and symptomatic
hyperlactatemia/lactic acidosis have been reported in patients receiving both didanosine
and ribavirin. Coadministration of didanosine and ribavirin is not recommended.
Carcinogenesis and Mutagenesis
Lifetime carcinogenicity studies were conducted in mice and rats for 22 and 24 months,
respectively. In the mouse study, initial doses of 120, 800, and 1200 mg/kg/day for each
sex were lowered after 8 months to 120, 210, and 210 mg/kg/day for females and 120, 300,
and 600 mg/kg/day for males. The two higher doses exceeded the maximally tolerated
dose in females and the high dose exceeded the maximally tolerated dose in males. The
low dose in females represented 0.68-fold maximum human exposure and the intermediate
dose in males represented 1.7-fold maximum human exposure based on relative AUC
comparisons. In the rat study, initial doses were 100, 250, and 1000 mg/kg/day, and the
high dose was lowered to 500 mg/kg/day after 18 months. The upper dose in male and
female rats represented 3-fold maximum human exposure.
Didanosine induced no significant increase in neoplastic lesions in mice or rats at
maximally tolerated doses.
Didanosine was positive in the following genetic toxicology assays: 1) the
Escherichia coli tester strain WP2 uvrA bacterial mutagenicity assay; 2) the
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L5178Y/TK+/-mouse lymphoma mammalian cell gene mutation assay; 3) the in vitro
chromosomal aberrations assay in cultured human peripheral lymphocytes; 4) the in vitro
chromosomal aberrations assay in Chinese Hamster Lung cells; and 5) the BALB/c 3T3 in
vitro transformation assay. No evidence of mutagenicity was observed in an Ames
Salmonella bacterial mutagenicity assay or in rat and mouse in vivo micronucleus assays.
Pregnancy, Reproduction, and Fertility
Pregnancy Category B. Reproduction studies have been performed in rats and rabbits at
doses up to 12 and 14.2 times the estimated human exposure (based upon plasma levels),
respectively, and have revealed no evidence of impaired fertility or harm to the fetus due to
didanosine. At approximately 12 times the estimated human exposure, didanosine was
slightly toxic to female rats and their pups during mid and late lactation. These rats
showed reduced food intake and body weight gains but the physical and functional
development of the offspring was not impaired and there were no major changes in the F2
generation. A study in rats showed that didanosine and/or its metabolites are transferred to
the fetus through the placenta. Animal reproduction studies are not always predictive of
human response.
There are no adequate and well-controlled studies of didanosine in pregnant
women. Didanosine should be used during pregnancy only if the potential benefit justifies
the potential risk.
Fatal lactic acidosis has been reported in pregnant women who received the
combination of didanosine and stavudine with other antiretroviral agents. It is unclear if
pregnancy augments the risk of lactic acidosis/hepatic steatosis syndrome reported in
nonpregnant individuals receiving nucleoside analogues (see WARNINGS: Lactic
Acidosis/Severe Hepatomegaly with Steatosis). The combination of didanosine and
stavudine should be used with caution during pregnancy and is recommended only if
the potential benefit clearly outweighs the potential risk. Health care providers caring
for HIV-infected pregnant women receiving didanosine should be alert for early diagnosis
of lactic acidosis/hepatic steatosis syndrome.
Antiretroviral Pregnancy Registry: To monitor maternal-fetal outcomes of
pregnant women exposed to didanosine and other antiretroviral agents, an Antiretroviral
Pregnancy Registry has been established. Physicians are encouraged to register patients by
calling 1-800-258-4263.
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Nursing Mothers
The Centers for Disease Control and Prevention recommend that HIV-infected
mothers not breast-feed their infants to avoid risking postnatal transmission of HIV.
A study in rats showed that following oral administration, didanosine and/or its
metabolites were excreted into the milk of lactating rats. It is not known if didanosine is
excreted in human milk. Because of both the potential for HIV transmission and the
potential for serious adverse reactions in nursing infants, mothers should be instructed
not to breast-feed if they are receiving VIDEX.
Pediatric Use
Use of VIDEX in pediatric patients from 2 weeks of age through adolescence is supported
by evidence from adequate and well-controlled studies of VIDEX in adults and pediatric
patients
(see
INDICATIONS
AND
USAGE:
Clinical
Studies,
CLINICAL
PHARMACOLOGY,
ADVERSE
REACTIONS,
and
DOSAGE
AND
ADMINISTRATION).
Dosing recommendations for VIDEX in patients less than 2 weeks of age cannot be
made because the pharmacokinetics of didanosine in these children are too variable to
determine an appropriate dose.
Geriatric Use
In an Expanded Access Program for patients with advanced HIV infection, patients aged
65 years and older had a higher frequency of pancreatitis (10%) than younger patients
(5%) (see WARNINGS). Clinical studies of didanosine did not include sufficient numbers
of subjects aged 65 years and over to determine whether they respond differently than
younger subjects. Didanosine is known to be substantially excreted by the kidney, and the
risk of toxic reactions to this drug may be greater in patients with impaired renal function.
Because elderly patients are more likely to have decreased renal function, care should be
taken in dose selection. In addition, renal function should be monitored and dosage
adjustments should be made accordingly (see DOSAGE AND ADMINISTRATION:
Dose Adjustment).
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ADVERSE REACTIONS
A SERIOUS TOXICITY OF VIDEX (didanosine) IS PANCREATITIS, WHICH MAY
BE FATAL (see WARNINGS). OTHER IMPORTANT TOXICITIES INCLUDE
LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS; RETINAL
CHANGES AND OPTIC NEURITIS; AND PERIPHERAL NEUROPATHY (see
WARNINGS and PRECAUTIONS).
When VIDEX is used in combination with other agents with similar toxicities,
the incidence of these toxicities may be higher than when VIDEX is used alone. Thus,
patients treated with VIDEX in combination with stavudine, with or without
hydroxyurea, may be at increased risk for pancreatitis and hepatotoxicity, which may
be fatal, and severe peripheral neuropathy (see WARNINGS and PRECAUTIONS).
Adults: Selected clinical adverse events that occurred in adult patients in clinical
studies with VIDEX are provided in Tables 9 and 10.
Table 9:
Selected Clinical Adverse Events from Monotherapy
Studies
Percent of Patients
ACTG 116A
ACTG 116B/117
Adverse Events
VIDEX
n=197
zidovudine
n=212
VIDEX
n=298
zidovudine
n=304
Diarrhea
19
15
28
21
Peripheral Neurologic
Symptoms/Neuropathy
17
14
20
12
Rash/Pruritus
7
8
9
5
Abdominal Pain
13
8
7
8
Pancreatitis
7
3
6
2
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Table 10:
Selected Clinical Adverse Events from Combination
Studies
Percent of Patientsa
AI454-148b
START 2b
Adverse Events
VIDEX +
stavudine +
nelfinavir
n=482
zidovudine +
lamivudine +
nelfinavir
n=248
VIDEX +
stavudine +
indinavir
n=102
zidovudine +
lamivudine +
indinavir
n=103
Diarrhea
70
60
45
39
Nausea
28
40
53
67
Headache
21
30
46
37
Peripheral Neurologic
Symptoms/Neuropathy
26
6
21
10
Rash
13
16
30
18
Vomiting
12
14
30
35
Pancreatitis (see below)
1
*
<1
*
a Percentages based on treated subjects.
b Median duration of treatment 48 weeks.
* This event was not observed in this study arm.
Pancreatitis resulting in death was observed in one patient who received
VIDEX (didanosine) plus stavudine plus nelfinavir in Study Al454-148 and in one
patient who received VIDEX plus stavudine plus indinavir in the START 2 study. In
addition, pancreatitis resulting in death was observed in 2 of 68 patients who received
VIDEX plus stavudine plus indinavir plus hydroxyurea in an ACTG clinical trial (see
WARNINGS).
The frequency of pancreatitis is dose related. In phase 3 studies, incidence ranged
from 1% to 10% with doses higher than are currently recommended and from 1% to 7%
with recommended dose.
Selected laboratory abnormalities in clinical studies with VIDEX are shown in
Tables 11-13.
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Table 11:
Selected Laboratory Abnormalities from Monotherapy Studies
Percent of Patients
ACTG 116A
ACTG 116B/117
VIDEX
zidovudine
VIDEX
zidovudine
Parameter
n=197
n=212
n=298
n=304
SGOT (AST) (>5 x ULN)
9
4
7
6
SGPT (ALT) (>5 x ULN)
9
6
6
6
Alkaline phosphatase (>5 x ULN)
4
1
1
1
Amylase (≥1.4 x ULN)
17
12
15
5
Uric acid (>12 mg/dL)
3
1
2
1
ULN = upper limit of normal.
Table 12:
Selected Laboratory Abnormalities from Combination Studies
(Grades 3-4)
Percent of Patientsa
AI454-148b
START 2b
VIDEX +
stavudine +
nelfinavir
zidovudine +
lamivudine +
nelfinavir
VIDEX +
stavudine +
indinavir
zidovudine +
lamivudine +
indinavir
Parameter
n=482
n=248
n=102
n=103
Bilirubin (>2.6 x ULN)
<1
<1
16
8
SGOT (AST) (>5 x ULN)
3
2
7
7
SGPT (ALT) (>5 x ULN)
3
3
8
5
GGT (>5 x ULN)
NC
NC
5
2
Lipase (>2 x ULN)
7
2
5
5
Amylase (>2 x ULN)
NC
NC
8
2
ULN = upper limit of normal.
NC = Not Collected.
a Percentages based on treated subjects.
b Median duration of treatment 48 weeks.
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Table 13:
Selected Laboratory Abnormalities from Combination
Studies (All Grades)
Percent of Patientsa
AI454-148b
START 2b
Parameter
VIDEX +
stavudine +
nelfinavir
n=482
zidovudine +
lamivudine +
nelfinavir
n=248
VIDEX +
stavudine +
indinavir
n=102
zidovudine +
lamivudine +
indinavir
n=103
Bilirubin
7
3
68
55
SGOT (AST)
42
23
53
20
SGPT (ALT)
37
24
50
18
GGT
NC
NC
28
12
Lipase
17
11
26
19
Amylase
NC
NC
31
17
NC = Not Collected.
a Percentages based on treated subjects.
b Median duration of treatment 48 weeks.
Observed during Clinical Practice: The following events have been identified
during postapproval use of VIDEX (didanosine). Because they are reported voluntarily
from a population of unknown size, estimates of frequency cannot be made. These events
have been chosen for inclusion due to their seriousness, frequency of reporting, causal
connection to VIDEX, or a combination of these factors.
Body as a Whole – alopecia, anaphylactoid reaction, asthenia, chills/fever, pain,
and redistribution/accumulation of body fat (see PRECAUTIONS: Fat
Redistribution).
Digestive Disorders – anorexia, dyspepsia, and flatulence.
Exocrine Gland Disorders – pancreatitis (including fatal cases) (see
WARNINGS), sialoadenitis, parotid gland enlargement, dry mouth, and dry eyes.
Hematologic Disorders – anemia, leukopenia, and thrombocytopenia.
Liver – symptomatic hyperlactatemia/lactic acidosis and hepatic steatosis (see
WARNINGS); hepatitis and liver failure.
Metabolic Disorders – diabetes mellitus, hypoglycemia, and hyperglycemia.
Musculoskeletal Disorders – myalgia (with or without increases in creatine kinase),
rhabdomyolysis including acute renal failure and hemodialysis, arthralgia, and
myopathy.
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Ophthalmologic Disorders – Retinal depigmentation and optic neuritis (see
WARNINGS).
Pediatric Patients: In clinical trials, 743 pediatric patients between 2 weeks and
18 years of age have been treated with VIDEX. Adverse events and laboratory
abnormalities reported to occur in these patients were generally consistent with the safety
profile of didanosine in adults.
In pediatric phase 1 studies, pancreatitis occurred in 2 of 60 (3%) patients treated at
entry doses below 300 mg/m2/day and in 5 of 38 (13%) patients treated at higher doses. In
study ACTG 152, pancreatitis occurred in none of the 281 pediatric patients who received
didanosine 120 mg/m2 q12h and in <1% of the 274 pediatric patients who received
didanosine 90 mg/m2 q12h in combination with zidovudine (see INDICATIONS AND
USAGE: Clinical Studies).
Retinal changes and optic neuritis have been reported in pediatric patients.
OVERDOSAGE
There is no known antidote for VIDEX (didanosine) overdosage. In phase 1 studies, in
which VIDEX was initially administered at doses ten times the currently recommended
dose, toxicities included: pancreatitis, peripheral neuropathy, diarrhea, hyperuricemia, and
hepatic dysfunction. Didanosine is not dialyzable by peritoneal dialysis, although there is
some
clearance
by
hemodialysis
(see
CLINICAL
PHARMACOLOGY:
Pharmacokinetics).
DOSAGE AND ADMINISTRATION
Dosage
All VIDEX formulations should be administered on an empty stomach, at least 30
minutes before or 2 hours after eating. For either a once-daily or twice-daily regimen,
patients must take at least two of the appropriate strength tablets at each dose to
provide adequate buffering and prevent gastric acid degradation of didanosine.
Because of the need for adequate buffering, the 200-mg strength tablet should only be
used as a component of a once-daily regimen. To reduce the risk of gastrointestinal
side effects, patients should take no more than four tablets at each dose.
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Adults: The preferred dosing frequency of VIDEX is twice daily because there is
more evidence to support the effectiveness of this dosing regimen. Once-daily dosing
should be considered only for adult patients whose management requires once-daily dosing
of VIDEX (see INDICATIONS AND USAGE: Clinical Studies). The daily dose in adult
patients is dependent on weight as outlined in Table 14.
Table 14:
Adult Dosinga
Recommended VIDEX Dose by Patient Weight
≥60 kg
<60 kg
Preferred dosing
200 mg twice daily
125 mg twice daily
Dosing for patients whose
management requires once-daily
frequency
400 mg once daily
250 mg once daily
a The 200-mg strength tablet should only be used as a component of a once-daily regimen.
Pediatric Patients: The recommended dose of VIDEX (didanosine) in pediatric
patients between 2 weeks and 8 months of age is 100 mg/m2 twice daily, and the
recommended VIDEX dose for pediatric patients older than 8 months is 120 mg/m2 twice
daily.
Dosing recommendations for VIDEX in patients less than 2 weeks of age cannot be
made because the pharmacokinetics of didanosine in these children are too variable to
determine an appropriate dose. There are no data on once-daily dosing of VIDEX in
pediatric patients.
Dose Adjustment
Clinical and laboratory signs suggestive of pancreatitis should prompt dose
suspension and careful evaluation of the possibility of pancreatitis. VIDEX use should
be discontinued in patients with confirmed pancreatitis (see WARNINGS and
PRECAUTIONS: Drug Interactions).
Patients with symptoms of peripheral neuropathy may tolerate a reduced dose of
VIDEX after resolution of the symptoms of peripheral neuropathy upon drug
discontinuation. If neuropathy recurs after resumption of VIDEX, permanent
discontinuation of VIDEX should be considered.
Concomitant Therapy: Tenofovir disoproxil fumarate. A dose reduction of
VIDEX to 250 mg (adults weighing ≥60 kg with creatinine clearance ≥60 mL/min) or 200
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Page 31 of 75
mg (adults weighing <60 kg with creatinine clearance ≥60 mL/min) once daily is
recommended. VIDEX and tenofovir may be taken together in the fasted state.
Alternatively, if tenofovir is taken with food, VIDEX should be taken on an empty
stomach (at least 30 minutes before food or 2 hours after food). The appropriate dose of
VIDEX coadministered with tenofovir in patients with creatinine clearance <60
mL/min has not been established. [See CLINICAL PHARMACOLOGY: Drug
Interactions and PRECAUTIONS: Drug Interactions; see the complete prescribing
information for VIDEX EC (enteric-coated formulation of didanosine) for results of drug
interaction studies of tenofovir with reduced doses of the enteric-coated formulation of
didanosine.]
Renal Impairment: In adult patients with impaired renal function, the dose of
VIDEX should be adjusted to compensate for the slower rate of elimination. The
recommended doses and dosing intervals of VIDEX in adult patients with renal
insufficiency are presented in Table 15.
Table 15:
Recommended Dosage of VIDEX in Renal Impairmenta
Recommended VIDEX Dose by Patient Weight
Creatinine Clearance
(mL/min)
≥60 kg
<60 kg
≥60
200 mg twice dailyb
125 twice dailyb
30-59
200 mg once daily
or 100 mg twice daily
150 mg once daily
or 75 mg twice daily
10-29
150 mg once daily
100 mg once daily
<10
100 mg once daily
75 mg once daily
a Two VIDEX Chewable/Dispersible Buffered tablets must be taken with each dose; different strengths of
tablets may be combined to yield the recommended dose.
b 400 mg once daily (≥60 kg) or 250 mg once daily (<60 kg) for patients whose management requires once-
daily frequency of administration.
Urinary excretion is also a major route of elimination of didanosine in pediatric
patients; therefore, the clearance of didanosine may be altered in children with renal
impairment. Although there are insufficient data to recommend a specific dose adjustment
of VIDEX in this patient population, a reduction in the dose and/or an increase in the
interval between doses should be considered.
Patients Requiring Continuous Ambulatory Peritoneal Dialysis (CAPD) or
Hemodialysis:
For
patients
requiring
CAPD
or
hemodialysis,
follow
dosing
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Page 32 of 75
recommendations for patients with creatinine clearance less than 10 mL/min, shown in Table
15. It is not necessary to administer a supplemental dose of VIDEX following hemodialysis.
Hepatic Impairment and Toxicity: See WARNINGS.
Method of Preparation
VIDEX Chewable/Dispersible Buffered Tablets
Adult Dosing: To provide adequate buffering, at least two of the appropriate
strength tablets, but no more than four tablets, should be thoroughly chewed or dispersed
in at least 1 ounce of water prior to consumption (see PRECAUTIONS: Information for
Patients). To disperse tablets, add 2 tablets to at least 1 ounce of drinking water. Stir until
a uniform dispersion forms, and drink the entire dispersion immediately. If additional
flavoring is desired, the dispersion may be diluted with one ounce of clear apple juice. Stir
the further diluted dispersion just prior to consumption. The dispersion with clear apple
juice is stable at room temperature, 62° to 73°F (17° to 23°C), for up to one hour.
VIDEX Pediatric Powder for Oral Solution
Prior to dispensing, the pharmacist must constitute dry powder with Purified Water, USP,
to an initial concentration of 20 mg/mL and immediately mix the resulting solution with
antacid to a final concentration of 10 mg/mL as follows:
20 mg/mL Initial Solution: Constitute the product to 20 mg/mL by adding 100
mL or 200 mL of Purified Water, USP, to the 2 g or 4 g of VIDEX powder, respectively, in
the product bottle.
10 mg/mL Final Admixture: 1. Immediately mix one part of the 20 mg/mL initial
solution with one part of Maximum Strength Mylanta® Liquid for a final dispensing
concentration of 10 mg VIDEX per mL. For patient home use, the admixture should be
dispensed in appropriately sized, flint-glass or plastic (HDPE, PET, or PETG) bottles with
child-resistant closures. This admixture is stable for 30 days under refrigeration, 36° to 46°
F (2° to 8° C).
2. Instruct the patient to shake the admixture thoroughly prior to use and to store
the tightly closed container in the refrigerator, 36° to 46° F (2° to 8° C), up to 30 days.
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HOW SUPPLIED
VIDEX® (didanosine) Chewable/Dispersible Buffered Tablets are round, off white to
light orange/yellow with a mottled appearance, orange-flavored, tablets embossed with
"VIDEX" on one side and the product strength on the other. The tablets are available in
the following strengths of VIDEX: 25, 50, 100, 150, and 200 mg. Sixty tablets are
packaged in bottles with child-resistant closures.
The tablets should be stored in tightly closed bottles at 59° to 86° F (15° to
30° C). If dispersed in water, the dose may be held for up to 1 hour at ambient
temperature.
VIDEX (didanosine) Pediatric Powder for Oral Solution is supplied in 4- and 8-
ounce glass bottles containing 2 g or 4 g of VIDEX, respectively.
The bottles of powder should be stored at 59° to 86° F (15° to 30° C). The VIDEX
admixture may be stored up to 30 days in a refrigerator, 36° to 46° F (2° to 8° C). Discard
any unused portion after 30 days.
The NDC numbers for the previously described VIDEX products are:
Table 16
NDC NO.
Packaging Information
Product Strength
VIDEX® Chewable/Dispersible Buffered Tablets
0087-6650-01
60 tablets/bottle
25 mg/tablet
0087-6651-01
60 tablets/bottle
50 mg/tablet
0087-6652-01
60 tablets/bottle
100 mg/tablet
0087-6653-01
60 tablets/bottle
150 mg/tablet
0087-6665-15
60 tablets/bottle
200 mg/tablet
VIDEX® Pediatric Powder for Oral Solution
0087-6632-41
One bottle per carton
2 g/bottle
0087-6633-41
One bottle per carton
4 g/bottle
US Patent Nos.: 4,861,759, 5,254,539, 5,616,566 and 5,880,106.
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Page 34 of 75
HANDLING AND DISPOSAL
Spill, Leak, and Disposal Procedure
Avoid generating dust during clean-up of powdered products; use wet mop or damp
sponge. Clean surface with soap and water as necessary. Containerize larger spills.
There is no single preferred method of disposal of containerized waste. Disposal
options include incineration, landfill, or sewer as dictated by specific circumstances and
relevant national, state, and local regulations.
Mylanta® is a registered trademark of Johnson & Johnson-Merck Consumer Pharmaceuticals Company.
Bristol-Myers Squibb Virology
Bristol-Myers Squibb Company
Princeton, NJ 08543 USA
1196181A2
Revised July 2006
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Patient Information
Rx only
VIDEX®
(generic name = didanosine also known as ddI)
VIDEX® (didanosine) Chewable/Dispersible Buffered Tablets
VIDEX® (didanosine) Pediatric Powder for Oral Solution
What is VIDEX?
VIDEX (pronounced VY dex) is a prescription medicine used in combination with other
drugs to treat children and adults who are infected with HIV (the human
immunodeficiency virus, the virus that causes AIDS). VIDEX belongs to a class of drugs
called nucleoside analogues. By reducing the growth of HIV, VIDEX helps your body
maintain its supply of CD4 cells, which are important for fighting HIV and other
infections.
VIDEX will not cure your HIV infection. At present there is no cure for HIV infection.
Even while taking VIDEX, you may continue to have HIV-related illnesses, including
infections with other disease-producing organisms. Continue to see your doctor regularly and
report any medical problems that occur.
VIDEX does not prevent a patient infected with HIV from passing the virus to
other people. To protect others, you must continue to practice safe sex and take precautions
to prevent others from coming in contact with your blood and other body fluids.
There is limited information on the effects of long-term use of VIDEX.
Who should not take VIDEX?
Do not take VIDEX if you are allergic to any of its ingredients, including its active ingredient,
didanosine and the inactive ingredients. (See Inactive Ingredients at the end of this leaflet.)
Tell your doctor if you think you have had an allergic reaction to any of these ingredients.
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How should I take VIDEX? How should I store it?
Your doctor will determine your dose based on your body weight, kidney and liver function,
other medicines you are taking, and any side effects that you may have had with VIDEX or
other medicines. Take VIDEX on an empty stomach - that means at least 30 minutes before
or 2 hours after eating. Do not take VIDEX with food. Try not to miss a dose, but if you do,
take it as soon as possible. If it is almost time for the next dose, skip the missed dose and
continue your regular dosing schedule.
Chewable/Dispersible Tablets: Each VIDEX tablet contains antacid. Each
time you take VIDEX, you must take at least two, but not more than four,
tablets. This is because VIDEX tablets contain an antacid to reduce the amount of
acid in your stomach. If you have too much acid, the medicine will break down.
However, too much antacid may cause stomach problems.
—DO NOT swallow VIDEX tablets whole. Chew the tablets well or mix them in
water. Many patients drop the tablets in at least one ounce of water and stir well
before swallowing. If you choose to mix the tablets in water, you may add one
ounce (2 tablespoons) of clear apple juice to the mixture for flavor (do not use any
other kind of juice).
—Store tablets in a tightly closed container at room temperature away from heat
and out of the reach of children and pets. Do NOT store the tablets in a damp place
such as a bathroom medicine cabinet or near the kitchen sink.
Pediatric Oral Solution: Your pharmacist will prepare the oral solution. Shake
the solution well before each use. Store in the refrigerator. Throw away any
unused portion after 30 days.
If you have kidney disease: If your kidneys are not working properly, your doctor
will need to do regular tests to check how they are working while you take VIDEX.
Your doctor may also lower your dosage of VIDEX.
What should I do if someone takes an overdose of VIDEX?
If someone may have taken an overdose of VIDEX, get medical help right away. Contact
their doctor or a poison control center.
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What should I avoid while taking VIDEX?
Alcohol. Do not drink alcohol while taking VIDEX since alcohol may increase your risk
of pancreatitis (pain and inflammation of the pancreas) or liver damage.
Other medicines. Other medicines, including those you can buy without a prescription,
may interfere with the actions of VIDEX or may increase the possibility or severity of side
effects. Do not take any medicine, vitamin supplement, or other health preparation
without first checking with your doctor.
Antacids. Since VIDEX contains some of the same ingredients found in antacids,
any side effects related to VIDEX’s ingredients may get worse if you also take an
antacid.
Medicines at the same time you take your VIDEX dose. Some medicines should
not be taken at the same time of day that you take VIDEX. Check with your
doctor.
Pregnancy. It is not known if VIDEX can harm a human fetus. Also, pregnant women
have experienced serious side effects when taking VIDEX in combination with ZERIT
(stavudine), also known as d4T, and other HIV medicines. VIDEX should be used during
pregnancy only after discussion with your doctor. Tell your doctor if you become
pregnant or plan to become pregnant while taking VIDEX.
Nursing. Studies have shown VIDEX is in the breast milk of animals getting the drug. It
may also be in human breast milk. The Centers for Disease Control and Prevention (CDC)
recommends that HIV-infected mothers not breast-feed. This should reduce the risk of
passing HIV infection to their babies and the potential for serious adverse reactions in
nursing infants. Therefore, do not nurse a baby while taking VIDEX.
What are the possible side effects of VIDEX?
Pancreatitis. Pancreatitis is a dangerous inflammation of the pancreas that may cause
death. Tell your doctor right away if you or a child taking VIDEX develops stomach
pain, nausea, or vomiting. These can be signs of pancreatitis. Before starting VIDEX
therapy, let your doctor know if you or a child for whom it has been prescribed has ever had
pancreatitis. This condition is more likely to happen in people who have had it before. It is
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also more likely in people with advanced HIV disease. However, it can occur at any stage of
HIV disease. It may be more common in patients with kidney problems, those who drink
alcohol, and those who are also treated with stavudine or hydroxyurea. If you get pancreatitis,
your doctor will tell you to stop taking VIDEX.
Lactic acidosis, severe liver enlargement, and liver failure, including deaths, have been
reported among patients taking VIDEX (including pregnant women). Symptoms that may
indicate a liver problem are:
• feeling very weak, tired, or uncomfortable,
• unusual or unexpected stomach discomfort,
• feeling cold,
• feeling dizzy or lightheaded,
• suddenly developing a slow or irregular heartbeat.
Lactic acidosis is a medical emergency that must be treated in a hospital.
If you notice any of these symptoms or if your medical condition changes, stop taking
VIDEX and call your doctor right away. Women, overweight patients, and those who have
been treated for a long time with other medicines used to treat HIV infection are more likely to
develop lactic acidosis. Your doctor should check your liver function periodically while you
are taking VIDEX. You should be especially careful if you have a history of heavy alcohol use
or a liver problem.
Vision changes. VIDEX may affect the nerves in your eyes. Because of this, you should have
regular eye examinations. You should also report any changes in vision to your doctor right
away. This includes, for example, seeing colors abnormally or blurred vision.
Peripheral neuropathy. This is a problem with the nerves in your hands or feet. The nerve
problem may be serious. Tell your doctor right away if you or a child taking VIDEX has
continuing numbness, tingling, or pain in the feet or hands. A child may not recognize these
symptoms or know to tell you that his or her feet or hands are numb, burning, tingling, or
painful. Ask your child’s doctor how to find out if your child is developing peripheral
neuropathy.
Before starting VIDEX therapy, let your doctor know if you or a child for whom it has
been prescribed has ever had peripheral neuropathy. This condition is more likely to happen in
people who have had it before. It is also more likely in patients taking medicines that affect the
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nerves and in people with advanced HIV disease. However, it can occur at any stage of HIV
disease. If you get peripheral neuropathy, your doctor will tell you to stop taking VIDEX.
After stopping VIDEX, the symptoms may get worse for a short time and then get better. Once
symptoms of peripheral neuropathy go away completely, you and your doctor should decide if
starting VIDEX is right for you. If so, you might be started at a lower dose.
Special note about other medicines. If you take VIDEX along with other medicines with
similar side effects, you may increase the chance of having these side effects. For example,
using VIDEX in combination with other medicines that may cause pancreatitis, peripheral
neuropathy, or liver problems (including stavudine and hydroxyurea) may increase your chance
of having these side effects.
Other side effects: The most common side effects in adults taking VIDEX are diarrhea,
neuropathy (nerve disorders), chills or fever, rash, abdominal pain, weakness, headache, and
nausea and vomiting. Children may have similar side effects as adults.
Changes in body fat have been seen in some patients taking antiretroviral therapy.
These changes may include increased amount of fat in the upper back and neck (“buffalo
hump”), breast, and around the trunk. Loss of fat from the legs, arms, and face may also
happen. The cause and long-term health effects of these conditions are not known at this time.
What else should I know about VIDEX?
If you have phenylketonuria: Each Chewable/Dispersible Tablet contains 36.5 mg of
phenylalanine.
Inactive Ingredients:
Chewable/Dispersible Tablets: calcium carbonate, magnesium hydroxide,
aspartame, sorbitol, mandarin orange flavor, polyplasdone, microcrystalline
cellulose, and magnesium stearate.
Pediatric Oral Solution: Maximum Strength Mylanta® Liquid.
This medicine was prescribed for your particular condition. Do not use VIDEX for another condition or give
it to others. Keep VIDEX and all medicines out of the reach of children. Throw away VIDEX when it is
outdated or no longer needed by flushing it down the toilet or pouring it down the sink.
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This summary does not include everything there is to know about VIDEX. Medicines are sometimes
prescribed for purposes other than those listed in a Patient Information Leaflet. If you have questions or concerns, or
want more information about VIDEX, your physician and pharmacist have the complete prescribing information
upon which this leaflet is based. You may want to read it and discuss it with your doctor or other healthcare
professional. Remember, no written summary can replace careful discussion with your doctor.
Mylanta® is a registered trademark of Johnson & Johnson-Merck Consumer Pharmaceuticals Company.
Bristol-Myers Squibb Virology
Bristol-Myers Squibb Company
Princeton, NJ 08543 USA
This Patient Information Leaflet has been approved by the U.S. Food and Drug Administration.
Revised July 2006
1196181A2
Based on package insert dated July 2006
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Page 41 of 75
Rx only
VIDEX® EC (didanosine)
VIDEX® EC (didanosine) Delayed-Release Capsules
Enteric-Coated Beadlets
(Patient Information Leaflet Included)
WARNING
FATAL AND NONFATAL PANCREATITIS HAVE OCCURRED DURING
THERAPY WITH DIDANOSINE USED ALONE OR IN COMBINATION
REGIMENS
IN
BOTH
TREATMENT-NAIVE
AND
TREATMENT-
EXPERIENCED
PATIENTS,
REGARDLESS
OF
DEGREE
OF
IMMUNOSUPPRESSION. VIDEX EC SHOULD BE SUSPENDED IN PATIENTS
WITH SUSPECTED PANCREATITIS AND DISCONTINUED IN PATIENTS
WITH CONFIRMED PANCREATITIS (SEE WARNINGS).
LACTIC
ACIDOSIS
AND
SEVERE
HEPATOMEGALY
WITH
STEATOSIS, INCLUDING FATAL CASES, HAVE BEEN REPORTED WITH
THE USE OF NUCLEOSIDE ANALOGUES ALONE OR IN COMBINATION,
INCLUDING DIDANOSINE AND OTHER ANTIRETROVIRALS. FATAL
LACTIC ACIDOSIS HAS BEEN REPORTED IN PREGNANT WOMEN WHO
RECEIVED THE COMBINATION OF DIDANOSINE AND STAVUDINE WITH
OTHER
ANTIRETROVIRAL
AGENTS.
THE
COMBINATION
OF
DIDANOSINE AND STAVUDINE SHOULD BE USED WITH CAUTION
DURING PREGNANCY AND IS RECOMMENDED ONLY IF THE POTENTIAL
BENEFIT CLEARLY OUTWEIGHS THE POTENTIAL RISK (SEE WARNINGS
AND PRECAUTIONS: PREGNANCY).
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DESCRIPTION
VIDEX® EC is the brand name for an enteric-coated formulation of didanosine (ddI), a
synthetic purine nucleoside analogue active against the Human Immunodeficiency Virus
(HIV). VIDEX EC (didanosine) Delayed-Release Capsules, containing enteric-coated
beadlets, are available for oral administration in strengths of 125, 200, 250, and 400 mg of
didanosine. The inactive ingredients in the beadlets include carboxymethylcellulose
sodium 12, diethyl phthalate, methacrylic acid copolymer, sodium hydroxide, sodium
starch glycolate, and talc. The capsule shells contain colloidal silicon dioxide, gelatin,
sodium lauryl sulfate, and titanium dioxide. The capsules are imprinted with edible inks.
Didanosine is also available as buffered formulations. Please consult the
prescribing information for VIDEX (didanosine) Chewable/Dispersible Buffered Tablets
and Pediatric Powder for Oral Solution for additional information.
The chemical name for didanosine is 2',3'-dideoxyinosine. The structural formula
is:
Didanosine is a white crystalline powder with the molecular formula C10H12N4O3
and a molecular weight of 236.2. The aqueous solubility of didanosine at 25° C and pH of
approximately 6 is 27.3 mg/mL. Didanosine is unstable in acidic solutions. For example, at
pH <3 and 37° C, 10% of didanosine decomposes to hypoxanthine in less than 2 minutes.
In VIDEX EC, an enteric coating is used to protect didanosine from degradation by
stomach acid.
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MICROBIOLOGY
Mechanism of Action
Didanosine is a synthetic nucleoside analogue of the naturally occurring nucleoside
deoxyadenosine in which the 3'-hydroxyl group is replaced by hydrogen. Intracellularly,
didanosine is converted by cellular enzymes to the active metabolite, dideoxyadenosine
5'-triphosphate. Dideoxyadenosine 5'-triphosphate inhibits the activity of HIV-1 reverse
transcriptase both by competing with the natural substrate, deoxyadenosine 5'-triphosphate,
and by its incorporation into viral DNA causing termination of viral DNA chain
elongation.
In Vitro HIV Susceptibility
The in vitro anti-HIV-1 activity of didanosine was evaluated in a variety of HIV-1 infected
lymphoblastic cell lines and monocyte/macrophage cell cultures. The concentration of
drug necessary to inhibit viral replication by 50% (IC50) ranged from 2.5 to 10 µM (1 µM
= 0.24 µg/mL) in lymphoblastic cell lines and 0.01 to 0.1 µM in monocyte/macrophage
cell cultures. The relationship between in vitro susceptibility of HIV to didanosine and the
inhibition of HIV replication in humans has not been established.
Drug Resistance
HIV-1 isolates with reduced sensitivity to didanosine have been selected in vitro and were
also obtained from patients treated with didanosine. Genetic analysis of isolates from
didanosine-treated patients showed mutations in the reverse transcriptase gene that resulted
in the amino acid substitutions K65R, L74V, and M184V. The L74V mutation was most
frequently observed in clinical isolates. Phenotypic analysis of HIV-1 isolates from 60
patients (some with prior zidovudine treatment) receiving 6 to 24 months of didanosine
monotherapy showed that isolates from 10 of 60 patients exhibited an average of a 10-fold
decrease in susceptibility to didanosine in vitro compared to baseline isolates. Clinical
isolates that exhibited a decrease in didanosine susceptibility harbored one or more
didanosine-associated mutations. The clinical relevance of genotypic and phenotypic
changes associated with didanosine therapy has not been established.
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Cross-resistance
HIV-1 isolates from 2 of 39 patients receiving combination therapy for up to 2 years with
zidovudine and didanosine exhibited decreased susceptibility to zidovudine, didanosine,
zalcitabine, stavudine, and lamivudine in vitro. These isolates harbored five mutations
(A62V, V75I, F77L, F116Y, and Q151M) in the reverse transcriptase gene. The clinical
relevance of these observations has not been established.
CLINICAL PHARMACOLOGY
Animal Toxicology
Evidence of a dose-limiting skeletal muscle toxicity has been observed in mice and rats
(but not in dogs) following long-term (greater than 90 days) dosing with didanosine at
doses that were approximately 1.2 to 12 times the estimated human exposure. The
relationship of this finding to the potential of didanosine to cause myopathy in humans is
unclear. However, human myopathy has been associated with administration of
didanosine and other nucleoside analogues.
Pharmacokinetics
The pharmacokinetic parameters of didanosine are summarized in Table 1. Didanosine is
rapidly absorbed, with peak plasma concentrations generally observed from 0.25 to 1.50
hours following oral dosing with a buffered formulation. Increases in plasma didanosine
concentrations were dose proportional over the range of 50 to 400 mg. Steady-state
pharmacokinetic parameters did not differ significantly from values obtained after a single
dose. Binding of didanosine to plasma proteins in vitro was low (<5%). Based on data
from in vitro and animal studies, it is presumed that the metabolism of didanosine in man
occurs by the same pathways responsible for the elimination of endogenous purines.
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Table 1:
Pharmacokinetic Parameters for Didanosine in Adults
Parameter
Mean ± SD
n
Oral bioavailability
42 ± 12%
6
Apparent volume of distribution
1.08 ± 0.22 L/kg
6
CSF-plasma ratiob
21 ± 0.03%
5
Systemic clearanceb
13.0 ± 1.6 mL/min/kg
6
Renal clearancea
5.5 ± 2.1 mL/min/kg
6
Elimination half-lifea
1.5 ± 0.4 h
6
Urinary recovery of didanosinea
18 ± 8%
6
CSF = cerebrospinal fluid.
a following oral administration of a buffered formulation.
b following IV administration.
c mean ± SE.
Comparison of Didanosine Formulations
In VIDEX EC, the active ingredient, didanosine, is protected against degradation by
stomach acid by the use of an enteric coating on the beadlets in the capsule. The enteric
coating dissolves when the beadlets empty into the small intestine, the site of drug
absorption. With buffered formulations of didanosine, administration with antacid provides
protection from degradation by stomach acid.
In healthy volunteers, as well as subjects infected with HIV, the area under the
plasma concentration time curve (AUC) is equivalent for didanosine administered as the
VIDEX EC formulation relative to a buffered tablet formulation. The peak plasma
concentration (CMAX) of didanosine, administered as VIDEX EC, is reduced approximately
40% relative to didanosine buffered tablets. The time to the peak concentration (TMAX)
increases from approximately 0.67 hours for didanosine buffered tablets to 2.0 hours for
VIDEX EC.
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Effect of Food on Absorption of Didanosine
In the presence of food, the CMAX and AUC for VIDEX EC were reduced by
approximately 46% and 19%, respectively, compared to the fasting state. VIDEX EC
should be taken on an empty stomach.
Special Populations
Renal Insufficiency
It is recommended that the VIDEX EC (didanosine) dose be modified in patients with
reduced creatinine clearance and in patients receiving maintenance hemodialysis (see
DOSAGE AND ADMINISTRATION). Data from two studies using a buffered
formulation of didanosine indicated that the apparent oral clearance of didanosine
decreased and the terminal elimination half-life increased as creatinine clearance decreased
(see Table 2). Following oral administration, didanosine was not detectable in peritoneal
dialysate fluid (n=6); recovery in hemodialysate (n=5) ranged from 0.6% to 7.4% of the
dose over a 3-4 hour dialysis period. The absolute bioavailability of didanosine was not
affected in patients requiring dialysis.
Table 2:
Mean ± SD Pharmacokinetic Parameters for Didanosine
Following a Single Oral Dose of a Buffered Formulation
Creatinine Clearance (mL/min)
Parameter
≥ 90
(n=12)
60-90
(n=6)
30-59
(n=6)
10-29
(n=3)
Dialysis
Patients
(n=11)
CLcr (mL/min)
112 ± 22
68 ± 8
46 ± 8
13 ± 5
ND
CL/F (mL/min)
2164 ± 638
1566 ± 833
1023 ± 378
628 ± 104
543 ± 174
CLR (mL/min)
458 ± 164
247 ± 153
100 ± 44
20 ± 8
<10
T½ (h)
1.42 ± 0.33
1.59 ± 0.13
1.75 ± 0.43
2.0 ± 0.3
4.1 ± 1.2
ND = not determined due to anuria.
CLcr = creatinine clearance.
CL/F = apparent oral clearance.
CLR = renal clearance.
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Pediatric Patients
The pharmacokinetics of didanosine administered as VIDEX EC have not been studied in
pediatric patients.
Geriatric Patients
Didanosine pharmacokinetics have not been studied in patients over 65 years of age (see
PRECAUTIONS: Geriatric Use).
Gender
The effects of gender on didanosine pharmacokinetics have not been studied.
Drug Interactions (See also PRECAUTIONS: Drug Interactions.)
Ribavirin has been shown in vitro to increase intracellular triphosphate levels of
didanosine, which could cause or worsen clinical toxicities (see PRECAUTIONS: Drug
Interactions).
VIDEX EC
Tables 3 and 4 summarize the effects on AUC and CMAX, with a 90% confidence interval
(CI) when available, following coadministration of VIDEX EC with a variety of drugs.
Clinical recommendations based on drug interaction studies for drugs in bold font are
included
in
PRECAUTIONS:
Drug
Interactions
and
DOSAGE
AND
ADMINISTRATION.
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Table 3:
Results of Drug Interaction Studies with VIDEX EC: Effects of
Coadministered Drug on Didanosine Plasma AUC and CMAX
Valuesa
Drug
Didanosine Dosage
n
AUC of Didanosine
(90% CI)
CMAX of Didanosine
(90% CI)
tenofovir,b 300 mg
once daily with a
light mealc
400 mg single dose
fasting 2 h before
tenofovir
26
↑ 48% (31, 67%)
↑ 48% (25, 76%)
tenofovir,b 300 mg
once daily with a
light mealc
400 mg single dose
with tenofovir and
a light meal
25
↑ 60% (44, 79%)
↑ 64% (41, 89%)
tenofovir,b 300 mg
once daily with a
light mealc
200 mg single dose
with tenofovir and
a light meal
33
↑ 16% (6, 27%)d
↓ 12% (−25, 3%)d
250 mg single dose
with tenofovir and
a light meal
33
↔ (−13, 5%)e
↓ 20% (−32, −7%)e
325 mg single dose
with tenofovir and
a light meal
33
↑ 13% (3, 24%)e
↓ 11% (−24, 4%)e
↑ indicates increase.
↓ indicates decrease.
↔ indicates no change, or mean increase or decrease of <10%.
a All studies conducted in healthy volunteers ≥60 kg with creatinine clearance ≥60 mL/min.
b tenofovir disoproxil fumarate.
c 373 kcalories, 8.2 grams fat.
d Compared with VIDEX EC 250 mg administered alone under fasting conditions.
e Compared with VIDEX EC 400 mg administered alone under fasting conditions.
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Table 4:
Results of Drug Interaction Studies with VIDEX EC: Effects of
Didanosine on Coadministered Drug Plasma AUC and CMAX
Valuesa
Drug
Didanosine Dosage
n
AUC of
Coadministered Drug
CMAX of Coadministered
Drug
ciprofloxacin, 750 mg
single dose
400 mg single dose
16
↔
↔
indinavir, 800 mg
single dose
400 mg single dose
23
↔
↔
ketoconazole, 200 mg
single dose
400 mg single dose
21
↔
↔
tenofovir,b 300 mg
once daily with a
light mealc
400 mg single dose
fasting 2 h before
tenofovir
25
↔
↔
tenofovir,b 300 mg
once daily with a
light mealc
400 mg single dose
with tenofovir and
a light meal
25
↔
↔
↔ indicates no change, or mean increase or decrease of <10%.
a All studies conducted in healthy volunteers ≥60 kg with creatinine clearance ≥60 mL/min.
b tenofovir disoproxil fumarate.
c 373 kcalories, 8.2 grams fat.
Didanosine Buffered Formulations
Tables 5 and 6 summarize the effects on AUC and CMAX, with a 90% or 95% CI when
available, following coadministration of buffered formulations of didanosine with a variety
of drugs. Except as noted in table footnotes, the results of these studies may be expected to
apply to VIDEX EC. For most of the listed drugs, no clinically significant
pharmacokinetic interactions were noted. Clinical recommendations based on drug
interaction studies for drugs in bold font are included in PRECAUTIONS: Drug
Interactions and DOSAGE AND ADMINISTRATION (for tenofovir).
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Table 5:
Results of Drug Interaction Studies with Buffered
Formulations of Didanosine: Effects of Coadministered Drug
on Didanosine Plasma AUC and CMAX Values
Drugs With Clinical Recommendations Regarding Coadministration (see PRECAUTIONS: Drug
Interactions)
Drug
Didanosine Dosage
n
AUC of Didanosine
(95% CI)
CMAX of Didanosine
(95% CI)
allopurinol
renally impaired, 300 mg/day
200 mg single dose
2
↑ 312%
↑ 232%
healthy volunteer, 300 mg/day for
7 days
400 mg single dose
14
↑ 113%
↑ 69%
ganciclovir, 1000 mg q8h,
2 h after didanosine
200 mg q12h
12
↑ 111%
NA
methadone, chronic maintenance
dose
200 mg single dose
16, 10a
↓ 57%
↓ 66%
tenofovir,b 300 mg once daily 1 h
after didanosine
250c or 400 mg once
daily for 7 days
14
↑ 44%
(31, 59%)d
↑ 28%
(11, 48%)d
No Clinically Significant Interaction Observed
Drug
Didanosine Dosage
n
AUC of Didanosine
(95% CI)
CMAX of Didanosine
(95% CI)
ciprofloxacin, 750 mg q12h for 3
days, 2 h before didanosine
200 mg q12h for 3 days
8e
↓ 16%
↓ 28%
indinavir, 800 mg single dose
simultaneous
200 mg single dose
16
↔
↔
1 h before didanosine
200 mg single dose
16
↓ 17% (-27, -7%)d
↓ 13% (-28, 5%)d
ketoconazole, 200 mg/day for 4
days, 2 h before didanosine
375 mg q12h for 4 days
12e
↔
↓12%
loperamide, 4 mg q6h for 1 day
300 mg single dose
12e
↔
↓23%
metoclopramide, 10 mg single dose
300 mg single dose
12e
↔
↑13%
ranitidine, 150 mg single dose, 2 h
before didanosine
375 mg single dose
12e
↑14%
↑13%
rifabutin, 300 or 600 mg/day for 12
days
167 or 250 mg q12h for
12 days
11
↑ 13% (-1, 27%)
↑ 17% (-4, 38%)
ritonavir, 600 mg q12h for 4 days
200 mg q12h for 4 days
12
↓ 13% (0, 23%)
↓ 16% (5, 26%)
stavudine, 40 mg q12h for 4 days
100 mg q12h for 4 days
10
↔
↔
sulfamethoxazole, 1000 mg single
dose
200 mg single dose
8e
↔
↔
trimethoprim, 200 mg single dose
200 mg single dose
8e
↔
↑ 17% (-23, 77%)
zidovudine, 200 mg q8h for 3 days
200 mg q12h for 3 days
6e
↔
↔
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Table 5:
Results of Drug Interaction Studies with Buffered
Formulations of Didanosine: Effects of Coadministered Drug
on Didanosine Plasma AUC and CMAX Values
↑
indicates increase.
↓
indicates decrease.
↔ indicates no change, or mean increase or decrease of <10%.
a
Parallel-group design; entries are subjects receiving combination and control regimens, respectively.
b
tenofovir disoproxil fumarate.
c
patients <60 kg with creatinine clearance ≥60 mL/min.
d
90% Cl.
e
HIV-infected patients.
NA Not available.
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Table 6:
Results of Drug Interaction Studies with Buffered
Formulations of Didanosine: Effects of Didanosine on
Coadministered Drug Plasma AUC and CMAX Values
No Clinically Significant Interaction Observed
Drug
Didanosine Dosage
n
AUC of
Coadministered Drug
(95% CI)
CMAX of
Coadministered Drug
(95% CI)
dapsone, 100 mg single dose
200 mg q12h for 14 days
6a
↔
↔
delavirdine, 400 mg single
dose
simultaneous
1 h before didanosine
125 or 200 mg q12h
125 or 200 mg q12h
12a
12a
↓ 32%b
↑ 20%
↓ 53%b
↑ 18%
ganciclovir, 1000 mg q8h,
2 h after didanosine
200 mg q12h
12a
↓21%
NA
nelfinavir, 750 mg single
dose, 1 h after didanosine
200 mg single dose
10a
↑12%
↔
ranitidine, 150 mg single
dose, 2 h before didanosine
375 mg single dose
12a
↓16%
↔
ritonavir, 600 mg q12h for
4 days
200 mg q12h for 4 days
12
↔
↔
stavudine, 40 mg q12h for
4 days
100 mg q12h for 4 days
10a
↔
↑17%
sulfamethoxazole, 1000 mg
single dose
200 mg single dose
8a
↓ 11% (-17, -4%)
↓ 12% (-28, 8%)
tenofovir,c 300 mg once
daily 1 h after didanosine
250d or 400 mg once daily
for 7 days
14
↔
↔
trimethoprim, 200 mg single
dose
200 mg single dose
8a
↑ 10% (-9, 34%)
↓ 22% (-59, 49%)
zidovudine, 200 mg q8h for
3 days
200 mg q12h for 3 days
6a
↓ 10% (-27, 11%)
↓ 16.5% (-53, 47%)
↑
indicates increase.
↓
indicates decrease.
↔ indicates no change, or mean increase or decrease of <10%.
a
HIV-infected patients.
b
This result is probably related to the buffer and is not expected to occur with VIDEX EC.
c
tenofovir disoproxil fumarate.
d
patients <60 kg with creatinine clearance ≥60 mL/min.
NA Not available.
INDICATIONS AND USAGE
VIDEX EC (didanosine) in combination with other antiretroviral agents is indicated
for the treatment of HIV-1 infection in adults. (See Clinical Studies.)
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Clinical Studies
Study Al454-152 was a 48-week, randomized, open-label study comparing VIDEX EC
(400 mg once daily) plus stavudine (40 mg twice daily) plus nelfinavir (750 mg three times
daily) to zidovudine (300 mg) plus lamivudine (150 mg) combination tablets twice daily
plus nelfinavir (750 mg three times daily) in 511 treatment-naive patients, with a mean
CD4 cell count of 411 cells/mm3 (range 39 to 1105 cells/mm3) and a mean plasma HIV-1
RNA of 4.71 log10 copies/mL (range 2.8 to 5.9 log10 copies/mL) at baseline. Patients were
primarily males (72%) and Caucasian (53%) with a mean age of 35 years (range 18 to 73
years). The percentages of patients with HIV RNA <400 and <50 copies/mL and outcomes
of patients through 48 weeks are summarized in Figure 1 and Table 7, respectively.
Figure 1
Treatment Response Through Week 48*, AI454-152
0
20
40
60
80
100
0
12
24
36
48
Study Week
Percent of Patients
] < 400 c/mL
] < 50 c/mL
VIDEX EC+stavudine+nelfinavir, n=258
zidovudine/lamivudine+nelfinavir, n=253
*Percent of patients at each time point who have HIV RNA <400 or
<50 copies/mL and do not meet any criteria for treatment failure (eg,
virologic failure or discontinuation for any reason).
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Table 7:
Outcomes of Randomized Treatment Through Week 48, AI454-152
Percent of Patients with HIV RNA <400 copies/mL (<50 copies/mL)
VIDEX EC + stavudine +
zidovudine/lamivudinea +
nelfinavir
nelfinavir
Outcome
n=258
n=253
Responderb,c
55% (33%)
56% (33%)
Virologic failured
22% (45%)
21% (43%)
Death or discontinued due to
disease progression
1% (1%)
2% (2%)
Discontinued due to adverse event
6% (6%)
7% (7%)
Discontinued due to other reasonse
16% (16%)
15% (16%)
a Zidovudine/lamivudine combination tablet.
b Corresponds to rates at Week 48 in Figure 1.
c Subjects achieved and maintained confirmed HIV RNA <400 copies/mL (<50 copies/mL) through
Week 48.
d Includes viral rebound at or before Week 48 and failure to achieve confirmed HIV RNA <400 copies/mL
(<50 copies/mL) through Week 48.
e Includes lost to follow-up, subject’s withdrawal, discontinuation due to physician’s decision, never treated,
and other reasons.
CONTRAINDICATION
VIDEX EC (didanosine) is contraindicated in patients with previously demonstrated
clinically significant hypersensitivity to any component of the formulation.
WARNINGS
1. Pancreatitis
FATAL AND NONFATAL PANCREATITIS HAVE OCCURRED DURING
THERAPY WITH DIDANOSINE USED ALONE OR IN COMBINATION
REGIMENS
IN
BOTH
TREATMENT-NAIVE
AND
TREATMENT-
EXPERIENCED
PATIENTS,
REGARDLESS
OF
DEGREE
OF
IMMUNOSUPPRESSION. VIDEX EC SHOULD BE SUSPENDED IN PATIENTS
WITH SIGNS OR SYMPTOMS OF PANCREATITIS AND DISCONTINUED IN
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PATIENTS WITH CONFIRMED PANCREATITIS. PATIENTS TREATED WITH
VIDEX EC IN COMBINATION WITH STAVUDINE, WITH OR WITHOUT
HYDROXYUREA, MAY BE AT INCREASED RISK FOR PANCREATITIS.
When treatment with life-sustaining drugs known to cause pancreatic toxicity is
required, suspension of VIDEX EC therapy is recommended. In patients with risk factors
for pancreatitis, VIDEX EC should be used with extreme caution and only if clearly
indicated. Patients with advanced HIV infection, especially the elderly, are at increased
risk of pancreatitis and should be followed closely. Patients with renal impairment may be
at greater risk for pancreatitis if treated without dose adjustment.
The frequency of pancreatitis is dose related. In phase 3 studies with buffered
formulations of didanosine, incidence ranged from 1% to 10% with doses higher than are
currently recommended and 1% to 7% with recommended dose.
2. Lactic Acidosis/Severe Hepatomegaly with Steatosis
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases,
have been reported with the use of nucleoside analogues alone or in combination,
including didanosine and other antiretrovirals. A majority of these cases have been in
women. Obesity and prolonged nucleoside exposure may be risk factors. Fatal lactic
acidosis has been reported in pregnant women who received the combination of didanosine
and stavudine with other antiretroviral agents. The combination of didanosine and
stavudine should be used with caution during pregnancy and is recommended only if the
potential benefit clearly outweighs the potential risk (see PRECAUTIONS: Pregnancy).
Particular caution should be exercised when administering VIDEX EC to any patient with
known risk factors for liver disease; however, cases have also been reported in patients
with no known risk factors. Treatment with VIDEX EC should be suspended in any
patient who develops clinical or laboratory findings suggestive of symptomatic
hyperlactatemia, lactic acidosis, or pronounced hepatotoxicity (which may include
hepatomegaly and steatosis even in the absence of marked transaminase elevations).
3. Retinal Changes and Optic Neuritis
Retinal changes and optic neuritis have been reported in patients taking didanosine.
Periodic retinal examinations should be considered for patients receiving VIDEX EC. (See
ADVERSE REACTIONS.)
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4. Hepatic Impairment and Toxicity
It is unknown if hepatic impairment significantly affects didanosine pharmaco-
kinetics. Therefore, these patients should be monitored closely for evidence of didanosine
toxicity. The safety and efficacy of VIDEX EC have not been established in HIV-infected
patients with significant underlying liver disease. During combination antiretroviral
therapy, patients with preexisting liver dysfunction, including chronic active hepatitis,
have an increased frequency of liver function abnormalities, including severe and
potentially fatal hepatic adverse events, and should be monitored according to standard
practice. If there is evidence of worsening liver disease in such patients, interruption or
discontinuation of treatment must be considered.
Hepatotoxicity and hepatic failure resulting in death were reported during
postmarketing surveillance in HIV-infected patients treated with hydroxyurea and other
antiretroviral agents. Fatal hepatic events were reported most often in patients treated with
the combination of hydroxyurea, didanosine, and stavudine. This combination should be
avoided.
PRECAUTIONS
Dosing
VIDEX EC should be administered once daily on an empty stomach.
Peripheral Neuropathy
Peripheral neuropathy, manifested by numbness, tingling, or pain in the hands or feet, has
been reported in patients receiving didanosine therapy. Peripheral neuropathy has occurred
more frequently in patients with advanced HIV disease, in patients with a history of
neuropathy, or in patients being treated with neurotoxic drug therapy, including stavudine.
Peripheral neuropathy, which was severe in some cases, has been reported in HIV-infected
patients receiving hydroxyurea in combination with antiretroviral agents, including
didanosine, with or without stavudine (see ADVERSE REACTIONS).
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Fat Redistribution
Redistribution/accumulation of body fat including central obesity, dorsocervical fat
enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and
“cushingoid appearance” have been observed in patients receiving antiretroviral therapy.
The mechanism and long-term consequences of these events are currently unknown. A
causal relationship has not been established.
Immune Reconstitution Syndrome
Immune reconstitution syndrome has been reported in patients treated with combination
antiretroviral therapy, including VIDEX EC. During the initial phase of combination
antiretroviral treatment, patients whose immune system responds may develop an
inflammatory response to indolent or residual opportunistic infections (such as
Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia
[PCP], or tuberculosis), which may necessitate further evaluation and treatment.
General
Patients with Renal Impairment
Patients with renal impairment (creatinine clearance <60 mL/min) may be at greater risk of
toxicity from didanosine due to decreased drug clearance (see CLINICAL
PHARMACOLOGY). A dose reduction is recommended in these patients (see DOSAGE
AND ADMINISTRATION).
Hyperuricemia
Didanosine has been associated with asymptomatic hyperuricemia; treatment suspension
may be necessary if clinical measures aimed at reducing uric acid levels fail.
Information for Patients (See Patient Information Leaflet)
Patients should be informed that a serious toxicity of didanosine, used alone and in
combination regimens, is pancreatitis, which may be fatal.
Patients should also be aware that peripheral neuropathy, manifested by numbness,
tingling, or pain in hands or feet, may develop during therapy with VIDEX EC
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(didanosine). Patients should be counseled that peripheral neuropathy occurs with greatest
frequency in patients with advanced HIV disease or a history of peripheral neuropathy, and
that dose modification and/or discontinuation of VIDEX EC may be required if toxicity
develops.
Patients should be informed that when didanosine is used in combination with other
agents with similar toxicities, the incidence of adverse events may be higher than when
didanosine is used alone. These patients should be followed closely.
Patients should be cautioned about the use of medications or other substances,
including alcohol, that may exacerbate VIDEX EC toxicities.
VIDEX EC is not a cure for HIV infection, and patients may continue to develop
HIV-associated illnesses, including opportunistic infection. Therefore, patients should
remain under the care of a physician when using VIDEX EC. Patients should be advised
that VIDEX EC therapy has not been shown to reduce the risk of transmission of HIV to
others through sexual contact or blood contamination. Patients should be informed that the
long-term effects of VIDEX EC are unknown at this time.
Patients should be informed that redistribution or accumulation of body fat may
occur in patients receiving antiretroviral therapy and that the cause and long-term health
effects of these conditions are not known at this time.
Drug Interactions (see also CLINICAL PHARMACOLOGY: Drug
Interactions)
Drug interactions that have been established based on drug interaction studies are listed
with the pharmacokinetic results in CLINICAL PHARMACOLOGY: Drug
Interactions (Tables 3-6). The clinical recommendations based on the results of these
studies are listed in Table 8.
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Table 8:
Established Drug Interactions Based on Studies with
VIDEX EC or Studies with Buffered Formulations of
Didanosine and Expected to Occur with VIDEX EC
Coadministration Not Recommended Based on Drug Interaction Studies (see CLINICAL
PHARMACOLOGY: Drug Interactions for Magnitude of Interaction)
Drug
Effect
Clinical Comment
allopurinol
↑ didanosine concentration
Coadministration not recommended.
Alteration in Dose or Regimen Recommended Based on Drug Interaction Studies (see CLINICAL
PHARMACOLOGY: Drug Interactions for Magnitude of Interaction)
Drug
Effect
Clinical Comment
ganciclovir
↑ didanosine concentration
Appropriate doses for this combination, with
respect to efficacy and safety, have not been
established.
methadone
↓ didanosine concentration
Appropriate doses for this combination, with
respect to efficacy and safety, have not been
established.
tenofovir disoproxil
fumarate
↑ didanosine concentration
A dose reduction of VIDEX EC to 250 mg
(adults weighing ≥60 kg with creatinine
clearance ≥60 mL/min) or 200 mg (adults
weighing <60 kg with creatinine clearance
≥60 mL/min) once daily taken together with
tenofovir and a light meal (≤400 kcalories and
≤20% fat) or in the fasted state is
recommended. Patients should be monitored
for didanosine-associated toxicities and
clinical response (see below).
↑ indicates increase.
↓ indicates decrease.
Coadministration of VIDEX EC with drugs that are known to cause
pancreatitis may increase the risk of this toxicity (see WARNINGS: Pancreatitis).
Predicted drug interactions with VIDEX EC are listed in Table 9.
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Table 9:
Predicted Drug Interactions with VIDEX EC
Drug or Drug Class
Effect
Clinical Comment
Drugs that may cause
pancreatic toxicity
↑ risk of pancreatitis
Use only with extreme caution.a
Neurotoxic drugs
↑ risk of neuropathy
Use with caution.b
Ribavirin
↑ risk of toxicity
Ribavirin has been shown in vitro to increase
intracellular triphosphate levels of didanosine.
Coadministration is not recommended (see
below).
↑ indicates increase.
a Only if other drugs are not available and if clearly indicated. If treatment with life-sustaining drugs that
cause pancreatic toxicity is required, suspension of VIDEX EC is recommended (see WARNINGS:
Pancreatitis).
b See PRECAUTIONS: Peripheral Neuropathy.
Nucleoside/nucleotide analogues
Tenofovir disoproxil fumarate. Exposure to didanosine is increased when coadministered
with tenofovir (see Tables 3, 5, and 8). Increased exposure may cause or worsen
didanosine-related
clinical
toxicities,
including
pancreatitis,
symptomatic
hyperlactatemia/lactic acidosis, and peripheral neuropathy. Coadministration of
tenofovir with VIDEX EC should be undertaken with caution, and patients should be
monitored closely for didanosine-related toxicities and clinical response. VIDEX EC
should be suspended if signs or symptoms of pancreatitis, symptomatic
hyperlactatemia, or lactic acidosis develop (see WARNINGS). Administration of
reduced doses of VIDEX EC with tenofovir and a light meal resulted in didanosine
exposures (AUC) similar to the recommended doses of VIDEX EC given alone in the
fasted state (see Table 3). Therefore, when administered with tenofovir, a dose reduction
of VIDEX EC to 250 mg (adults weighing ≥60 kg with creatinine clearance ≥60 mL/min)
or 200 mg (adults weighing <60 kg with creatinine clearance ≥60 mL/min) once daily is
recommended, and both drugs may be taken together with a light meal (≤400 kcalories,
≤20% fat) or in the fasted state (see DOSAGE AND ADMINISTRATION).
Coadministration of didanosine with food decreases didanosine concentrations. Thus,
although not studied, it is possible that coadministration with heavier meals could reduce
didanosine concentrations further.
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Page 61 of 75
Ribavirin. Exposure to the active metabolite of didanosine (dideoxyadenosine 5'-
triphosphate) is increased when didanosine is coadministered with ribavirin (see Table 9).
Fatal hepatic failure, as well as peripheral neuropathy, pancreatitis, and symptomatic
hyperlactatemia/lactic acidosis have been reported in patients receiving both didanosine
and ribavirin. Coadministration of didanosine and ribavirin is not recommended.
Carcinogenesis and Mutagenesis
Lifetime carcinogenicity studies were conducted in mice and rats for 22 and 24 months,
respectively. In the mouse study, initial doses of 120, 800, and 1200 mg/kg/day for each
sex were lowered after 8 months to 120, 210, and 210 mg/kg/day for females and 120, 300,
and 600 mg/kg/day for males. The two higher doses exceeded the maximally tolerated
dose in females and the high dose exceeded the maximally tolerated dose in males. The
low dose in females represented 0.68-fold maximum human exposure and the intermediate
dose in males represented 1.7-fold maximum human exposure based on relative AUC
comparisons. In the rat study, initial doses were 100, 250, and 1000 mg/kg/day, and the
high dose was lowered to 500 mg/kg/day after 18 months. The upper dose in male and
female rats represented 3-fold maximum human exposure.
Didanosine induced no significant increase in neoplastic lesions in mice or rats at
maximally tolerated doses.
Didanosine was positive in the following genetic toxicology assays: 1) the
Escherichia coli tester strain WP2 uvrA bacterial mutagenicity assay; 2) the
L5178Y/TK+/- mouse lymphoma mammalian cell gene mutation assay; 3) the in vitro
chromosomal aberrations assay in cultured human peripheral lymphocytes; 4) the in vitro
chromosomal aberrations assay in Chinese Hamster Lung cells; and 5) the BALB/c 3T3 in
vitro transformation assay. No evidence of mutagenicity was observed in an Ames
Salmonella bacterial mutagenicity assay or in rat and mouse in vivo micronucleus assays.
Pregnancy, Reproduction, and Fertility
Pregnancy Category B. Reproduction studies have been performed in rats and rabbits at
doses up to 12 and 14.2 times the estimated human exposure (based upon plasma levels),
respectively, and have revealed no evidence of impaired fertility or harm to the fetus due to
didanosine. At approximately 12 times the estimated human exposure, didanosine was
slightly toxic to female rats and their pups during mid and late lactation. These rats showed
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Page 62 of 75
reduced food intake and body weight gains but the physical and functional development of
the offspring was not impaired and there were no major changes in the F2 generation. A
study in rats showed that didanosine and/or its metabolites are transferred to the fetus
through the placenta. Animal reproduction studies are not always predictive of human
response.
There are no adequate and well-controlled studies of didanosine in pregnant
women. Didanosine should be used during pregnancy only if the potential benefit justifies
the potential risk.
Fatal lactic acidosis has been reported in pregnant women who received the
combination of didanosine and stavudine with other antiretroviral agents. It is unclear if
pregnancy augments the risk of lactic acidosis/hepatic steatosis syndrome reported in
nonpregnant individuals receiving nucleoside analogues (see WARNINGS: Lactic
Acidosis/Severe Hepatomegaly with Steatosis). The combination of didanosine and
stavudine should be used with caution during pregnancy and is recommended only if
the potential benefit clearly outweighs the potential risk. Health care providers caring
for HIV-infected pregnant women receiving didanosine should be alert for early diagnosis
of lactic acidosis/hepatic steatosis syndrome.
Antiretroviral Pregnancy Registry: To monitor maternal-fetal outcomes of
pregnant women exposed to didanosine and other antiretroviral agents, an Antiretroviral
Pregnancy Registry has been established. Physicians are encouraged to register patients by
calling 1-800-258-4263.
Nursing Mothers
The Centers for Disease Control and Prevention recommend that HIV-infected
mothers not breast-feed their infants to avoid risking postnatal transmission of HIV.
A study in rats showed that following oral administration, didanosine and/or its
metabolites were excreted into the milk of lactating rats. It is not known if didanosine is
excreted in human milk. Because of both the potential for HIV transmission and the
potential for serious adverse reactions in nursing infants, mothers should be instructed
not to breast-feed if they are receiving VIDEX EC (didanosine).
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Pediatric Use
The safety and efficacy of VIDEX EC in pediatric patients have not been established.
Please consult the complete prescribing information for VIDEX (didanosine)
Chewable/Dispersible Buffered Tablets and Pediatric Powder for Oral Solution for dosage
and administration of didanosine to pediatric patients.
Geriatric Use
In an Expanded Access Program using a buffered formulation of didanosine for the
treatment of advanced HIV infection, patients aged 65 years and older had a higher
frequency of pancreatitis (10%) than younger patients (5%) (see WARNINGS). Clinical
studies of didanosine, including those for VIDEX EC, did not include sufficient numbers
of subjects aged 65 years and over to determine whether they respond differently than
younger subjects. Didanosine is known to be substantially excreted by the kidney, and the
risk of toxic reactions to this drug may be greater in patients with impaired renal function.
Because elderly patients are more likely to have decreased renal function, care should be
taken in dose selection. In addition, renal function should be monitored and dosage
adjustments should be made accordingly (see DOSAGE AND ADMINISTRATION:
Dose Adjustment).
ADVERSE REACTIONS
A SERIOUS TOXICITY OF DIDANOSINE IS PANCREATITIS, WHICH MAY BE
FATAL (see WARNINGS). OTHER IMPORTANT TOXICITIES INCLUDE LACTIC
ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS; RETINAL CHANGES
AND OPTIC NEURITIS; AND PERIPHERAL NEUROPATHY (see WARNINGS and
PRECAUTIONS).
When didanosine is used in combination with other agents with similar
toxicities, the incidence of these toxicities may be higher than when didanosine is used
alone. Thus, patients treated with VIDEX EC in combination with stavudine, with or
without hydroxyurea, may be at increased risk for pancreatitis and hepatotoxicity,
which may be fatal, and severe peripheral neuropathy (see WARNINGS and
PRECAUTIONS).
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Selected clinical adverse events that occurred in a study of VIDEX EC in
combination with other antiretroviral agents are provided in Table 10.
Table 10:
Selected Clinical Adverse Events, Study AI454-152a
Percent of Patientsb
VIDEX EC +
stavudine +
nelfinavir
zidovudine/
lamivudinec +
nelfinavir
Adverse Events
n=258
n=253
Diarrhea
57
58
Peripheral Neurologic
Symptoms/Neuropathy
25
11
Nausea
24
36
Headache
22
17
Rash
14
12
Vomiting
14
19
Pancreatitis (see below)
<1
*
a Median duration of treatment was 62 weeks in the VIDEX EC + stavudine + nelfinavir group and
61 weeks in the zidovudine/lamivudine + nelfinavir group.
b Percentages based on treated patients.
c Zidovudine/lamivudine combination tablet.
* This event was not observed in this study arm.
In clinical trials using a buffered formulation of didanosine, pancreatitis
resulting in death was observed in one patient who received didanosine plus
stavudine plus nelfinavir, one patient who received didanosine plus stavudine plus
indinavir, and 2 of 68 patients who received didanosine plus stavudine plus indinavir
plus hydroxyurea. In an early access program, pancreatitis resulting in death was
observed in one patient who received VIDEX EC plus stavudine plus hydroxyurea
plus ritonavir plus indinavir plus efavirenz (see WARNINGS).
The frequency of pancreatitis is dose related. In phase 3 studies with buffered
formulations of didanosine, incidence ranged from 1% to 10% with doses higher than are
currently recommended and 1% to 7% with recommended dose.
Selected laboratory abnormalities that occurred in a study of VIDEX EC in
combination with other antiretroviral agents are shown in Table 11.
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Page 65 of 75
Table 11:
Selected Laboratory Abnormalities, Study AI454-152a
Percent of Patientsb
VIDEX EC + stavudine
+ nelfinavir
n=258
zidovudine/lamivudinec
+ nelfinavir
n=253
Parameter
Grades 3-4d
All Grades
Grades 3-4d
All Grades
SGOT (AST)
5
46
5
19
SGPT (ALT)
6
44
5
22
Lipase
5
23
2
13
Bilirubin
<1
9
<1
3
a Median duration of treatment was 62 weeks in the VIDEX EC + stavudine + nelfinavir group
and 61 weeks in the zidovudine/lamivudine + nelfinavir group.
b Percentages based on treated patients.
c Zidovudine/lamivudine combination tablet.
d >5 x ULN for SGOT and SGPT, ≥2.1 x ULN for lipase, and ≥2.6 x ULN for bilirubin (ULN =
upper limit of normal).
Observed During Clinical Practice
The following events have been identified during postapproval use of didanosine buffered
formulations. Because they are reported voluntarily from a population of unknown size,
estimates of frequency cannot be made. These events have been chosen for inclusion due
to their seriousness, frequency of reporting, causal connection to didanosine, or a
combination of these factors.
Body as a Whole – abdominal pain, alopecia, anaphylactoid reaction, asthenia,
chills/fever,
pain,
and
redistribution/accumulation
of
body
fat
(see
PRECAUTIONS: Fat Redistribution).
Digestive Disorders – anorexia, dyspepsia, and flatulence.
Exocrine Gland Disorders – pancreatitis (including fatal cases) (see
WARNINGS), sialoadenitis, parotid gland enlargement, dry mouth, and dry eyes.
Hematologic Disorders – anemia, leukopenia, and thrombocytopenia.
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Liver – symptomatic hyperlactatemia/lactic acidosis and hepatic steatosis (see
WARNINGS); hepatitis and liver failure.
Metabolic Disorders – diabetes mellitus, elevated serum alkaline phosphatase
level, elevated serum amylase level, elevated serum gamma-glutamyltransferase
level, elevated serum uric acid level, hypoglycemia, and hyperglycemia.
Musculoskeletal Disorders – myalgia (with or without increases in creatine kinase),
rhabdomyolysis including acute renal failure and hemodialysis, arthralgia, and
myopathy.
Ophthalmologic Disorders – Retinal depigmentation and optic neuritis (see
WARNINGS).
OVERDOSAGE
There is no known antidote for didanosine overdosage. In phase 1 studies, in which
buffered formulations of didanosine were initially administered at doses ten times the
currently recommended dose, toxicities included: pancreatitis, peripheral neuropathy,
diarrhea, hyperuricemia, and hepatic dysfunction. Didanosine is not dialyzable by
peritoneal dialysis, although there is some clearance by hemodialysis (see CLINICAL
PHARMACOLOGY: Pharmacokinetics).
DOSAGE AND ADMINISTRATION
Dosage
Adults
VIDEX EC (didanosine) should be administered on an empty stomach.
VIDEX EC Delayed-Release Capsules should be swallowed intact.
The recommended daily dose is dependent on body weight and is administered as
one capsule given on a once-daily schedule as outlined in Table 12.
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Table 12:
Dosing of VIDEX EC Delayed-Release Capsules
Patient Weight
Dosage
≥60 kg
400 mg once daily
<60 kg
250 mg once daily
Pediatric Patients
VIDEX EC has not been studied in pediatric patients. Please consult the complete
prescribing information for VIDEX (didanosine) Chewable/Dispersible Buffered Tablets
and Pediatric Powder for Oral Solution for dosage and administration of didanosine to
pediatric patients.
Dose Adjustment
Clinical and laboratory signs suggestive of pancreatitis should prompt dose
suspension and careful evaluation of the possibility of pancreatitis. VIDEX EC use
should be discontinued in patients with confirmed pancreatitis (see WARNINGS and
PRECAUTIONS: Drug Interactions).
Based on data with buffered didanosine formulations, patients with symptoms of
peripheral neuropathy may tolerate a reduced dose of VIDEX EC after resolution of the
symptoms of peripheral neuropathy upon drug interruption. If neuropathy recurs after
resumption of VIDEX EC, permanent discontinuation of VIDEX EC should be considered.
Concomitant Therapy
Tenofovir disoproxil fumarate. A dose reduction of VIDEX EC to 250 mg (adults
weighing ≥60 kg with creatinine clearance ≥60 mL/min) or 200 mg (adults weighing <60
kg with creatinine clearance ≥60 mL/min) once daily taken together with tenofovir and a
light meal (≤400 kcalories, ≤20% fat) or in the fasted state is recommended. The
appropriate dose of VIDEX EC coadministered with tenofovir in patients with
creatinine clearance <60 mL/min has not been established. (See CLINICAL
PHARMACOLOGY: Drug Interactions and PRECAUTIONS: Drug Interactions.)
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Renal Impairment
Dosing recommendations for VIDEX EC and VIDEX buffered formulations are different
for patients with renal impairment. Please consult the complete prescribing information on
administration of VIDEX (didanosine) buffered formulations to patients with renal
impairment.
In adult patients with impaired renal function, the dose of VIDEX EC should be
adjusted to compensate for the slower rate of elimination. The recommended doses and
dosing intervals of VIDEX EC in adult patients with renal insufficiency are presented in
Table 13.
Table 13:
Recommended Dosage of VIDEX EC in Renal
Impairment by Body Weighta
Dosage
Creatinine
Clearance
(mL/min)
≥60 kg
<60 kg
≥60
400 once daily
250 once daily
30-59
200 once daily
125 once daily
10-29
125 once daily
125 once daily
<10
125 once daily
b
a Based on studies using a buffered formulation of didanosine.
b Not suitable for use in patients <60 kg with CLcr <10 mL/min. An alternate formulation of
didanosine should be used.
Patients Requiring Continuous Ambulatory Peritoneal Dialysis (CAPD) or
Hemodialysis
For patients requiring CAPD or hemodialysis, follow dosing recommendations for patients
with creatinine clearance less than 10 mL/min, shown in Table 13. It is not necessary to
administer a supplemental dose of didanosine following hemodialysis.
Hepatic Impairment and Toxicity: See WARNINGS.
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HOW SUPPLIED
VIDEX® EC (didanosine) Delayed-Release Capsules are white, opaque capsules that are
packaged in bottles with child-resistant closures as described in Table 14.
Table 14:
VIDEX EC Delayed-Release Capsules
125 mg capsule imprinted with BMS 125 mg 6671 in Tan
NDC No. 0087-6671-17
30 capsules/bottle
200 mg capsule imprinted with BMS 200 mg 6672 in Green
NDC No. 0087-6672-17
30 capsules/bottle
250 mg capsule imprinted with BMS 250 mg 6673 in Blue
NDC No. 0087-6673-17
30 capsules/bottle
400 mg capsule imprinted with BMS 400 mg 6674 in Red
NDC No. 0087-6674-17
30 capsules/bottle
The capsules should be stored in tightly closed containers at 25° C (77° F).
Excursions between 15° and 30° C (59° and 86° F) are permitted [see USP Controlled
Room Temperature].
HANDLING AND DISPOSAL
Disposal options include incineration, landfill, or sewer as dictated by specific
circumstances and relevant national, state, and local regulations.
US Patent Nos: 4,861,759, 5,254,539, 5,616,566, and 5,880,106 (didanosine).
Patent also Pending (didanosine capsules).
Bristol-Myers Squibb Virology
Bristol-Myers Squibb Company
Princeton, NJ 08543 USA
1196180A2
Revised July 2006
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PATIENT INFORMATION
Rx only
VIDEX® EC
(generic name = didanosine also known as ddI)
VIDEX® EC (didanosine) Delayed-Release Capsules
Enteric-Coated Beadlets
What is VIDEX EC?
VIDEX EC (pronounced VY dex ee see) is a prescription medicine used in combination
with other drugs to treat adults who are infected with HIV (the human immunodeficiency
virus, the virus that causes AIDS). VIDEX EC belongs to a class of drugs called
nucleoside analogues. By reducing the growth of HIV, VIDEX EC helps your body
maintain its supply of CD4 cells, which are important for fighting HIV and other
infections.
VIDEX EC will not cure your HIV infection. At present there is no cure for HIV
infection. Even while taking VIDEX EC, you may continue to have HIV-related illnesses,
including infections with other disease-producing organisms. Continue to see your doctor
regularly and report any medical problems that occur.
VIDEX EC does not prevent a patient infected with HIV from passing the virus to
other people. To protect others, you must continue to practice safe sex and take precautions
to prevent others from coming in contact with your blood and other body fluids.
There is limited information on the antiviral response of long-term use of
VIDEX EC.
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In VIDEX EC, an enteric coating is used to protect the medicine while it is in your
stomach since stomach acids can break it down. The enteric coating dissolves when the
medicine reaches your small intestine.
Who should not take VIDEX EC?
Do not take VIDEX EC if you are allergic to any of its ingredients, including its active
ingredient, didanosine, and the inactive ingredients. (See Inactive Ingredients at the end
of this leaflet.) Tell your doctor if you think you have had an allergic reaction to any of
these ingredients.
Because it has only been studied in adults, VIDEX EC is not recommended for
children.
How should I take VIDEX EC?
How should I store it?
VIDEX EC should only be taken once daily. Your doctor will determine your dose based
on your body weight, kidney and liver function, other medicines you are taking, and any
side effects that you may have had with VIDEX EC or other medicines. Take VIDEX EC
on an empty stomach. Do not take VIDEX EC with food. Swallow the capsule whole;
do not open it. Try not to miss a dose, but if you do, take it as soon as possible. If it is
almost time for the next dose, skip the missed dose and continue your regular dosing
schedule.
Store capsules in a tightly closed container at room temperature away from heat
and out of the reach of children and pets.
If you have kidney disease: If your kidneys are not working properly, your doctor will
need to do regular tests to check how they are working while you take VIDEX EC. Your
doctor may also lower your dosage of VIDEX EC.
What should I do if someone takes an overdose of VIDEX EC?
If someone may have taken an overdose of VIDEX EC, get medical help right away.
Contact their doctor or a poison control center.
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What should I avoid while taking VIDEX EC?
Alcohol. Do not drink alcohol while taking VIDEX EC since alcohol may increase your
risk of pancreatitis (pain and inflammation of the pancreas) or liver damage.
Other medicines. Other medicines, including those you can buy without a prescription,
may interfere with the actions of VIDEX EC or may increase the possibility or severity of
side effects. Do not take any medicine, vitamin supplement, or other health
preparation without first checking with your doctor.
Pregnancy. It is not known if VIDEX EC can harm a human fetus. Also, pregnant women
have experienced serious side effects when taking didanosine (the active ingredient in
VIDEX EC) in combination with ZERIT (stavudine), also known as d4T, and other HIV
medicines. VIDEX EC should be used during pregnancy only after discussion with your
doctor. Tell your doctor if you become pregnant or plan to become pregnant while
taking VIDEX EC.
Nursing. Studies have shown didanosine (the active ingredient in VIDEX EC) is in the
breast milk of animals getting the drug. It may also be in human breast milk. The Centers
for Disease Control and Prevention (CDC) recommends that HIV-infected mothers not
breast-feed. This should reduce the risk of passing HIV infection to their babies and the
potential for serious adverse reactions in nursing infants. Therefore, do not nurse a baby
while taking VIDEX EC.
What are the possible side effects of VIDEX EC?
Pancreatitis. Pancreatitis is a dangerous inflammation of the pancreas that may cause
death. Tell your doctor right away if you develop stomach pain, nausea, or vomiting.
These can be signs of pancreatitis. Before starting VIDEX EC therapy, let your doctor
know if you have ever had pancreatitis. This condition is more likely to happen in people who
have had it before. It is also more likely in people with advanced HIV disease. However, it can
occur at any stage of HIV disease. It may be more common in patients with kidney problems,
those who drink alcohol, and those who are also treated with stavudine or hydroxyurea. If you
get pancreatitis, your doctor will tell you to stop taking VIDEX EC.
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Lactic acidosis, severe liver enlargement, and liver failure, including deaths, have been
reported among patients taking VIDEX EC (including pregnant women). Symptoms that
may indicate a liver problem are:
•
feeling very weak, tired, or uncomfortable,
•
unusual or unexpected stomach discomfort,
•
feeling cold,
•
feeling dizzy or lightheaded,
•
suddenly developing a slow or irregular heartbeat.
Lactic acidosis is a medical emergency that must be treated in a hospital.
If you notice any of these symptoms or if your medical condition changes, stop
taking VIDEX EC and call your doctor right away. Women, overweight patients, and
those who have been treated for a long time with other medicines used to treat HIV
infection are more likely to develop lactic acidosis. Your doctor should check your liver
function periodically while you are taking VIDEX EC. You should be especially careful if
you have a history of heavy alcohol use or a liver problem.
Vision changes. VIDEX EC may affect the nerves in your eyes. Because of this, you
should have regular eye examinations. You should also report any changes in vision to
your doctor right away. This includes, for example, seeing colors abnormally or blurred
vision.
Peripheral neuropathy. This is a problem with the nerves in your hands or feet. The
nerve problem may be serious. Tell your doctor right away if you have continuing
numbness, tingling, or pain in the feet or hands.
Before starting VIDEX EC therapy, let your doctor know if you have ever had
peripheral neuropathy. This condition is more likely to happen in people who have had it
before. It is also more likely in patients taking medicines that affect the nerves and in
people with advanced HIV disease. However, it can occur at any stage of HIV disease. If
you get peripheral neuropathy, your doctor will tell you to stop taking VIDEX EC. After
stopping VIDEX EC, the symptoms may get worse for a short time and then get better.
Once symptoms of peripheral neuropathy go away completely, you and your doctor should
decide if starting VIDEX EC is right for you. If so, you might be started at a lower dose.
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Special note about other medicines. If you take VIDEX EC along with other medicines
with similar side effects, you may increase the chance of having these side effects. For
example, using VIDEX EC in combination with other medicines that may cause
pancreatitis, peripheral neuropathy, or liver problems (including stavudine and
hydroxyurea) may increase your chance of having these side effects.
Other side effects: The most common side effects in adults taking VIDEX EC in
combination with other HIV drugs included diarrhea, nausea, headache, vomiting, and
rash.
Changes in body fat have been seen in some patients taking antiretroviral therapy.
These changes may include increased amount of fat in the upper back and neck (“buffalo
hump”), breast, and around the trunk. Loss of fat from the legs, arms, and face may also
happen. The cause and long-term health effects of these conditions are not known at this
time.
Inactive Ingredients:
Carboxymethylcellulose sodium 12, diethyl phthalate, methacrylic acid copolymer, sodium
hydroxide, sodium starch glycolate, talc, colloidal silicon dioxide, gelatin, sodium lauryl
sulfate, and titanium dioxide.
This medicine was prescribed for your particular condition. Do not use VIDEX EC for another condition or
give it to others. Keep VIDEX EC and all medicines out of the reach of children. Throw away VIDEX EC
when it is outdated or no longer needed by flushing it down the toilet or pouring it down the sink.
This summary does not include everything there is to know about VIDEX EC. Medicines are sometimes
prescribed for purposes other than those listed in a Patient Information Leaflet. If you have questions or concerns, or
want more information about VIDEX EC, your physician and pharmacist have the complete prescribing information
upon which this leaflet is based. You may want to read it and discuss it with your doctor or other healthcare
professional. Remember, no written summary can replace careful discussion with your doctor.
Bristol-Myers Squibb Virology
Bristol-Myers Squibb Company
Princeton, NJ 08543 USA
This Patient Information Leaflet has been approved by the U.S. Food and Drug Administration.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-154/S-049
NDA 20-155/S-038
NDA 20-156/S-039
NDA 21-183/S-015
Page 75 of 75
1196180A2
Revised July 2006
Based on package insert dated July 2006
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
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|
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|
12,280
|
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use VIDEX
safely and effectively. See full prescribing information for VIDEX.
VIDEX (didanosine, USP) Pediatric Powder for Oral Solution
Initial U.S. Approval: 1991
WARNING: PANCREATITIS, LACTIC ACIDOSIS and
HEPATOMEGALY with STEATOSIS
See full prescribing information for complete boxed warning.
•
Fatal and nonfatal pancreatitis. VIDEX should be suspended in
patients with suspected pancreatitis and discontinued in patients
with confirmed pancreatitis. (5.1)
•
Lactic acidosis and severe hepatomegaly with steatosis, including
fatal cases. Fatal lactic acidosis has been reported in pregnant
women who received the combination of didanosine and
stavudine. (5.2)
---------------------------RECENT MAJOR CHANGES---------------------------
Dosage and Administration
Dosage Adjustment (2.3)
06/2009
Contraindications
Allopurinol (4.1)
06/2009
Ribavirin (4.2)
06/2009
---------------------------INDICATIONS AND USAGE----------------------------
VIDEX (didanosine, USP) is a nucleoside reverse transcriptase inhibitor for
use in combination with other antiretroviral agents for the treatment of human
immunodeficiency virus (HIV)-1 infection. (1)
------------------------DOSAGE AND ADMINISTRATION----------------------
•
Adult patients: Administered on an empty stomach at least 30 minutes
before or 2 hours after eating. Dosing is based on body weight. (2.1)
at least 60 kg
less than 60 kg
Preferred dosing
200 mg twice daily
125 mg twice daily
Dosing for patients whose
management requires once-
daily frequency
400 mg once daily
250 mg once daily
•
Pediatric patients (2 weeks old to 18 years old): Administered on an
empty stomach at least 30 minutes before or 2 hours after eating.
−
Between 2 weeks and 8 months old, dosing is 100 mg/m2 twice
daily.
−
For those greater than 8 months old, dosing is 120 mg/m2 twice
daily but not to exceed the adult dosing recommendation. (2.1)
•
Renal impairment: Dose reduction is recommended. (2.2)
•
Coadministration with tenofovir: Dose reduction is recommended.
Patients should be monitored closely for didanosine-associated adverse
reactions. (2.3, 7.1)
----------------------DOSAGE FORMS AND STRENGTHS---------------------
•
4-ounce glass bottle containing 2 g of VIDEX (3)
•
8-ounce glass bottle containing 4 g of VIDEX (3)
------------------------------CONTRAINDICATIONS-------------------------------
Coadministration with allopurinol or ribavirin is contraindicated. (4.1 and
4.2)
------------------------WARNINGS AND PRECAUTIONS-----------------------
•
Pancreatitis: Suspension or discontinuation of didanosine may be
necessary. (5.1)
•
Lactic acidosis and severe hepatomegaly with steatosis: Suspend
didanosine in patients who develop clinical symptoms or signs with or
without laboratory findings. (5.2)
•
Hepatic toxicity: Interruption or discontinuation of didanosine must be
considered upon worsening of liver disease. (5.3)
•
Patients may develop peripheral neuropathy (5.4), retinal changes and
optic neuritis (5.5), immune reconstitution syndrome (5.6), and
redistribution/accumulation of body fat (5.7).
-------------------------------ADVERSE REACTIONS------------------------------
•
In adults, the most common adverse reactions (greater than 10%, all
grades) are diarrhea, peripheral neurologic symptoms/neuropathy,
abdominal pain, nausea, headache, rash, and vomiting. (6.1)
•
Adverse reactions in pediatric patients were consistent with those in
adults. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers
Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch
--------------------------------DRUG INTERACTIONS-----------------------------
Coadministration of VIDEX can alter the concentration of other drugs and
other drugs may alter the concentration of didanosine. The potential drug-drug
interactions must be considered prior to and during therapy. (4, 7, 12.3)
------------------------USE IN SPECIFIC POPULATIONS-----------------------
Pregnancy: Fatal lactic acidosis has been reported in pregnant women who
received both didanosine and stavudine with other agents. This combination
should be used with caution during pregnancy and only if the potential benefit
clearly outweighs the potential risk. (5.2, 8.1) Physicians are encouraged to
register patients in the Antiretroviral Pregnancy Registry by calling
1-800-258-4263.
See 17 for PATIENT COUNSELING INFORMATION and FDA-
approved patient labeling
Revised: 06/2009
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: PANCREATITIS, LACTIC ACIDOSIS AND
HEPATOMEGALY WITH STEATOSIS
1
INDICATIONS AND USAGE
2
DOSAGE AND ADMINISTRATION
2.1
Recommended Dosage (Adult and Pediatric Patients)
2.2
Renal Impairment
2.3
Dosage Adjustment
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICA IONS
T
4.1
Allopurinol
4.2
Ribavirin
5
WARNINGS AND PRECAUTIONS
5.1
Pancreatitis
5.2
Lactic Acidosis/Severe Hepatomegaly with Steatosis
5.3
Hepatic Toxicity
5.4
Peripheral Neuropathy
5.5
Retinal Changes and Optic Neuritis
5.6
Immune Reconstitution Syndrome
5.7
Fat Redistribution
6
ADVERSE REACTIONS
6.1
Clinical Trials Experience
6.2
Postmarketing Experience
7
DRUG INTERACTIONS
7.1
Established Drug Interactions
7.2
Predicted Drug Interactions
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
8.3
Nursing Mothers
8.4
Pediatric Use
8.5
Geriatric Use
8.6
Renal Impairment
10
OVERDOSAGE
11
DESCRIPTION
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
12.3
Pharmacokinetics
12.4
Microbiology
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
13.2
Animal Toxicology and/or Pharmacology
14
CLINICAL STUDIES
14.1
Adult Patients
14.2
Pediatric Patients
16
HOW SUPPLIED/STORAGE AND HANDLING
17
PATIENT COUNSELING INFORMATION
17.1
Pancreatitis
17.2
Peripheral Neuropathy
17.3
Lactic Acidosis and Severe Hepatomegaly with Steatosis
17.4
Hepatic Toxicity
17.5
Retinal Changes and Optic Neuritis
17.6
Fat Redistribution
17.7
Concomitant Therapy
17.8
General Information
17.9
FDA-Approved Patient Labeling
*Sections or subsections omitted from the full prescribing
information are not listed
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
FULL PRESCRIBING INFORMATION
WARNING: PANCREATITIS, LACTIC ACIDOSIS and
HEPATOMEGALY with STEATOSIS
Fatal and nonfatal pancreatitis has occurred during therapy with VIDEX used
alone or in combination regimens in both treatment-naive and treatment-
experienced patients, regardless of degree of immunosuppression. VIDEX should be
suspended in patients with suspected pancreatitis and discontinued in patients with
confirmed pancreatitis [see Warnings and Precautions (5.1)].
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have
been reported with the use of nucleoside analogues alone or in combination,
including didanosine and other antiretrovirals. Fatal lactic acidosis has been
reported in pregnant women who received the combination of didanosine and
stavudine with other antiretroviral agents. The combination of didanosine and
stavudine should be used with caution during pregnancy and is recommended only
if the potential benefit clearly outweighs the potential risk [see Warnings and
Precautions (5.2)].
2
1
INDICATIONS AND USAGE
3
VIDEX® (didanosine, USP), also known as ddI, in combination with other antiretroviral
4
agents is indicated for the treatment of human immunodeficiency virus (HIV)-1 infection
5
[see Clinical Studies (14)].
6
2
DOSAGE AND ADMINISTRATION
7
VIDEX should be administered on an empty stomach, at least 30 minutes before or
8
2 hours after eating.
9
2.1
Recommended Dosage (Adult and Pediatric Patients)
10
The preferred dosing frequency of VIDEX is twice daily because there is more evidence
11
to support the effectiveness of this dosing regimen. Once-daily dosing should be
12
considered only for patients whose management requires once-daily dosing of VIDEX
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
13
[see Clinical Studies (14)]. The recommended adult total daily dose is based on body
14
weight (kg) (see Table 1).
Table 1:
Recommended Dosage (Adult)
Preferred dosing
Dosing for patients whose management
requires once-daily frequency
at least 60 kg
200 mg twice daily
400 mg once daily
less than 60 kg
125 mg twice daily
250 mg once daily
15
16
17
18
Pediatric Patients (2 weeks old to 18 years old): The recommended dose of VIDEX
(didanosine) in pediatric patients between 2 weeks old and 8 months old is 100 mg/m2
twice daily, and the recommended VIDEX dose for pediatric patients greater than 8
months old is 120 mg/m2 twice daily but not to exceed the adult dosing recommendation.
19
20
21
Dosing recommendations in patients less than 2 weeks of age cannot be made because the
pharmacokinetics of didanosine in these children are too variable to determine an
appropriate dose. There are no data on once-daily dosing of VIDEX in pediatric patients.
22
2.2
Renal Impairment
23
Adult Patients
24
25
26
In adult patients with impaired renal function, the dose of VIDEX should be adjusted to
compensate for the slower rate of elimination. The recommended doses and dosing
intervals of VIDEX in adult patients with renal insufficiency are presented in Table 2.
Table 2:
Recommended Dosage in Patients with Renal Impairment
Creatinine Clearance
(mL/min)
at least 60
30-59
10-29
less than 10
Recommended VIDEX Dose by Patient Weight
at least 60 kg
less than 60 kg
200 mg twice dailya
125 mg twice dailya
200 mg once daily
or 100 mg twice daily
150 mg once daily
or 75 mg twice daily
150 mg once daily
100 mg once daily
100 mg once daily
75 mg once daily
a 400 mg once daily (at least 60 kg) or 250 mg once daily (less than 60 kg) for patients whose
management requires once-daily frequency of administration.
4
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
27
Pediatric Patients
28
Urinary excretion is also a major route of elimination of didanosine in pediatric patients;
29
therefore, the clearance of didanosine may be altered in pediatric patients with renal
30
impairment. Although there are insufficient data to recommend a specific dose
31
adjustment of VIDEX in this patient population, a reduction in the dose should be
32
considered (see Table 2).
33
Patients Requiring Continuous Ambulatory Peritoneal Dialysis (CAPD) or
34
Hemodialysis
35
For patients requiring CAPD or hemodialysis, follow dosing recommendations for
36
patients with creatinine clearance of less than 10 mL/min, shown in Table 2. It is not
37
necessary to administer a supplemental dose of VIDEX following hemodialysis.
38
2.3
Dosage Adjustment
39
Concomitant Therapy with Tenofovir Disoproxil Fumarate
40
In patients who are also taking tenofovir disoproxil fumarate, a dose reduction of VIDEX
41
to 250 mg (adults weighing at least 60 kg with creatinine clearance of at least
42
60 mL/min) or 200 mg (adults weighing less than 60 kg with creatinine clearance of at
43
least 60 mL/min) once daily is recommended. VIDEX and tenofovir disoproxil fumarate
44
may be taken together in the fasted state. Alternatively, if tenofovir disoproxil fumarate is
45
taken with food, VIDEX should be taken on an empty stomach (at least 30 minutes
46
before food or 2 hours after food). The appropriate dose of VIDEX coadministered with
47
tenofovir disoproxil fumarate in patients with creatinine clearance of less than 60 mL/min
48
has not been established. ([See Drug Interactions (7) and Clinical Pharmacology (12.3)];
49
see the complete prescribing information for VIDEX EC (enteric-coated formulation of
50
didanosine) for results of drug interaction studies of tenofovir disoproxil fumarate with
51
reduced doses of the enteric-coated formulation of didanosine.)
52
Hepatic Impairment
53
No dose adjustment is required in patients with hepatic impairment [see Warnings and
54
Precautions (5.3) and Clinical Pharmacology (12.3)].
5
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
55
3
DOSAGE FORMS AND STRENGTHS
56
VIDEX (didanosine, USP) Pediatric Powder for Oral Solution is supplied in 4- and
57
8-ounce glass bottles containing 2 g or 4 g of VIDEX, respectively.
58
4
CONTRAINDICATIONS
59
These recommendations are based on either drug interaction studies or observed clinical
60
toxicities.
61
4.1
Allopurinol
62
Coadministration of didanosine and allopurinol is contraindicated because systemic
63
exposures of didanosine are increased, which may increase didanosine-associated toxicity
64
[see Clinical Pharmacology (12.3)].
65
4.2
Ribavirin
66
Coadministration of didanosine and ribavirin is contraindicated because exposures of the
67
active metabolite of didanosine (dideoxyadenosine 5’-triphosphate) are increased. Fatal
68
hepatic failure, as well as peripheral neuropathy, pancreatitis, and symptomatic
69
hyperlactatemia/lactic acidosis have been reported in patients receiving both didanosine
70
and ribavirin.
71
5
WARNINGS AND PRECAUTIONS
72
5.1
Pancreatitis
73
Fatal and nonfatal pancreatitis has occurred during therapy with VIDEX used
74
alone or in combination regimens in both treatment-naive and treatment
75
experienced patients, regardless of degree of immunosuppression. VIDEX should be
76
suspended in patients with signs or symptoms of pancreatitis and discontinued in
77
patients with confirmed pancreatitis. Patients treated with VIDEX in combination
78
with stavudine may be at increased risk for pancreatitis.
79
When treatment with life-sustaining drugs known to cause pancreatic toxicity is required,
80
suspension of VIDEX (didanosine) therapy is recommended. In patients with risk factors
81
for pancreatitis, VIDEX should be used with extreme caution and only if clearly
6
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
82
indicated. Patients with advanced HIV-1 infection, especially the elderly, are at increased
83
risk of pancreatitis and should be followed closely. Patients with renal impairment may
84
be at greater risk for pancreatitis if treated without dose adjustment. The frequency of
85
pancreatitis is dose related. [See Adverse Reactions (6).]
86
5.2
Lactic Acidosis/Severe Hepatomegaly with Steatosis
87
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have
88
been reported with the use of nucleoside analogues alone or in combination,
89
including didanosine and other antiretrovirals. A majority of these cases have been in
90
women. Obesity and prolonged nucleoside exposure may be risk factors. Fatal lactic
91
acidosis has been reported in pregnant women who received the combination of
92
didanosine and stavudine with other antiretroviral agents. The combination of didanosine
93
and stavudine should be used with caution during pregnancy and is recommended only if
94
the potential benefit clearly outweighs the potential risk [see Use in Specific Populations
95
(8.1)]. Particular caution should be exercised when administering VIDEX to any patient
96
with known risk factors for liver disease; however, cases have also been reported in
97
patients with no known risk factors. Treatment with VIDEX should be suspended in any
98
patient who develops clinical signs or symptoms with or without laboratory findings
99
consistent with symptomatic hyperlactatemia, lactic acidosis, or pronounced
100
hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of
101
marked transaminase elevations).
102
5.3
Hepatic Toxicity
103
The safety and efficacy of VIDEX have not been established in HIV-infected patients
104
with significant underlying liver disease. During combination antiretroviral therapy,
105
patients with preexisting liver dysfunction, including chronic active hepatitis, have an
106
increased frequency of liver function abnormalities, including severe and potentially fatal
107
hepatic adverse events, and should be monitored according to standard practice. If there
108
is evidence of worsening liver disease in such patients, interruption or discontinuation of
109
treatment must be considered.
110
Hepatotoxicity and hepatic failure resulting in death were reported during postmarketing
111
surveillance in HIV-infected patients treated with hydroxyurea and other antiretroviral
112
agents. Fatal hepatic events were reported most often in patients treated with the
7
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
113
combination of hydroxyurea, didanosine, and stavudine. This combination should be
114
avoided. [See Adverse Reactions (6).]
115
5.4
Peripheral Neuropathy
116
Peripheral neuropathy, manifested by numbness, tingling, or pain in the hands or feet, has
117
been reported in patients receiving VIDEX therapy. Peripheral neuropathy has occurred
118
more frequently in patients with advanced HIV disease, in patients with a history of
119
neuropathy, or in patients being treated with neurotoxic drug therapy, including
120
stavudine. Discontinuation of VIDEX should be considered in patients who develop
121
peripheral neuropathy. [See Adverse Reactions (6).]
122
5.5
Retinal Changes and Optic Neuritis
123
Retinal changes and optic neuritis have been reported in adult and pediatric patients.
124
Periodic retinal examinations should be considered for patients receiving VIDEX [see
125
Adverse Reactions (6)].
126
5.6
Immune Reconstitution Syndrome
127
Immune reconstitution syndrome has been reported in patients treated with combination
128
antiretroviral therapy, including VIDEX. During the initial phase of combination
129
antiretroviral treatment, patients whose immune system responds may develop an
130
inflammatory response to indolent or residual opportunistic infections (such as
131
Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia
132
[PCP], or tuberculosis), which may necessitate further evaluation and treatment.
133
5.7
Fat Redistribution
134
Redistribution/accumulation of body fat including central obesity, dorsocervical fat
135
enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and
136
“cushingoid appearance” have been observed in patients receiving antiretroviral therapy.
137
The mechanism and long-term consequences of these events are currently unknown. A
138
causal relationship has not been established.
8
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
139
6
ADVERSE REACTIONS
140
The following adverse reactions are discussed in greater detail in other sections:
141
• Pancreatitis [see Boxed Warning, Warnings and Precautions (5.1)]
142
• Lactic acidosis/severe hepatomegaly with steatosis [see Boxed Warning, Warnings
143
and Precautions (5.2)]
144
• Hepatic toxicity [see Warnings and Precautions (5.3)]
145
• Peripheral neuropathy [see Warnings and Precautions (5.4)]
146
• Retinal changes and optic neuritis [see Warnings and Precautions (5.5)]
147
6.1
Clinical Trials Experience
148
Because clinical trials are conducted under widely varying conditions, adverse reaction
149
rates observed in the clinical trials of a drug cannot be directly compared to rates in the
150
clinical trials of another drug and may not reflect the rates observed in practice.
151
Adults
152
Selected clinical adverse reactions that occurred in adult patients in clinical studies with
153
VIDEX are provided in Tables 3 and 4.
Table 3:
Selected Clinical Adverse Reactions from Monotherapy
Studies
Percent of Patients*
ACTG 116A
ACTG 116B/117
VIDEX
zidovudine
VIDEX
zidovudine
Adverse Reactions
n=197
n=212
n=298
n=304
Diarrhea
19
15
28
21
Peripheral Neurologic
17
14
20
12
Symptoms/Neuropathy
Abdominal Pain
13
8
7
8
Rash/Pruritus
7
8
9
5
Pancreatitis
7
3
6
2
* The incidences reported included all severity grades and all reactions regardless of causality.
9
154
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 4:
Selected Clinical Adverse Reactions from Combination Studies
Percent of Patientsa,c
b
b
AI454-148
START 2
VIDEX +
zidovudine +
VIDEX +
zidovudine +
stavudine +
lamivudine +
stavudine +
lamivudine +
nelfinavir
nelfinavir
indinavir
indinavir
Adverse Reactions
n=482
n=248
n=102
n=103
Diarrhea
70
60
45
39
Nausea
28
40
53
67
Peripheral Neurologic
26
6
21
10
Symptoms/Neuropathy
Headache
21
30
46
37
Rash
13
16
30
18
Vomiting
12
14
30
35
Pancreatitis (see below)
1
*
less than 1
*
a Percentages based on treated subjects.
b Median duration of treatment 48 weeks.
c The incidences reported included all severity grades and all reactions regardless of causality.
* This event was not observed in this study arm.
155
Pancreatitis resulting in death was observed in one patient who received VIDEX
156
(didanosine) plus stavudine plus nelfinavir in Study Al454-148 and in one patient who
157
received VIDEX plus stavudine plus indinavir in the START 2 study. In addition,
158
pancreatitis resulting in death was observed in 2 of 68 patients who received VIDEX plus
159
stavudine plus indinavir plus hydroxyurea in an ACTG clinical trial [see Warnings and
160
Precautions (5)].
161
The frequency of pancreatitis is dose related. In phase 3 studies, incidence ranged from
162
1% to 10% with doses higher than are currently recommended and from 1% to 7% with
163
recommended dose.
164
Selected laboratory abnormalities in clinical studies with VIDEX are shown in
165
Tables 5-7.
10
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
166
Table 5:
Selected Laboratory Abnormalities from Monotherapy Studies
Percent of Patients
ACTG 116A
ACTG 116B/117
VIDEX
zidovudine
VIDEX
zidovudine
Parameter
n=197
n=212
n=298
n=304
SGOT (AST) (greater than 5 x ULN)
9
4
7
6
SGPT (ALT) (greater than 5 x ULN)
9
6
6
6
Alkaline phosphatase (greater than 5 x
4
1
1
1
ULN)
Amylase (at least 1.4 x ULN)
17
12
15
5
Uric acid (greater than 12 mg/dL)
3
1
2
1
ULN = upper limit of normal.
Table 6:
Selected Laboratory Abnormalities from Combination Studies
(Grades 3-4)
Percent of Patientsa
b
b
AI454-148
START 2
VIDEX +
zidovudine +
VIDEX +
zidovudine +
stavudine +
lamivudine +
stavudine +
lamivudine +
nelfinavir
nelfinavir
indinavir
indinavir
Parameter
n=482
n=248
n=102
n=103
Bilirubin (greater than 2.6 x
less than 1
less than 1
16
8
ULN)
SGOT (AST) (greater than 5 x
3
2
7
7
ULN)
SGPT (ALT) (greater than 5 x
3
3
8
5
ULN)
GGT (greater than 5 x ULN)
NC
NC
5
2
Lipase (greater than 2 x ULN)
7
2
5
5
Amylase (greater than 2 x
NC
NC
8
2
ULN)
ULN = upper limit of normal.
NC = Not Collected.
a Percentages based on treated subjects.
b Median duration of treatment 48 weeks.
11
167
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 7:
Selected Laboratory Abnormalities from Combination Studies
(All Grades)
Percent of Patientsa
AI454-148b
START 2b
Parameter
VIDEX +
stavudine +
nelfinavir
n=482
zidovudine +
lamivudine +
nelfinavir
n=248
VIDEX +
stavudine +
indinavir
n=102
zidovudine +
lamivudine +
indinavir
n=103
Bilirubin
7
3
68
55
SGOT (AST)
SGPT (ALT)
GGT
Lipase
42
37
NC
17
23
24
NC
11
53
50
28
26
20
18
12
19
Amylase
NC
NC
31
17
NC = Not Collected.
a Percentages based on treated subjects.
b Median duration of treatment 48 weeks.
168
Pediatric Patients
169
In clinical trials, 743 pediatric patients between 2 weeks and 18 years of age have been
170
treated with didanosine. Adverse reactions and laboratory abnormalities reported to occur
171
in these patients were generally consistent with the safety profile of didanosine in adults.
172
In pediatric phase 1 studies, pancreatitis occurred in 2 of 60 (3%) patients treated at entry
173
doses below 300 mg/m2/day and in 5 of 38 (13%) patients treated at higher doses. In
174
study ACTG 152, pancreatitis occurred in none of the 281 pediatric patients who received
175
didanosine 120 mg/m2 every 12 hours and in less than 1% of the 274 pediatric patients
176
who received didanosine 90 mg/m2 every 12 hours in combination with zidovudine [see
177
Clinical Studies (14)].
178
Retinal changes and optic neuritis have been reported in pediatric patients.
12
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
179
6.2
Postmarketing Experience
180
The following adverse reactions have been identified during postapproval use of
181
didanosine. Because they are reported voluntarily from a population of unknown size,
182
estimates of frequency cannot be made. These reactions have been chosen for inclusion
183
due to their seriousness, frequency of reporting, causal connection to VIDEX, or a
184
combination of these factors.
185
Blood and Lymphatic System Disorders – anemia, leukopenia, and
186
thrombocytopenia.
187
Body as a Whole – alopecia, anaphylactoid reaction, asthenia, chills/fever, pain,
188
and redistribution/accumulation of body fat [see Warnings and Precautions (5.7)].
189
Digestive Disorders – anorexia, dyspepsia, and flatulence.
190
Exocrine Gland Disorders – pancreatitis (including fatal cases) [see Boxed
191
Warning, Warnings and Precautions (5.1)], sialoadenitis, parotid gland
192
enlargement, dry mouth, and dry eyes.
193
Hepatobiliary Disorders – symptomatic hyperlactatemia/lactic acidosis and
194
hepatic steatosis [see Boxed Warning, Warnings and Precautions (5.2)]; hepatitis
195
and liver failure.
196
Metabolic Disorders – diabetes mellitus, hypoglycemia, and hyperglycemia.
197
Musculoskeletal Disorders – myalgia (with or without increases in creatine
198
kinase), rhabdomyolysis including acute renal failure and hemodialysis,
199
arthralgia, and myopathy.
200
Ophthalmologic Disorders – retinal depigmentation and optic neuritis [see
201
Warnings and Precautions (5.5)].
202
Use with Stavudine- and Hydroxyurea-Based Regimens
203
When didanosine is used in combination with other agents with similar toxicities, the
204
incidence of these toxicities may be higher than when didanosine is used alone. Thus,
205
patients treated with VIDEX in combination with stavudine, with or without
206
hydroxyurea, may be at increased risk for pancreatitis and hepatotoxicity, which may be
13
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
207
fatal, and severe peripheral neuropathy [see Warnings and Precautions (5)]. The
208
combination of VIDEX and hydroxyurea, with or without stavudine, should be avoided.
209
7
DRUG INTERACTIONS
210
7.1
Established Drug Interactions
211
Clinical recommendations based on the results of drug interaction studies are listed in
212
Table 8. Pharmacokinetic results of drug interactions studies are shown in Tables 12 and
213
13 [see Contraindications (4.1 and 4.2), Clinical Pharmacology (12.3)].
Table 8:
Established Drug Interactions with VIDEX
Drug
Effect
Clinical Comment
ciprofloxacin
↓ ciprofloxacin concentration Administer VIDEX at least 2 hours after or 6 hours
before ciprofloxacin.
delavirdine
↓ delavirdine concentration Administer VIDEX 1 hour after delavirdine.
ganciclovir
↑ didanosine concentration If there is no suitable alternative to ganciclovir, then
use in combination with VIDEX with caution.
Monitor for didanosine-associated toxicity.
indinavir
↓ indinavir concentration
Administer VIDEX 1 hour after indinavir.
methadone
↓ didanosine concentration Do not coadminister methadone with VIDEX
pediatric powder due to significant decreases in
didanosine concentrations. If coadministration of
methadone and didanosine is necessary, the
recommended formulation of didanosine is
VIDEX EC. Patients should be closely monitored for
adequate clinical response when VIDEX EC is
coadministered with methadone, including monitoring
for changes in HIV RNA viral load.
nelfinavir
No interaction 1 hour after Administer nelfinavir 1 hour after VIDEX.
didanosine
14
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 8:
Established Drug Interactions with VIDEX
Drug
Effect
Clinical Comment
tenofovir disoproxil
↑ didanosine concentration A dose reduction of VIDEX to the following dosage
fumarate
a
once daily is recommended.
•
250 mg (adults weighing at least 60 kg with
creatinine clearance of at least 60 mL/min)
•
200 mg (adults weighing less than 60 kg with
creatinine clearance of at least 60 mL/min)
VIDEX and tenofovir disoproxil fumarate may be
taken together in the fasted state. If tenofovir
disoproxil fumarate is taken with food, VIDEX should
be taken on an empty stomach (at least 30 minutes
before food or 2 hours after food). Patients should be
monitored for didanosine-associated toxicities and
clinical response.
↑ Indicates increase.
↓ Indicates decrease.
a The dosing recommendation for coadministration of VIDEX EC and tenofovir disoproxil fumarate with
respect to meal consumption differs from that of VIDEX. See the complete prescribing information for
VIDEX EC.
214
Exposure to didanosine is increased when coadministered with tenofovir disoproxil
215
fumarate [Table 8 and see Clinical Pharmacokinetics (12.3, Table 12)]. Increased
216
exposure may cause or worsen didanosine-related clinical toxicities, including
217
pancreatitis, symptomatic hyperlactatemia/lactic acidosis, and peripheral neuropathy.
218
Coadministration of tenofovir disoproxil fumarate with VIDEX should be undertaken
219
with caution, and patients should be monitored closely for didanosine-related toxicities
220
and clinical response. VIDEX should be suspended if signs or symptoms of pancreatitis,
221
symptomatic hyperlactatemia, or lactic acidosis develop [see Dosage and Administration
222
(2.3), Warnings and Precautions (5)]. Suppression of CD4 cell counts has been observed
223
in patients receiving tenofovir disoproxil fumarate with didanosine at a dose of 400 mg
224
daily.
225
7.2
Predicted Drug Interactions
226
Predicted drug interactions with VIDEX are listed in Table 9.
15
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 9:
Predicted Drug Interactions with VIDEX
Drug or Drug Class
Effect
Clinical Comment
Drugs that may cause
pancreatic toxicity
Neurotoxic drugs
Antacids containing
magnesium or aluminum
Azole antifungals
Quinolone antibiotics (see also
ciprofloxacin in Table 8)
Tetracycline antibiotics
↑ Indicates increase.
↓ Indicates decrease.
↓ antibiotic concentration
Consult package insert of the tetracycline.
Only if other drugs are not available and if clearly indicated. If treatment with life-sustaining drugs that
cause pancreatic toxicity is required, suspension of VIDEX is recommended [see Warnings and
Precautions (5.1)].
b [See Warnings and Precautions (5.5).]
227
8
USE IN SPECIFIC POPULATIONS
228
8.1
Pregnancy
229
Pregnancy Category B
230
Reproduction studies have been performed in rats and rabbits at doses up to 12 and
231
14.2 times the estimated human exposure (based upon plasma levels), respectively, and
232
have revealed no evidence of impaired fertility or harm to the fetus due to didanosine. At
233
approximately 12 times the estimated human exposure, didanosine was slightly toxic to
234
female rats and their pups during mid and late lactation. These rats showed reduced food
235
intake and body weight gains but the physical and functional development of the
236
offspring was not impaired and there were no major changes in the F2 generation. A
237
study in rats showed that didanosine and/or its metabolites are transferred to the fetus
238
through the placenta. Animal reproduction studies are not always predictive of human
239
response.
a
↑ risk of pancreatitis
↑ risk of neuropathy
↑ side effects associated with
antacid components
↓ ketoconazole or itraconazole
concentration
↓ quinolone concentration
Use only with extreme cautiona
b
Use with caution
Use caution with VIDEX Pediatric Powder
for Oral Solution
Administer drugs such as ketoconazole or
itraconazole at least 2 hours before
VIDEX.
Consult package insert of the quinolone.
16
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
240
There are no adequate and well-controlled studies of didanosine in pregnant women.
241
Didanosine should be used during pregnancy only if the potential benefit justifies the
242
potential risk.
243
Fatal lactic acidosis has been reported in pregnant women who received the combination
244
of didanosine and stavudine with other antiretroviral agents. It is unclear if pregnancy
245
augments the risk of lactic acidosis/hepatic steatosis syndrome reported in nonpregnant
246
individuals receiving nucleoside analogues [see Warnings and Precautions (5.2)]. The
247
combination of didanosine and stavudine should be used with caution during
248
pregnancy and is recommended only if the potential benefit clearly outweighs the
249
potential risk. Healthcare providers caring for HIV-infected pregnant women receiving
250
didanosine should be alert for early diagnosis of lactic acidosis/hepatic steatosis
251
syndrome.
252
Antiretroviral Pregnancy Registry
253
To monitor maternal-fetal outcomes of pregnant women exposed to didanosine and other
254
antiretroviral agents, an Antiretroviral Pregnancy Registry has been established.
255
Physicians are encouraged to register patients by calling 1-800-258-4263.
256
8.3
Nursing Mothers
257
The Centers for Disease Control and Prevention recommend that HIV-infected
258
mothers not breast-feed their infants to avoid risking postnatal transmission of HIV.
259
A study in rats showed that following oral administration, didanosine and/or its
260
metabolites were excreted into the milk of lactating rats. It is not known if didanosine is
261
excreted in human milk. Because of both the potential for HIV transmission and the
262
potential for serious adverse reactions in nursing infants, mothers should be instructed
263
not to breast-feed if they are receiving didanosine.
264
8.4
Pediatric Use
265
Use of didanosine in pediatric patients from 2 weeks of age through adolescence is
266
supported by evidence from adequate and well-controlled studies of VIDEX in adult and
267
pediatric patients [see Dosage and Administration (2), Adverse Reactions (6.1), Clinical
268
Pharmacology (12.3), and Clinical Studies (14)].
17
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
269
8.5
Geriatric Use
270
In an Expanded Access Program for patients with advanced HIV infection, patients aged
271
65 years and older had a higher frequency of pancreatitis (10%) than younger patients
272
(5%) [see Warnings and Precautions (5.1)]. Clinical studies of didanosine did not include
273
sufficient numbers of subjects aged 65 years and over to determine whether they respond
274
differently than younger subjects. Didanosine is known to be substantially excreted by
275
the kidney, and the risk of toxic reactions to this drug may be greater in patients with
276
impaired renal function. Because elderly patients are more likely to have decreased renal
277
function, care should be taken in dose selection. In addition, renal function should be
278
monitored and dosage adjustments should be made accordingly [see Dosage and
279
Administration (2.2)].
280
8.6
Renal Impairment
281
Patients with renal impairment (creatinine clearance of less than 60 mL/min) may be at
282
greater risk of toxicity from didanosine due to decreased drug clearance [see Clinical
283
Pharmacology (12.3)]. A dose reduction is recommended for these patients [see Dosage
284
and Administration (2)].
285
10
OVERDOSAGE
286
There is no known antidote for VIDEX (didanosine) overdosage. In phase 1 studies, in
287
which VIDEX was initially administered at doses ten times the currently recommended
288
dose, toxicities included: pancreatitis, peripheral neuropathy, diarrhea, hyperuricemia,
289
and hepatic dysfunction. Didanosine is not dialyzable by peritoneal dialysis, although
290
there is some clearance by hemodialysis [see Clinical Pharmacology (12.3)].
291
11
DESCRIPTION
292
VIDEX® is a brand name for didanosine, USP, a synthetic purine nucleoside analogue
293
active against HIV-1.
294
Didanosine is available as VIDEX, a Pediatric Powder for Oral Solution [see How
295
Supplied/Storage and Handling (16)] and as VIDEX® EC Delayed-Release Capsules,
296
containing enteric-coated beadlets [consult prescribing information for VIDEX EC
297
(didanosine)].
18
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
298
The chemical name for didanosine is 2′,3′-dideoxyinosine. The structural formula is: Structural Formula
299
Didanosine is a white crystalline powder with the molecular formula C10H12N4O3 and a
300
molecular weight of 236.2. The aqueous solubility of didanosine at 25° C and pH of
301
approximately 6 is 27.3 mg/mL. Didanosine is unstable in acidic solutions. For example,
302
at pH less than 3 and 37° C, 10% of didanosine decomposes to hypoxanthine in less than
303
2 minutes.
304
12
CLINICAL PHARMACOLOGY
305
12.1
Mechanism of Action
306
Didanosine is an antiviral agent [see Clinical Pharmacology (12.4)].
307
12.3
Pharmacokinetics
308
The pharmacokinetic parameters of didanosine are summarized in Table 10. Didanosine
309
is rapidly absorbed, with peak plasma concentrations generally observed from 0.25 to
310
1.50 hours following oral dosing. Increases in plasma didanosine concentrations were
311
dose proportional over the range of 50 to 400 mg. Steady-state pharmacokinetic
312
parameters did not differ significantly from values obtained after a single dose. Binding
313
of didanosine to plasma proteins in vitro was low (less than 5%). Based on data from
314
in vitro and animal studies, it is presumed that the metabolism of didanosine in man
315
occurs by the same pathways responsible for the elimination of endogenous purines.
19
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 10:
Mean ± SD Pharmacokinetic Parameters for Didanosine in
Adult and Pediatric Patients
b
Pediatric Patients
8 months to
2 weeks to
Parameter
Adult Patientsa
n
19 years
n
4 months
n
Oral bioavailability (%)
42 ± 12
6
25 ± 20
46
ND
Apparent volume of
2
43.70 ± 8.90
6
28 ± 15
49
ND
distributionc (L/m )
d
46%
CSF-plasma ratio
21 ± 0.03%e
5
7
ND
(range 12-85%)
Systemic clearancec
526 ± 64.7
6
516 ± 184
49
ND
(mL/min/m2)
Renal clearancef (mL/min/m2)
223 ± 85.0
6
240 ± 90
15
ND
Apparent oral clearanceg
1252 ± 154
6
2064 ± 736
48
1353 ± 759
41
(mL/min/m2)
Elimination half-lifef (h)
1.5 ± 0.4
6
0.8 ± 0.3
60
1.2 ± 0.3
21
Urinary recovery of
f
18 ± 8
6
18 ± 10
15
ND
didanosine (%)
CSF = cerebrospinal fluid, ND = not determined.
a Parameter units for adults were converted to the same units in pediatric patients to facilitate comparisons
among populations: mean adult body weight = 70 kg and mean adult body surface area = 1.73 m2.
b In 1-day old infants (n=10), the mean ± SD apparent oral clearance was 1523 ± 1176 mL/min/m2 and
half-life was 2.0 ± 0.7 h.
c Following IV administration.
d Following IV administration in adults and IV or oral administration in pediatric patients.
e Mean ± SE.
f Following oral administration.
g Apparent oral clearance estimate was determined as the ratio of the mean systemic clearance and the
mean oral bioavailability estimate.
316
Effect of Food
317
Didanosine peak plasma concentrations (Cmax) and area under the plasma concentration
318
time curve (AUC) were decreased by approximately 55% when VIDEX tablets were
319
administered up to 2 hours after a meal. Administration of VIDEX tablets up to
20
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
320
30 minutes before a meal did not result in any significant changes in bioavailability [see
321
Dosage and Administration (2)]. VIDEX should be taken on an empty stomach.
322
Special Populations
323
Renal Insufficiency: Data from two studies in adults indicated that the apparent oral
324
clearance of didanosine decreased and the terminal elimination half-life increased as
325
creatinine clearance decreased (see Table 11). Following oral administration, didanosine
326
was not detectable in peritoneal dialysate fluid (n=6); recovery in hemodialysate (n=5)
327
ranged from 0.6% to 7.4% of the dose over a 3-4 hour dialysis period. The absolute
328
bioavailability of didanosine was not affected in patients requiring dialysis. [See Dosage
329
and Administration (2.2).]
Table 11:
Mean ± SD Pharmacokinetic Parameters for Didanosine
Following a Single Oral Dose
Creatinine Clearance (mL/min)
at least 90
60-90
30-59
10-29
Dialysis Patients
Parameter
n=12
n=6
n=6
n=3
n=11
CLcr (mL/min)
112 ± 22
68 ± 8
46 ± 8
13 ± 5
ND
CL/F (mL/min)
2164 ± 638
1566 ± 833
1023 ± 378
628 ± 104
543 ± 174
CLR (mL/min)
458 ± 164
247 ± 153
100 ± 44
20 ± 8
less than 10
T½ (h)
1.42 ± 0.33
1.59 ± 0.13
1.75 ± 0.43
2.0 ± 0.3
4.1 ± 1.2
ND = not determined due to anuria.
CLcr = creatinine clearance.
CL/F = apparent oral clearance.
CLR = renal clearance.
330
Hepatic Impairment: The pharmacokinetics of didanosine have been studied in 12 non
331
HIV-infected subjects with moderate (n=8) to severe (n=4) hepatic impairment (Child
332
Pugh Class B or C). Mean AUC and Cmax values following a single 400 mg dose of
333
didanosine were approximately 13% and 19% higher, respectively, in patients with
334
hepatic impairment compared to matched healthy subjects. No dose adjustment is needed,
335
because a similar range and distribution of AUC and Cmax values was observed for
336
subjects with hepatic impairment and matched healthy controls. [See Dosage and
337
Administration (2.3).]
21
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
338
Pediatric Patients: The pharmacokinetics of didanosine have been evaluated in HIV
339
exposed and HIV-infected pediatric patients from birth to adulthood. Overall, the
340
pharmacokinetics of didanosine in pediatric patients are similar to those of didanosine in
341
adults. Didanosine plasma concentrations appear to increase in proportion to oral doses
342
ranging from 25 to 120 mg/m2 in pediatric patients less than 5 months old and from 80 to
343
180 mg/m2 in children above 8 months old. For information on controlled clinical studies
344
in pediatric patients, see Clinical Studies (14.2) and Use in Specific Populations (8.4).
345
Geriatric Patients: Didanosine pharmacokinetics have not been studied in patients over
346
65 years of age [see Use in Specific Populations (8.5)].
347
Gender: The effects of gender on didanosine pharmacokinetics have not been studied.
348
Drug Interactions
349
Tables 12 and 13 summarize the effects on AUC and Cmax, with a 95% confidence
350
interval (CI) when available, following coadministration of VIDEX (didanosine) with a
351
variety of drugs. Drug-drug interactions for VIDEX buffered tablets are applicable to the
352
VIDEX pediatric powder formulation and are noted in Tables 12 and 13. For clinical
353
recommendations based on drug interaction studies for drugs in bold font, see Dosage
354
and Administration (2.3 for Concomitant Therapy with Tenofovir Disoproxil Fumarate)
355
and Drug Interactions (7.3).
Table 12:
Results of Drug Interaction Studies with VIDEX: Effects of
Coadministered Drug on Didanosine Plasma AUC and Cmax
Values
% Change of Didanosine
Pharmacokinetic Parametersa
Drug
Didanosine Dosage
n
AUC of
Didanosine
(95% CI)
Cmax of
Didanosine
(95% CI)
allopurinol,
renally impaired, 300 mg/day
healthy volunteer, 300 mg/day for
7 days
ciprofloxacin, 750 mg every
12 hours for 3 days, 2 hours before
didanosine
200 mg single dose
400 mg single dose
200 mg every 12 hours
for 3 days
2
14
8b
↑ 312%
↑ 113%
↓ 16%
↑ 232%
↑ 69%
↓ 28%
22
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 12:
Results of Drug Interaction Studies with VIDEX: Effects of
Coadministered Drug on Didanosine Plasma AUC and Cmax
Values
% Change of Didanosine
Pharmacokinetic Parametersa
AUC of
Cmax of
Didanosine
Didanosine
Drug
Didanosine Dosage
n
(95% CI)
(95% CI)
ganciclovir,1000 mg every 8 hours,
2 hours after didanosine
indinavir, 800 mg single dose,
simultaneous
1 hour before didanosine
ketoconazole, 200 mg/day for
4 days, 2 hours before didanosine
methadone, chronic maintenance
f
dose
g,h
tenofovir,
300 mg once daily,
1 hour after didanosine
loperamide, 4 mg every 6 hours for
1 day
metoclopramide, 10 mg single dose
ranitidine, 150 mg single dose,
2 hours before didanosine
rifabutin, 300 or 600 mg/day for
12 days
ritonavir, 600 mg every 12 hours for
4 days
stavudine, 40 mg every 12 hours for
4 days
sulfamethoxazole, 1000 mg single
dose
trimethoprim, 200 mg single dose
zidovudine, 200 mg every 8 hours
for 3 days
200 mg every 12 hours
200 mg single dose
200 mg single dose
375 mg every 12 hours
for 4 days
200 mg single dose
400 mg single dose
250i or 400 mg once
daily for 7 days
300 mg single dose
300 mg single dose
375 mg single dose
167 or 250 mg every
12 hours for 12 days
200 mg every 12 hours
for 4 days
100 mg every 12 hours
for 4 days
200 mg single dose
200 mg single dose
200 mg every 12 hours
for 3 days
12
16
16
b
12
d
16
15,16e
14
b
12
b
12
b
12
11
12
10
b
8
b
8
b
6
↑ 111%
NA
↔
↔
↓ 17%
↓ 13%
(-27, - 7%)c
(-28, 5%)c
↔
↓ 12%
↓ 57%
↓ 66%
↓ 29%
↓ 41%
(-40, -16%)c
(-54, -26%)c
↑ 44%
↑ 28%
(31, 59%)c
(11, 48%)c
↔
↓ 23%
↔
↑ 13%
↑ 14%
↑ 13%
↑ 13%
↑ 17%
(-1, 27%)
(-4, 38%)
↓ 13%
↓ 16%
(0, 23%)
(5, 26%)
↔
↔
↔
↔
↑ 17%
↔
(-23, 77%)
↔
↔
↑ Indicates increase.
↓ Indicates decrease.
↔ Indicates no change, or mean increase or decrease of less than 10%.
23
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
356
Table 12:
Results of Drug Interaction Studies with VIDEX: Effects of
Coadministered Drug on Didanosine Plasma AUC and Cmax
Values
% Change of Didanosine
Pharmacokinetic Parametersa
AUC of
Cmax of
Didanosine
Didanosine
Drug
Didanosine Dosage
n
(95% CI)
(95% CI)
a The 95% confidence intervals for the percent change in the pharmacokinetic parameter are displayed.
b HIV-infected patients.
c 90% CI.
d Comparisons are made to a parallel control group not receiving methadone (n=10).
e Comparisons are made to historical controls (n=68, pooled from 3 studies) conducted in healthy subjects.
The number of subjects evaluated for AUC and Cmax is 15 and 16, respectively.
f For results of drug interaction studies between the enteric-coated formulation of didanosine (VIDEX EC)
and methadone, see the complete prescribing information for VIDEX EC.
g Tenofovir disoproxil fumarate.
h For results of drug interaction studies between the enteric-coated formulation of didanosine (VIDEX EC)
and tenofovir disoproxil fumarate, see the complete prescribing information for VIDEX EC.
i Patients less than 60 kg with creatinine clearance of at least 60 mL/min.
NA = Not available.
Table 13:
Results of Drug Interaction Studies with VIDEX: Effects of
Didanosine on Coadministered Drug Plasma AUC and Cmax
Values
% Change of Coadministered Drug
Pharmacokinetic Parametersa
AUC of
Cmax of
Coadministered
Coadministered
Drug
Drug
Drug
Didanosine Dosage
n
(95% CI)
(95% CI)
ciprofloxacin,
200 mg every 12 hours
b
750 mg every 12 hours for
8
↓ 26%
↓ 16%
for 3 days
3 days, 2 hours before didanosine
750 mg single dose
buffered placebo tablet
12
↓ 98%
↓ 93%
24
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 13:
Results of Drug Interaction Studies with VIDEX: Effects of
Didanosine on Coadministered Drug Plasma AUC and Cmax
Values
% Change of Coadministered Drug
Pharmacokinetic Parametersa
AUC of
Cmax of
Coadministered
Coadministered
Drug
Drug
Drug
Didanosine Dosage
n
(95% CI)
(95% CI)
125 or 200 mg every
delavirdine, 400 mg single dose
b
↓ 32%
↓ 53%
12 hours
12
simultaneous 1 hour before
125 or 200 mg every
b
12
didanosine
↑ 20%
↑ 18%
12 hours
ganciclovir, 1000 mg every
b
200 mg every 12 hours
12
↓ 21%
NA
8 hours, 2 hours after didanosine
indinavir, 800 mg single dose
simultaneous
200 mg single dose
16
↓ 84%
↓ 82%
1 hour before didanosine
200 mg single dose
16
↓ 11%
↓ 4%
ketoconazole, 200 mg/day for
375 mg every 12 hours
b
12
↓ 14%
↓ 20%
4 days, 2 hours before didanosine
for 4 days
nelfinavir, 750 mg single dose,
b
200 mg single dose
10
↑ 12%
↔
1 hour after didanosine
200 mg every 12 hours
b
dapsone, 100 mg single dose
6
↔
↔
for 14 days
ranitidine, 150 mg single dose,
375 mg single dose
12b
↓ 16%
↔
2 hours before didanosine
ritonavir, 600 mg every 12 hours
200 mg every 12 hours
12
↔
↔
for 4 days
for 4 days
stavudine, 40 mg every 12 hours
100 mg every 12 hours
b
10
↔
↑ 17%
for 4 days
for 4 days
sulfamethoxazole, 1000 mg
b
↓ 11%
↓ 12%
200 mg single dose
8
single dose
(-17, -4%)
(-28, 8%)
d
tenofovir,c 300 mg once daily
250 or 400 mg once
14
↔
↔
1 hour after didanosine
daily for 7 days
trimethoprim, 200 mg single
b
↑ 10%
↓ 22%
200 mg single dose
8
dose
(-9, 34%)
(-59, 49%)
zidovudine, 200 mg every
200 mg every 12 hours
b
↓ 10%
↓ 16.5%
6
8 hours for 3 days
for 3 days
(-27, 11%)
(-53, 47%)
↑ Indicates increase.
↓ Indicates decrease.
↔ Indicates no change, or mean increase or decrease of less than 10%.
a The 95% confidence intervals for the percent change in the pharmacokinetic parameter are displayed.
b HIV-infected patients.
25
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 13:
Results of Drug Interaction Studies with VIDEX: Effects of
Didanosine on Coadministered Drug Plasma AUC and Cmax
Values
% Change of Coadministered Drug
Pharmacokinetic Parametersa
AUC of
Cmax of
Coadministered
Coadministered
Drug
Drug
Drug
Didanosine Dosage
n
(95% CI)
(95% CI)
c Tenofovir disoproxil fumarate.
d Patients less than 60 kg with creatinine clearance of at least 60 mL/min.
NA = Not available.
357
12.4
Microbiology
358
Mechanism of Action
359
Didanosine is a synthetic nucleoside analogue of the naturally occurring nucleoside
360
deoxyadenosine in which the 3’-hydroxyl group is replaced by hydrogen. Intracellularly,
361
didanosine is converted by cellular enzymes to the active metabolite, dideoxyadenosine
362
5’-triphosphate. Dideoxyadenosine 5’-triphosphate inhibits the activity of HIV-1 reverse
363
transcriptase both by competing with the natural substrate, deoxyadenosine
364
5’-triphosphate, and by its incorporation into viral DNA causing termination of viral
365
DNA chain elongation.
366
Antiviral Activity in Cell Culture
367
The anti-HIV-1 activity of didanosine was evaluated in a variety of HIV-1 infected
368
lymphoblastic cell lines and monocyte/macrophage cell cultures. The concentration of
369
drug necessary to inhibit viral replication by 50% (EC50) ranged from 2.5 to 10 µM
370
(1 µM = 0.24 µg/mL) in lymphoblastic cell lines and 0.01 to 0.1 µM in
371
monocyte/macrophage cell cultures.
372
Resistance
373
HIV-1 isolates with reduced sensitivity to didanosine have been selected in cell culture
374
and were also obtained from patients treated with didanosine. Genetic analysis of isolates
26
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
375
from didanosine-treated patients showed mutations in the reverse transcriptase gene that
376
resulted in the amino acid substitutions K65R, L74V, and M184V. The L74V substitution
377
was most frequently observed in clinical isolates. Phenotypic analysis of HIV-1 isolates
378
from 60 patients (some with prior zidovudine treatment) receiving 6 to 24 months of
379
didanosine monotherapy showed that isolates from 10 of 60 patients exhibited an average
380
of a 10-fold decrease in susceptibility to didanosine in cell culture compared to baseline
381
isolates. Clinical isolates that exhibited a decrease in didanosine susceptibility harbored
382
one or more didanosine resistance-associated substitutions.
383
Cross-resistance
384
HIV-1 isolates from 2 of 39 patients receiving combination therapy for up to 2 years with
385
didanosine and zidovudine exhibited decreased susceptibility to didanosine, lamivudine,
386
stavudine, zalcitabine, and zidovudine in cell culture. These isolates harbored five
387
substitutions (A62V, V75I, F77L, F116Y, and Q151M) in the reverse transcriptase gene.
388
In data from clinical studies, the presence of thymidine analogue mutations (M41L,
389
D67N, L210W, T215Y, K219Q) has been shown to decrease the response to didanosine.
390
13
NONCLINICAL TOXICOLOGY
391
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
392
Lifetime carcinogenicity studies were conducted in mice and rats for 22 and 24 months,
393
respectively. In the mouse study, initial doses of 120, 800, and 1200 mg/kg/day for each
394
sex were lowered after 8 months to 120, 210, and 210 mg/kg/day for females and 120,
395
300, and 600 mg/kg/day for males. The two higher doses exceeded the maximally
396
tolerated dose in females and the high dose exceeded the maximally tolerated dose in
397
males. The low dose in females represented 0.68-fold maximum human exposure and the
398
intermediate dose in males represented 1.7-fold maximum human exposure based on
399
relative AUC comparisons. In the rat study, initial doses were 100, 250, and
400
1000 mg/kg/day, and the high dose was lowered to 500 mg/kg/day after 18 months. The
401
upper dose in male and female rats represented 3-fold maximum human exposure.
402
Didanosine induced no significant increase in neoplastic lesions in mice or rats at
403
maximally tolerated doses.
27
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
404
Didanosine was positive in the following genetic toxicology assays: 1) the Escherichia
405
coli tester strain WP2 uvrA bacterial mutagenicity assay; 2) the L5178Y/TK+/- mouse
406
lymphoma mammalian cell gene mutation assay; 3) the in vitro chromosomal aberrations
407
assay in cultured human peripheral lymphocytes; 4) the in vitro chromosomal aberrations
408
assay in Chinese Hamster Lung cells; and 5) the BALB/c 3T3 in vitro transformation
409
assay. No evidence of mutagenicity was observed in an Ames Salmonella bacterial
410
mutagenicity assay or in rat and mouse in vivo micronucleus assays.
411
13.2
Animal Toxicology and/or Pharmacology
412
Evidence of a dose-limiting skeletal muscle toxicity has been observed in mice and rats
413
(but not in dogs) following long-term (greater than 90 days) dosing with didanosine at
414
doses that were approximately 1.2 to 12 times the estimated human exposure. The
415
relationship of this finding to the potential of VIDEX (didanosine) to cause myopathy in
416
humans is unclear. However, human myopathy has been associated with administration
417
of VIDEX and other nucleoside analogues.
418
14
CLINICAL STUDIES
419
14.1
Adult Patients
420
Combination Therapy
421
START 2 was a multicenter, randomized, open-label study comparing VIDEX (200 mg
422
twice daily)/stavudine/indinavir to zidovudine/lamivudine/indinavir in 205 treatment
423
naive patients. Both regimens resulted in a similar magnitude of suppression of HIV-1
424
RNA levels and increases in CD4 cell counts through 48 weeks.
425
Study A1454-148 was a randomized, open-label, multicenter study comparing treatment
426
with VIDEX (400 mg once daily) plus stavudine (40 mg twice daily) and nelfinavir
427
(750 mg three times daily) versus zidovudine (300 mg twice daily) plus lamivudine
428
(150 mg twice daily) and nelfinavir (750 mg three times daily) in 756 treatment-naive
429
patients, with a median CD4 cell count of 340 cells/mm3 (range 80 to 1568 cells/mm3)
430
and a median plasma HIV-1 RNA of 4.69 log10 copies/mL (range 2.6 to 5.9 log10
431
copies/mL) at baseline. Median CD4 cell count increases at 48 weeks were
432
188 cells/mm3 in both treatment groups. Treatment response and outcomes through
433
48 weeks are shown in Figure 1 and Table 14.
28
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
G
r
ap
h
a
n
d
C
h
a
r
t
4
a Patients achieved virologic response [two consecutive viral loads less than 400 (less than 50) copies/mL]
and maintained it to Week 48.
b Includes viral rebound and failing to achieve confirmed less than 400 (less than 50) copies/mL by
Week 48.
c Includes lost to follow-up, noncompliance, withdrawal, and pregnancy.
29
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
435
Monotherapy
436
The efficacy of VIDEX was demonstrated in two randomized, double-blind studies
437
comparing VIDEX, given on a twice-daily schedule, to zidovudine, given three times
438
daily, in 617 (ACTG 116A, conducted 1989-1992) and 913 (ACTG 116B/117, conducted
439
1989-1991) patients with symptomatic HIV infection or AIDS who were treated for more
440
than one year. In treatment-naive patients (ACTG 116A), the rate of HIV disease
441
progression or death was similar between the treatment groups; mortality rates were 26%
442
for patients receiving VIDEX and 21% for patients receiving zidovudine. Of the patients
443
who had received previous zidovudine treatment (ACTG 116B/117), those treated with
444
VIDEX had a lower rate of HIV disease progression or death (32%) compared to those
445
treated with zidovudine (41%); however, survival rates were similar between the
446
treatment groups.
447
Studies have demonstrated that the clinical benefit of monotherapy with antiretrovirals,
448
including VIDEX, was time limited.
449
14.2
Pediatric Patients
450
Efficacy in pediatric patients was demonstrated in a randomized, double-blind, controlled
451
study (ACTG 152, conducted 1991-1995) involving 831 patients 3 months to 18 years of
452
age treated for more than 1.5 years with zidovudine (180 mg/m2 every 6 hours), VIDEX
453
(120 mg/m2 every 12 hours), or zidovudine (120 mg/m2 every 6 hours) plus VIDEX
454
(90 mg/m2 every 12 hours). Patients treated with VIDEX or VIDEX plus zidovudine had
455
lower rates of HIV-1 disease progression or death compared with those treated with
456
zidovudine alone.
457
16
HOW SUPPLIED/STORAGE AND HANDLING
458
VIDEX (didanosine, USP) Pediatric Powder for Oral Solution is supplied as shown in
459
Table 15:
30
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 15:
VIDEX Pediatric Powder for Oral Solution
NDC NO.
Packaging Information
Product Quantity
0087-6632-41
One, 4-ounce glass, bottle per carton
2 g/bottle
0087-6633-41
One, 8-ounce glass, bottle per carton
4 g/bottle
460
Prior to dispensing, the pharmacist must reconstitute dry powder with Purified Water,
461
USP, to an initial concentration of 20 mg/mL and immediately mix the resulting solution
462
with antacid to a final concentration of 10 mg/mL as follows:
463
20 mg/mL Initial Solution
464
Reconstitute the product to 20 mg/mL by adding 100 mL or 200 mL of Purified Water,
465
USP, to the 2 g or 4 g of VIDEX powder, respectively, in the product bottle.
466
10 mg/mL Final Admixture
467
1. Immediately mix one part of the 20 mg/mL initial solution with one part of Maximum
468
Strength Mylanta® Liquid for a final dispensing concentration of 10 mg VIDEX per
469
mL. For patient home use, the admixture should be dispensed in appropriately sized,
470
flint-glass or plastic (HDPE, PET, or PETG) bottles with child-resistant closures.
471
2. Instruct the patient to shake the admixture thoroughly prior to use and to store the
472
tightly closed container in the refrigerator.
473
Storage
474
The bottles of powder should be stored at 59° F to 86° F (15° C to 30° C). The VIDEX
475
admixture may be stored up to 30 days in a refrigerator, 36° F to 46° F (2° C to 8° C).
476
Discard any unused portion after 30 days.
477
______________________
478
Mylanta® is a registered trademark of Johnson & Johnson-Merck Consumer
479
Pharmaceuticals Company.
31
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
480
17
PATIENT COUNSELING INFORMATION
481
See FDA-approved Patient Labeling (17.6)
482
17.1
Pancreatitis
483
Patients should be informed that a serious toxicity of VIDEX, used alone and in
484
combination regimens, is pancreatitis, which may be fatal.
485
17.2
Peripheral Neuropathy
486
Patients should be informed that peripheral neuropathy, manifested by numbness,
487
tingling, or pain in hands or feet, may develop during therapy with VIDEX. Patients
488
should be counseled that peripheral neuropathy occurs with greatest frequency in patients
489
with advanced HIV-1 disease or a history of peripheral neuropathy, and that
490
discontinuation of VIDEX may be required if toxicity develops.
491
17.3
Lactic Acidosis and Severe Hepatomegaly with
492
Steatosis
493
Patients should be informed that lactic acidosis and severe hepatomegaly with steatosis,
494
including fatal cases, have been reported with the use of nucleoside analogues alone or in
495
combination, including didanosine and other antiretrovirals.
496
17.4
Hepatic Toxicity
497
Patients should be informed that hepatotoxicity including fatal hepatic adverse events
498
were reported in patients with preexisting liver dysfunction. The safety and efficacy of
499
VIDEX have not been established in HIV-infected patients with significant underlying
500
liver disease.
501
17.5
Retinal Changes and Optic Neuritis
502
Patients should be informed that retinal changes and optic neuritis have been reported in
503
adult and pediatric patients.
32
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
504
17.6
Fat Redistribution
505
Patients should be informed that redistribution or accumulation of body fat may occur in
506
patients receiving antiretroviral therapy and that the cause and long-term health effects of
507
these conditions are not known at this time.
508
17.7
Concomitant Therapy
509
Patients should be informed that when VIDEX is used in combination with other agents
510
with similar toxicities, the incidence of adverse events may be higher than when VIDEX
511
is used alone. These patients should be followed closely.
512
Patients should be cautioned about the use of medications or other substances, including
513
alcohol, which may exacerbate VIDEX toxicities.
514
17.8
General Information
515
VIDEX (didanosine) is not a cure for HIV-1 infection, and patients may continue to
516
develop HIV-associated illnesses, including opportunistic infection. Therefore, patients
517
should remain under the care of a physician when using VIDEX. Patients should be
518
advised that VIDEX therapy has not been shown to reduce the risk of transmission of
519
HIV to others through sexual contact or blood contamination. Patients should be
520
informed that the long-term effects of VIDEX are unknown at this time.
521
Patients should be informed that the preferred dosing frequency of VIDEX is twice daily
522
because there is more evidence to support the effectiveness of this dosing frequency.
523
Once-daily dosing should be considered only for patients whose management requires
524
once-daily dosing of VIDEX.
33
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
525
17.9
FDA-Approved Patient Labeling
526
VIDEX®
527
(generic name = didanosine also known as ddI)
528
VIDEX® (didanosine, USP) Pediatric Powder for Oral Solution
529
What is VIDEX?
530
VIDEX (pronounced VY dex) is a prescription medicine used in combination with other
531
drugs to treat children and adults who are infected with HIV (the human
532
immunodeficiency virus, the virus that causes AIDS). VIDEX belongs to a class of drugs
533
called nucleoside analogues. By reducing the growth of HIV, VIDEX helps your body
534
maintain its supply of CD4 cells, which are important for fighting HIV and other
535
infections.
536
VIDEX will not cure your HIV infection. At present there is no cure for HIV infection.
537
Even while taking VIDEX, you may continue to have HIV-related illnesses, including
538
infections with other disease-producing organisms. Continue to see your doctor regularly
539
and report any medical problems that occur.
540
VIDEX does not prevent a patient infected with HIV from passing the virus to other
541
people. To protect others, you must continue to practice safe sex and take precautions to
542
prevent others from coming in contact with your blood and other body fluids.
543
There is limited information on the effects of long-term use of VIDEX.
544
Who should not take VIDEX?
545
Do not take VIDEX if you are allergic to any of its ingredients, including its active
546
ingredient, didanosine, and the inactive ingredients. (See Inactive Ingredients at the end
547
of this leaflet.) Tell your doctor if you think you have had an allergic reaction to any of
548
these ingredients.
34
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
549
How should I take VIDEX? How should I store it?
550
Your doctor will determine your dose based on your body weight, kidney and liver
551
function, other medicines you are taking, and any side effects that you may have had with
552
VIDEX or other medicines. Take VIDEX on an empty stomach - that means at least
553
30 minutes before or 2 hours after eating. Do not take VIDEX with food. Try not to
554
miss a dose, but if you do, take it as soon as possible. If it is almost time for the next
555
dose, skip the missed dose and continue your regular dosing schedule.
556
Your pharmacist will prepare the oral solution. Shake the solution well before each
557
use. Store in the refrigerator. Throw away any unused portion after 30 days.
558
If you have kidney disease: If your kidneys are not working properly, your doctor will
559
need to do regular tests to check how they are working while you take VIDEX. Your
560
doctor may also lower your dosage of VIDEX.
561
What should I do if someone takes an overdose of VIDEX?
562
If someone may have taken an overdose of VIDEX, get medical help right away. Contact
563
their doctor or a poison control center.
564
What should I avoid while taking VIDEX?
565
Alcohol. Do not drink alcohol while taking VIDEX since alcohol may increase your risk
566
of pancreatitis (pain and inflammation of the pancreas) or liver damage.
567
Allopurinol, also known as ZYLOPRIM®, ALOPRIM®, or others. Do not take
568
allopurinol while taking VIDEX because the risk of side-effects of didanosine are
569
increased.
570
Ribavirin, also known as COPEGUS®, REBETOL®, or others. Do not take ribavirin
571
while taking VIDEX because pancreatitis, peripheral neuropathy, lactic acidosis and fatal
572
liver damage have been reported. (See "What are the possible side effects of VIDEX?")
573
Other medicines. Other medicines, including those you can buy without a prescription,
574
may interfere with the actions of VIDEX or may increase the possibility or severity of
35
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
575
side effects. Do not take any medicine, vitamin supplement, or other health
576
preparation without first checking with your doctor.
577
Antacids. Since VIDEX is mixed with an antacid, any side effects related to
578
VIDEX’s ingredients may get worse if you also take an antacid.
579
Medicines at the same time you take your VIDEX dose. Some medicines should
580
not be taken at the same time of day that you take VIDEX. Check with your doctor.
581
Pregnancy. It is not known if VIDEX can harm a human fetus. Also, pregnant women
582
have experienced serious side effects when taking VIDEX in combination with ZERIT
583
(stavudine), also known as d4T, and other HIV medicines. VIDEX should be used during
584
pregnancy only after discussion with your doctor. Tell your doctor if you become
585
pregnant or plan to become pregnant while taking VIDEX.
586
Nursing. Studies have shown VIDEX is in the breast milk of animals getting the drug. It
587
may also be in human breast milk. The Centers for Disease Control and Prevention
588
(CDC) recommends that HIV-infected mothers not breast-feed. This should reduce the
589
risk of passing HIV infection to their babies and the potential for serious adverse
590
reactions in nursing infants. Therefore, do not nurse a baby while taking VIDEX.
591
What are the possible side effects of VIDEX?
592
Pancreatitis. Pancreatitis is a dangerous inflammation of the pancreas that may cause
593
death. Tell your doctor right away if you or a child taking VIDEX develops stomach
594
pain, nausea, or vomiting. These can be signs of pancreatitis. Before starting VIDEX
595
therapy, let your doctor know if you or a child for whom it has been prescribed has ever
596
had pancreatitis. This condition is more likely to happen in people who have had it
597
before. It is also more likely in people with advanced HIV disease. However, it can occur
598
at any stage of HIV disease. It may be more common in patients with kidney problems,
599
those who drink alcohol, and those who are also treated with stavudine. If you get
600
pancreatitis, your doctor will tell you to stop taking VIDEX.
36
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
601
Lactic acidosis, severe liver enlargement, and liver failure, including deaths, have
602
been reported among patients taking VIDEX (including pregnant women). Symptoms
603
that may indicate a liver problem are:
604
• feeling very weak, tired, or uncomfortable
605
• unusual or unexpected stomach discomfort
606
• feeling cold
607
• feeling dizzy or lightheaded
608
• suddenly developing a slow or irregular heartbeat
609
Lactic acidosis is a medical emergency that must be treated in a hospital.
610
If you notice any of these symptoms or if your medical condition changes, stop taking
611
VIDEX and call your doctor right away. Women, overweight patients, and those who
612
have been treated for a long time with other medicines used to treat HIV infection are
613
more likely to develop lactic acidosis. Your doctor should check your liver function
614
periodically while you are taking VIDEX. You should be especially careful if you have a
615
history of heavy alcohol use or a liver problem.
616
Vision changes. VIDEX (didanosine) may affect the nerves in your eyes. Because of
617
this, you should have regular eye examinations. You should also report any changes in
618
vision to your doctor right away. This includes, for example, seeing colors abnormally or
619
blurred vision.
620
Peripheral neuropathy. This is a problem with the nerves in your hands or feet. The
621
nerve problem may be serious. Tell your doctor right away if you or a child taking
622
VIDEX has continuing numbness, tingling, or pain in the feet or hands. A child may
623
not recognize these symptoms or know to tell you that his or her feet or hands are numb,
624
burning, tingling, or painful. Ask your child’s doctor how to find out if your child is
625
developing peripheral neuropathy.
626
Before starting VIDEX therapy, let your doctor know if you or a child for whom it has
627
been prescribed has ever had peripheral neuropathy. This condition is more likely to
628
happen in people who have had it before. It is also more likely in patients taking
629
medicines that affect the nerves and in people with advanced HIV disease. However, it
630
can occur at any stage of HIV disease. If you get peripheral neuropathy, your doctor will
631
tell you to stop taking VIDEX. After stopping VIDEX, the symptoms may get worse for
37
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
632
a short time and then get better. Once symptoms of peripheral neuropathy go away
633
completely, you and your doctor should decide if starting VIDEX again is right for you.
634
Special note about other medicines. If you take VIDEX along with other medicines
635
with similar side effects, you may increase the chance of having these side effects. For
636
example, using VIDEX in combination with other medicines that may cause pancreatitis,
637
peripheral neuropathy, or liver problems (including stavudine) may increase your chance
638
of having these side effects.
639
Other side effects: The most common side effects in adults taking VIDEX in
640
combination with other HIV drugs included diarrhea, neuropathy (nerve disorders), chills
641
or fever, rash, abdominal pain, weakness, headache, and nausea and vomiting. Children
642
may have similar side effects as adults.
643
Changes in body fat have been seen in some patients taking antiretroviral therapy. These
644
changes may include an increased amount of fat in the upper back and neck (“buffalo
645
hump”), breast, and around the trunk. Loss of fat from the legs, arms, and face may also
646
happen. The cause and long-term health effects of these conditions are not known at this
647
time.
648
Inactive Ingredients:
649
Pediatric Oral Solution: Maximum Strength Mylanta® Liquid.
650
__________________
651
This medicine was prescribed for your particular condition. Do not use VIDEX for
652
another condition or give it to others. Keep all medicines out of the reach of children and
653
pets at all times. Do not keep medicine that is out of date or that you no longer need.
654
Dispose of unused medicines through community take-back disposal programs when
655
available or place VIDEX in an unrecognizable closed container in the household trash.
38
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
656
This summary does not include everything there is to know about VIDEX. Medicines are
657
sometimes prescribed for purposes other than those listed in a Patient Information
658
Leaflet. If you have questions or concerns, or want more information about VIDEX, your
659
physician and pharmacist have the complete prescribing information upon which this
660
leaflet is based. You may want to read it and discuss it with your doctor or other
661
healthcare professional. Remember, no written summary can replace careful discussion
662
with your doctor.
663
VIDEX® and Zerit® are registered trademarks of Bristol-Myers Squibb Company. All
664
other trademarks are the property of their respective owners.
665
Bristol-Myers Squibb Company
666
Princeton, NJ 08543 USA
667
This Patient Information Leaflet has been approved by the U.S. Food and Drug
668
Administration.
669
XXXXXXX
Rev June 2009
39
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:46:55.875058
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020156s044lbl.pdf', 'application_number': 20156, 'submission_type': 'SUPPL ', 'submission_number': 44}
|
12,277
|
NDA 20-154/S-044
NDA 20-155/S-034
NDA 20-156/S-035
NDA 21-183/S-010
Page 3
Rx only
VIDEX EC (didanosine)
VIDEX EC (didanosine) Delayed-Release Capsules
Enteric-Coated Beadlets
(Patient Information Leaflet Included)
WARNING
FATAL AND NONFATAL PANCREATITIS HAVE OCCURRED DURING
THERAPY WITH DIDANOSINE USED ALONE OR IN COMBINATION
REGIMENS
IN
BOTH
TREATMENT-NAIVE
AND
TREATMENT-
EXPERIENCED
PATIENTS,
REGARDLESS
OF
DEGREE
OF
IMMUNOSUPPRESSION. VIDEX EC SHOULD BE SUSPENDED IN
PATIENTS WITH SUSPECTED PANCREATITIS AND DISCONTINUED IN
PATIENTS WITH CONFIRMED PANCREATITIS (SEE WARNINGS).
LACTIC
ACIDOSIS
AND
SEVERE
HEPATOMEGALY
WITH
STEATOSIS, INCLUDING FATAL CASES, HAVE BEEN REPORTED
WITH THE USE OF NUCLEOSIDE ANALOGUES ALONE OR IN
COMBINATION,
INCLUDING
DIDANOSINE
AND
OTHER
ANTIRETROVIRALS.
FATAL
LACTIC
ACIDOSIS
HAS
BEEN
REPORTED
IN
PREGNANT
WOMEN
WHO
RECEIVED
THE
COMBINATION OF DIDANOSINE AND STAVUDINE WITH OTHER
ANTIRETROVIRAL AGENTS. THE COMBINATION OF DIDANOSINE
AND STAVUDINE SHOULD BE USED WITH CAUTION DURING
PREGNANCY AND IS RECOMMENDED ONLY IF THE POTENTIAL
BENEFIT CLEARLY OUTWEIGHS THE POTENTIAL RISK (SEE
WARNINGS AND PRECAUTIONS: PREGNANCY).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-154/S-044
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DESCRIPTION
VIDEX® EC is the brand name for an enteric-coated formulation of didanosine (ddI), a synthetic
purine nucleoside analogue active against the Human Immunodeficiency Virus (HIV). VIDEX EC
(didanosine) Delayed-Release Capsules, containing enteric-coated beadlets, are available for oral
administration in strengths of 125, 200, 250, and 400 mg of didanosine. The inactive ingredients
in the beadlets include carboxymethylcellulose sodium 12, diethyl phthalate, methacrylic acid
copolymer, sodium hydroxide, sodium starch glycolate, and talc. The capsule shells contain
colloidal silicon dioxide, gelatin, sodium lauryl sulfate, and titanium dioxide. The capsules are
imprinted with edible inks.
Didanosine is also available as buffered formulations. Please consult the prescribing
information for VIDEX (didanosine) Chewable/Dispersible Buffered Tablets and Pediatric
Powder for Oral Solution for additional information.
The chemical name for didanosine is 2',3'-dideoxyinosine. The structural formula is:
Didanosine is a white crystalline powder with the molecular formula C10H12N4O3 and a
molecular weight of 236.2. The aqueous solubility of didanosine at 25° C and pH of
approximately 6 is 27.3 mg/mL. Didanosine is unstable in acidic solutions. For example, at pH <3
and 37° C, 10% of didanosine decomposes to hypoxanthine in less than 2 minutes. In VIDEX EC,
an enteric coating is used to protect didanosine from degradation by stomach acid.
MICROBIOLOGY
Mechanism of Action
Didanosine is a synthetic nucleoside analogue of the naturally occurring nucleoside
deoxyadenosine in which the 3'–hydroxyl group is replaced by hydrogen. Intracellularly,
didanosine is converted by cellular enzymes to the active metabolite, dideoxyadenosine
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5'-triphosphate. Dideoxyadenosine 5'–triphosphate inhibits the activity of HIV–1 reverse
transcriptase both by competing with the natural substrate, deoxyadenosine 5'–triphosphate, and
by its incorporation into viral DNA causing termination of viral DNA chain elongation.
In Vitro HIV Susceptibility
The in vitro anti-HIV-1 activity of didanosine was evaluated in a variety of HIV-1 infected
lymphoblastic cell lines and monocyte/macrophage cell cultures. The concentration of drug
necessary to inhibit viral replication by 50% (IC50) ranged from 2.5 to 10 µM (1 µM = 0.24
µg/mL) in lymphoblastic cell lines and 0.01 to 0.1 µM in monocyte/macrophage cell cultures. The
relationship between in vitro susceptibility of HIV to didanosine and the inhibition of HIV
replication in humans has not been established.
Drug Resistance
HIV-1 isolates with reduced sensitivity to didanosine have been selected in vitro and were also
obtained from patients treated with didanosine. Genetic analysis of isolates from didanosine-
treated patients showed mutations in the reverse transcriptase gene that resulted in the amino acid
substitutions K65R, L74V, and M184V. The L74V mutation was most frequently observed in
clinical isolates. Phenotypic analysis of HIV-1 isolates from 60 patients (some with prior
zidovudine treatment) receiving 6 to 24 months of didanosine monotherapy showed that isolates
from 10 of 60 patients exhibited an average of a 10-fold decrease in susceptibility to didanosine in
vitro compared to baseline isolates. Clinical isolates that exhibited a decrease in didanosine
susceptibility harbored one or more didanosine-associated mutations. The clinical relevance of
genotypic and phenotypic changes associated with didanosine therapy has not been established.
Cross-resistance
HIV-1 isolates from 2 of 39 patients receiving combination therapy for up to 2 years with
zidovudine and didanosine exhibited decreased susceptibility to zidovudine, didanosine,
zalcitabine, stavudine, and lamivudine in vitro. These isolates harbored five mutations (A62V,
V75I, F77L, F116Y, and Q151M) in the reverse transcriptase gene. The clinical relevance of these
observations has not been established.
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CLINICAL PHARMACOLOGY
Animal Toxicology
Evidence of a dose-limiting skeletal muscle toxicity has been observed in mice and rats (but not in
dogs) following long-term (greater than 90 days) dosing with didanosine at doses that were
approximately 1.2 to 12 times the estimated human exposure. The relationship of this finding to
the potential of didanosine to cause myopathy in humans is unclear. However, human myopathy
has been associated with administration of didanosine and other nucleoside analogues.
Pharmacokinetics
The pharmacokinetic parameters of didanosine are summarized in Table 1. Didanosine is rapidly
absorbed, with peak plasma concentrations generally observed from 0.25 to 1.50 hours following
oral dosing with a buffered formulation. Increases in plasma didanosine concentrations were dose
proportional over the range of 50 to 400 mg. Steady-state pharmacokinetic parameters did not
differ significantly from values obtained after a single dose. Binding of didanosine to plasma
proteins in vitro was low (<5%). Based on data from in vitro and animal studies, it is presumed
that the metabolism of didanosine in man occurs by the same pathways responsible for the
elimination of endogenous purines.
Pharmacokinetic Parameters for Didanosine in Adults
Parameter
Mean ± SD
n
Oral bioavailabilitya
42 ± 12%
6
Apparent volume of distributionb
1.08 ± 0.22 L/kg
6
CSF-plasma ratiob
21 ± 0.03%c
5
Systemic clearanceb
13.0 ± 1.6 mL/min/kg
6
Renal clearancea
5.5 ± 2.1 mL/min/kg
6
Elimination half-lifea
1.5 ± 0.4 h
6
Urinary recovery of didanosinea
18 ± 8%
6
CSF = cerebrospinal fluid.
a following oral administration of a buffered formulation.
b following IV administration.
c mean ± SE.
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Comparison of Didanosine Formulations
In VIDEX EC, the active ingredient, didanosine, is protected against degradation by stomach acid
by the use of an enteric coating on the beadlets in the capsule. The enteric coating dissolves when
the beadlets empty into the small intestine, the site of drug absorption. With buffered
formulations of didanosine, administration with antacid provides protection from degradation by
stomach acid.
In healthy volunteers, as well as subjects infected with HIV, the area under the plasma
concentration time curve (AUC) is equivalent for didanosine administered as the VIDEX EC
formulation relative to a buffered tablet formulation. The peak plasma concentration (CMAX) of
didanosine, administered as VIDEX EC, is reduced approximately 40% relative to didanosine
buffered tablets. The time to the peak concentration (TMAX) increases from approximately 0.67
hours for didanosine buffered tablets to 2.0 hours for VIDEX EC.
Effect of Food on Absorption of Didanosine
In the presence of food, the CMAX and AUC for VIDEX EC were reduced by approximately 46%
and 19%, respectively, compared to the fasting state. VIDEX EC should be taken on an empty
stomach.
Special Populations
Renal Insufficiency
It is recommended that the VIDEX EC (didanosine) dose be modified in patients with reduced
creatinine clearance and in patients receiving maintenance hemodialysis (see DOSAGE AND
ADMINISTRATION). Data from two studies using a buffered formulation of didanosine
indicated that the apparent oral clearance of didanosine decreased and the terminal elimination
half-life increased as creatinine clearance decreased (see Table 2). Following oral administration,
didanosine was not detectable in peritoneal dialysate fluid (n=6); recovery in hemodialysate (n=5)
ranged from 0.6% to 7.4% of the dose over a 3-4 hour dialysis period. The absolute
bioavailability of didanosine was not affected in patients requiring dialysis.
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Mean ± SD Pharmacokinetic Parameters for Didanosine Following a Single
Oral Dose of a Buffered Formulation
Creatinine Clearance (mL/min)
Parameter
≥ 90
(n=12)
60-90
(n=6)
30-59
(n=6)
10-29
(n=3)
Dialysis
Patients
(n=11)
CLcr
(mL/min)
112 ± 22
68 ± 8
46 ± 8
13 ± 5
ND
CL/F
(mL/min)
2164 ±
638
1566 ±
833
1023 ±
378
628 ±
104
543 ±
174
CLR
(mL/min)
458 ±
164
247 ±
153
100 ±
44
20 ± 8
<10
T½ (h)
1.42 ±
0.33
1.59 ±
0.13
1.75 ±
0.43
2.0 ±
0.3
4.1 ± 1.2
ND = not determined due to anuria.
CLcr = creatinine clearance.
CL/F = apparent oral clearance.
CLR = renal clearance.
Pediatric Patients
The pharmacokinetics of didanosine administered as VIDEX EC have not been studied in
pediatric patients.
Geriatric Patients
Didanosine pharmacokinetics have not been studied in patients over 65 years of age (see
PRECAUTIONS: Geriatric Use).
Gender
The effects of gender on didanosine pharmacokinetics have not been studied.
Drug Interactions (See also PRECAUTIONS: Drug Interactions.)
Ribavirin has been shown in vitro to increase intracellular triphosphate levels of didanosine,
which could cause or worsen clinical toxicities (see PRECAUTIONS: Drug Interactions).
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VIDEX EC
Tables 3 and 4 summarize the effects on AUC and CMAX, with a 90% confidence interval (CI)
when available, following coadministration of VIDEX EC with a variety of drugs. Clinical
recommendations based on drug interaction studies for drugs in bold font are included in
PRECAUTIONS: Drug Interactions and DOSAGE AND ADMINISTRATION.
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Results of Drug Interaction Studies with VIDEX EC: Effects of Coadministered
Drug on Didanosine Plasma AUC and CMAX Valuesa
Drug
Didanosine
Dosage
n
AUC of
Didanosine
(90% CI)
CMAX of
Didanosine
(90% CI)
tenofovir,b 300
mg once daily
with a light
mealc
400 mg single
dose fasting 2
h before
tenofovir
2
6
↑ 48% (31,
67%)
↑ 48% (25, 76%)
tenofovir,b 300
mg once daily
with a light
mealc
400 mg single
dose with
tenofovir and a
light meal
2
5
↑ 60% (44,
79%)
↑ 64% (41, 89%)
tenofovir,b 300
mg once daily
with a light
mealc
200 mg single
dose with
tenofovir and a
light meal
3
3
↑ 16% (6,
27%)d
↓ 12% (−25, 3%)d
250 mg single
dose with
tenofovir and a
light meal
3
3
↔ (−13, 5%)e
↓ 20% (−32, −7%)e
325 mg single
dose with
tenofovir and a
light meal
3
3
↑ 13% (3,
24%)e
↓ 11% (−24, 4%)e
↑ indicates increase.
↓ indicates decrease.
↔ indicates no change, or mean increase or decrease of <10%.
a All studies conducted in healthy volunteers ≥60 kg with creatinine clearance ≥60 mL/min.
b tenofovir disoproxil fumarate.
c 373 kcalories, 8.2 grams fat.
d Compared with VIDEX EC 250 mg administered alone under fasting conditions.
e Compared with VIDEX EC 400 mg administered alone under fasting conditions.
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Results of Drug Interaction Studies with VIDEX EC: Effects of Didanosine on
Coadministered Drug Plasma AUC and CMAX Valuesa
Drug
Didanosine
Dosage
n
AUC of
Coadministered
Drug
CMAX of
Coadministered
Drug
ciprofloxacin,
750 mg single
dose
400 mg single
dose
1
6
↔
↔
indinavir, 800
mg single
dose
400 mg single
dose
2
3
↔
↔
ketoconazole,
200 mg single
dose
400 mg single
dose
2
1
↔
↔
tenofovir,b 300
mg once daily
with a light
mealc
400 mg single
dose fasting 2
h before
tenofovir
2
5
↔
↔
tenofovir,b 300
mg once daily
with a light
mealc
400 mg single
dose with
tenofovir and a
light meal
2
5
↔
↔
↔ indicates no change, or mean increase or decrease of <10%.
a All studies conducted in healthy volunteers ≥60 kg with creatinine clearance ≥60 mL/min.
b tenofovir disoproxil fumarate.
c 373 kcalories, 8.2 grams fat.
Didanosine Buffered Formulations
Tables 5 and 6 summarize the effects on AUC and CMAX, with a 90% or 95% CI when available,
following coadministration of buffered formulations of didanosine with a variety of drugs.
Except as noted in table footnotes, the results of these studies may be expected to apply to
VIDEX EC. For most of the listed drugs, no clinically significant pharmacokinetic interactions
were noted. Clinical recommendations based on drug interaction studies for drugs in bold font are
included in PRECAUTIONS: Drug Interactions and DOSAGE AND ADMINISTRATION
(for tenofovir).
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Results of Drug Interaction Studies with Buffered Formulations of Didanosine:
Effects of Coadministered Drug on Didanosine Plasma AUC and CMAX Values
Drugs With Clinical Recommendations Regarding Coadministration (see PRECAUTIONS: Drug
Interactions)
Drug
Didanosine
Dosage
n
AUC of
Didanosine
(95% CI)
CMAX of
Didanosine
(95% CI)
allopurinol
renally impaired, 300
mg/day
200 mg single
dose
2
↑ 312%
↑ 232%
healthy volunteer, 300
mg/day for 7 days
400 mg single
dose
1
4
↑ 113%
↑ 69%
ganciclovir, 1000 mg q8h,
2 h after didanosine
200 mg q12h
1
2
↑ 111%
NA
methadone, chronic
maintenance dose
200 mg single
dose
1
6
,
1
0
a
↓ 57%
↓ 66%
tenofovir,b 300 mg once
daily 1 h after didanosine
250c or 400 mg
once daily for 7
days
1
4
↑ 44%
(31, 59%)d
↑ 28%
(11, 48%)d
No Clinically Significant Interaction Observed
Drug
Didanosine
Dosage
n
AUC of
Didanosine
(95% CI)
CMAX of
Didanosine
(95% CI)
ciprofloxacin, 750 mg q12h
for 3 days, 2 h before
didanosine
200 mg q12h for
3 days
8
e
↓ 16%
↓ 28%
indinavir, 800 mg single
dose
simultaneous
200 mg single
dose
1
6
↔
↔
1 h before didanosine
200 mg single
dose
1
6
↓ 17% (-27,
-7%)d
↓ 13% (-28,
5%)d
ketoconazole, 200 mg/day
for 4 days, 2 h before
didanosine
375 mg q12h for
4 days
1
2
e
↔
↓12%
loperamide, 4 mg q6h for 1
day
300 mg single
dose
1
2
e
↔
↓23%
metoclopramide, 10 mg
single dose
300 mg single
dose
1
2
e
↔
↑13%
ranitidine, 150 mg single
dose, 2 h before didanosine
375 mg single
dose
1
2
e
↑14%
↑13%
rifabutin, 300 or 600
mg/day for 12 days
167 or 250 mg
q12h for 12 days
1
1
↑ 13% (-1,
27%)
↑ 17% (-4,
38%)
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Results of Drug Interaction Studies with Buffered Formulations of Didanosine:
Effects of Coadministered Drug on Didanosine Plasma AUC and CMAX Values
ritonavir, 600 mg q12h for
4 days
200 mg q12h for
4 days
1
2
↓ 13% (0,
23%)
↓ 16% (5,
26%)
stavudine, 40 mg q12h for 4
days
100 mg q12h for
4 days
1
0
↔
↔
sulfamethoxazole, 1000 mg
single dose
200 mg single
dose
8
e
↔
↔
trimethoprim, 200 mg
single dose
200 mg single
dose
8
e
↔
↑ 17% (-23,
77%)
zidovudine, 200 mg q8h for
3 days
200 mg q12h for
3 days
6
e
↔
↔
↑ indicates increase.
↓ indicates decrease.
↔ indicates no change, or mean increase or decrease of <10%.
a Parallel-group design; entries are subjects receiving combination and control regimens, respectively.
b tenofovir disoproxil fumarate.
c patients <60 kg with creatinine clearance >60 mL/min.
d 90% Cl.
e HIV-infected patients.
NA Not available.
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Results of Drug Interaction Studies with Buffered Formulations of
Didanosine: Effects of Didanosine on Coadministered Drug Plasma AUC and
CMAX Values
No Clinically Significant Interaction Observed
Drug
Didanosine
Dosage
AUC of
Coadminister
ed Drug (95%
CI)
CMAX of
Coadminister
ed Drug (95%
CI)
dapsone, 100 mg
single dose
200 mg q12h for
14 days
↔
↔
delavirdine, 400 mg
single dose
simultaneous
1 h before didanosine
125 or 200 mg
q12h
125 or 200 mg
q12h
↓ 32%b
↑ 20%
↓ 53%b
↑ 18%
ganciclovir, 1000 mg
q8h, 2 h after
didanosine
200 mg q12h
↓21%
NA
nelfinavir, 750 mg
single dose, 1 h after
didanosine
200 mg single dose
↑12%
↔
ranitidine, 150 mg
single dose, 2 h
before didanosine
375 mg single dose
↓16%
↔
ritonavir, 600 mg
q12h for 4 days
200 mg q12h for 4
days
↔
↔
stavudine, 40 mg
q12h for 4 days
100 mg q12h for 4
days
↔
↑17%
sulfamethoxazole,
1000 mg single dose
200 mg single dose
↓ 11% (-17, -
4%)
↓ 12% (-28,
8%)
tenofovir,c 300 mg
once daily 1 h after
didanosine
250d or 400 mg once
daily for 7 days
↔
↔
trimethoprim, 200 mg
single dose
200 mg single dose
↑ 10% (-9,
34%)
↓ 22% (-59,
49%)
zidovudine, 200 mg
q8h for 3 days
200 mg q12h for 3
days
↓ 10% (-27,
11%)
↓ 16.5% (-53,
47%)
↑ indicates increase.
↓ indicates decrease.
↔ indicates no change, or mean increase or decrease of <10%.
a HIV-infected patients.
b This result is probably related to the buffer and is not expected to occur with VIDEX EC.
c tenofovir disoproxil fumarate.
d patients <60 kg with creatinine clearance >60 mL/min.
NA Not available.
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INDICATIONS AND USAGE
VIDEX EC (didanosine) in combination with other antiretroviral agents is indicated for the
treatment of HIV-1 infection in adults. (See Clinical Studies.)
Clinical Studies
Study Al454-152 was a 48-week, randomized, open-label study comparing VIDEX EC (400 mg
once daily) plus stavudine (40 mg twice daily) plus nelfinavir (750 mg three times daily) to
zidovudine (300 mg) plus lamivudine (150 mg) combination tablets twice daily plus nelfinavir
(750 mg three times daily) in 511 treatment-naive patients, with a mean CD4 cell count of 411
cells/mm3 (range 39 to 1105 cells/mm3) and a mean plasma HIV-1 RNA of 4.71 log10 copies/mL
(range 2.8 to 5.9 log10 copies/mL) at baseline. Patients were primarily males (72%) and
Caucasian (53%) with a mean age of 35 years (range 18 to 73 years). The percentages of patients
with HIV RNA <400 and <50 copies/mL and outcomes of patients through 48 weeks are
summarized in Figure 1 and Table 7, respectively.
Figure 1
Treatment Response Through Week 48*, AI454-152
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*Percent of patients at each time point who have HIV RNA <400 or <50 copies/mL and do not
meet any criteria for treatment failure (eg, virologic failure or discontinuation for any reason).
0
20
40
60
80
100
0
12
24
36
48
Study Week
Percent of Patients
] < 400 c/mL
] < 50 c/mL
VIDEX EC+stavudine+nelfinavir, n=258
zidovudine/lamivudine+nelfinavir, n=253
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Outcomes of Randomized Treatment Through Week 48, AI454-152
Percent of Patients with HIV RNA <400 copies/mL (<50
copies/mL)
VIDEX EC + stavudine +
zidovudine/lamivudinea +
nelfinavir
nelfinavir
Outcome
n=258
n=253
Responderb,c
55% (33%)
56% (33%)
Virologic failured
22% (45%)
21% (43%)
Death or discontinued due
to disease progression
1% (1%)
2% (2%)
Discontinued due to
adverse event
6% (6%)
7% (7%)
Discontinued due to other
reasonse
16% (16%)
15% (16%)
a Zidovudine/lamivudine combination tablet.
b Corresponds to rates at Week 48 in Figure 1.
c Subjects achieved and maintained confirmed HIV RNA <400 copies/mL (<50 copies/mL) through
Week 48.
d Includes viral rebound at or before Week 48 and failure to achieve confirmed HIV RNA <400
copies/mL (<50 copies/mL) through Week 48.
e Includes lost to follow-up, subject’s withdrawal, discontinuation due to physician’s decision, never
treated, and other reasons.
CONTRAINDICATION
VIDEX EC (didanosine) is contraindicated in patients with previously demonstrated clinically
significant hypersensitivity to any component of the formulation.
WARNINGS
1. Pancreatitis
FATAL AND NONFATAL PANCREATITIS HAVE OCCURRED DURING
THERAPY WITH DIDANOSINE USED ALONE OR IN COMBINATION REGIMENS
IN BOTH TREATMENT-NAIVE AND TREATMENT-EXPERIENCED PATIENTS,
REGARDLESS OF DEGREE OF IMMUNOSUPPRESSION. VIDEX EC SHOULD BE
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SUSPENDED IN PATIENTS WITH SIGNS OR SYMPTOMS OF PANCREATITIS AND
DISCONTINUED IN PATIENTS WITH CONFIRMED PANCREATITIS. PATIENTS
TREATED WITH VIDEX EC IN COMBINATION WITH STAVUDINE, WITH OR
WITHOUT HYDROXYUREA, MAY BE AT INCREASED RISK FOR PANCREATITIS.
When treatment with life-sustaining drugs known to cause pancreatic toxicity is required,
suspension of VIDEX EC therapy is recommended. In patients with risk factors for pancreatitis,
VIDEX EC should be used with extreme caution and only if clearly indicated. Patients with
advanced HIV infection, especially the elderly, are at increased risk of pancreatitis and should be
followed closely. Patients with renal impairment may be at greater risk for pancreatitis if treated
without dose adjustment.
The frequency of pancreatitis is dose related. In phase 3 studies with buffered
formulations of didanosine, incidence ranged from 1% to 10% with doses higher than are
currently recommended and 1% to 7% with recommended dose.
2. Lactic Acidosis/Severe Hepatomegaly with Steatosis
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have
been reported with the use of nucleoside analogues alone or in combination, including
didanosine and other antiretrovirals. A majority of these cases have been in women. Obesity
and prolonged nucleoside exposure may be risk factors. Fatal lactic acidosis has been reported in
pregnant women who received the combination of didanosine and stavudine with other
antiretroviral agents. The combination of didanosine and stavudine should be used with caution
during pregnancy and is recommended only if the potential benefit clearly outweighs the
potential risk (see PRECAUTIONS: Pregnancy). Particular caution should be exercised when
administering VIDEX EC to any patient with known risk factors for liver disease; however, cases
have also been reported in patients with no known risk factors. Treatment with VIDEX EC
should be suspended in any patient who develops clinical or laboratory findings suggestive of
symptomatic hyperlactatemia, lactic acidosis, or pronounced hepatotoxicity (which may include
hepatomegaly and steatosis even in the absence of marked transaminase elevations).
3. Retinal Changes and Optic Neuritis
Retinal changes and optic neuritis have been reported in patients taking didanosine.
Periodic retinal examinations should be considered for patients receiving VIDEX EC. (See
ADVERSE REACTIONS.)
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For current labeling information, please visit https://www.fda.gov/drugsatfda
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PRECAUTIONS
Dosing
VIDEX EC should be administered once daily on an empty stomach.
Peripheral Neuropathy
Peripheral neuropathy, manifested by numbness, tingling, or pain in the hands or feet, has been
reported in patients receiving didanosine therapy. Peripheral neuropathy has occurred more
frequently in patients with advanced HIV disease, in patients with a history of neuropathy, or in
patients being treated with neurotoxic drug therapy, including stavudine (see ADVERSE
REACTIONS).
Fat Redistribution
Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement
(buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid
appearance” have been observed in patients receiving antiretroviral therapy. The mechanism and
long-term consequences of these events are currently unknown. A causal relationship has not
been established.
General
Patients with Renal Impairment
Patients with renal impairment (creatinine clearance <60 mL/min) may be at greater risk of
toxicity
from
didanosine
due
to
decreased
drug
clearance
(see
CLINICAL
PHARMACOLOGY). A dose reduction is recommended in these patients (see DOSAGE AND
ADMINISTRATION).
Patients with Hepatic Impairment
It is unknown if hepatic impairment significantly affects didanosine pharmacokinetics. Therefore,
these patients should be monitored closely for evidence of didanosine toxicity.
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Hyperuricemia
Didanosine has been associated with asymptomatic hyperuricemia; treatment suspension may be
necessary if clinical measures aimed at reducing uric acid levels fail.
Information for Patients (See Patient Information Leaflet.)
Patients should be informed that a serious toxicity of didanosine, used alone and in combination
regimens, is pancreatitis, which may be fatal.
Patients should also be aware that peripheral neuropathy, manifested by numbness,
tingling, or pain in hands or feet, may develop during therapy with VIDEX EC (didanosine).
Patients should be counseled that peripheral neuropathy occurs with greatest frequency in
patients with advanced HIV disease or a history of peripheral neuropathy, and that dose
modification and/or discontinuation of VIDEX EC may be required if toxicity develops.
Patients should be informed that when didanosine is used in combination with other
agents with similar toxicities, the incidence of adverse events may be higher than when
didanosine is used alone. These patients should be followed closely.
Patients should be cautioned about the use of medications or other substances, including
alcohol, that may exacerbate VIDEX EC toxicities.
VIDEX EC is not a cure for HIV infection, and patients may continue to develop HIV-
associated illnesses, including opportunistic infection. Therefore, patients should remain under
the care of a physician when using VIDEX EC. Patients should be advised that VIDEX EC
therapy has not been shown to reduce the risk of transmission of HIV to others through sexual
contact or blood contamination. Patients should be informed that the long-term effects of VIDEX
EC are unknown at this time.
Patients should be informed that redistribution or accumulation of body fat may occur in
patients receiving antiretroviral therapy and that the cause and long-term health effects of these
conditions are not known at this time.
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Drug Interactions (see also CLINICAL PHARMACOLOGY: Drug
Interactions)
Drug interactions that have been established based on drug interaction studies are listed with the
pharmacokinetic results in CLINICAL PHARMACOLOGY: Drug Interactions (Tables 3-6).
The clinical recommendations based on the results of these studies are listed in Table 8.
Established Drug Interactions Based on Studies with VIDEX EC or Studies
with Buffered Formulations of Didanosine and Expected to Occur with
VIDEX EC
Coadministration Not Recommended Based on Drug Interaction Studies (see CLINICAL
PHARMACOLOGY: Drug Interactions for Magnitude of Interaction)
Drug
Effect
Clinical Comment
allopurinol
↑ didanosine
concentration
Coadministration not recommended.
Alteration in Dose or Regimen Recommended Based on Drug Interaction Studies (see
CLINICAL PHARMACOLOGY: Drug Interactions for Magnitude of Interaction)
Drug
Effect
Clinical Comment
ganciclovir
↑ didanosine
concentration
Appropriate doses for this combination,
with respect to efficacy and safety,
have not been established.
methadone
↓ didanosine
concentration
Appropriate doses for this combination,
with respect to efficacy and safety,
have not been established.
tenofovir
disoproxil
fumarate
↑ didanosine
concentration
A dose reduction of VIDEX EC to 250
mg (adults weighing ≥60 kg with
creatinine clearance ≥60 mL/min) or
200 mg (adults weighing <60 kg with
creatinine clearance ≥60 mL/min) once
daily taken together with tenofovir and
a light meal (≤400 kcalories and ≤20%
fat) or in the fasted state is
recommended. Patients should be
monitored for didanosine-associated
toxicities (see below).
↑ indicates increase.
↓ indicates decrease.
Coadministration of VIDEX EC with drugs that are known to cause pancreatitis
may increase the risk of this toxicity (see WARNINGS: Pancreatitis). Predicted drug
interactions with VIDEX EC are listed in Table 9.
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Predicted Drug Interactions with VIDEX EC
Drug or Drug
Class
Effect
Clinical Comment
Drugs that may
cause pancreatic
toxicity
↑ risk of pancreatitis
Use only with extreme caution.a
Neurotoxic drugs
↑ risk of neuropathy
Use with caution.b
Ribavirin
↑ risk of toxicity
Ribavirin has been shown in vitro to
increase intracellular triphosphate
levels of didanosine. Coadministration
is not recommended (see below).
↑ indicates increase.
a Only if other drugs are not available and if clearly indicated. If treatment with life-sustaining drugs
that cause pancreatic toxicity is required, suspension of VIDEX EC is recommended (see
WARNINGS: Pancreatitis).
b See PRECAUTIONS: Peripheral Neuropathy.
Nucleoside/nucleotide analogues
Tenofovir disoproxil fumarate. Exposure to didanosine is increased when coadministered with
tenofovir (see Tables 3, 5, and 8). Increased exposure may cause or worsen didanosine-
related clinical toxicities, including pancreatitis, symptomatic hyperlactatemia/lactic
acidosis, and peripheral neuropathy. Coadministration of tenofovir with VIDEX EC should
be undertaken with caution, and patients should be monitored closely for didanosine-
related toxicities. VIDEX EC should be suspended if signs or symptoms of pancreatitis,
symptomatic hyperlactatemia, or lactic acidosis develop (see WARNINGS). Administration
of reduced doses of VIDEX EC with tenofovir and a light meal resulted in didanosine exposures
(AUC) similar to the recommended doses of VIDEX EC given alone in the fasted state (see
Table 3). Therefore, when administered with tenofovir, a dose reduction of VIDEX EC to 250
mg (adults weighing ≥60 kg with creatinine clearance ≥60 mL/min) or 200 mg (adults weighing
<60 kg with creatinine clearance ≥60 mL/min) once daily is recommended, and both drugs may
be taken together with a light meal (≤400 kcalories, ≤20% fat) or in the fasted state (see
DOSAGE AND ADMINISTRATION). Coadministration of didanosine with food decreases
didanosine concentrations. Thus, although not studied, it is possible that coadministration with
heavier meals could reduce didanosine concentrations further.
Ribavirin. Exposure to the active metabolite of didanosine (dideoxyadenosine 5'-triphosphate) is
increased when didanosine is coadministered with ribavirin (see Table 9). Fatal hepatic failure, as
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well as peripheral neuropathy, pancreatitis, and symptomatic hyperlactatemia/lactic acidosis have
been reported in patients receiving both didanosine and ribavirin. Coadministration of didanosine
and ribavirin is not recommended.
Carcinogenesis and Mutagenesis
Lifetime carcinogenicity studies were conducted in mice and rats for 22 and 24 months,
respectively. In the mouse study, initial doses of 120, 800, and 1200 mg/kg/day for each sex were
lowered after 8 months to 120, 210, and 210 mg/kg/day for females and 120, 300, and 600
mg/kg/day for males. The two higher doses exceeded the maximally tolerated dose in females
and the high dose exceeded the maximally tolerated dose in males. The low dose in females
represented 0.68-fold maximum human exposure and the intermediate dose in males represented
1.7-fold maximum human exposure based on relative AUC comparisons. In the rat study, initial
doses were 100, 250, and 1000 mg/kg/day, and the high dose was lowered to 500 mg/kg/day after
18 months. The upper dose in male and female rats represented 3-fold maximum human
exposure.
Didanosine induced no significant increase in neoplastic lesions in mice or rats at
maximally tolerated doses.
Didanosine was positive in the following genetic toxicology assays: 1) the Escherichia
coli tester strain WP2 uvrA bacterial mutagenicity assay; 2) the L5178Y/TK+/- mouse lymphoma
mammalian cell gene mutation assay; 3) the in vitro chromosomal aberrations assay in cultured
human peripheral lymphocytes; 4) the in vitro chromosomal aberrations assay in Chinese
Hamster Lung cells; and 5) the BALB/c 3T3 in vitro transformation assay. No evidence of
mutagenicity was observed in an Ames Salmonella bacterial mutagenicity assay or in rat and
mouse in vivo micronucleus assays.
Pregnancy, Reproduction, and Fertility
Pregnancy Category B. Reproduction studies have been performed in rats and rabbits at doses up
to 12 and 14.2 times the estimated human exposure (based upon plasma levels), respectively, and
have revealed no evidence of impaired fertility or harm to the fetus due to didanosine. At
approximately 12 times the estimated human exposure, didanosine was slightly toxic to female
rats and their pups during mid and late lactation. These rats showed reduced food intake and body
weight gains but the physical and functional development of the offspring was not impaired and
there were no major changes in the F2 generation. A study in rats showed that didanosine and/or
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its metabolites are transferred to the fetus through the placenta. Animal reproduction studies are
not always predictive of human response.
There are no adequate and well-controlled studies of didanosine in pregnant women.
Didanosine should be used during pregnancy only if the potential benefit justifies the potential
risk.
Fatal lactic acidosis has been reported in pregnant women who received the combination
of didanosine and stavudine with other antiretroviral agents. It is unclear if pregnancy augments
the risk of lactic acidosis/hepatic steatosis syndrome reported in nonpregnant individuals
receiving nucleoside analogues (see WARNINGS: Lactic Acidosis/Severe Hepatomegaly with
Steatosis). The combination of didanosine and stavudine should be used with caution
during pregnancy and is recommended only if the potential benefit clearly outweighs the
potential risk. Health care providers caring for HIV-infected pregnant women receiving
didanosine should be alert for early diagnosis of lactic acidosis/hepatic steatosis syndrome.
Antiretroviral Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant
women exposed to didanosine and other antiretroviral agents, an Antiretroviral Pregnancy
Registry has been established. Physicians are encouraged to register patients by calling 1-800-
258-4263.
Nursing Mothers
The Centers for Disease Control and Prevention recommend that HIV-infected mothers not
breast-feed their infants to avoid risking postnatal transmission of HIV. A study in rats
showed that following oral administration, didanosine and/or its metabolites were excreted into
the milk of lactating rats. It is not known if didanosine is excreted in human milk. Because of
both the potential for HIV transmission and the potential for serious adverse reactions in nursing
infants, mothers should be instructed not to breast-feed if they are receiving VIDEX EC
(didanosine).
Pediatric Use
The safety and efficacy of VIDEX EC in pediatric patients have not been established. Please
consult the complete prescribing information for VIDEX (didanosine) Chewable/Dispersible
Buffered Tablets and Pediatric Powder for Oral Solution for dosage and administration of
didanosine to pediatric patients.
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Geriatric Use
In an Expanded Access Program using a buffered formulation of didanosine for the treatment of
advanced HIV infection, patients aged 65 years and older had a higher frequency of pancreatitis
(10%) than younger patients (5%) (see WARNINGS). Clinical studies of didanosine, including
those for VIDEX EC, did not include sufficient numbers of subjects aged 65 years and over to
determine whether they respond differently than younger subjects. Didanosine is known to be
substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in
patients with impaired renal function. Because elderly patients are more likely to have decreased
renal function, care should be taken in dose selection. In addition, renal function should be
monitored and dosage adjustments should be made accordingly (see DOSAGE AND
ADMINISTRATION: Dose Adjustment).
ADVERSE REACTIONS
A SERIOUS TOXICITY OF DIDANOSINE IS PANCREATITIS, WHICH MAY BE FATAL
(see
WARNINGS).
OTHER
IMPORTANT
TOXICITIES
INCLUDE
LACTIC
ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS; RETINAL CHANGES AND
OPTIC
NEURITIS;
AND
PERIPHERAL
NEUROPATHY
(see
WARNINGS
and
PRECAUTIONS).
When didanosine is used in combination with other agents with similar toxicities, the
incidence of these toxicities may be higher than when didanosine is used alone. Thus,
patients treated with VIDEX EC in combination with stavudine, with or without
hydroxyurea, may be at increased risk for pancreatitis, which may be fatal, and
hepatotoxicity (see WARNINGS). Patients treated with VIDEX EC in combination with
stavudine may also be at increased risk for peripheral neuropathy (see PRECAUTIONS).
Selected clinical adverse events that occurred in a study of VIDEX EC in combination
with other antiretroviral agents are provided in Table 10.
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Selected Clinical Adverse Events, Study AI454-152a
Percent of Patientsb
VIDEX EC +
stavudine +
nelfinavir
zidovudine/
lamivudinec +
nelfinavir
Adverse Events
n=258
n=253
Diarrhea
57
58
Peripheral
Neurologic
Symptoms/Neuro
pathy
25
11
Nausea
24
36
Headache
22
17
Rash
14
12
Vomiting
14
19
Pancreatitis (see
below)
<1
*
a Median duration of treatment was 62 weeks in the VIDEX EC + stavudine + nelfinavir group
and 61 weeks in the zidovudine/lamivudine + nelfinavir group.
b Percentages based on treated patients.
c Zidovudine/lamivudine combination tablet.
* This event was not observed in this study arm.
In clinical trials using a buffered formulation of didanosine, pancreatitis resulting in
death was observed in one patient who received didanosine plus stavudine plus nelfinavir,
one patient who received didanosine plus stavudine plus indinavir, and 2 of 68 patients who
received didanosine plus stavudine plus indinavir plus hydroxyurea. In an early access
program, pancreatitis resulting in death was observed in one patient who received VIDEX
EC plus stavudine plus hydroxyurea plus ritonavir plus indinavir plus efavirenz (see
WARNINGS).
The frequency of pancreatitis is dose related. In phase 3 studies with buffered
formulations of didanosine, incidence ranged from 1% to 10% with doses higher than are
currently recommended and 1% to 7% with recommended dose.
Selected laboratory abnormalities that occurred in a study of VIDEX EC in combination
with other antiretroviral agents are shown in Table 11.
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Selected Laboratory Abnormalities, Study AI454-152a
Percent of Patientsb
VIDEX EC + stavudine
+ nelfinavir
n=258
zidovudine/lamivudinec
+ nelfinavir
n=253
Parameter
Grades 3-
4d
All Grades
Grades 3-
4d
All Grades
SGOT
(AST)
5
46
5
19
SGPT
(ALT)
6
44
5
22
Lipase
5
23
2
13
Bilirubin
<1
9
<1
3
a Median duration of treatment was 62 weeks in the VIDEX EC + stavudine + nelfinavir
group and 61 weeks in the zidovudine/lamivudine + nelfinavir group.
b Percentages based on treated patients.
c Zidovudine/lamivudine combination tablet.
d >5 x ULN for SGOT and SGPT, ≥2.1 x ULN for lipase, and ≥2.6 x ULN for bilirubin
(ULN = upper limit of normal).
Observed During Clinical Practice
The following events have been identified during postapproval use of didanosine buffered
formulations. Because they are reported voluntarily from a population of unknown size, estimates
of frequency cannot be made. These events have been chosen for inclusion due to their
seriousness, frequency of reporting, causal connection to didanosine, or a combination of these
factors.
Body as a Whole – abdominal pain, alopecia, anaphylactoid reaction, asthenia, chills/fever, pain,
and redistribution/accumulation of body fat (see PRECAUTIONS: Fat Redistribution).
Digestive Disorders- anorexia, dyspepsia, and flatulence.
Exocrine Gland Disorders – pancreatitis (including fatal cases) (see WARNINGS), sialoadenitis,
parotid gland enlargement, dry mouth, and dry eyes.
Hematologic Disorders - anemia, leukopenia, and thrombocytopenia.
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Liver - symptomatic hyperlactatemia/lactic acidosis and hepatic steatosis (see WARNINGS);
hepatitis and liver failure.
Metabolic Disorders - diabetes mellitus, elevated serum alkaline phosphatase level, elevated
serum amylase level, elevated serum gamma-glutamyltransferase level, elevated serum uric acid
level, hypoglycemia, and hyperglycemia.
Musculoskeletal Disorders - myalgia (with or without increases in creatine kinase),
rhabdomyolysis including acute renal failure and hemodialysis, arthralgia, and myopathy.
Ophthalmologic Disorders - Retinal depigmentation and optic neuritis (see WARNINGS).
OVERDOSAGE
There is no known antidote for didanosine overdosage. In phase 1 studies, in which buffered
formulations of didanosine were initially administered at doses ten times the currently
recommended dose, toxicities included: pancreatitis, peripheral neuropathy, diarrhea,
hyperuricemia and hepatic dysfunction. Didanosine is not dialyzable by peritoneal dialysis,
although there is some clearance by hemodialysis (see CLINICAL PHARMACOLOGY:
Pharmacokinetics).
DOSAGE AND ADMINISTRATION
Dosage
Adults
VIDEX EC (didanosine) should be administered on an empty stomach.
VIDEX EC Delayed-Release Capsules should be swallowed intact.
The recommended daily dose is dependent on body weight and is administered as one
capsule given on a once-daily schedule as outlined in Table 12.
Dosing of VIDEX EC Delayed-Release Capsules
Patient Weight
Dosage
≥60 kg
400 mg once daily
<60 kg
250 mg once daily
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Pediatric Patients
VIDEX EC has not been studied in pediatric patients. Please consult the complete prescribing
information for VIDEX (didanosine) Chewable/Dispersible Buffered Tablets and Pediatric
Powder for Oral Solution for dosage and administration of didanosine to pediatric patients.
Dose Adjustment
Clinical and laboratory signs suggestive of pancreatitis should prompt dose suspension and
careful evaluation of the possibility of pancreatitis. VIDEX EC use should be discontinued
in patients with confirmed pancreatitis (see WARNINGS and PRECAUTIONS: Drug
Interactions).
Based on data with buffered didanosine formulations, patients with symptoms of
peripheral neuropathy may tolerate a reduced dose of VIDEX EC after resolution of the
symptoms of peripheral neuropathy upon drug interruption. If neuropathy recurs after resumption
of VIDEX EC, permanent discontinuation of VIDEX EC should be considered.
Concomitant Therapy
Tenofovir disoproxil fumarate. A dose reduction of VIDEX EC to 250 mg (adults weighing ≥60
kg with creatinine clearance ≥60 mL/min) or 200 mg (adults weighing <60 kg with creatinine
clearance ≥60 mL/min) once daily taken together with tenofovir and a light meal (≤400 kcalories,
≤20% fat) or in the fasted state is recommended. The appropriate dose of VIDEX EC
coadministered with tenofovir in patients with creatinine clearance <60 mL/min has not
been established. (See CLINICAL PHARMACOLOGY: Drug Interactions and
PRECAUTIONS: Drug Interactions.)
Renal Impairment
Dosing recommendations for VIDEX EC and VIDEX buffered formulations are different for
patients with renal impairment. Please consult the complete prescribing information on
administration of VIDEX (didanosine) buffered formulations to patients with renal impairment.
In adult patients with impaired renal function, the dose of VIDEX EC should be adjusted
to compensate for the slower rate of elimination. The recommended doses and dosing intervals of
VIDEX EC in adult patients with renal insufficiency are presented in Table 13.
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Recommended Dosage of VIDEX EC in Renal Impairment by Body
Weighta
Dosage
Creatinine
Clearance
(mL/min)
≥60 kg
<60 kg
≥60
400 once daily
250 once daily
30-59
200 once daily
125 once daily
10-29
125 once daily
125 once daily
<10
125 once daily
b
a Based on studies using a buffered formulation of didanosine.
b Not suitable for use in patients <60 kg with CLcr <10 mL/min. An alternate formulation
of didanosine should be used.
Patients Requiring Continuous Ambulatory Peritoneal Dialysis (CAPD) or
Hemodialysis
For patients requiring CAPD or hemodialysis, follow dosing recommendations for patients with
creatinine clearance less than 10 mL/min, shown in Table 13. It is not necessary to administer a
supplemental dose of didanosine following hemodialysis.
Hepatic Impairment (See WARNINGS and PRECAUTIONS.)
HOW SUPPLIED
VIDEX® EC (didanosine) Delayed-Release Capsules are white, opaque capsules that are
packaged in bottles with child-resistant closures as described in Table 14.
VIDEX EC Delayed-Release Capsules
125 mg capsule imprinted with BMS 125 mg 6671 in Tan
NDC No. 0087-6671-17
30 capsules/bottle
200 mg capsule imprinted with BMS 200 mg 6672 in Green
NDC No. 0087-6672-17
30 capsules/bottle
250 mg capsule imprinted with BMS 250 mg 6673 in Blue
NDC No. 0087-6673-17
30 capsules/bottle
400 mg capsule imprinted with BMS 400 mg 6674 in Red
NDC No. 0087-6674-17
30 capsules/bottle
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The capsules should be stored in tightly closed containers at 25° C (77° F). Excursions
between 15° and 30° C (59° and 86° F) are permitted [see USP Controlled Room Temperature].
HANDLING AND DISPOSAL
Disposal options include incineration, landfill, or sewer as dictated by specific circumstances and
relevant national, state, and local regulations.
US Patent Nos: 4,861,759, 5,254,539, and 5,880,106 (didanosine).
Patent also Pending (didanosine capsules).
Bristol-Myers Squibb Virology
Bristol-Myers Squibb Company
Princeton, NJ 08543 USA
XXXXX-XX XXXXXXXXX
Revised ____________
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PATIENT INFORMATION
Rx only
VIDEX® EC
(generic name = didanosine also known as ddI)
VIDEX® EC (didanosine) Delayed-Release Capsules
Enteric-Coated Beadlets
What is VIDEX EC?
VIDEX EC (pronounced VY dex ee see) is a prescription medicine used in combination with
other drugs to treat adults who are infected with HIV (the human immunodeficiency virus, the
virus that causes AIDS). VIDEX EC belongs to a class of drugs called nucleoside analogues. By
reducing the growth of HIV, VIDEX EC helps your body maintain its supply of CD4 cells, which
are important for fighting HIV and other infections.
VIDEX EC will not cure your HIV infection. At present there is no cure for HIV
infection. Even while taking VIDEX EC, you may continue to have HIV-related illnesses,
including infections with other disease-producing organisms. Continue to see your doctor
regularly and report any medical problems that occur.
VIDEX EC does not prevent a patient infected with HIV from passing the virus to other
people. To protect others, you must continue to practice safe sex and take precautions to prevent
others from coming in contact with your blood and other body fluids.
There is limited information on the antiviral response of long-term use of VIDEX EC.
In VIDEX EC, an enteric coating is used to protect the medicine while it is in your
stomach since stomach acids can break it down. The enteric coating dissolves when the medicine
reaches your small intestine.
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Who should not take VIDEX EC?
Do not take VIDEX EC if you are allergic to any of its ingredients, including its active
ingredient, didanosine, and the inactive ingredients. (See Inactive Ingredients at the end of this
leaflet.) Tell your doctor if you think you have had an allergic reaction to any of these
ingredients.
Because it has only been studied in adults, VIDEX EC is not recommended for children.
How should I take VIDEX EC?
How should I store it?
VIDEX EC should only be taken once daily. Your doctor will determine your dose based on your
body weight, kidney and liver function, other medicines you are taking, and any side effects that
you may have had with VIDEX EC or other medicines. Take VIDEX EC on an empty stomach.
Do not take VIDEX EC with food. Swallow the capsule whole; do not open it. Try not to miss a
dose, but if you do, take it as soon as possible. If it is almost time for the next dose, skip the
missed dose and continue your regular dosing schedule.
Store capsules in a tightly closed container at room temperature away from heat and
out of the reach of children and pets.
If you have kidney disease: If your kidneys are not working properly, your doctor will need to
do regular tests to check how they are working while you take VIDEX EC. Your doctor may also
lower your dosage of VIDEX EC.
What should I do if someone takes an overdose of VIDEX EC?
If someone may have taken an overdose of VIDEX EC, get medical help right away. Contact
their doctor or a poison control center.
What should I avoid while taking VIDEX EC?
Alcohol. Do not drink alcohol while taking VIDEX EC since alcohol may increase your risk of
pancreatitis (pain and inflammation of the pancreas) or liver damage.
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Other medicines. Other medicines, including those you can buy without a prescription, may
interfere with the actions of VIDEX EC or may increase the possibility or severity of side effects.
Do not take any medicine, vitamin supplement, or other health preparation without first
checking with your doctor.
Pregnancy. It is not known if VIDEX EC can harm a human fetus. Also, pregnant women have
experienced serious side effects when taking didanosine (the active ingredient in VIDEX EC) in
combination with ZERIT (stavudine), also known as d4T, and other HIV medicines. VIDEX EC
should be used during pregnancy only after discussion with your doctor. Tell your doctor if you
become pregnant or plan to become pregnant while taking VIDEX EC.
Nursing. Studies have shown didanosine (the active ingredient in VIDEX EC) is in the breast
milk of animals getting the drug. It may also be in human breast milk. The Centers for Disease
Control and Prevention (CDC) recommends that HIV-infected mothers not breast-feed. This
should reduce the risk of passing HIV infection to their babies and the potential for serious
adverse reactions in nursing infants. Therefore, do not nurse a baby while taking VIDEX EC.
What are the possible side effects of VIDEX EC?
Pancreatitis. Pancreatitis is a dangerous inflammation of the pancreas that may cause death.
Tell your doctor right away if you develop stomach pain, nausea, or vomiting. These can be
signs of pancreatitis. Before starting VIDEX EC therapy, let your doctor know if you have ever
had pancreatitis. This condition is more likely to happen in people who have had it before. It is also
more likely in people with advanced HIV disease. However, it can occur at any stage of HIV disease.
It may be more common in patients with kidney problems, those who drink alcohol, and those who are
also treated with stavudine or hydroxyurea. If you get pancreatitis, your doctor will tell you to stop
taking VIDEX EC.
Lactic acidosis, severe liver enlargement, and liver failure, including deaths, have been
reported among patients taking VIDEX EC (including pregnant women). Symptoms that may
indicate a liver problem are:
• feeling very weak, tired, or uncomfortable,
• unusual or unexpected stomach discomfort,
• feeling cold,
• feeling dizzy or lightheaded,
• suddenly developing a slow or irregular heartbeat.
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Lactic acidosis is a medical emergency that must be treated in a hospital.
If you notice any of these symptoms or if your medical condition changes, stop taking
VIDEX EC and call your doctor right away. Women, overweight patients, and those who have
been treated for a long time with other medicines used to treat HIV infection are more likely to
develop lactic acidosis. Your doctor should check your liver function periodically while you are
taking VIDEX EC. You should be especially careful if you have a history of heavy alcohol use or
a liver problem.
Vision changes. VIDEX EC may affect the nerves in your eyes. Because of this, you should have
regular eye examinations. You should also report any changes in vision to your doctor right
away. This includes, for example, seeing colors abnormally or blurred vision.
Peripheral neuropathy. This is a problem with the nerves in your hands or feet. The nerve
problem may be serious. Tell your doctor right away if you have continuing numbness,
tingling, or pain in the feet or hands.
Before starting VIDEX EC therapy, let your doctor know if you have ever had peripheral
neuropathy. This condition is more likely to happen in people who have had it before. It is also
more likely in patients taking medicines that affect the nerves and in people with advanced HIV
disease. However, it can occur at any stage of HIV disease. If you get peripheral neuropathy,
your doctor will tell you to stop taking VIDEX EC. After stopping VIDEX EC, the symptoms
may get worse for a short time and then get better. Once symptoms of peripheral neuropathy go
away completely, you and your doctor should decide if starting VIDEX EC is right for you. If
so, you might be started at a lower dose.
Special note about other medicines. If you take VIDEX EC along with other medicines with
similar side effects, you may increase the chance of having these side effects. For example, using
VIDEX EC in combination with other medicines that may cause pancreatitis, peripheral
neuropathy, or liver problems (including stavudine and hydroxyurea) may increase your chance
of having these side effects.
Other side effects: The most common side effects in adults taking VIDEX EC in combination
with other HIV drugs included diarrhea, nausea, headache, vomiting, and rash.
Changes in body fat have been seen in some patients taking antiretroviral therapy. These
changes may include increased amount of fat in the upper back and neck (“buffalo hump”),
breast, and around the trunk. Loss of fat from the legs, arms, and face may also happen. The
cause and long-term health effects of these conditions are not known at this time.
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Inactive Ingredients:
Carboxymethylcellulose sodium 12, diethyl phthalate, methacrylic acid copolymer, sodium
hydroxide, sodium starch glycolate, talc, colloidal silicon dioxide, gelatin, sodium lauryl sulfate,
and titanium dioxide.
This medicine was prescribed for your particular condition. Do not use VIDEX EC for another condition or give it to
others. Keep VIDEX EC and all medicines out of the reach of children. Throw away VIDEX EC when it is outdated
or no longer needed by flushing it down the toilet or pouring it down the sink.
This summary does not include everything there is to know about VIDEX EC. Medicines are sometimes
prescribed for purposes other than those listed in a Patient Information Leaflet. If you have questions or concerns, or want
more information about VIDEX EC, your physician and pharmacist have the complete prescribing information upon which
this leaflet is based. You may want to read it and discuss it with your doctor or other healthcare professional. Remember, no
written summary can replace careful discussion with your doctor.
Bristol-Myers Squibb Virology
Bristol-Myers Squibb Company
Princeton, NJ 08543 USA
This Patient Information Leaflet has been approved by the U.S. Food and Drug Administration.
XXXXX-XX
XXXXXXXXX
Revised _____________________
Based on package insert dated ______________________
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Rx only
VIDEX (didanosine)
VIDEX (didanosine) Chewable/Dispersible Buffered Tablets
VIDEX (didanosine) Pediatric Powder for Oral Solution
(Patient Information Leaflet Included)
WARNING
FATAL AND NONFATAL PANCREATITIS HAVE OCCURRED DURING THERAPY
WITH VIDEX USED ALONE OR IN COMBINATION REGIMENS IN BOTH
TREATMENT-NAIVE
AND
TREATMENT-EXPERIENCED
PATIENTS,
REGARDLESS OF DEGREE OF IMMUNOSUPPRESSION. VIDEX SHOULD BE
SUSPENDED
IN
PATIENTS
WITH
SUSPECTED
PANCREATITIS
AND
DISCONTINUED
IN
PATIENTS
WITH
CONFIRMED
PANCREATITIS
(SEE
WARNINGS).
LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS,
INCLUDING FATAL CASES, HAVE BEEN REPORTED WITH THE USE OF
NUCLEOSIDE
ANALOGUES
ALONE
OR
IN
COMBINATION,
INCLUDING
DIDANOSINE AND OTHER ANTIRETROVIRALS. FATAL LACTIC ACIDOSIS HAS
BEEN REPORTED IN PREGNANT WOMEN WHO RECEIVED THE COMBINATION
OF DIDANOSINE AND STAVUDINE WITH OTHER ANTIRETROVIRAL AGENTS.
THE COMBINATION OF DIDANOSINE AND STAVUDINE SHOULD BE USED WITH
CAUTION DURING PREGNANCY AND IS RECOMMENDED ONLY IF THE
POTENTIAL BENEFIT CLEARLY OUTWEIGHS THE POTENTIAL RISK (SEE
WARNINGS AND PRECAUTIONS: PREGNANCY).
DESCRIPTION
VIDEX (didanosine) is a brand name for didanosine (ddI), a synthetic purine nucleoside
analogue
active
against
the
Human
Immunodeficiency
Virus
(HIV).
VIDEX
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Chewable/Dispersible Buffered Tablets are available for oral administration in strengths of 25,
50, 100, 150, and 200 mg of didanosine. Each tablet is buffered with calcium carbonate and
magnesium hydroxide. VIDEX tablets also contain aspartame, sorbitol, microcrystalline
cellulose, polyplasdone, mandarin-orange flavor, and magnesium stearate.
VIDEX Pediatric Powder for Oral Solution is supplied for oral administration in 4- or 8-ounce
glass bottles containing 2 or 4 grams of didanosine, respectively.
Didanosine is also available as an enteric-coated formulation (VIDEX® EC Delayed-Release
Capsules). Please consult the prescribing information for VIDEX EC (didanosine).
The chemical name for didanosine is 2',3'-dideoxyinosine. The structural formula is:
Didanosine is a white crystalline powder with the molecular formula C10H12N4O3 and a
molecular weight of 236.2. The aqueous solubility of didanosine at 25° C and pH of
approximately 6 is 27.3 mg/mL. Didanosine is unstable in acidic solutions. For example, at pH
<3 and 37° C, 10% of didanosine decomposes to hypoxanthine in less than 2 minutes.
MICROBIOLOGY
Mechanism of Action
Didanosine is a synthetic nucleoside analogue of the naturally occurring nucleoside
deoxyadenosine in which the 3'-hydroxyl group is replaced by hydrogen. Intracellularly,
didanosine is converted by cellular enzymes to the active metabolite, dideoxyadenosine
5'-triphosphate. Dideoxyadenosine 5'-triphosphate inhibits the activity of HIV-1 reverse
transcriptase both by competing with the natural substrate, deoxyadenosine 5'-triphosphate, and
by its incorporation into viral DNA causing termination of viral DNA chain elongation.
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In Vitro HIV Susceptibility
The in vitro anti-HIV-1 activity of didanosine was evaluated in a variety of HIV-1 infected
lymphoblastic cell lines and monocyte/macrophage cell cultures. The concentration of drug
necessary to inhibit viral replication by 50% (IC50) ranged from 2.5 to 10 µM (1 µM =
0.24 µg/mL) in lymphoblastic cell lines and 0.01 to 0.1 µM in monocyte/macrophage cell
cultures. The relationship between in vitro susceptibility of HIV to didanosine and the inhibition
of HIV replication in humans has not been established.
Drug Resistance
HIV-1 isolates with reduced sensitivity to didanosine have been selected in vitro and were also
obtained from patients treated with didanosine. Genetic analysis of isolates from didanosine-
treated patients showed mutations in the reverse transcriptase gene that resulted in the amino acid
substitutions K65R, L74V, and M184V. The L74V mutation was most frequently observed in
clinical isolates. Phenotypic analysis of HIV-1 isolates from 60 patients (some with prior
zidovudine treatment) receiving 6 to 24 months of didanosine monotherapy showed that isolates
from 10 of 60 patients exhibited an average of a 10-fold decrease in susceptibility to didanosine
in vitro compared to baseline isolates. Clinical isolates that exhibited a decrease in didanosine
susceptibility harbored one or more didanosine-associated mutations. The clinical relevance of
genotypic and phenotypic changes associated with didanosine therapy has not been established.
Cross-resistance
HIV-1 isolates from 2 of 39 patients receiving combination therapy for up to 2 years with
zidovudine and didanosine exhibited decreased susceptibility to zidovudine, didanosine,
zalcitabine, stavudine, and lamivudine in vitro. These isolates harbored five mutations (A62V,
V75I, F77L, F116Y, and Q151M) in the reverse transcriptase gene. The clinical relevance of
these observations has not been established.
CLINICAL PHARMACOLOGY
Animal Toxicology
Evidence of a dose-limiting skeletal muscle toxicity has been observed in mice and rats (but not
in dogs) following long-term (greater than 90 days) dosing with didanosine at doses that were
approximately 1.2 to 12 times the estimated human exposure. The relationship of this finding to
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the potential of VIDEX (didanosine) to cause myopathy in humans is unclear. However, human
myopathy has been associated with administration of VIDEX and other nucleoside analogues.
Pharmacokinetics
The pharmacokinetic parameters of didanosine are summarized in Table 1. Didanosine is rapidly
absorbed, with peak plasma concentrations generally observed from 0.25 to 1.50 hours following
oral dosing. Increases in plasma didanosine concentrations were dose proportional over the
range of 50 to 400 mg. Steady-state pharmacokinetic parameters did not differ significantly from
values obtained after a single dose. Binding of didanosine to plasma proteins in vitro was low
(<5%). Based on data from in vitro and animal studies, it is presumed that the metabolism of
didanosine in man occurs by the same pathways responsible for the elimination of endogenous
purines.
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Mean ± SD Pharmacokinetic Parameters for Didanosine in Adult and Pediatric
Patients
Pediatric Patientsb
Parameter
Adult
Patients
a
8 months to
19 years
2 weeks to 4
months
Oral
bioavailability (%)
42 ± 12
25 ± 20
ND
Apparent volume
of distributionc
(L/m2)
43.70 ±
8.90
28 ± 15
ND
CSF-plasma ratiod
21 ±
0.03%e
46%
(range 12-
85%)
ND
Systemic
clearancec
(mL/min/m2)
526 ±
64.7
516 ± 184
ND
Renal clearancef
(mL/min/m2)
223 ±
85.0
240 ± 90
ND
Apparent oral
clearanceg
(mL/min/m2)
1252 ±
154
2064 ± 736
1353 ± 759
Elimination half-
lifef (h)
1.5 ±
0.4
0.8 ± 0.3
1.2 ± 0.3
Urinary recovery
of didanosinef (%)
18 ± 8
18 ± 10
ND
CSF = cerebrospinal fluid, ND = not determined.
a Parameter units for adults were converted to the same units in pediatric patients to facilitate
comparisons among populations: mean adult body weight = 70 kg and mean adult body surface area
= 1.73 m2.
b In 1-day old infants (n=10), the mean ± SD apparent oral clearance was 1523 ± 1176 mL/min/m2 and
half-life was 2.0 ± 0.7 h.
c Following IV administration.
d Following IV administration in adults and IV or oral administration in pediatric patients.
e Mean ± SE.
f Following oral administration.
g Apparent oral clearance estimate was determined as the ratio of the mean systemic clearance and the
mean oral bioavailability estimate.
Effect of Food on Absorption of Didanosine: Didanosine peak plasma concentrations
(CMAX) and area under the plasma concentration time curve (AUC) were decreased by
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approximately 55% when VIDEX tablets were administered up to 2 hours after a meal.
Administration of VIDEX tablets up to 30 minutes before a meal did not result in any significant
changes in bioavailability. VIDEX should be taken on an empty stomach, at least 30 minutes
before or 2 hours after eating. (See DOSAGE AND ADMINISTRATION.)
Special Populations
Renal Insufficiency: It is recommended that the VIDEX (didanosine) dose be modified in
patients with reduced creatinine clearance and in patients receiving maintenance hemodialysis
(see DOSAGE AND ADMINISTRATION). Data from two studies in adults indicated that the
apparent oral clearance of didanosine decreased and the terminal elimination half-life increased
as creatinine clearance decreased (see Table 2). Following oral administration, didanosine was
not detectable in peritoneal dialysate fluid (n=6); recovery in hemodialysate (n=5) ranged from
0.6% to 7.4% of the dose over a 3-4 hour dialysis period. The absolute bioavailability of
didanosine was not affected in patients requiring dialysis.
Mean ± SD Pharmacokinetic Parameters for Didanosine Following a Single
Oral Dose
Creatinine Clearance (mL/min)
Paramet
er
≥ 90
(n=12)
60-90
(n=6)
30-59
(n=6)
10-29
(n=3)
Dialysis
Patients
(n=11)
CLcr
(mL/min
)
112 ±
22
68 ± 8
46 ± 8
13 ± 5
ND
CL/F
(mL/min
)
2164 ±
638
1566 ±
833
1023 ±
378
628 ±
104
543 ± 174
CLR
(mL/min
)
458 ±
164
247 ±
153
100 ±
44
20 ± 8
<10
T½ (h)
1.42 ±
0.33
1.59 ±
0.13
1.75 ±
0.43
2.0 ±
0.3
4.1 ± 1.2
ND = not determined due to anuria.
CLcr = creatinine clearance.
CL/F = apparent oral clearance.
CLR = renal clearance.
Pediatric Patients: The pharmacokinetics of didanosine have been evaluated in HIV-
exposed and -infected pediatric patients from birth to 19 years of age (see Table 1). Overall, the
pharmacokinetics of didanosine in pediatric patients are similar to those of didanosine in adults.
Didanosine plasma concentrations appear to increase in proportion to oral doses ranging from 25
to 120 mg/m2 in pediatric patients less than 5 months old and from 80 to 180 mg/m2 in children
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above 8 months old. For information on controlled clinical studies in pediatric patients, see
INDICATIONS AND USAGE: Clinical Studies and PRECAUTIONS: Pediatric Use.
Geriatric Patients: Didanosine pharmacokinetics have not been studied in patients over 65
years of age.
Gender: The effects of gender on didanosine pharmacokinetics have not been studied.
Drug Interactions: Ribavirin has been shown in vitro to increase intracellular triphosphate
levels of didanosine, which could cause or worsen clinical toxicities (see PRECAUTIONS:
Drug Interactions).
Tables 3 and 4 summarize the effects on AUC and CMAX, with a 90% or 95% confidence
interval (CI) when available, following coadministration of VIDEX with a variety of drugs. For
most of the listed drugs, no clinically significant pharmacokinetic interactions were observed.
Clinical recommendations based on drug interaction studies for drugs in bold font are included in
PRECAUTIONS: Drug Interactions and DOSAGE AND ADMINISTRATION (for
tenofovir).
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Results of Drug Interaction Studies with VIDEX: Effects of Coadministered Drug on
Didanosine Plasma AUC and CMAX Values
Drugs With Clinical Recommendations Regarding Coadministration (see PRECAUTIONS: Drug Interactions)
Drug
Didanosine
Dosage
n
AUC of
Didanosine
(95% CI)
CMAX of
Didanosine
(95% CI)
allopurinol
renally impaired, 300 mg/day
200 mg single dose
2
↑ 312%
↑ 232%
healthy volunteer, 300 mg/day
for 7 days
400 mg single dose
14
↑ 113%
↑ 69%
ciprofloxacin, 750 mg q12h
for 3 days, 2 h before
didanosine
200 mg q12h for 3
days
8a
↓ 16%
↓ 28%
ganciclovir, 1000 mg q8h, 2 h
after didanosine
200 mg q12h
12
↑ 111%
NA
indinavir, 800 mg single dose
simultaneous
1 h before didanosine
200 mg single dose
200 mg single dose
16
16
↔
↓ 17% (-27,
- 7%)b
↔
↓ 13% (-28,
5%)b
ketoconazole, 200 mg/day for
4 days, 2 h before
didanosine
375 mg q12h for 4
days
12
a
↔
↓ 12%
methadone, chronic
maintenance dose
200 mg single dose
16,
10
c
↓ 57%
↓ 66%
tenofovir,d,e 300 mg once
daily 1 h after didanosine
250f or 400 mg
once daily for 7
days
14
↑ 44%
(31, 59%)b
↑ 28%
(11, 48%)b
No Clinically Significant Interaction Observed
Drug
Didanosine
Dosage
n
AUC of
Didanosine
(95% CI)
CMAX of
Didanosine
(95% CI)
loperamide, 4 mg q6h for 1
day
300 mg single
dose
12
a
↔
↓ 23%
metoclopramide, 10 mg single
dose
300 mg single
dose
12
a
↔
↑ 13%
ranitidine, 150 mg single
dose, 2 h before didanosine
375 mg single
dose
12
a
↑ 14%
↑ 13%
rifabutin, 300 or 600 mg/day
for 12 days
167 or 250 mg
q12h for 12 days
11
↑ 13% (-1,
27%)
↑ 17% (-4,
38%)
ritonavir, 600 mg q12h for 4
days
200 mg q12h for 4
days
12
↓ 13% (0,
23%)
↓ 16% (5,
26%)
stavudine, 40 mg q12h for 4
days
100 mg q12h for 4
days
10
↔
↔
sulfamethoxazole, 1000 mg
single dose
200 mg single
dose
8a
↔
↔
trimethoprim, 200 mg single
dose
200 mg single
dose
8a
↔
↑ 17% (-23,
77%)
zidovudine, 200 mg q8h for 3
days
200 mg q12h for 3
days
6a
↔
↔
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Results of Drug Interaction Studies with VIDEX: Effects of Coadministered Drug on
Didanosine Plasma AUC and CMAX Values
↑ indicates increase.
↓ indicates decrease.
↔ indicates no change, or mean increase or decrease of <10%.
a
HIV-infected patients.
b
90% CI.
c Parallel-group design; entries are subjects receiving combination and control regimens, respectively.
d tenofovir disoproxil fumarate.
e For results of drug interaction studies between the enteric-coated formulation of didanosine (VIDEX EC) and
tenofovir, see the complete prescribing information for VIDEX EC.
f patients <60 kg with creatinine clearance >60 mL/min.
NA Not available.
Results of Drug Interaction Studies with VIDEX: Effects of Didanosine on
Coadministered Drug Plasma AUC and CMAX Values
Drugs With Clinical Recommendations Regarding Coadministration (see PRECAUTIONS: Drug
Interactions)
Drug
Didanosine
Dosage
n
AUC of
Coadministe
red Drug
(95% CI)
CMAX of
Coadministe
red Drug
(95% CI)
ciprofloxacin
750 mg q12h for 3 days, 2 h
before didanosine
750 mg single dose
200 mg q12h for 3
days
buffered placebo
tablet
8
a
1
2
↓ 26%
↓ 98%
↓ 16%
↓ 93%
delavirdine, 400 mg single
dose
simultaneous
1 h before didanosine
125 or 200 mg q12h
125 or 200 mg q12h
1
2
a
1
2
a
↓ 32%
↑ 20%
↓ 53%
↑ 18%
ganciclovir, 1000 mg q8h, 2
h after didanosine
200 mg q12h
1
2
a
↓ 21%
NA
indinavir, 800 mg single
dose
simultaneous
1 h before didanosine
200 mg single dose
200 mg single dose
1
6
1
6
↓ 84%
↓ 11%
↓ 82%
↓ 4%
ketoconazole, 200 mg/day
for 4 days, 2 h before
didanosine
375 mg q12h for 4
days
1
2
a
↓ 14%
↓ 20%
nelfinavir, 750 mg single
dose, 1 h after didanosine
200 mg single dose
1
0
a
↑ 12%
↔
No Clinically Significant Interaction Observed
Drug
Didanosine Dosage
n
AUC of
Coadministe
red Drug
CMAX of
Coadministe
red Drug
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Results of Drug Interaction Studies with VIDEX: Effects of Didanosine on
Coadministered Drug Plasma AUC and CMAX Values
(95% CI)
(95% CI)
dapsone, 100 mg single dose
200 mg q12h for 14
days
6
a
↔
↔
ranitidine, 150 mg single
dose, 2 h before
didanosine
375 mg single dose
1
2
a
↓ 16%
↔
ritonavir, 600 mg q12h for 4
days
200 mg q12h for 4
days
1
2
↔
↔
stavudine, 40 mg q12h for 4
days
100 mg q12h for 4
days
1
0
a
↔
↑ 17%
sulfamethoxazole, 1000 mg
single dose
200 mg single dose
8
a
↓ 11% (-17,
-4%)
↓ 12% (-28,
8%)
tenofovir,b 300 mg once
daily 1 h after didanosine
250c or 400 mg
once daily for 7
days
1
4
↔
↔
trimethoprim, 200 mg single
dose
200 mg single dose
8
a
↑ 10% (-9,
34%)
↓ 22% (-59,
49%)
zidovudine, 200 mg q8h for 3
days
200 mg q12h for 3
days
6
a
↓ 10% (-27,
11%)
↓ 16.5% (-
53, 47%)
↑ indicates increase.
↓ indicates decrease.
↔ indicates no change, or mean increase or decrease of <10%.
a
HIV-infected patients.
b tenofovir disoproxil fumarate.
c patients <60 kg with creatinine clearance >60 mL/min.
NA Not available.
INDICATIONS AND USAGE
VIDEX in combination with other antiretroviral agents is indicated for the treatment of
HIV-1 infection (see Clinical Studies).
Clinical Studies
Combination Therapy
START 2 was a multicenter, randomized, open-label study comparing VIDEX (200 mg twice
daily)/stavudine/indinavir to zidovudine/lamivudine/indinavir in 205 treatment-naive patients.
Both regimens resulted in a similar magnitude of suppression of HIV RNA levels and increases
in CD4 cell counts through 48 weeks.
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Study A1454-148 was a randomized, open-label, multicenter study comparing treatment with
VIDEX (400 mg once daily) plus stavudine (40 mg twice daily) and nelfinavir (750 mg three
times daily) versus zidovudine (300 mg twice daily) plus lamivudine (150 mg twice daily) and
nelfinavir (750 mg three times daily) in 756 treatment-naive patients, with a median CD4 cell
count of 340 cells/mm3 (range 80 to 1568 cells/mm3) and a median plasma HIV-1 RNA of 4.69
log10 copies/mL (range 2.6 to 5.9 log10 copies/mL) at baseline. Median CD4 cell count increases
at 48 weeks were 188 cells/mm3 in both treatment groups. Treatment response and outcomes
through 48 weeks are shown in Figure 1 and Table 5.
re 1:
Treatment Response Through Week 48*, AI454-148
* Percent of patients at each time point who have HIV RNA <400 or <50 copies/mL, are on their original
study medication (except stavudine-zidovudine switches), and have not experienced an AIDS-defining
event.
0
20
40
60
80
100
0
8
16
24
32
40
48
Study Week
Percent of patients
] < 400 c/mL
] < 50 c/mL
VIDEX+stavudine+nelfinavir (n=503)
zidovudine+lamivudine+nelfinavir (n=253)
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Outcomes of Randomized Treatment through Week 48, AI454-148
Percent of Patients with HIV RNA <400 copies/mL (<50
copies/mL)
VIDEX/stavudine/nelfina
vir
lamivudine/zidovudine/ne
lfinavir
Week 48 Status
n=503
n=253
Responder a
50* (34*)
59 (47)
Virologic failureb
36 (57)
32 (48)
Death or disease progression
<1 (<1)
1 (<1)
Discontinued due to adverse
events
4 (2)
2 (<1)
Discontinued due to other
reasonsc
6 (3)
4 (2)
Never initiated treatment
4 (4)
2 (2)
* p <0.05 for the differences between treatment groups, by Cochran-Mantel-Haenszel test.
a Patients achieved virologic response [two consecutive viral loads <400 (<50) copies/mL] and
maintained it to Week 48.
b Includes viral rebound and failing to achieve confirmed <400 (<50) copies/mL by Week 48.
c Includes lost to follow-up, noncompliance, withdrawal, and pregnancy.
Monotherapy
The efficacy of VIDEX was demonstrated in two randomized, double-blind studies comparing
VIDEX, given on a twice-daily schedule, to zidovudine, given three times daily, in 617 (ACTG
116A, conducted 1989-1992) and 913 (ACTG116B/117, conducted 1989-1991) patients with
symptomatic HIV infection or AIDS who were treated for more than one year. In treatment-
naive patients (ACTG 116A), the rate of HIV disease progression or death was similar between
the treatment groups; mortality rates were 26% for patients receiving VIDEX and 21% for
patients receiving zidovudine. Of the patients who had received previous zidovudine treatment
(ACTG 116B/117), those treated with VIDEX had a lower rate of HIV disease progression or
death (32%) compared to those treated with zidovudine (41%); however, survival rates were
similar between the treatment groups.
Efficacy in pediatric patients was demonstrated in a randomized, double-blind, controlled study
(ACTG 152, conducted 1991-1995) involving 831 patients 3 months to 18 years of age treated
for more than 1.5 years with zidovudine (180 mg/m2 q6h), VIDEX (120 mg/m2 q12h), or
zidovudine (120 mg/m2 q6h) plus VIDEX (90 mg/m2 q12h). Patients treated with VIDEX or
VIDEX plus zidovudine had lower rates of HIV disease progression or death compared with
those treated with zidovudine alone.
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Studies have demonstrated that the clinical benefit of monotherapy with antiretrovirals,
including VIDEX, was time limited.
CONTRAINDICATION
VIDEX (didanosine) is contraindicated in patients with previously demonstrated clinically
significant hypersensitivity to any of the components of the formulations.
WARNINGS
1.
Pancreatitis
FATAL AND NONFATAL PANCREATITIS HAVE OCCURRED DURING THERAPY
WITH VIDEX USED ALONE OR IN COMBINATION REGIMENS IN BOTH
TREATMENT-NAIVE
AND
TREATMENT-EXPERIENCED
PATIENTS,
REGARDLESS OF DEGREE OF IMMUNOSUPPRESSION. VIDEX SHOULD BE
SUSPENDED IN PATIENTS WITH SIGNS OR SYMPTOMS OF PANCREATITIS AND
DISCONTINUED IN PATIENTS WITH CONFIRMED PANCREATITIS. PATIENTS
TREATED WITH VIDEX IN COMBINATION WITH STAVUDINE, WITH OR
WITHOUT HYDROXYUREA, MAY BE AT INCREASED RISK FOR PANCREATITIS.
When treatment with life-sustaining drugs known to cause pancreatic toxicity is required,
suspension of VIDEX (didanosine) therapy is recommended. In patients with risk factors for
pancreatitis, VIDEX should be used with extreme caution and only if clearly indicated. Patients
with advanced HIV infection, especially the elderly, are at increased risk of pancreatitis and
should be followed closely. Patients with renal impairment may be at greater risk for pancreatitis
if treated without dose adjustment.
The frequency of pancreatitis is dose related. In phase 3 studies, incidence ranged from
1% to 10% with doses higher than are currently recommended and 1% to 7% with recommended
dose.
In pediatric phase 1 studies, pancreatitis occurred in 3% (2/60) of patients treated at entry
doses below 300 mg/m2/day and in 13% (5/38) of patients treated at higher doses. In study
ACTG 152, pancreatitis occurred in none of the 281 pediatric patients who received didanosine
120 mg/m2 q12h and in <1% of the 274 pediatric patients who received didanosine 90 mg/m2
q12h in combination with zidovudine. VIDEX use should be suspended in pediatric patients with
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signs or symptoms of pancreatitis and discontinued in pediatric patients with confirmed
pancreatitis.
2.
Lactic Acidosis/Severe Hepatomegaly with Steatosis
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have
been reported with the use of nucleoside analogues alone or in combination, including
didanosine and other antiretrovirals. A majority of these cases have been in women. Obesity
and prolonged nucleoside exposure may be risk factors. Fatal lactic acidosis has been reported in
pregnant women who received the combination of didanosine and stavudine with other
antiretroviral agents. The combination of didanosine and stavudine should be used with caution
during pregnancy and is recommended only if the potential benefit clearly outweighs the
potential risk (see PRECAUTIONS: Pregnancy). Particular caution should be exercised when
administering VIDEX to any patient with known risk factors for liver disease; however, cases
have also been reported in patients with no known risk factors. Treatment with VIDEX should
be suspended in any patient who develops clinical or laboratory findings suggestive of
symptomatic hyperlactatemia, lactic acidosis, or pronounced hepatotoxicity (which may include
hepatomegaly and steatosis even in the absence of marked transaminase elevations).
3.
Retinal Changes and Optic Neuritis
Retinal changes and optic neuritis have been reported in adult and pediatric patients.
Periodic retinal examinations should be considered for patients receiving VIDEX. (See
ADVERSE REACTIONS.)
PRECAUTIONS
Frequency of Dosing
The preferred dosing frequency of VIDEX is twice daily because there is more evidence to
support the effectiveness of this dosing frequency. Once-daily dosing should be considered only
for adult patients whose management requires once-daily dosing of VIDEX (see INDICATIONS
AND USAGE: Clinical Studies).
VIDEX should be taken on an empty stomach, at least 30 minutes before or 2 hours after
eating.
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Peripheral Neuropathy
Peripheral neuropathy, manifested by numbness, tingling, or pain in the hands or feet, has been
reported in patients receiving VIDEX therapy. Peripheral neuropathy has occurred more
frequently in patients with advanced HIV disease, in patients with a history of neuropathy, or in
patients being treated with neurotoxic drug therapy, including stavudine (see ADVERSE
REACTIONS).
Fat Redistribution
Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement
(buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid
appearance” have been observed in patients receiving antiretroviral therapy. The mechanism and
long-term consequences of these events are currently unknown. A causal relationship has not
been established.
General
Patients with Phenylketonuria: VIDEX Chewable/Dispersible Buffered Tablets contain the
following quantities of phenylalanine:
All Strengths
Phenylalanine per 2-tablet dose
73 mg
Phenylalanine per tablet
36.5 mg
Patients with Renal Impairment: Patients with renal impairment (creatinine clearance <60
mL/min) may be at greater risk of toxicity from VIDEX due to decreased drug clearance (see
CLINICAL PHARMACOLOGY). A dose reduction is recommended in these patients (see
DOSAGE AND ADMINISTRATION). The magnesium content of each buffered tablet of
VIDEX is 8.6 mEq. This may present an excessive load of magnesium to patients with significant
renal impairment, particularly after prolonged dosing.
Patients with Hepatic Impairment: It is unknown if hepatic impairment significantly
affects didanosine pharmacokinetics. Therefore, these patients should be monitored closely for
evidence of didanosine toxicity.
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Hyperuricemia: VIDEX has been associated with asymptomatic hyperuricemia; treatment
suspension may be necessary if clinical measures aimed at reducing uric acid levels fail.
Information for Patients (See Patient Information Leaflet.)
Patients should be informed that a serious toxicity of VIDEX used alone and in combination
regimens, is pancreatitis, which may be fatal.
Patients should be informed that the preferred dosing frequency of VIDEX is twice daily
because there is more evidence to support the effectiveness of this dosing frequency. Once-daily
dosing should be considered only for adult patients whose management requires once-daily
dosing of VIDEX.
Patients should also be aware that peripheral neuropathy, manifested by numbness,
tingling, or pain in hands or feet, may develop during therapy with VIDEX. Patients should be
counseled that peripheral neuropathy occurs with greatest frequency in patients with advanced
HIV disease or a history of peripheral neuropathy, and that dose modification and/or
discontinuation of VIDEX may be required if toxicity develops.
Patients should be informed that when VIDEX is used in combination with other agents
with similar toxicities, the incidence of adverse events may be higher than when VIDEX is used
alone. These patients should be followed closely.
Patients should be cautioned about the use of medications or other substances, including
alcohol, that may exacerbate VIDEX toxicities.
Patients should be advised that to ensure proper acid neutralization in the stomach they
must take at least two of the appropriate strength VIDEX tablets at each dose. To reduce the risk
of gastrointestinal side effects from excess antacid, patients should take no more than four
VIDEX tablets at each dose.
VIDEX (didanosine) is not a cure for HIV infection, and patients may continue to develop
HIV-associated illnesses, including opportunistic infection. Therefore, patients should remain
under the care of a physician when using VIDEX. Patients should be advised that VIDEX
therapy has not been shown to reduce the risk of transmission of HIV to others through sexual
contact or blood contamination. Patients should be informed that the long-term effects of VIDEX
are unknown at this time.
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Patients should be informed that redistribution or accumulation of body fat may occur in
patients receiving antiretroviral therapy and that the cause and long-term health effects of these
conditions are not known at this time.
Drug Interactions (see also CLINICAL PHARMACOLOGY: Drug
Interactions)
Drug interactions that have been established based on drug interaction studies are listed with the
pharmacokinetic results in CLINICAL PHARMACOLOGY: Drug Interactions (Tables 3 and
4). The clinical recommendations based on the results of these studies are listed in Table 7.
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Established Drug Interactions with VIDEX
Coadministration Not Recommended Based on Drug Interaction Studies (see CLINICAL
PHARMACOLOGY: Drug Interactions for Magnitude of Interaction)
Drug
Effect
Clinical Comment
allopurinol
↑ didanosine concentration
Coadministration not recommended.
Alteration in Dose or Regimen Recommended Based on Drug Interaction Studies (see CLINICAL
PHARMACOLOGY: Drug Interactions for Magnitude of Interaction)
Drug
Effect
Clinical Comment
ciprofloxaci
n
↓ ciprofloxacin concentration
Administer VIDEX at least 2 hours
after or 6 hours before ciprofloxacin.
delavirdine
↓ delavirdine concentration
Administer VIDEX 1 hour after
delavirdine.
ganciclovir
↑ didanosine concentration
Appropriate doses for this
combination, with respect to efficacy
and safety, have not been
established.
indinavir
↓ indinavir concentration
Administer VIDEX 1 hour after
indinavir.
methadone
↓ didanosine concentration
Appropriate doses for this
combination, with respect to efficacy
and safety, have not been
established.
nelfinavir
No interaction 1 hour after
didanosine
Administer nelfinavir 1 hour after
VIDEX.
tenofovir
disoproxil
fumarate
↑ didanosine concentration
A dose reduction of VIDEX to 250
mg (adults weighing ≥60 kg with
creatinine clearance ≥60 mL/min) or
200 mg (adults weighing <60 kg
with creatinine clearance ≥60
mL/min) once daily is recommended.
VIDEX and tenofovir may be taken
together in the fasted state.
Alternatively, if tenofovir is taken
with food, VIDEX should be taken
on an empty stomach (at least 30
minutes before food or 2 hours after
food). Patients should be monitored
for didanosine-associated toxicities
(see below).
↑ indicates increase.
↓ indicates decrease.
Coadministration of VIDEX with drugs that are known to cause pancreatitis may
increase the risk of this toxicity (see WARNINGS: Pancreatitis). Because VIDEX
formulations either contain buffers or are mixed with antacids before administration, interactions
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may be anticipated with drugs whose absorption can be affected by the level of acidity in the
stomach and with drugs that have been demonstrated to interact with antacids containing
magnesium, calcium, or aluminum. Predicted drug interactions with VIDEX are listed in Table
8.
Predicted Drug Interactions with VIDEX
Use with Caution or Not Recommended, Risk of Adverse Reactions May Be Increased
Drug or Drug Class
Effect
Clinical Comment
Drugs that may cause
pancreatic toxicity
↑ risk of pancreatitis
Use only with extreme caution.a
Neurotoxic drugs
↑ risk of neuropathy
Use with caution.b
Antacids containing
magnesium or
aluminum
↑ side effects associated
with antacid
components
Use caution with VIDEX
Chewable/Dispersible Buffered
Tablets and Pediatric Powder for
Oral Solution.
Ribavirin
↑ risk of toxicity
Ribavirin has been shown in vitro to
increase intracellular triphosphate
levels of didanosine.
Coadministration is not
recommended (see below).
Use with Caution, Plasma Concentrations May Be Decreased by Coadministration with VIDEX
Drug Class
Effect
Clinical Comment
Azole antifungals
↓ ketoconazole or
itraconazole
concentration
Administer drugs such as
ketoconazole or itraconazole at least
2 hours before VIDEX.
Quinolone antibiotics
(see also ciprofloxacin
in Table 7)
↓ quinolone
concentration
Consult package insert of the
quinolone.
Tetracycline antibiotics
↓ antibiotic
concentration
Consult package insert of the
tetracycline.
↑ indicates increase.
↓ indicates decrease.
a Only if other drugs are not available and if clearly indicated. If treatment with life-sustaining drugs
that cause pancreatic toxicity is required, suspension of VIDEX is recommended (see WARNINGS:
Pancreatitis).
b See PRECAUTIONS: Peripheral Neuropathy.
Nucleoside/nucleotide analogues
Tenofovir disoproxil fumarate. Exposure to didanosine is increased when coadministered with
tenofovir (see Table 3). Increased exposure may cause or worsen didanosine-related clinical
toxicities, including pancreatitis, symptomatic hyperlactatemia/lactic acidosis, and
peripheral neuropathy. Coadministration of tenofovir with VIDEX should be undertaken
with caution, and patients should be monitored closely for didanosine-related toxicities.
VIDEX should be suspended if signs or symptoms of pancreatitis, symptomatic
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hyperlactatemia, or lactic acidosis develop (see WARNINGS). A dose reduction of VIDEX to
250 mg (adults weighing ≥60 kg with creatinine clearance ≥60 mL/min) or 200 mg (adults
weighing <60 kg with creatinine clearance ≥60 mL/min) once daily is recommended. VIDEX
and tenofovir may be taken together in the fasted state. Alternatively, if tenofovir is taken with
food, VIDEX should be taken on an empty stomach, at least 30 minutes before food or 2 hours
after food (see DOSAGE AND ADMINISTRATION). (The dosing recommendation for
coadministration of VIDEX EC and tenofovir disoproxil fumarate with respect to meal
consumption differs from that of VIDEX. See the complete prescribing information for VIDEX
EC.)
Ribavirin. Exposure to the active metabolite of didanosine (dideoxyadenosine 5’-triphosphate) is
increased when didanosine is coadministered with ribavirin (see Table 8). Fatal hepatic failure, as
well as peripheral neuropathy, pancreatitis, and symptomatic hyperlactatemia/lactic acidosis have
been reported in patients receiving both didanosine and ribavirin. Coadministration of didanosine
and ribavirin is not recommended.
Carcinogenesis and Mutagenesis
Lifetime carcinogenicity studies were conducted in mice and rats for 22 and 24 months,
respectively. In the mouse study, initial doses of 120, 800, and 1200 mg/kg/day for each sex
were lowered after 8 months to 120, 210, and 210 mg/kg/day for females and 120, 300, and 600
mg/kg/day for males. The two higher doses exceeded the maximally tolerated dose in females
and the high dose exceeded the maximally tolerated dose in males. The low dose in females
represented 0.68-fold maximum human exposure and the intermediate dose in males represented
1.7-fold maximum human exposure based on relative AUC comparisons. In the rat study, initial
doses were 100, 250, and 1000 mg/kg/day, and the high dose was lowered to 500 mg/kg/day after
18 months. The upper dose in male and female rats represented 3-fold maximum human
exposure.
Didanosine induced no significant increase in neoplastic lesions in mice or rats at
maximally tolerated doses.
Didanosine was positive in the following genetic toxicology assays: 1) the Escherichia
coli tester strain WP2 uvrA bacterial mutagenicity assay; 2) the L5178Y/TK+/- mouse lymphoma
mammalian cell gene mutation assay; 3) the in vitro chromosomal aberrations assay in cultured
human peripheral lymphocytes; 4) the in vitro chromosomal aberrations assay in Chinese
Hamster Lung cells; and 5) the BALB/c 3T3 in vitro transformation assay. No evidence of
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mutagenicity was observed in an Ames Salmonella bacterial mutagenicity assay or in rat and
mouse in vivo micronucleus assays.
Pregnancy, Reproduction, and Fertility
Pregnancy Category B. Reproduction studies have been performed in rats and rabbits at doses up
to 12 and 14.2 times the estimated human exposure (based upon plasma levels), respectively, and
have revealed no evidence of impaired fertility or harm to the fetus due to didanosine. At
approximately 12 times the estimated human exposure, didanosine was slightly toxic to female
rats and their pups during mid and late lactation. These rats showed reduced food intake and
body weight gains but the physical and functional development of the offspring was not impaired
and there were no major changes in the F2 generation. A study in rats showed that didanosine
and/or its metabolites are transferred to the fetus through the placenta. Animal reproduction
studies are not always predictive of human response.
There are no adequate and well-controlled studies of didanosine in pregnant women.
Didanosine should be used during pregnancy only if the potential benefit justifies the potential
risk.
Fatal lactic acidosis has been reported in pregnant women who received the combination
of didanosine and stavudine with other antiretroviral agents. It is unclear if pregnancy augments
the risk of lactic acidosis/hepatic steatosis syndrome reported in nonpregnant individuals
receiving nucleoside analogues (see WARNINGS: Lactic Acidosis/Severe Hepatomegaly with
Steatosis). The combination of didanosine and stavudine should be used with caution
during pregnancy and is recommended only if the potential benefit clearly outweighs the
potential risk. Health care providers caring for HIV-infected pregnant women receiving
didanosine should be alert for early diagnosis of lactic acidosis/hepatic steatosis syndrome.
Antiretroviral Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant
women exposed to didanosine and other antiretroviral agents, an Antiretroviral Pregnancy
Registry has been established. Physicians are encouraged to register patients by calling 1-800-
258-4263.
Nursing Mothers
The Centers for Disease Control and Prevention recommend that HIV-infected mothers not
breast-feed their infants to avoid risking postnatal transmission of HIV. A study in rats
showed that following oral administration, didanosine and/or its metabolites were excreted into
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the milk of lactating rats. It is not known if didanosine is excreted in human milk. Because of
both the potential for HIV transmission and the potential for serious adverse reactions in nursing
infants, mothers should be instructed not to breast-feed if they are receiving VIDEX.
Pediatric Use
Use of VIDEX in pediatric patients from 2 weeks of age through adolescence is supported by
evidence from adequate and well-controlled studies of VIDEX in adults and pediatric patients
(see INDICATIONS AND USAGE: Clinical Studies, CLINICAL PHARMACOLOGY,
ADVERSE REACTIONS, and DOSAGE AND ADMINISTRATION).
Dosing recommendations for VIDEX in patients less than 2 weeks of age cannot be made
because the pharmacokinetics of didanosine in these children are too variable to determine an
appropriate dose.
Geriatric Use
In an Expanded Access Program for patients with advanced HIV infection, patients aged 65 years
and older had a higher frequency of pancreatitis (10%) than younger patients (5%) (see
WARNINGS). Clinical studies of didanosine did not include sufficient numbers of subjects aged
65 years and over to determine whether they respond differently than younger subjects.
Didanosine is known to be substantially excreted by the kidney, and the risk of toxic reactions to
this drug may be greater in patients with impaired renal function. Because elderly patients are
more likely to have decreased renal function, care should be taken in dose selection. In addition,
renal function should be monitored and dosage adjustments should be made accordingly (see
DOSAGE AND ADMINISTRATION: Dose Adjustment).
ADVERSE REACTIONS
A SERIOUS TOXICITY OF VIDEX (didanosine) IS PANCREATITIS, WHICH MAY BE
FATAL (see WARNINGS). OTHER IMPORTANT TOXICITIES INCLUDE LACTIC
ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS; RETINAL CHANGES AND
OPTIC
NEURITIS;
AND
PERIPHERAL
NEUROPATHY
(see
WARNINGS
and
PRECAUTIONS).
When VIDEX is used in combination with other agents with similar toxicities, the
incidence of these toxicities may be higher than when VIDEX is used alone. Thus, patients
treated with VIDEX in combination with stavudine, with or without hydroxyurea, may be
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at increased risk for pancreatitis, which may be fatal, and hepatotoxicity (see
WARNINGS). Patients treated with VIDEX in combination with stavudine may also be at
increased risk for peripheral neuropathy (see PRECAUTIONS).
Adults: Selected clinical adverse events that occurred in adult patients in clinical studies with
VIDEX are provided in Tables 9 and 10.
Selected Clinical Adverse Events from Monotherapy Studies
Percent of Patients
ACTG 116A
ACTG 116B/117
Adverse Events
VID
EX
n=19
7
zidovudin
e
n=212
VIDEX
n=298
zidovudin
e
n=304
Diarrhea
19
15
28
21
Peripheral Neurologic
Symptoms/Neuropat
hy
17
14
20
12
Rash/Pruritus
7
8
9
5
Abdominal Pain
13
8
7
8
Pancreatitis
7
3
6
2
Selected Clinical Adverse Events from Combination Studies
Percent of Patientsa
AI454-148b
START 2b
Adverse Events
VIDE
X +
stavu
dine
+
nelfin
avir
n=48
2
zidovudin
e +
lamivudin
e +
nelfinavir
n=248
VIDEX
+
stavudin
e +
indinavi
r
n=102
zidovudin
e +
lamivudin
e +
indinavir
n=103
Diarrhea
70
60
45
39
Nausea
28
40
53
67
Headache
21
30
46
37
Peripheral Neurologic
Symptoms/Neuropat
hy
26
6
21
10
Rash
13
16
30
18
Vomiting
12
14
30
35
Pancreatitis (see
below)
1
*
<1
*
a Percentages based on treated subjects.
b Median duration of treatment 48 weeks.
* This event was not observed in this study arm.
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Pancreatitis resulting in death was observed in one patient who received VIDEX
(didanosine) plus stavudine plus nelfinavir in Study Al454-148 and in one patient who
received VIDEX plus stavudine plus indinavir in the START 2 study. In addition,
pancreatitis resulting in death was observed in 2 of 68 patients who received VIDEX plus
stavudine plus indinavir plus hydroxyurea in an ACTG clinical trial (see WARNINGS).
The frequency of pancreatitis is dose related. In phase 3 studies, incidence ranged from
1% to 10% with doses higher than are currently recommended and from 1% to 7% with
recommended dose.
Selected laboratory abnormalities in clinical studies with VIDEX are shown in Tables 11-
13.
Selected Laboratory Abnormalities from Monotherapy Studies
Percent of Patients
ACTG 116A
ACTG 116B/117
VIDEX
zidovudine
VIDEX
zidovudin
e
Parameter
n=197
n=212
n=298
n=304
SGOT (AST) (>5 x ULN)
9
4
7
6
SGPT (ALT) (>5 x ULN)
9
6
6
6
Alkaline phosphatase
(>5 x ULN)
4
1
1
1
Amylase (≥1.4 x ULN)
17
12
15
5
Uric acid (>12 mg/dL)
3
1
2
1
ULN = upper limit of normal.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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NDA 20-155/S-034
NDA 20-156/S-035
NDA 21-183/S-010
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Selected Laboratory Abnormalities from Combination Studies (Grades 3-4)
Percent of Patientsa
AI454-148b
START 2b
VIDEX +
stavudine
+
nelfinavir
zidovudine
+
lamivudine
+ nelfinavir
VIDEX
+
stavudine
+
indinavir
zidovudine
+
lamivudine
+ indinavir
Parameter
n=482
n=248
n=102
n=103
Bilirubin (>2.6 x
ULN)
<1
<1
16
8
SGOT (AST) (>5 x
ULN)
3
2
7
7
SGPT (ALT) (>5 x
ULN)
3
3
8
5
GGT (>5 x ULN)
NC
NC
5
2
Lipase (>2 x ULN)
7
2
5
5
Amylase (>2 x ULN)
NC
NC
8
2
ULN = upper limit of normal.
NC = Not Collected.
a Percentages based on treated subjects.
b Median duration of treatment 48 weeks.
Selected Laboratory Abnormalities from Combination Studies (All
Grades)
Percent of Patientsa
AI454-148b
START 2b
Parameter
VIDE
X +
stavud
ine +
nelfina
vir
n=482
zidovudin
e +
lamivudin
e +
nelfinavir
n=248
VIDE
X +
stavudi
ne +
indinav
ir
n=102
zidovudin
e +
lamivudin
e +
indinavir
n=103
Bilirubin
7
3
68
55
SGOT (AST)
42
23
53
20
SGPT (ALT)
37
24
50
18
GGT
NC
NC
28
12
Lipase
17
11
26
19
Amylase
NC
NC
31
17
NC = Not Collected.
a Percentages based on treated subjects.
b Median duration of treatment 48 weeks.
Observed during Clinical Practice: The following events have been identified during
postapproval use of VIDEX (didanosine). Because they are reported voluntarily from a
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NDA 21-183/S-010
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population of unknown size, estimates of frequency cannot be made. These events have been
chosen for inclusion due to their seriousness, frequency of reporting, causal connection to
VIDEX, or a combination of these factors.
Body as a Whole - alopecia, anaphylactoid reaction, asthenia, chills/fever, pain, and
redistribution/accumulation of body fat (see PRECAUTIONS: Fat Redistribution).
Digestive Disorders- anorexia, dyspepsia, and flatulence.
Exocrine Gland Disorders – pancreatitis (including fatal cases) (see WARNINGS), sialoadenitis,
parotid gland enlargement, dry mouth, and dry eyes.
Hematologic Disorders - anemia, leukopenia, and thrombocytopenia.
Liver - symptomatic hyperlactatemia/lactic acidosis and hepatic steatosis (see WARNINGS);
hepatitis and liver failure.
Metabolic Disorders - diabetes mellitus, hypoglycemia, and hyperglycemia.
Musculoskeletal Disorders - myalgia (with or without increases in creatine kinase),
rhabdomyolysis including acute renal failure and hemodialysis, arthralgia, and myopathy.
Ophthalmologic Disorders - Retinal depigmentation and optic neuritis (see WARNINGS).
Pediatric Patients: In clinical trials, 743 pediatric patients between 2 weeks and 18
years of age have been treated with VIDEX. Adverse events and laboratory abnormalities
reported to occur in these patients were generally consistent with the safety profile of didanosine
in adults.
In pediatric phase 1 studies, pancreatitis occurred in 2 of 60 (3%) patients treated at entry
doses below 300 mg/m2/day and in 5 of 38 (13%) patients treated at higher doses. In study
ACTG 152, pancreatitis occurred in none of the 281 pediatric patients who received didanosine
120 mg/m2 q12h and in <1% of the 274 pediatric patients who received didanosine 90 mg/m2
q12h in combination with zidovudine (see INDICATIONS AND USAGE: Clinical Studies).
Retinal changes and optic neuritis have been reported in pediatric patients.
OVERDOSAGE
There is no known antidote for VIDEX (didanosine) overdosage. In phase 1 studies, in which
VIDEX was initially administered at doses ten times the currently recommended dose, toxicities
included: pancreatitis, peripheral neuropathy, diarrhea, hyperuricemia and hepatic dysfunction.
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Didanosine is not dialyzable by peritoneal dialysis, although there is some clearance by
hemodialysis (see CLINICAL PHARMACOLOGY: Pharmacokinetics).
DOSAGE AND ADMINISTRATION
Dosage
All VIDEX formulations should be administered on an empty stomach, at least 30 minutes
before or 2 hours after eating. For either a once-daily or twice-daily regimen, patients must
take at least two of the appropriate strength tablets at each dose to provide adequate
buffering and prevent gastric acid degradation of didanosine. Because of the need for
adequate buffering, the 200-mg strength tablet should only be used as a component of a
once-daily regimen. To reduce the risk of gastrointestinal side effects, patients should take
no more than four tablets at each dose.
Adults: The preferred dosing frequency of VIDEX is twice daily because there is more
evidence to support the effectiveness of this dosing regimen. Once-daily dosing should be
considered only for adult patients whose management requires once-daily dosing of VIDEX (see
INDICATIONS AND USAGE: Clinical Studies). The daily dose in adult patients is dependent
on weight as outlined in Table 14.
Adult Dosinga
Recommended VIDEX Dose by Patient Weight
≥60 kg
<60 kg
Preferred dosing
200 mg twice daily
125 mg twice daily
Dosing for patients whose
management requires once-
daily frequency
400 mg once daily
250 mg once daily
a The 200-mg strength tablet should only be used as a component of a once-daily
regimen.
Pediatric Patients: The recommended dose of VIDEX (didanosine) in pediatric patients
between 2 weeks and 8 months of age is 100 mg/m2 twice daily, and the recommended VIDEX
dose for pediatric patients older than 8 months is 120 mg/m2 twice daily.
Dosing recommendations for VIDEX in patients less than 2 weeks of age cannot be made
because the pharmacokinetics of didanosine in these children are too variable to determine an
appropriate dose. There are no data on once-daily dosing of VIDEX in pediatric patients.
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Dose Adjustment
Clinical and laboratory signs suggestive of pancreatitis should prompt dose suspension and
careful evaluation of the possibility of pancreatitis. VIDEX use should be discontinued in
patients with confirmed pancreatitis (see WARNINGS and PRECAUTIONS: Drug
Interactions).
Patients with symptoms of peripheral neuropathy may tolerate a reduced dose of VIDEX after
resolution of the symptoms of peripheral neuropathy upon drug discontinuation. If neuropathy
recurs after resumption of VIDEX, permanent discontinuation of VIDEX should be considered.
Concomitant Therapy: Tenofovir disoproxil fumarate. A dose reduction of VIDEX to
250 mg (adults weighing ≥60 kg with creatinine clearance ≥60 mL/min) or 200 mg (adults
weighing <60 kg with creatinine clearance ≥60 mL/min) once daily is recommended. VIDEX
and tenofovir may be taken together in the fasted state. Alternatively, if tenofovir is taken with
food, VIDEX should be taken on an empty stomach (at least 30 minutes before food or 2 hours
after food). The appropriate dose of VIDEX coadministered with tenofovir in patients with
creatinine clearance <60 mL/min has not been established. [See CLINICAL
PHARMACOLOGY: Drug Interactions and PRECAUTIONS: Drug Interactions; see the
complete prescribing information for VIDEX EC (enteric-coated formulation of didanosine) for
results of drug interaction studies of tenofovir with reduced doses of the enteric-coated
formulation of didanosine.]
Renal Impairment: In adult patients with impaired renal function, the dose of VIDEX
should be adjusted to compensate for the slower rate of elimination. The recommended doses
and dosing intervals of VIDEX in adult patients with renal insufficiency are presented in Table
15.
Recommended Dosage of VIDEX in Renal Impairmenta
Recommended VIDEX Dose by Patient Weight
Creatinine
Clearance
(mL/min)
≥60 kg
<60 kg
≥60
200 mg twice dailyb
125 twice dailyb
30-59
200 mg once daily
or 100 mg twice daily
150 mg once daily
or 75 mg twice daily
10-29
150 mg once daily
100 mg once daily
<10
100 mg once daily
75 mg once daily
a Two VIDEX Chewable/Dispersible Buffered tablets must be taken with each dose; different strengths
of tablets may be combined to yield the recommended dose.
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NDA 21-183/S-010
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Recommended Dosage of VIDEX in Renal Impairmenta
b 400 mg once daily (≥60 kg) or 250 mg once daily (<60 kg) for patients whose management requires
once-daily frequency of administration.
Urinary excretion is also a major route of elimination of didanosine in pediatric patients;
therefore, the clearance of didanosine may be altered in children with renal impairment.
Although there are insufficient data to recommend a specific dose adjustment of VIDEX in this
patient population, a reduction in the dose and/or an increase in the interval between doses should
be considered.
Patients Requiring Continuous Ambulatory Peritoneal Dialysis (CAPD) or
Hemodialysis: For patients requiring CAPD or hemodialysis, follow dosing recommendations for
patients with creatinine clearance less than 10 mL/min, shown in Table 15. It is not necessary to
administer a supplemental dose of VIDEX following hemodialysis.
Hepatic Impairment: See WARNINGS and PRECAUTIONS.
Method of Preparation
VIDEX Chewable/Dispersible Buffered Tablets
Adult Dosing: To provide adequate buffering, at least two of the appropriate strength
tablets, but no more than four tablets, should be thoroughly chewed or dispersed in at least 1
ounce of water prior to consumption (see PRECAUTIONS: Information for Patients). To
disperse tablets, add 2 tablets to at least 1 ounce of drinking water. Stir until a uniform
dispersion forms, and drink the entire dispersion immediately. If additional flavoring is desired,
the dispersion may be diluted with one ounce of clear apple juice. Stir the further diluted
dispersion just prior to consumption. The dispersion with clear apple juice is stable at room
temperature, 62° to 73°F (17° to 23°C), for up to one hour.
VIDEX Pediatric Powder for Oral Solution
Prior to dispensing, the pharmacist must constitute dry powder with Purified Water, USP, to an
initial concentration of 20 mg/mL and immediately mix the resulting solution with antacid to a
final concentration of 10 mg/mL as follows:
20 mg/mL Initial Solution: Constitute the product to 20 mg/mL by adding 100 mL or 200 mL
of Purified Water, USP, to the 2 g or 4 g of VIDEX powder, respectively, in the product bottle.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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10 mg/mL Final Admixture: 1. Immediately mix one part of the 20 mg/mL initial solution
with one part of either Maximum Strength Mylanta® Liquid or Extra Strength Maalox® Plus
Suspension for a final dispensing concentration of 10 mg VIDEX per mL. For patient home use,
the admixture should be dispensed in appropriately sized, flint-glass or plastic (HDPE, PET, or
PETG) bottles with child-resistant closures. This admixture is stable for 30 days under
refrigeration, 36° to 46° F (2° to 8° C).
2. Instruct the patient to shake the admixture thoroughly prior to use and to store the tightly
closed container in the refrigerator, 36° to 46° F (2° to 8° C), up to 30 days.
HOW SUPPLIED
VIDEX® (didanosine) Chewable/Dispersible Buffered Tablets are round, off white to light
orange/yellow with a mottled appearance, orange-flavored, tablets embossed with "VIDEX" on
one side and the product strength on the other. The tablets are available in the following
strengths of VIDEX: 25, 50, 100, 150, and 200 mg. Sixty tablets are packaged in bottles with
child-resistant closures.
The tablets should be stored in tightly closed bottles at 59° to 86° F (15° to 30° C). If
dispersed in water, the dose may be held for up to 1 hour at ambient temperature.
VIDEX (didanosine) Pediatric Powder for Oral Solution is supplied in 4- and 8-ounce glass
bottles containing 2 g or 4 g of VIDEX, respectively.
The bottles of powder should be stored at 59° to 86° F (15° to 30° C). The VIDEX admixture
may be stored up to 30 days in a refrigerator, 36° to 46° F (2° to 8° C). Discard any unused portion
after 30 days.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-154/S-044
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NDA 20-156/S-035
NDA 21-183/S-010
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The NDC numbers for the previously described VIDEX products are:
NDC NO.
Packaging Information
Product Strength
VIDEX Chewable/Dispersible Buffered Tablets
0087-6650-01
60 tablets/bottle
25 mg/tablet
0087-6651-01
60 tablets/bottle
50 mg/tablet
0087-6652-01
60 tablets/bottle
100 mg/tablet
0087-6653-01
60 tablets/bottle
150 mg/tablet
0087-6665-15
60 tablets/bottle
200 mg/tablet
VIDEX Pediatric Powder for Oral Solution
0087-6632-41
One bottle per carton
2 g/bottle
0087-6633-41
One bottle per carton
4 g/bottle
US Patent Nos.: 4,861,759, 5,254,539, and 5,880,106.
HANDLING AND DISPOSAL
Spill, Leak, and Disposal Procedure
Avoid generating dust during clean-up of powdered products; use wet mop or damp sponge.
Clean surface with soap and water as necessary. Containerize larger spills.
There is no single preferred method of disposal of containerized waste. Disposal
options include incineration, landfill, or sewer as dictated by specific circumstances and relevant
national, state, and local regulations.
Mylanta® is a registered trademark of Johnson & Johnson-Merck Consumer Pharmaceuticals Company.
Maalox® is a registered trademark of Novartis Consumer Health, Inc.
Bristol-Myers Squibb Virology
Bristol-Myers Squibb Company
Princeton, NJ 08543 USA
XXXXX-XX XXXXXXXXX
Revised _________________
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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NDA 20-156/S-035
NDA 21-183/S-010
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Patient Information
Rx only
VIDEX®
(generic name = didanosine also known as ddI)
VIDEX® (didanosine) Chewable/Dispersible Buffered Tablets
VIDEX® (didanosine) Pediatric Powder for Oral Solution
What is VIDEX?
VIDEX (pronounced VY dex) is a prescription medicine used in combination with other drugs to
treat children and adults who are infected with HIV (the human immunodeficiency virus, the
virus that causes AIDS). VIDEX belongs to a class of drugs called nucleoside analogues. By
reducing the growth of HIV, VIDEX helps your body maintain its supply of CD4 cells, which are
important for fighting HIV and other infections.
VIDEX will not cure your HIV infection. At present there is no cure for HIV infection. Even
while taking VIDEX, you may continue to have HIV-related illnesses, including infections with other
disease-producing organisms. Continue to see your doctor regularly and report any medical problems
that occur.
VIDEX does not prevent a patient infected with HIV from passing the virus to other
people. To protect others, you must continue to practice safe sex and take precautions to prevent
others from coming in contact with your blood and other body fluids.
There is limited information on the effects of long-term use of VIDEX.
Who should not take VIDEX?
Do not take VIDEX if you are allergic to any of its ingredients, including its active ingredient,
didanosine and the inactive ingredients. (See Inactive Ingredients at the end of this leaflet.) Tell your
doctor if you think you have had an allergic reaction to any of these ingredients.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
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Page 69
How should I take VIDEX? How should I store it?
Your doctor will determine your dose based on your body weight, kidney and liver function, other
medicines you are taking, and any side effects that you may have had with VIDEX or other medicines.
Take VIDEX on an empty stomach - that means at least 30 minutes before or 2 hours after
eating. Do not take VIDEX with food. Try not to miss a dose, but if you do, take it as soon as
possible. If it is almost time for the next dose, skip the missed dose and continue your regular dosing
schedule.
Chewable/Dispersible Tablets: Each VIDEX tablet contains antacid. Each time you take
VIDEX, you must take at least two, but not more than four, tablets. This is because VIDEX
tablets contain an antacid to reduce the amount of acid in your stomach. If you have too much
acid, the medicine will break down. However, too much antacid may cause stomach problems.
—DO NOT swallow VIDEX tablets whole. Chew the tablets well or mix them in water. Many
patients drop the tablets in at least one ounce of water and stir well before swallowing. If you
choose to mix the tablets in water, you may add one ounce (2 tablespoons) of clear apple juice to
the mixture for flavor (do not use any other kind of juice).
—Store tablets in a tightly closed container at room temperature away from heat and out of the
reach of children and pets. Do NOT store the tablets in a damp place such as a bathroom
medicine cabinet or near the kitchen sink.
Pediatric Oral Solution: Your pharmacist will prepare the oral solution. Shake the solution
well before each use. Store in the refrigerator. Throw away any unused portion after 30 days.
If you have kidney disease: If your kidneys are not working properly, your doctor will need
to do regular tests to check how they are working while you take VIDEX. Your doctor may
also lower your dosage of VIDEX.
What should I do if someone takes an overdose of VIDEX?
If someone may have taken an overdose of VIDEX, get medical help right away. Contact their
doctor or a poison control center.
What should I avoid while taking VIDEX?
Alcohol. Do not drink alcohol while taking VIDEX since alcohol may increase your risk of
pancreatitis (pain and inflammation of the pancreas) or liver damage.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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Other medicines. Other medicines, including those you can buy without a prescription, may
interfere with the actions of VIDEX or may increase the possibility or severity of side effects. Do
not take any medicine, vitamin supplement, or other health preparation without first
checking with your doctor.
Antacids. Since VIDEX contains some of the same ingredients found in antacids, any side
effects related to VIDEX’s ingredients may get worse if you also take an antacid.
Medicines at the same time you take your VIDEX dose. Some medicines should not be taken
at the same time of day that you take VIDEX. Check with your doctor.
Pregnancy. It is not known if VIDEX can harm a human fetus. Also, pregnant women have
experienced serious side effects when taking VIDEX in combination with ZERIT (stavudine),
also known as d4T, and other HIV medicines. VIDEX should be used during pregnancy only
after discussion with your doctor. Tell your doctor if you become pregnant or plan to become
pregnant while taking VIDEX.
Nursing. Studies have shown VIDEX is in the breast milk of animals getting the drug. It may
also be in human breast milk. The Centers for Disease Control and Prevention (CDC)
recommends that HIV-infected mothers not breast-feed. This should reduce the risk of passing
HIV infection to their babies and the potential for serious adverse reactions in nursing infants.
Therefore, do not nurse a baby while taking VIDEX.
What are the possible side effects of VIDEX?
Pancreatitis. Pancreatitis is a dangerous inflammation of the pancreas that may cause death.
Tell your doctor right away if you or a child taking VIDEX develops stomach pain, nausea, or
vomiting. These can be signs of pancreatitis. Before starting VIDEX therapy, let your doctor
know if you or a child for whom it has been prescribed has ever had pancreatitis. This condition is
more likely to happen in people who have had it before. It is also more likely in people with advanced
HIV disease. However, it can occur at any stage of HIV disease. It may be more common in patients
with kidney problems, those who drink alcohol, and those who are also treated with stavudine or
hydroxyurea. If you get pancreatitis, your doctor will tell you to stop taking VIDEX.
Lactic acidosis, severe liver enlargement, and liver failure, including deaths, have been
reported among patients taking VIDEX (including pregnant women). Symptoms that may
indicate a liver problem are:
•
feeling very weak, tired, or uncomfortable,
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For current labeling information, please visit https://www.fda.gov/drugsatfda
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NDA 21-183/S-010
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•
unusual or unexpected stomach discomfort,
•
feeling cold,
•
feeling dizzy or lightheaded,
•
suddenly developing a slow or irregular heartbeat.
Lactic acidosis is a medical emergency that must be treated in a hospital.
If you notice any of these symptoms or if your medical condition changes, stop taking VIDEX
and call your doctor right away. Women, overweight patients, and those who have been treated for a
long time with other medicines used to treat HIV infection are more likely to develop lactic acidosis.
Your doctor should check your liver function periodically while you are taking VIDEX. You should
be especially careful if you have a history of heavy alcohol use or a liver problem.
Vision changes. VIDEX may affect the nerves in your eyes. Because of this, you should have regular
eye examinations. You should also report any changes in vision to your doctor right away. This
includes, for example, seeing colors abnormally or blurred vision.
Peripheral neuropathy. This is a problem with the nerves in your hands or feet. The nerve problem
may be serious. Tell your doctor right away if you or a child taking VIDEX has continuing
numbness, tingling, or pain in the feet or hands. A child may not recognize these symptoms or know
to tell you that his or her feet or hands are numb, burning, tingling, or painful. Ask your child’s doctor
how to find out if your child is developing peripheral neuropathy.
Before starting VIDEX therapy, let your doctor know if you or a child for whom it has been
prescribed has ever had peripheral neuropathy. This condition is more likely to happen in people who
have had it before. It is also more likely in patients taking medicines that affect the nerves and in
people with advanced HIV disease. However, it can occur at any stage of HIV disease. If you get
peripheral neuropathy, your doctor will tell you to stop taking VIDEX. After stopping VIDEX, the
symptoms may get worse for a short time and then get better. Once symptoms of peripheral
neuropathy go away completely, you and your doctor should decide if starting VIDEX is right for you.
If so, you might be started at a lower dose.
Special note about other medicines. If you take VIDEX along with other medicines with similar
side effects, you may increase the chance of having these side effects. For example, using VIDEX in
combination with other medicines that may cause pancreatitis, peripheral neuropathy, or liver
problems (including stavudine and hydroxyurea) may increase your chance of having these side
effects.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-154/S-044
NDA 20-155/S-034
NDA 20-156/S-035
NDA 21-183/S-010
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Other side effects: The most common side effects in adults taking VIDEX are diarrhea, neuropathy
(nerve disorders), chills or fever, rash, abdominal pain, weakness, headache, and nausea and vomiting.
Children may have similar side effects as adults.
Changes in body fat have been seen in some patients taking antiretroviral therapy. These changes
may include increased amount of fat in the upper back and neck (“buffalo hump”), breast, and around
the trunk. Loss of fat from the legs, arms, and face may also happen. The cause and long-term health
effects of these conditions are not known at this time.
What else should I know about VIDEX?
If you have phenylketonuria: Each Chewable/Dispersible Tablet contains 36.5 mg of
phenylalanine.
Inactive Ingredients:
Chewable/Dispersible Tablets: calcium carbonate, magnesium hydroxide, aspartame, sorbitol,
mandarin orange flavor, polyplasdone, microcrystalline cellulose, and magnesium stearate.
Pediatric Oral Solution: Maximum Strength Mylanta Liquid or Extra Strength Maalox Plus.
This medicine was prescribed for your particular condition. Do not use VIDEX for another condition or give it to
others. Keep VIDEX and all medicines out of the reach of children. Throw away VIDEX when it is outdated or no
longer needed by flushing it down the toilet or pouring it down the sink.
This summary does not include everything there is to know about VIDEX. Medicines are sometimes prescribed for
purposes other than those listed in a Patient Information Leaflet. If you have questions or concerns, or want more
information about VIDEX, your physician and pharmacist have the complete prescribing information upon which this leaflet
is based. You may want to read it and discuss it with your doctor or other healthcare professional. Remember, no written
summary can replace careful discussion with your doctor.
Mylanta® is a registered trademark of Johnson & Johnson-Merck Consumer Pharmaceuticals Company.
Maalox® is a registered trademark of Novartis Consumer Health, Inc.
Bristol-Myers Squibb Virology
Bristol-Myers Squibb Company
Princeton, NJ 08543 USA
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-154/S-044
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NDA 20-156/S-035
NDA 21-183/S-010
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This Patient Information Leaflet has been approved by the U.S. Food and Drug Administration.
Revised _________________
XXXXX-XX
Based on package insert dated _____________
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:46:55.943373
|
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|
12,281
|
OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use VIDEX
safely and effectively. See full prescribing information for VIDEX.
VIDEX (didanosine, USP) Pediatric Powder for Oral Solution
Initial U.S. Approval: 1991
WARNING: PANCREATITIS, LACTIC ACIDOSIS and
HEPATOMEGALY with STEATOSIS
See full prescribing information for complete boxed warning.
•
Fatal and nonfatal pancreatitis. VIDEX should be suspended in
patients with suspected pancreatitis and discontinued in patients
with confirmed pancreatitis. (5.1)
•
Lactic acidosis and severe hepatomegaly with steatosis, including
fatal cases. Fatal lactic acidosis has been reported in pregnant
women who received the combination of didanosine and
stavudine. (5.2)
---------------------------RECENT MAJOR CHANGES---------------------------
Dosage and Administration
Dosage Adjustment (2.3)
06/2009
Contraindications
Allopurinol (4.1)
06/2009
Ribavirin (4.2)
06/2009
Warnings and Precautions
Non-cirrhotic Portal Hypertension (5.4)
01/2010
---------------------------INDICATIONS AND USAGE----------------------------
VIDEX (didanosine, USP) is a nucleoside reverse transcriptase inhibitor for
use in combination with other antiretroviral agents for the treatment of human
immunodeficiency virus (HIV)-1 infection. (1)
------------------------DOSAGE AND ADMINISTRATION----------------------
•
Adult patients: Administered on an empty stomach at least 30 minutes
before or 2 hours after eating. Dosing is based on body weight. (2.1)
at least 60 kg
less than 60 kg
Preferred dosing
200 mg twice daily
125 mg twice daily
Dosing for patients whose
management requires once-
daily frequency
400 mg once daily
250 mg once daily
•
Pediatric patients (2 weeks old to 18 years old): Administered on an
empty stomach at least 30 minutes before or 2 hours after eating.
−
Between 2 weeks and 8 months old, dosing is 100 mg/m2 twice
daily.
−
For those greater than 8 months old, dosing is 120 mg/m2 twice
daily but not to exceed the adult dosing recommendation. (2.1)
•
Renal impairment: Dose reduction is recommended. (2.2)
•
Coadministration with tenofovir: Dose reduction is recommended.
Patients should be monitored closely for didanosine-associated adverse
reactions. (2.3, 7.1)
----------------------DOSAGE FORMS AND STRENGTHS---------------------
•
4-ounce glass bottle containing 2 g of VIDEX (3)
•
8-ounce glass bottle containing 4 g of VIDEX (3)
------------------------------CONTRAINDICATIONS-------------------------------
Coadministration with allopurinol or ribavirin is contraindicated. (4.1 and
4.2)
------------------------WARNINGS AND PRECAUTIONS-----------------------
•
Pancreatitis: Suspension or discontinuation of didanosine may be
necessary. (5.1)
•
Lactic acidosis and severe hepatomegaly with steatosis: Suspend
didanosine in patients who develop clinical symptoms or signs with or
without laboratory findings. (5.2)
•
Hepatic toxicity: Interruption or discontinuation of didanosine must be
considered upon worsening of liver disease. (5.3)
•
Non-cirrhotic portal hypertension: Discontinue didanosine in patients
with evidence of non-cirrhotic portal hypertension. (5.4)
•
Patients may develop peripheral neuropathy (5.5), retinal changes and
optic neuritis (5.6), immune reconstitution syndrome (5.7), and
redistribution/accumulation of body fat (5.8).
-------------------------------ADVERSE REACTIONS------------------------------
•
In adults, the most common adverse reactions (greater than 10%, all
grades) are diarrhea, peripheral neurologic symptoms/neuropathy,
abdominal pain, nausea, headache, rash, and vomiting. (6.1)
•
Adverse reactions in pediatric patients were consistent with those in
adults. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers
Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch
--------------------------------DRUG INTERACTIONS-----------------------------
Coadministration of VIDEX can alter the concentration of other drugs and
other drugs may alter the concentration of didanosine. The potential drug-drug
interactions must be considered prior to and during therapy. (4, 7, 12.3)
------------------------USE IN SPECIFIC POPULATIONS-----------------------
Pregnancy: Fatal lactic acidosis has been reported in pregnant women who
received both didanosine and stavudine with other agents. This combination
should be used with caution during pregnancy and only if the potential benefit
clearly outweighs the potential risk. (5.2, 8.1) Physicians are encouraged to
register patients in the Antiretroviral Pregnancy Registry by calling
1-800-258-4263.
See 17 for PATIENT COUNSELING INFORMATION and Medication
Guide
Revised: 01/2010
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: PANCREATITIS, LACTIC ACIDOSIS AND
HEPATOMEGALY WITH STEATOSIS
1
INDICATIONS AND USAGE
2
DOSAGE AND ADMINISTRATION
2.1
Recommended Dosage (Adult and Pediatric Patients)
2.2
Renal Impairment
2.3
Dosage Adjustment
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICA IONS
T
4.1
Allopurinol
4.2
Ribavirin
5
WARNINGS AND PRECAUTIONS
5.1
Pancreatitis
5.2
Lactic Acidosis/Severe Hepatomegaly with Steatosis
5.3
Hepatic Toxicity
5.4
Non-cirrhotic Portal Hypertension
5.5
Peripheral Neuropathy
5.6
Retinal Changes and Optic Neuritis
5.7
Immune Reconstitution Syndrome
5.8
Fat Redistribution
6
ADVERSE REACTIONS
6.1
Clinical Trials Experience
6.2
Postmarketing Experience
7
DRUG INTERACTIONS
7.1
Established Drug Interactions
7.2
Predicted Drug Interactions
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
8.3
Nursing Mothers
8.4
Pediatric Use
8.5
Geriatric Use
8.6
Renal Impairment
10
OVERDOSAGE
11
DESCRIPTION
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
12.3
Pharmacokinetics
12.4
Microbiology
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
13.2
Animal Toxicology and/or Pharmacology
14
CLINICAL STUDIES
14.1
Adult Patients
14.2
Pediatric Patients
16
HOW SUPPLIED/STORAGE AND HANDLING
17
PATIENT COUNSELING INFORMATION
17.1
Pancreatitis
17.2
Peripheral Neuropathy
17.3
Lactic Acidosis and Severe Hepatomegaly with Steatosis
17.4
Hepatic Toxicity
17.5
Non-cirrhotic Portal Hypertension
17.6
Retinal Changes and Optic Neuritis
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
17.7
Fat Redistribution
*Sections or subsections omitted from the full prescribing information
17.8
Concomitant Therapy
are not listed
17.9
General Information
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
FULL PRESCRIBING INFORMATION
WARNING: PANCREATITIS, LACTIC ACIDOSIS and
HEPATOMEGALY with STEATOSIS
Fatal and nonfatal pancreatitis has occurred during therapy with VIDEX used
alone or in combination regimens in both treatment-naive and treatment-
experienced patients, regardless of degree of immunosuppression. VIDEX should be
suspended in patients with suspected pancreatitis and discontinued in patients with
confirmed pancreatitis [see Warnings and Precautions (5.1)].
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have
been reported with the use of nucleoside analogues alone or in combination,
including didanosine and other antiretrovirals. Fatal lactic acidosis has been
reported in pregnant women who received the combination of didanosine and
stavudine with other antiretroviral agents. The combination of didanosine and
stavudine should be used with caution during pregnancy and is recommended only
if the potential benefit clearly outweighs the potential risk [see Warnings and
Precautions (5.2)].
2
1
INDICATIONS AND USAGE
3
VIDEX® (didanosine, USP), also known as ddI, in combination with other antiretroviral agents
4
is indicated for the treatment of human immunodeficiency virus (HIV)-1 infection [see Clinical
5
Studies (14)].
6
2
DOSAGE AND ADMINISTRATION
7
VIDEX should be administered on an empty stomach, at least 30 minutes before or 2 hours after
8
eating.
9
2.1
Recommended Dosage (Adult and Pediatric Patients)
10
The preferred dosing frequency of VIDEX is twice daily because there is more evidence to
11
support the effectiveness of this dosing regimen. Once-daily dosing should be considered only
12
for patients whose management requires once-daily dosing of VIDEX [see Clinical Studies (14)].
13
The recommended adult total daily dose is based on body weight (kg) (see Table 1).
3
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 1:
Recommended Dosage (Adult)
Preferred dosing
Dosing for patients whose management
requires once-daily frequency
at least 60 kg
200 mg twice daily
400 mg once daily
less than 60 kg
125 mg twice daily
250 mg once daily
14
15
16
17
Pediatric Patients (2 weeks old to 18 years old): The recommended dose of VIDEX
(didanosine) in pediatric patients between 2 weeks old and 8 months old is 100 mg/m2 twice
daily, and the recommended VIDEX dose for pediatric patients greater than 8 months old is
120 mg/m2 twice daily but not to exceed the adult dosing recommendation.
18
19
20
Dosing recommendations in patients less than 2 weeks of age cannot be made because the
pharmacokinetics of didanosine in these children are too variable to determine an appropriate
dose. There are no data on once-daily dosing of VIDEX in pediatric patients.
21
2.2
Renal Impairment
22
Adult Patients
23
24
25
In adult patients with impaired renal function, the dose of VIDEX should be adjusted to
compensate for the slower rate of elimination. The recommended doses and dosing intervals of
VIDEX in adult patients with renal insufficiency are presented in Table 2.
Table 2:
Recommended Dosage in Patients with Renal Impairment
Creatinine Clearance
(mL/min)
at least 60
30-59
10-29
less than 10
Recommended VIDEX Dose by Patient Weight
at least 60 kg
less than 60 kg
200 mg twice dailya
125 mg twice dailya
200 mg once daily
or 100 mg twice daily
150 mg once daily
or 75 mg twice daily
150 mg once daily
100 mg once daily
100 mg once daily
75 mg once daily
4
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 2:
Recommended Dosage in Patients with Renal Impairment
a 400 mg once daily (at least 60 kg) or 250 mg once daily (less than 60 kg) for patients whose
management requires once-daily frequency of administration.
26
Pediatric Patients
27
Urinary excretion is also a major route of elimination of didanosine in pediatric patients,
28
therefore the clearance of didanosine may be altered in pediatric patients with renal impairment.
29
Although there are insufficient data to recommend a specific dose adjustment of VIDEX in this
30
patient population, a reduction in the dose should be considered (see Table 2).
31
Patients Requiring Continuous Ambulatory Peritoneal Dialysis (CAPD) or
32
Hemodialysis
33
For patients requiring CAPD or hemodialysis, follow dosing recommendations for patients with
34
creatinine clearance of less than 10 mL/min, shown in Table 2. It is not necessary to administer a
35
supplemental dose of VIDEX following hemodialysis.
36
2.3
Dosage Adjustment
37
Concomitant Therapy with Tenofovir Disoproxil Fumarate
38
In patients who are also taking tenofovir disoproxil fumarate, a dose reduction of VIDEX to
39
250 mg (adults weighing at least 60 kg with creatinine clearance of at least 60 mL/min) or
40
200 mg (adults weighing less than 60 kg with creatinine clearance of at least 60 mL/min) once
41
daily is recommended. VIDEX and tenofovir disoproxil fumarate may be taken together in the
42
fasted state. Alternatively, if tenofovir disoproxil fumarate is taken with food, VIDEX should be
43
taken on an empty stomach (at least 30 minutes before food or 2 hours after food). The
44
appropriate dose of VIDEX coadministered with tenofovir disoproxil fumarate in patients with
45
creatinine clearance of less than 60 mL/min has not been established. ([See Drug Interactions (7)
46
and Clinical Pharmacology (12.3)]; see the complete prescribing information for VIDEX EC
47
(enteric-coated formulation of didanosine) for results of drug interaction studies of tenofovir
48
disoproxil fumarate with reduced doses of the enteric-coated formulation of didanosine.)
5
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
49
Hepatic Impairment
50
No dose adjustment is required in patients with hepatic impairment [see Warnings and
51
Precautions (5.3) and Clinical Pharmacology (12.3)].
52
3
DOSAGE FORMS AND STRENGTHS
53
VIDEX (didanosine, USP) Pediatric Powder for Oral Solution is supplied in 4- and 8-ounce
54
glass bottles containing 2 g or 4 g of VIDEX, respectively.
55
4
CONTRAINDICATIONS
56
These recommendations are based on either drug interaction studies or observed clinical
57
toxicities.
58
4.1
Allopurinol
59
Coadministration of didanosine and allopurinol is contraindicated because systemic exposures of
60
didanosine are increased, which may increase didanosine-associated toxicity [see Clinical
61
Pharmacology (12.3)].
62
4.2
Ribavirin
63
Coadministration of didanosine and ribavirin is contraindicated because exposures of the active
64
metabolite of didanosine (dideoxyadenosine 5′-triphosphate) are increased. Fatal hepatic failure,
65
as well as peripheral neuropathy, pancreatitis, and symptomatic hyperlactatemia/lactic acidosis
66
have been reported in patients receiving both didanosine and ribavirin.
67
5
WARNINGS AND PRECAUTIONS
68
5.1
Pancreatitis
69
Fatal and nonfatal pancreatitis has occurred during therapy with VIDEX used alone or in
70
combination regimens in both treatment-naive and treatment-experienced patients,
71
regardless of degree of immunosuppression. VIDEX should be suspended in patients with
72
signs or symptoms of pancreatitis and discontinued in patients with confirmed pancreatitis.
73
Patients treated with VIDEX in combination with stavudine may be at increased risk for
74
pancreatitis.
6
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
75
When treatment with life-sustaining drugs known to cause pancreatic toxicity is required,
76
suspension of VIDEX (didanosine) therapy is recommended. In patients with risk factors for
77
pancreatitis, VIDEX should be used with extreme caution and only if clearly indicated. Patients
78
with advanced HIV-1 infection, especially the elderly, are at increased risk of pancreatitis and
79
should be followed closely. Patients with renal impairment may be at greater risk for pancreatitis
80
if treated without dose adjustment. The frequency of pancreatitis is dose related. [See Adverse
81
Reactions (6).]
82
5.2
Lactic Acidosis/Severe Hepatomegaly with Steatosis
83
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been
84
reported with the use of nucleoside analogues alone or in combination, including
85
didanosine and other antiretrovirals. A majority of these cases have been in women. Obesity
86
and prolonged nucleoside exposure may be risk factors. Fatal lactic acidosis has been reported in
87
pregnant women who received the combination of didanosine and stavudine with other
88
antiretroviral agents. The combination of didanosine and stavudine should be used with caution
89
during pregnancy and is recommended only if the potential benefit clearly outweighs the
90
potential risk [see Use in Specific Populations (8.1)]. Particular caution should be exercised
91
when administering VIDEX to any patient with known risk factors for liver disease; however,
92
cases have also been reported in patients with no known risk factors. Treatment with VIDEX
93
should be suspended in any patient who develops clinical signs or symptoms with or without
94
laboratory findings consistent with symptomatic hyperlactatemia, lactic acidosis, or pronounced
95
hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked
96
transaminase elevations).
97
5.3
Hepatic Toxicity
98
The safety and efficacy of VIDEX have not been established in HIV-infected patients with
99
significant underlying liver disease. During combination antiretroviral therapy, patients with
100
preexisting liver dysfunction, including chronic active hepatitis, have an increased frequency of
101
liver function abnormalities, including severe and potentially fatal hepatic adverse events, and
102
should be monitored according to standard practice. If there is evidence of worsening liver
103
disease in such patients, interruption or discontinuation of treatment must be considered.
104
Hepatotoxicity and hepatic failure resulting in death were reported during postmarketing
105
surveillance in HIV-infected patients treated with hydroxyurea and other antiretroviral agents.
106
Fatal hepatic events were reported most often in patients treated with the combination of
7
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
107
hydroxyurea, didanosine, and stavudine. This combination should be avoided. [See Adverse
108
Reactions (6).]
109
5.4
Non-cirrhotic Portal Hypertension
110
Postmarketing cases of non-cirrhotic portal hypertension have been reported, including cases
111
leading to liver transplantation or death. Cases of didanosine-associated non-cirrhotic portal
112
hypertension were confirmed by liver biopsy in patients with no evidence of viral hepatitis.
113
Onset of signs and symptoms ranged from months to years after start of didanosine therapy.
114
Common presenting features included elevated liver enzymes, esophageal varices, hematemesis,
115
ascites, and splenomegaly.
116
Patients receiving VIDEX should be monitored for early signs of portal hypertension (eg,
117
thrombocytopenia and splenomegaly) during routine medical visits. Appropriate laboratory
118
testing including liver enzymes, serum bilirubin, albumin, complete blood count, and
119
international normalized ratio (INR) and ultrasonography should be considered. VIDEX should
120
be discontinued in patients with evidence of non-cirrhotic portal hypertension.
121
5.5
Peripheral Neuropathy
122
Peripheral neuropathy, manifested by numbness, tingling, or pain in the hands or feet, has been
123
reported in patients receiving VIDEX therapy. Peripheral neuropathy has occurred more
124
frequently in patients with advanced HIV disease, in patients with a history of neuropathy, or in
125
patients being treated with neurotoxic drug therapy, including stavudine. Discontinuation of
126
VIDEX should be considered in patients who develop peripheral neuropathy. [See Adverse
127
Reactions (6).]
128
5.6
Retinal Changes and Optic Neuritis
129
Retinal changes and optic neuritis have been reported in adult and pediatric patients. Periodic
130
retinal examinations should be considered for patients receiving VIDEX [see Adverse Reactions
131
(6)].
132
5.7
Immune Reconstitution Syndrome
133
Immune reconstitution syndrome has been reported in patients treated with combination
134
antiretroviral therapy, including VIDEX. During the initial phase of combination antiretroviral
135
treatment, patients whose immune system responds may develop an inflammatory response to
8
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
136
indolent or residual opportunistic infections (such as Mycobacterium avium infection,
137
cytomegalovirus, Pneumocystis jiroveci pneumonia [PCP], or tuberculosis), which may
138
necessitate further evaluation and treatment.
139
5.8
Fat Redistribution
140
Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement
141
(buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid
142
appearance” have been observed in patients receiving antiretroviral therapy. The mechanism and
143
long-term consequences of these events are currently unknown. A causal relationship has not
144
been established.
145
6
ADVERSE REACTIONS
146
The following adverse reactions are discussed in greater detail in other sections:
147
• Pancreatitis [see Boxed Warning, Warnings and Precautions (5.1)]
148
• Lactic acidosis/severe hepatomegaly with steatosis [see Boxed Warning, Warnings and
149
Precautions (5.2)]
150
• Hepatic toxicity [see Warnings and Precautions (5.3)]
151
• Non-cirrhotic portal hypertension [see Warnings and Precautions (5.4)]
152
• Peripheral neuropathy [see Warnings and Precautions (5.5)]
153
• Retinal changes and optic neuritis [see Warnings and Precautions (5.6)]
154
6.1
Clinical Trials Experience
155
Because clinical trials are conducted under widely varying conditions, adverse reaction rates
156
observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials
157
of another drug and may not reflect the rates observed in practice.
158
Adults
159
Selected clinical adverse reactions that occurred in adult patients in clinical studies with VIDEX
160
are provided in Tables 3 and 4.
Table 3:
Selected Clinical Adverse Reactions from Monotherapy Studies
Percent of Patients*
9
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
161
Table 3:
Selected Clinical Adverse Reactions from Monotherapy Studies
Percent of Patients*
ACTG 116A
ACTG 116B/117
VIDEX
zidovudine
VIDEX
zidovudine
Adverse Reactions
n=197
n=212
n=298
n=304
Diarrhea
19
15
28
21
Peripheral Neurologic
17
14
20
12
Symptoms/Neuropathy
Abdominal Pain
13
8
7
8
Rash/Pruritus
7
8
9
5
Pancreatitis
7
3
6
2
* The incidences reported included all severity grades and all reactions regardless of causality.
Table 4:
Selected Clinical Adverse Reactions from Combination Studies
Percent of Patientsa,c
b
b
AI454-148
START 2
VIDEX +
zidovudine +
VIDEX +
zidovudine +
stavudine +
lamivudine +
stavudine +
lamivudine +
nelfinavir
nelfinavir
indinavir
indinavir
Adverse Reactions
n=482
n=248
n=102
n=103
Diarrhea
70
60
45
39
Nausea
28
40
53
67
Peripheral Neurologic
26
6
21
10
Symptoms/Neuropathy
Headache
21
30
46
37
Rash
13
16
30
18
Vomiting
12
14
30
35
Pancreatitis (see below)
1
*
less than 1
*
a Percentages based on treated subjects.
b Median duration of treatment 48 weeks.
c The incidences reported included all severity grades and all reactions regardless of causality.
* This event was not observed in this study arm.
162
Pancreatitis resulting in death was observed in one patient who received VIDEX (didanosine)
163
plus stavudine plus nelfinavir in Study Al454-148 and in one patient who received VIDEX plus
10
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
171
164
stavudine plus indinavir in the START 2 study. In addition, pancreatitis resulting in death was
165
observed in 2 of 68 patients who received VIDEX plus stavudine plus indinavir plus
166
hydroxyurea in an ACTG clinical trial [see Warnings and Precautions (5)].
167
The frequency of pancreatitis is dose related. In phase 3 studies, incidence ranged from 1% to
168
10% with doses higher than are currently recommended and from 1% to 7% with recommended
169
dose.
170
Selected laboratory abnormalities in clinical studies with VIDEX are shown in Tables 5-7.
Table 5:
Selected Laboratory Abnormalities from Monotherapy Studies
Percent of Patients
ACTG 116A
ACTG 116B/117
VIDEX
zidovudine
VIDEX
zidovudine
Parameter
n=197
n=212
n=298
n=304
SGOT (AST) (greater than 5 x ULN)
9
4
7
6
SGPT (ALT) (greater than 5 x ULN)
9
6
6
6
Alkaline phosphatase (greater than 5 x
4
1
1
1
ULN)
Amylase (at least 1.4 x ULN)
17
12
15
5
Uric acid (greater than 12 mg/dL)
3
1
2
1
ULN = upper limit of normal.
Table 6:
Selected Laboratory Abnormalities from Combination Studies
(Grades 3-4)
Percent of Patientsa
b
b
AI454-148
START 2
VIDEX +
zidovudine +
VIDEX +
zidovudine +
stavudine +
lamivudine +
stavudine +
lamivudine +
nelfinavir
nelfinavir
indinavir
indinavir
Parameter
n=482
n=248
n=102
n=103
Bilirubin (greater than 2.6 x
less than 1
less than 1
16
8
ULN)
SGOT (AST) (greater than 5 x
3
2
7
7
ULN)
SGPT (ALT) (greater than 5 x
3
3
8
5
11
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
172
Table 6:
Selected Laboratory Abnormalities from Combination Studies
(Grades 3-4)
Percent of Patientsa
b
b
AI454-148
START 2
VIDEX +
zidovudine +
VIDEX +
zidovudine +
stavudine +
lamivudine +
stavudine +
lamivudine +
nelfinavir
nelfinavir
indinavir
indinavir
Parameter
n=482
n=248
n=102
n=103
ULN)
GGT (greater than 5 x ULN)
NC
NC
5
2
Lipase (greater than 2 x ULN)
7
2
5
5
Amylase (greater than 2 x ULN)
NC
NC
8
2
ULN = upper limit of normal.
NC = Not Collected.
a Percentages based on treated subjects.
b Median duration of treatment 48 weeks.
Table 7:
Selected Laboratory Abnormalities from Combination Studies (All
Grades)
Percent of Patientsa
b
b
AI454-148
START 2
VIDEX +
zidovudine +
VIDEX +
zidovudine +
stavudine +
lamivudine +
stavudine +
lamivudine +
nelfinavir
nelfinavir
indinavir
indinavir
Parameter
n=482
n=248
n=102
n=103
Bilirubin
7
3
68
55
SGOT (AST)
42
23
53
20
SGPT (ALT)
37
24
50
18
GGT
NC
NC
28
12
Lipase
17
11
26
19
Amylase
NC
NC
31
17
NC = Not Collected.
a Percentages based on treated subjects.
b Median duration of treatment 48 weeks.
12
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
173
Pediatric Patients
174
In clinical trials, 743 pediatric patients between 2 weeks and 18 years of age have been treated
175
with didanosine. Adverse reactions and laboratory abnormalities reported to occur in these
176
patients were generally consistent with the safety profile of didanosine in adults.
177
In pediatric phase 1 studies, pancreatitis occurred in 2 of 60 (3%) patients treated at entry doses
178
below 300 mg/m2/day and in 5 of 38 (13%) patients treated at higher doses. In study ACTG 152,
179
pancreatitis occurred in none of the 281 pediatric patients who received didanosine 120 mg/m2
180
every 12 hours and in less than 1% of the 274 pediatric patients who received didanosine
181
90 mg/m2 every 12 hours in combination with zidovudine [see Clinical Studies (14)].
182
Retinal changes and optic neuritis have been reported in pediatric patients.
183
6.2
Postmarketing Experience
184
The following adverse reactions have been identified during postapproval use of didanosine.
185
Because they are reported voluntarily from a population of unknown size, estimates of frequency
186
cannot be made. These reactions have been chosen for inclusion due to their seriousness,
187
frequency of reporting, causal connection to VIDEX, or a combination of these factors.
188
Blood and Lymphatic System Disorders – anemia, leukopenia, and thrombocytopenia.
189
Body as a Whole – alopecia, anaphylactoid reaction, asthenia, chills/fever, pain, and
190
redistribution/accumulation of body fat [see Warnings and Precautions (5.8)].
191
Digestive Disorders – anorexia, dyspepsia, and flatulence.
192
Exocrine Gland Disorders – pancreatitis (including fatal cases) [see Boxed Warning,
193
Warnings and Precautions (5.1)], sialoadenitis, parotid gland enlargement, dry mouth,
194
and dry eyes.
195
Hepatobiliary Disorders – symptomatic hyperlactatemia/lactic acidosis and hepatic
196
steatosis [see Boxed Warning, Warnings and Precautions (5.2)]; non-cirrhotic portal
197
hypertension [see Warnings and Precautions (5.4)]; hepatitis and liver failure.
198
Metabolic Disorders – diabetes mellitus, hypoglycemia, and hyperglycemia.
13
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For current labeling information, please visit https://www.fda.gov/drugsatfda
199
Musculoskeletal Disorders – myalgia (with or without increases in creatine kinase),
200
rhabdomyolysis including acute renal failure and hemodialysis, arthralgia, and myopathy.
201
Ophthalmologic Disorders – retinal depigmentation and optic neuritis [see Warnings and
202
Precautions (5.6)].
203
Use with Stavudine- and Hydroxyurea-Based Regimens
204
When didanosine is used in combination with other agents with similar toxicities, the incidence
205
of these toxicities may be higher than when didanosine is used alone. Thus, patients treated with
206
VIDEX in combination with stavudine, with or without hydroxyurea, may be at increased risk
207
for pancreatitis and hepatotoxicity, which may be fatal, and severe peripheral neuropathy [see
208
Warnings and Precautions (5)]. The combination of VIDEX and hydroxyurea, with or without
209
stavudine, should be avoided.
210
7
DRUG INTERACTIONS
211
7.1
Established Drug Interactions
212
Clinical recommendations based on the results of drug interaction studies are listed in Table 8.
213
Pharmacokinetic results of drug interactions studies are shown in Tables 12 and 13 [see
214
Contraindications (4.1 and 4.2), Clinical Pharmacology (12.3)].
Table 8:
Established Drug Interactions with VIDEX
Drug
Effect
Clinical Comment
ciprofloxacin
↓ ciprofloxacin concentration Administer VIDEX at least 2 hours after or 6 hours before
ciprofloxacin.
delavirdine
↓ delavirdine concentration
Administer VIDEX 1 hour after delavirdine.
ganciclovir
↑ didanosine concentration
If there is no suitable alternative to ganciclovir, then use in
combination with VIDEX with caution. Monitor for
didanosine-associated toxicity.
indinavir
↓ indinavir concentration
Administer VIDEX 1 hour after indinavir.
methadone
↓ didanosine concentration
Do not coadminister methadone with VIDEX pediatric
powder due to significant decreases in didanosine
concentrations. If coadministration of methadone and
didanosine is necessary, the recommended formulation of
didanosine is VIDEX EC. Patients should be closely
monitored for adequate clinical response when VIDEX EC
is coadministered with methadone, including monitoring
14
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 8:
Established Drug Interactions with VIDEX
Drug
Effect
Clinical Comment
for changes in HIV RNA viral load.
nelfinavir
No interaction 1 hour after
Administer nelfinavir 1 hour after VIDEX.
didanosine
tenofovir disoproxil
↑ didanosine concentration
A dose reduction of VIDEX to the following dosage once
fumarate
daily is recommended.a
•
250 mg (adults weighing at least 60 kg with creatinine
clearance of at least 60 mL/min)
•
200 mg (adults weighing less than 60 kg with
creatinine clearance of at least 60 mL/min)
VIDEX and tenofovir disoproxil fumarate may be taken
together in the fasted state. If tenofovir disoproxil
fumarate is taken with food, VIDEX should be taken on an
empty stomach (at least 30 minutes before food or 2 hours
after food). Patients should be monitored for didanosine
associated toxicities and clinical response.
↑ Indicates increase.
↓ Indicates decrease.
a The dosing recommendation for coadministration of VIDEX EC and tenofovir disoproxil fumarate with respect to
meal consumption differs from that of VIDEX. See the complete prescribing information for VIDEX EC.
215
Exposure to didanosine is increased when coadministered with tenofovir disoproxil fumarate
216
[Table 8 and see Clinical Pharmacokinetics (12.3, Table 12)]. Increased exposure may cause or
217
worsen
didanosine-related
clinical
toxicities,
including
pancreatitis,
symptomatic
218
hyperlactatemia/lactic acidosis, and peripheral neuropathy. Coadministration of tenofovir
219
disoproxil fumarate with VIDEX should be undertaken with caution, and patients should be
220
monitored closely for didanosine-related toxicities and clinical response. VIDEX should be
221
suspended if signs or symptoms of pancreatitis, symptomatic hyperlactatemia, or lactic acidosis
222
develop [see Dosage and Administration (2.3), Warnings and Precautions (5)]. Suppression of
223
CD4 cell counts has been observed in patients receiving tenofovir disoproxil fumarate with
224
didanosine at a dose of 400 mg daily.
225
7.2
Predicted Drug Interactions
226
Predicted drug interactions with VIDEX are listed in Table 9.
15
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 9:
Predicted Drug Interactions with VIDEX
Drug or Drug Class
Effect
Clinical Comment
a
Drugs that may cause pancreatic
↑ risk of pancreatitis
Use only with extreme caution
toxicity
Neurotoxic drugs
↑ risk of neuropathy
Use with cautionb
Antacids containing magnesium
↑ side effects associated with
Use caution with VIDEX Pediatric Powder for
or aluminum
antacid components
Oral Solution
Azole antifungals
↓ ketoconazole or itraconazole Administer drugs such as ketoconazole or
concentration
itraconazole at least 2 hours before VIDEX.
Quinolone antibiotics (see also
↓ quinolone concentration
Consult package insert of the quinolone.
ciprofloxacin in Table 8)
Tetracycline antibiotics
↓ antibiotic concentration
Consult package insert of the tetracycline.
↑ Indicates increase.
↓ Indicates decrease.
a Only if other drugs are not available and if clearly indicated. If treatment with life-sustaining drugs that cause
pancreatic toxicity is required, suspension of VIDEX is recommended [see Warnings and Precautions (5.1)].
b [See Warnings and Precautions (5.6).]
227
8
USE IN SPECIFIC POPULATIONS
228
8.1
Pregnancy
229
Pregnancy Category B
230
Reproduction studies have been performed in rats and rabbits at doses up to 12 and 14.2 times
231
the estimated human exposure (based upon plasma levels), respectively, and have revealed no
232
evidence of impaired fertility or harm to the fetus due to didanosine. At approximately 12 times
233
the estimated human exposure, didanosine was slightly toxic to female rats and their pups during
234
mid and late lactation. These rats showed reduced food intake and body weight gains but the
235
physical and functional development of the offspring was not impaired and there were no major
236
changes in the F2 generation. A study in rats showed that didanosine and/or its metabolites are
237
transferred to the fetus through the placenta. Animal reproduction studies are not always
238
predictive of human response.
16
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For current labeling information, please visit https://www.fda.gov/drugsatfda
239
There are no adequate and well-controlled studies of didanosine in pregnant women. Didanosine
240
should be used during pregnancy only if the potential benefit justifies the potential risk.
241
Fatal lactic acidosis has been reported in pregnant women who received the combination of
242
didanosine and stavudine with other antiretroviral agents. It is unclear if pregnancy augments the
243
risk of lactic acidosis/hepatic steatosis syndrome reported in nonpregnant individuals receiving
244
nucleoside analogues [see Warnings and Precautions (5.2)]. The combination of didanosine
245
and stavudine should be used with caution during pregnancy and is recommended only if
246
the potential benefit clearly outweighs the potential risk. Healthcare providers caring for
247
HIV-infected pregnant women receiving didanosine should be alert for early diagnosis of lactic
248
acidosis/hepatic steatosis syndrome.
249
Antiretroviral Pregnancy Registry
250
To monitor maternal-fetal outcomes of pregnant women exposed to didanosine and other
251
antiretroviral agents, an Antiretroviral Pregnancy Registry has been established. Physicians are
252
encouraged to register patients by calling 1-800-258-4263.
253
8.3
Nursing Mothers
254
The Centers for Disease Control and Prevention recommend that HIV-infected mothers
255
not breast-feed their infants to avoid risking postnatal transmission of HIV. A study in rats
256
showed that following oral administration, didanosine and/or its metabolites were excreted into
257
the milk of lactating rats. It is not known if didanosine is excreted in human milk. Because of
258
both the potential for HIV transmission and the potential for serious adverse reactions in nursing
259
infants, mothers should be instructed not to breast-feed if they are receiving didanosine.
260
8.4
Pediatric Use
261
Use of didanosine in pediatric patients from 2 weeks of age through adolescence is supported by
262
evidence from adequate and well-controlled studies of VIDEX in adult and pediatric patients
263
[see Dosage and Administration (2), Adverse Reactions (6.1), Clinical Pharmacology (12.3), and
264
Clinical Studies (14)].
265
8.5
Geriatric Use
266
In an Expanded Access Program for patients with advanced HIV infection, patients aged
267
65 years and older had a higher frequency of pancreatitis (10%) than younger patients (5%) [see
17
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
268
Warnings and Precautions (5.1)]. Clinical studies of didanosine did not include sufficient
269
numbers of subjects aged 65 years and over to determine whether they respond differently than
270
younger subjects. Didanosine is known to be substantially excreted by the kidney, and the risk of
271
toxic reactions to this drug may be greater in patients with impaired renal function. Because
272
elderly patients are more likely to have decreased renal function, care should be taken in dose
273
selection. In addition, renal function should be monitored and dosage adjustments should be
274
made accordingly [see Dosage and Administration (2.2)].
275
8.6
Renal Impairment
276
Patients with renal impairment (creatinine clearance of less than 60 mL/min) may be at greater
277
risk of toxicity from didanosine due to decreased drug clearance [see Clinical Pharmacology
278
(12.3)]. A dose reduction is recommended for these patients [see Dosage and Administration
279
(2)].
280
10
OVERDOSAGE
281
There is no known antidote for VIDEX (didanosine) overdosage. In phase 1 studies, in which
282
VIDEX was initially administered at doses ten times the currently recommended dose, toxicities
283
included: pancreatitis, peripheral neuropathy, diarrhea, hyperuricemia, and hepatic dysfunction.
284
Didanosine is not dialyzable by peritoneal dialysis, although there is some clearance by
285
hemodialysis [see Clinical Pharmacology (12.3)].
286
11
DESCRIPTION
287
VIDEX® is a brand name for didanosine, USP, a synthetic purine nucleoside analogue active
288
against HIV-1.
289
Didanosine is available as VIDEX, a Pediatric Powder for Oral Solution [see How
290
Supplied/Storage and Handling (16)] and as VIDEX® EC Delayed-Release Capsules, containing
291
enteric-coated beadlets [consult prescribing information for VIDEX EC (didanosine)].
18
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
292
The chemical name for didanosine is 2′,3′-dideoxyinosine. The structural formula is: Structural Formula
293
Didanosine is a white crystalline powder with the molecular formula C10H12N4O3 and a
294
molecular weight of 236.2. The aqueous solubility of didanosine at 25° C and pH of
295
approximately 6 is 27.3 mg/mL. Didanosine is unstable in acidic solutions. For example, at pH
296
less than 3 and 37° C, 10% of didanosine decomposes to hypoxanthine in less than 2 minutes.
297
12
CLINICAL PHARMACOLOGY
298
12.1
Mechanism of Action
299
Didanosine is an antiviral agent [see Clinical Pharmacology (12.4)].
300
12.3
Pharmacokinetics
301
The pharmacokinetic parameters of didanosine are summarized in Table 10. Didanosine is
302
rapidly absorbed, with peak plasma concentrations generally observed from 0.25 to 1.50 hours
303
following oral dosing. Increases in plasma didanosine concentrations were dose proportional
304
over the range of 50 to 400 mg. Steady-state pharmacokinetic parameters did not differ
305
significantly from values obtained after a single dose. Binding of didanosine to plasma proteins
306
in vitro was low (less than 5%). Based on data from in vitro and animal studies, it is presumed
307
that the metabolism of didanosine in man occurs by the same pathways responsible for the
308
elimination of endogenous purines.
19
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 10:
Mean ± SD Pharmacokinetic Parameters for Didanosine in Adult and
Pediatric Patients
b
Pediatric Patients
8 months to
2 weeks to
Parameter
Adult Patientsa
n
19 years
n
4 months
n
Oral bioavailability (%)
42 ± 12
6
25 ± 20
46
ND
Apparent volume of
2
43.70 ± 8.90
6
28 ± 15
49
ND
distributionc (L/m )
d
46%
CSF-plasma ratio
21 ± 0.03%e
5
7
ND
(range 12-85%)
Systemic clearancec
526 ± 64.7
6
516 ± 184
49
ND
(mL/min/m2)
Renal clearancef (mL/min/m2)
223 ± 85.0
6
240 ± 90
15
ND
Apparent oral clearanceg
1252 ± 154
6
2064 ± 736
48
1353 ± 759
41
(mL/min/m2)
Elimination half-lifef (h)
1.5 ± 0.4
6
0.8 ± 0.3
60
1.2 ± 0.3
21
Urinary recovery of
f
18 ± 8
6
18 ± 10
15
ND
didanosine (%)
CSF = cerebrospinal fluid, ND = not determined.
a Parameter units for adults were converted to the same units in pediatric patients to facilitate comparisons among
populations: mean adult body weight = 70 kg and mean adult body surface area = 1.73 m2.
b In 1-day old infants (n=10), the mean ± SD apparent oral clearance was 1523 ± 1176 mL/min/m2 and half-life was
2.0 ± 0.7 h.
c Following IV administration.
d Following IV administration in adults and IV or oral administration in pediatric patients.
e Mean ± SE.
f Following oral administration.
g Apparent oral clearance estimate was determined as the ratio of the mean systemic clearance and the mean oral
bioavailability estimate.
309
Effect of Food
310
Didanosine peak plasma concentrations (Cmax) and area under the plasma concentration time
311
curve (AUC) were decreased by approximately 55% when VIDEX tablets were administered up
312
to 2 hours after a meal. Administration of VIDEX tablets up to 30 minutes before a meal did not
20
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
313
result in any significant changes in bioavailability [see Dosage and Administration (2)]. VIDEX
314
should be taken on an empty stomach.
315
Special Populations
316
Renal Insufficiency: Data from two studies in adults indicated that the apparent oral clearance of
317
didanosine decreased and the terminal elimination half-life increased as creatinine clearance
318
decreased (see Table 11). Following oral administration, didanosine was not detectable in
319
peritoneal dialysate fluid (n=6); recovery in hemodialysate (n=5) ranged from 0.6% to 7.4% of
320
the dose over a 3-4 hour dialysis period. The absolute bioavailability of didanosine was not
321
affected in patients requiring dialysis. [See Dosage and Administration (2.2).]
Table 11:
Mean ± SD Pharmacokinetic Parameters for Didanosine Following a
Single Oral Dose
Creatinine Clearance (mL/min)
Parameter
at least 90
n=12
60-90
n=6
30-59
n=6
10-29
n=3
Dialysis Patients
n=11
CLcr (mL/min)
CL/F (mL/min)
CLR (mL/min)
112 ± 22
2164 ± 638
458 ± 164
68 ± 8
1566 ± 833
247 ± 153
46 ± 8
1023 ± 378
100 ± 44
13 ± 5
628 ± 104
20 ± 8
ND
543 ± 174
less than 10
T½ (h)
1.42 ± 0.33
1.59 ± 0.13
1.75 ± 0.43
2.0 ± 0.3
4.1 ± 1.2
ND = not determined due to anuria.
CLcr = creatinine clearance.
CL/F = apparent oral clearance.
CLR = renal clearance.
322
Hepatic Impairment: The pharmacokinetics of didanosine have been studied in 12 non-HIV
323
infected subjects with moderate (n=8) to severe (n=4) hepatic impairment (Child-Pugh Class B
324
or C). Mean AUC and Cmax values following a single 400 mg dose of didanosine were
325
approximately 13% and 19% higher, respectively, in patients with hepatic impairment compared
326
to matched healthy subjects. No dose adjustment is needed, because a similar range and
327
distribution of AUC and Cmax values was observed for subjects with hepatic impairment and
328
matched healthy controls. [See Dosage and Administration (2.3).]
329
Pediatric Patients: The pharmacokinetics of didanosine have been evaluated in HIV-exposed
330
and HIV-infected pediatric patients from birth to adulthood. Overall, the pharmacokinetics of
21
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
331
didanosine in pediatric patients are similar to those of didanosine in adults. Didanosine plasma
332
concentrations appear to increase in proportion to oral doses ranging from 25 to 120 mg/m2 in
333
pediatric patients less than 5 months old and from 80 to 180 mg/m2 in children above 8 months
334
old. For information on controlled clinical studies in pediatric patients, see Clinical Studies
335
(14.2) and Use in Specific Populations (8.4).
336
Geriatric Patients: Didanosine pharmacokinetics have not been studied in patients over 65 years
337
of age [see Use in Specific Populations (8.5)].
338
Gender: The effects of gender on didanosine pharmacokinetics have not been studied.
339
Drug Interactions
340
Tables 12 and 13 summarize the effects on AUC and Cmax, with a 95% confidence interval (CI)
341
when available, following coadministration of VIDEX (didanosine) with a variety of drugs.
342
Drug-drug interactions for VIDEX buffered tablets are applicable to the VIDEX pediatric
343
powder formulation and are noted in Tables 12 and 13. For clinical recommendations based on
344
drug interaction studies for drugs in bold font, see Dosage and Administration (2.3 for
345
Concomitant Therapy with Tenofovir Disoproxil Fumarate), Contraindications (4.1), and Drug
346
Interactions (7.1 and 7.2).
Table 12:
Results of Drug Interaction Studies with VIDEX: Effects of
Coadministered Drug on Didanosine Plasma AUC and Cmax Values
% Change of Didanosine
Pharmacokinetic Parametersa
AUC of
Cmax of
Didanosine
Didanosine
Drug
Didanosine Dosage
n
(95% CI)
(95% CI)
allopurinol,
renally impaired, 300 mg/day
200 mg single dose
2
↑ 312%
↑ 232%
healthy volunteer, 300 mg/day for
7 days
400 mg single dose
14
↑ 113%
↑ 69%
ciprofloxacin, 750 mg every 12 hours
for 3 days, 2 hours before didanosine
200 mg every 12 hours
for 3 days
8b
↓ 16%
↓ 28%
ganciclovir, 1000 mg every 8 hours, 2
hours after didanosine
200 mg every 12 hours
12
↑ 111%
NA
indinavir, 800 mg single dose,
simultaneous
200 mg single dose
16
↔
↔
1 hour before didanosine
200 mg single dose
16
↓ 17%
↓ 13%
22
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 12:
Results of Drug Interaction Studies with VIDEX: Effects of
Coadministered Drug on Didanosine Plasma AUC and Cmax Values
% Change of Didanosine
Pharmacokinetic Parametersa
AUC of
Cmax of
Didanosine
Didanosine
Drug
Didanosine Dosage
n
(95% CI)
(95% CI)
ketoconazole, 200 mg/day for 4 days, 2
hours before didanosine
methadone, chronic maintenance
f
dose
g,h
tenofovir,
300 mg once daily,
1 hour after didanosine
loperamide, 4 mg every 6 hours for
1 day
metoclopramide, 10 mg single dose
ranitidine, 150 mg single dose, 2 hours
before didanosine
rifabutin, 300 or 600 mg/day for
12 days
ritonavir, 600 mg every 12 hours for
4 days
stavudine, 40 mg every 12 hours for
4 days
sulfamethoxazole, 1000 mg single dose
trimethoprim, 200 mg single dose
zidovudine, 200 mg every 8 hours for
3 days
375 mg every 12 hours
for 4 days
200 mg single dose
400 mg single dose
250i mg or 400 mg once
daily for 7 days
300 mg single dose
300 mg single dose
375 mg single dose
167 mg or 250 mg every
12 hours for 12 days
200 mg every 12 hours
for 4 days
100 mg every 12 hours
for 4 days
200 mg single dose
200 mg single dose
200 mg every 12 hours
for 3 days
b
12
d
16
15,16e
14
b
12
b
12
b
12
11
12
10
b
8
b
8
b
6
(-27, - 7%)c
(-28, 5%)c
↔
↓ 12%
↓ 57%
↓ 66%
↓ 29%
↓ 41%
c
(-40, -16%)
(-54, -26%)c
↑ 44%
↑ 28%
c
(31, 59%)
(11, 48%)c
↔
↓ 23%
↔
↑ 13%
↑ 14%
↑ 13%
↑ 13%
↑ 17%
(-1, 27%)
(-4, 38%)
↓ 13%
↓ 16%
(0, 23%)
(5, 26%)
↔
↔
↔
↔
↑ 17%
↔
(-23, 77%)
↔
↔
↑ Indicates increase.
↓ Indicates decrease.
↔ Indicates no change, or mean increase or decrease of less than 10%.
a The 95% confidence intervals for the percent change in the pharmacokinetic parameter are displayed.
b HIV-infected patients.
c 90% CI.
d Comparisons are made to a parallel control group not receiving methadone (n=10).
23
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
347
Table 12:
Results of Drug Interaction Studies with VIDEX: Effects of
Coadministered Drug on Didanosine Plasma AUC and Cmax Values
% Change of Didanosine
Pharmacokinetic Parametersa
AUC of
Cmax of
Didanosine
Didanosine
Drug
Didanosine Dosage
n
(95% CI)
(95% CI)
e Comparisons are made to historical controls (n=68, pooled from 3 studies) conducted in healthy subjects. The
number of subjects evaluated for AUC and Cmax is 15 and 16, respectively.
f For results of drug interaction studies between the enteric-coated formulation of didanosine (VIDEX EC) and
methadone, see the complete prescribing information for VIDEX EC.
g Tenofovir disoproxil fumarate.
h For results of drug interaction studies between the enteric-coated formulation of didanosine (VIDEX EC) and
tenofovir disoproxil fumarate, see the complete prescribing information for VIDEX EC.
i Patients less than 60 kg with creatinine clearance of at least 60 mL/min.
NA = Not available.
Table 13:
Results of Drug Interaction Studies with VIDEX: Effects of
Didanosine on Coadministered Drug Plasma AUC and Cmax Values
% Change of Coadministered Drug
Pharmacokinetic Parametersa
AUC of
Cmax of
Coadministered
Coadministered
Drug
Drug
Drug
Didanosine Dosage
n
(95% CI)
(95% CI)
ciprofloxacin,
750 mg every 12 hours for 3 days, 2
hours before didanosine
750 mg single dose
delavirdine, 400 mg single dose
simultaneous 1 hour before
didanosine
ganciclovir, 1000 mg every 8 hours,
2 hours after didanosine
indinavir, 800 mg single dose
simultaneous
1 hour before didanosine
200 mg every 12 hours for
3 days
8b
↓ 26%
↓ 16%
buffered placebo tablet
12
↓ 98%
↓ 93%
125 mg or 200 mg every
12 hours
12b
↓ 32%
↓ 53%
125 mg or 200 mg every
12 hours
12b
↑ 20%
↑ 18%
200 mg every 12 hours
12b
↓ 21%
NA
200 mg single dose
16
↓ 84%
↓ 82%
200 mg single dose
16
↓ 11%
↓ 4%
24
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 13:
Results of Drug Interaction Studies with VIDEX: Effects of
Didanosine on Coadministered Drug Plasma AUC and Cmax Values
% Change of Coadministered Drug
Pharmacokinetic Parametersa
AUC of
Cmax of
Coadministered
Coadministered
Drug
Drug
Drug
Didanosine Dosage
n
(95% CI)
(95% CI)
ketoconazole, 200 mg/day for
375 mg every 12 hours for
b
12
↓ 14%
↓ 20%
4 days, 2 hours before didanosine
4 days
nelfinavir, 750 mg single dose,
b
200 mg single dose
10
↑ 12%
↔
1 hour after didanosine
200 mg every 12 hours for
b
dapsone, 100 mg single dose
6
↔
↔
14 days
ranitidine, 150 mg single dose,
b
375 mg single dose
12
↓ 16%
↔
2 hours before didanosine
ritonavir, 600 mg every 12 hours
200 mg every 12 hours for
12
↔
↔
for 4 days
4 days
stavudine, 40 mg every 12 hours for 100 mg every 12 hours for
b
10
↔
↑ 17%
4 days
4 days
sulfamethoxazole, 1000 mg single
b
↓ 11%
↓ 12%
200 mg single dose
8
dose
(-17, -4%)
(-28, 8%)
d
tenofovir,c 300 mg once daily
250 mg or 400 mg once
14
↔
↔
1 hour after didanosine
daily for 7 days
b
↑ 10%
↓ 22%
trimethoprim, 200 mg single dose
200 mg single dose
8
(-9, 34%)
(-59, 49%)
zidovudine, 200 mg every 8 hours
200 mg every 12 hours for
b
↓ 10%
↓ 16.5%
6
for 3 days
3 days
(-27, 11%)
(-53, 47%)
↑ Indicates increase.
↓ Indicates decrease.
↔ Indicates no change, or mean increase or decrease of less than 10%.
a The 95% confidence intervals for the percent change in the pharmacokinetic parameter are displayed.
b HIV-infected patients.
c Tenofovir disoproxil fumarate.
d Patients less than 60 kg with creatinine clearance of at least 60 mL/min.
NA = Not available.
25
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
348
12.4
Microbiology
349
Mechanism of Action
350
Didanosine is a synthetic nucleoside analogue of the naturally occurring nucleoside
351
deoxyadenosine in which the 3′-hydroxyl group is replaced by hydrogen. Intracellularly,
352
didanosine is converted by cellular enzymes to the active metabolite, dideoxyadenosine 5′
353
triphosphate. Dideoxyadenosine 5′-triphosphate inhibits the activity of HIV-1 reverse
354
transcriptase both by competing with the natural substrate, deoxyadenosine 5′-triphosphate, and
355
by its incorporation into viral DNA causing termination of viral DNA chain elongation.
356
Antiviral Activity in Cell Culture
357
The anti-HIV-1 activity of didanosine was evaluated in a variety of HIV-1 infected
358
lymphoblastic cell lines and monocyte/macrophage cell cultures. The concentration of drug
359
necessary to inhibit viral replication by 50% (EC50) ranged from 2.5 to 10 µM (1 µM =
360
0.24 µg/mL) in lymphoblastic cell lines and 0.01 to 0.1 µM in monocyte/macrophage cell
361
cultures.
362
Resistance
363
HIV-1 isolates with reduced sensitivity to didanosine have been selected in cell culture and were
364
also obtained from patients treated with didanosine. Genetic analysis of isolates from didanosine
365
treated patients showed mutations in the reverse transcriptase gene that resulted in the amino acid
366
substitutions K65R, L74V, and M184V. The L74V substitution was most frequently observed in
367
clinical isolates. Phenotypic analysis of HIV-1 isolates from 60 patients (some with prior
368
zidovudine treatment) receiving 6 to 24 months of didanosine monotherapy showed that isolates
369
from 10 of 60 patients exhibited an average of a 10-fold decrease in susceptibility to didanosine
370
in cell culture compared to baseline isolates. Clinical isolates that exhibited a decrease in
371
didanosine susceptibility harbored one or more didanosine resistance-associated substitutions.
372
Cross-resistance
373
HIV-1 isolates from 2 of 39 patients receiving combination therapy for up to 2 years with
374
didanosine and zidovudine exhibited decreased susceptibility to didanosine, lamivudine,
375
stavudine, zalcitabine, and zidovudine in cell culture. These isolates harbored five substitutions
376
In data from clinical
26
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377
studies, the presence of thymidine analogue mutations (M41L, D67N, L210W, T215Y, K219Q)
378
has been shown to decrease the response to didanosine.
379
13
NONCLINICAL TOXICOLOGY
380
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
381
Lifetime carcinogenicity studies were conducted in mice and rats for 22 and 24 months,
382
respectively. In the mouse study, initial doses of 120, 800, and 1200 mg/kg/day for each sex
383
were lowered after 8 months to 120, 210, and 210 mg/kg/day for females and 120, 300, and
384
600 mg/kg/day for males. The two higher doses exceeded the maximally tolerated dose in
385
females and the high dose exceeded the maximally tolerated dose in males. The low dose in
386
females represented 0.68-fold maximum human exposure and the intermediate dose in males
387
represented 1.7-fold maximum human exposure based on relative AUC comparisons. In the rat
388
study, initial doses were 100, 250, and 1000 mg/kg/day, and the high dose was lowered to
389
500 mg/kg/day after 18 months. The upper dose in male and female rats represented 3-fold
390
maximum human exposure.
391
Didanosine induced no significant increase in neoplastic lesions in mice or rats at maximally
392
tolerated doses.
393
Didanosine was positive in the following genetic toxicology assays: 1) the Escherichia coli tester
394
strain WP2 uvrA bacterial mutagenicity assay; 2) the L5178Y/TK+/- mouse lymphoma
395
mammalian cell gene mutation assay; 3) the in vitro chromosomal aberrations assay in cultured
396
human peripheral lymphocytes; 4) the in vitro chromosomal aberrations assay in Chinese
397
Hamster Lung cells; and 5) the BALB/c 3T3 in vitro transformation assay. No evidence of
398
mutagenicity was observed in an Ames Salmonella bacterial mutagenicity assay or in rat and
399
mouse in vivo micronucleus assays.
400
13.2
Animal Toxicology and/or Pharmacology
401
Evidence of a dose-limiting skeletal muscle toxicity has been observed in mice and rats (but not
402
in dogs) following long-term (greater than 90 days) dosing with didanosine at doses that were
403
approximately 1.2 to 12 times the estimated human exposure. The relationship of this finding to
404
the potential of VIDEX (didanosine) to cause myopathy in humans is unclear. However, human
405
myopathy has been associated with administration of VIDEX and other nucleoside analogues.
27
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
406
14
CLINICAL STUDIES
407
14.1
Adult Patients
408
Combination Therapy
409
START 2 was a multicenter, randomized, open-label study comparing VIDEX (200 mg twice
410
daily)/stavudine/indinavir to zidovudine/lamivudine/indinavir in 205 treatment-naive patients.
411
Both regimens resulted in a similar magnitude of suppression of HIV-1 RNA levels and
412
increases in CD4 cell counts through 48 weeks.
413
Study AI454-148 was a randomized, open-label, multicenter study comparing treatment with
414
VIDEX (400 mg once daily) plus stavudine (40 mg twice daily) and nelfinavir (750 mg three
415
times daily) versus zidovudine (300 mg twice daily) plus lamivudine (150 mg twice daily) and
416
nelfinavir (750 mg three times daily) in 756 treatment-naive patients, with a median CD4 cell
417
count of 340 cells/mm3 (range 80 to 1568 cells/mm3) and a median plasma HIV-1 RNA of
418
4.69 log10 copies/mL (range 2.6 to 5.9 log10 copies/mL) at baseline. Median CD4 cell count
419
increases at 48 weeks were 188 cells/mm3 in both treatment groups. Treatment response and
420
outcomes through 48 weeks are shown in Figure 1 and Table 14. Graph
28
421
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 14:
Outcomes of Randomized Treatment Through Week 48, AI454-148
Percent of Patients with HIV-1 RNA less than 400 copies/mL
(less than 50 copies/mL)
VIDEX/stavudine/nelfinavir
lamivudine/zidovudine/nelfinavir
Week 48 Status
n=503
n=253
Respondera
50* (34*)
59 (47)
Virologic failureb
36 (57)
32 (48)
Death or disease progression
less than 1 (less than 1)
1 (less than 1)
Discontinued due to adverse events
4 (2)
2 (less than 1)
Discontinued due to other reasonsc
6 (3)
4 (2)
Never initiated treatment
4 (4)
2 (2)
* p less than 0.05 for the differences between treatment groups, by Cochran-Mantel-Haenszel test.
a Patients achieved virologic response [two consecutive viral loads less than 400 (less than 50) copies/mL] and
maintained it to Week 48.
b Includes viral rebound and failing to achieve confirmed less than 400 (less than 50) copies/mL by Week 48.
c Includes lost to follow-up, noncompliance, withdrawal, and pregnancy.
422
Monotherapy
423
The efficacy of VIDEX was demonstrated in two randomized, double-blind studies comparing
424
VIDEX, given on a twice-daily schedule, to zidovudine, given three times daily, in 617 (ACTG
425
116A, conducted 1989-1992) and 913 (ACTG 116B/117, conducted 1989-1991) patients with
426
symptomatic HIV infection or AIDS who were treated for more than one year. In treatment
427
naive patients (ACTG 116A), the rate of HIV disease progression or death was similar between
428
the treatment groups; mortality rates were 26% for patients receiving VIDEX and 21% for
429
patients receiving zidovudine. Of the patients who had received previous zidovudine treatment
430
(ACTG 116B/117), those treated with VIDEX had a lower rate of HIV disease progression or
431
death (32%) compared to those treated with zidovudine (41%); however, survival rates were
432
similar between the treatment groups.
433
Studies have demonstrated that the clinical benefit of monotherapy with antiretrovirals, including
434
VIDEX, was time limited.
29
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435
14.2
Pediatric Patients
436
Efficacy in pediatric patients was demonstrated in a randomized, double-blind, controlled study
437
(ACTG 152, conducted 1991-1995) involving 831 patients 3 months to 18 years of age treated
438
for more than 1.5 years with zidovudine (180 mg/m2 every 6 hours), VIDEX (120 mg/m2 every
439
12 hours), or zidovudine (120 mg/m2 every 6 hours) plus VIDEX (90 mg/m2 every 12 hours).
440
Patients treated with VIDEX or VIDEX plus zidovudine had lower rates of HIV-1 disease
441
progression or death compared with those treated with zidovudine alone.
442
16
HOW SUPPLIED/STORAGE AND HANDLING
443
VIDEX (didanosine, USP) Pediatric Powder for Oral Solution is supplied as shown in Table 15:
Table 15:
VIDEX Pediatric Powder for Oral Solution
NDC NO.
Packaging Information
Product Quantity
0087-6632-41
One, 4-ounce glass, bottle per carton
2 g/bottle
0087-6633-41
One, 8-ounce glass, bottle per carton
4 g/bottle
444
Prior to dispensing, the pharmacist must reconstitute dry powder with Purified Water, USP, to an
445
initial concentration of 20 mg/mL and immediately mix the resulting solution with antacid to a
446
final concentration of 10 mg/mL as follows:
447
20 mg/mL Initial Solution
448
Reconstitute the product to 20 mg/mL by adding 100 mL or 200 mL of Purified Water, USP, to
449
the 2 g or 4 g of VIDEX powder, respectively, in the product bottle.
450
10 mg/mL Final Admixture
451
1. Immediately mix one part of the 20 mg/mL initial solution with one part of Maximum
452
Strength Mylanta® Liquid for a final dispensing concentration of 10 mg VIDEX per mL. For
453
patient home use, the admixture should be dispensed in appropriately sized, flint-glass or
454
plastic (HDPE, PET, or PETG) bottles with child-resistant closures.
455
2. Instruct the patient to shake the admixture thoroughly prior to use and to store the tightly
456
closed container in the refrigerator.
30
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
457
Storage
458
The bottles of powder should be stored at 59° F to 86° F (15° C to 30° C). The VIDEX
459
admixture may be stored up to 30 days in a refrigerator, 36° F to 46° F (2° C to 8° C). Discard
460
any unused portion after 30 days.
461
______________________
462
Mylanta® is a registered trademark of Johnson & Johnson-Merck Consumer Pharmaceuticals
463
Company.
464
17
PATIENT COUNSELING INFORMATION
465
See Medication Guide.
466
17.1
Pancreatitis
467
Patients should be informed that a serious toxicity of VIDEX, used alone and in combination
468
regimens, is pancreatitis, which may be fatal.
469
17.2
Peripheral Neuropathy
470
Patients should be informed that peripheral neuropathy, manifested by numbness, tingling, or
471
pain in hands or feet, may develop during therapy with VIDEX. Patients should be counseled
472
that peripheral neuropathy occurs with greatest frequency in patients with advanced HIV-1
473
disease or a history of peripheral neuropathy, and that discontinuation of VIDEX may be
474
required if toxicity develops.
475
17.3
Lactic Acidosis and Severe Hepatomegaly with Steatosis
476
Patients should be informed that lactic acidosis and severe hepatomegaly with steatosis,
477
including fatal cases, have been reported with the use of nucleoside analogues alone or in
478
combination, including didanosine and other antiretrovirals.
31
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For current labeling information, please visit https://www.fda.gov/drugsatfda
479
17.4
Hepatic Toxicity
480
Patients should be informed that hepatotoxicity including fatal hepatic adverse events were
481
reported in patients with preexisting liver dysfunction. The safety and efficacy of VIDEX have
482
not been established in HIV-infected patients with significant underlying liver disease.
483
17.5
Non-cirrhotic Portal Hypertension
484
Patients should be informed that non-cirrhotic portal hypertension has been reported in patients
485
taking VIDEX, including cases leading to liver transplantation or death.
486
17.6
Retinal Changes and Optic Neuritis
487
Patients should be informed that retinal changes and optic neuritis have been reported in adult
488
and pediatric patients.
489
17.7
Fat Redistribution
490
Patients should be informed that redistribution or accumulation of body fat may occur in patients
491
receiving antiretroviral therapy and that the cause and long-term health effects of these
492
conditions are not known at this time.
493
17.8
Concomitant Therapy
494
Patients should be informed that when VIDEX is used in combination with other agents with
495
similar toxicities, the incidence of adverse events may be higher than when VIDEX is used
496
alone. These patients should be followed closely.
497
Patients should be cautioned about the use of medications or other substances, including alcohol,
498
which may exacerbate VIDEX toxicities.
499
17.9
General Information
500
VIDEX (didanosine) is not a cure for HIV-1 infection, and patients may continue to develop
501
HIV-associated illnesses, including opportunistic infection. Therefore, patients should remain
502
under the care of a physician when using VIDEX. Patients should be advised that VIDEX
503
therapy has not been shown to reduce the risk of transmission of HIV to others through sexual
32
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
504
contact or blood contamination. Patients should be informed that the long-term effects of VIDEX
505
are unknown at this time.
506
Patients should be informed that the preferred dosing frequency of VIDEX is twice daily because
507
there is more evidence to support the effectiveness of this dosing frequency. Once-daily dosing
508
should be considered only for patients whose management requires once-daily dosing of VIDEX.
509
Patients should be instructed to not miss a dose but if they do, patients should take VIDEX as
510
soon as possible. Patients should be told that if it is almost time for the next dose, they should
511
skip the missed dose and continue with the regular dosing schedule.
512
Patients should be instructed to contact a poison control center or emergency room right away in
513
case of an overdose.
514
VIDEX has not been shown to prevent a patient infected with HIV from passing the virus to
515
other people. To protect others, patients should be advised to continue to practice safer sex and
516
take precautions to prevent others from coming in contact with infected blood and other body
517
fluids.
518
33
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:46:56.153589
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020156s046lbl.pdf', 'application_number': 20156, 'submission_type': 'SUPPL ', 'submission_number': 46}
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12,284
|
DIANEAL Peritoneal Dialysis Solution
For intraperitoneal administration only
DIANEAL
PD-2
Peritoneal
Dialysis
Solution
With 1.5%
Dextrose
DIANEAL
PD-2
Peritoneal
Dialysis
Solution
With 2.5%
Dextrose
DIANEAL
PD-2
Peritoneal
Dialysis
Solution
With
4.25%
Dextrose
DIANEAL
Low
Calcium
(2.5
mEq/L)
Peritoneal
Dialysis
Solution
With 1.5%
Dextrose
DIANEAL
Low
Calcium
(2.5
mEq/L)
Peritoneal
Dialysis
Solution
With 2.5%
Dextrose
DIANEAL
Low
Calcium
(2.5
mEq/L)
Peritoneal
Dialysis
Solution
With
4.25%
Dextrose
DESCRIPTION
DIANEAL Peritoneal Dialysis Solutions are sterile, nonpyrogenic solutions in AMBU-FLEX and
ULTRABAG containers for intraperitoneal administration only. The peritoneal dialysis solutions
contain no bacteriostatic or antimicrobial agents.
Composition, calculated osmolarity, pH, and ionic concentrations are shown in Tables 1-4.
DIANEAL is a hyperosmolar solution.
The plastic container is fabricated from polyvinyl chloride (PL 146 Plastic). Exposure to temperatures
above 25°C/77°F during transport and storage will lead to minor losses in moisture content. Higher
temperatures lead to greater losses. It is unlikely that these minor losses will lead to clinically
significant changes within the expiration period. The amount of water that can permeate from inside
the solution container into the overwrap is insufficient to affect the solution significantly.
Solutions in contact with the plastic container can leach out certain of its chemical components in
very small amounts within the expiration period, e.g. di-2-ethylhexyl phthalate (DEHP), up to 5 parts
per million; however, the safety of the plastic has been confirmed in tests in animals according to
USP biological tests for plastic containers as well as by cell culture toxicity studies.
CLINICAL PHARMACOLOGY
Mechanism of Action
DIANEAL is a hypertonic peritoneal dialysis solution containing dextrose, a monosaccharide, as the
primary osmotic agent. An osmotic gradient must be created between the peritoneal membrane and
the dialysis solution in order for ultrafiltration to occur. The hypertonic concentration of glucose in
DIANEAL exerts an osmotic pressure across the peritoneal membrane resulting in transcapillary
ultrafiltration. Like other peritoneal dialysis solutions, DIANEAL contains electrolytes to facilitate the
correction of electrolyte abnormalities. DIANEAL contains a buffer, lactate, to help normalize acid-
base abnormalities.
Pharmacokinetics of DIANEAL
Glucose content in DIANEAL is expressed as dextrose monohydrate and is available in three
concentrations: 1.5%, 2.5% and 4.25%.
Reference ID: 3698977
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Glucose is rapidly absorbed from the peritoneal cavity by diffusion and appears quickly in the
circulation due to the high glucose concentration gradient between DIANEAL compared to blood
capillary glucose level. Absorption per unit time will be the highest at the start of an exchange and
decreases over time. The rate of glucose absorption will be dependent upon the transport
characteristics of the patient’s peritoneal membrane as determined by a peritoneal equilibration test
(PET). Glucose absorption will also depend upon the concentration of glucose used for the
exchange and the length of the dwell. Glucose is metabolized by normal cellular pathways (e.g.
glycolysis) and provides a source of calories and may elevate blood glucose levels.
Transport of other molecules across the peritoneal membrane, such as lactate, will occur by
diffusion. Metabolism of lactate occurs in the liver and results in the generation of the bicarbonate.
Transport of other molecules will be dependent upon the molecular size of the solute, the
concentration gradient, and the effective peritoneal surface area as determined by the PET.
INDICATIONS AND USAGE
DIANEAL peritoneal dialysis solutions are indicated for patients in acute or chronic renal failure
when nondialytic medical therapy is judged to be inadequate.
CONTRAINDICATIONS
DIANEAL is contraindicated in patients with pre-existing severe lactic acidosis.
WARNINGS
Encapsulating Peritoneal Sclerosis (EPS) is considered to be a known, rare complication of
peritoneal dialysis therapy. EPS has been reported in patients using peritoneal dialysis solutions
including DIANEAL. Infrequently, fatal outcomes of EPS have been reported with DIANEAL.
Because Dianeal is a dextrose-based solution, patients with allergy to corn or corn products are at
increased risk for allergic reaction, which may include anaphylactic/anaphylactoid reactions. Stop the
infusion immediately, drain the solution from the peritoneal cavity and treat appropriately if any signs
or symptoms of a suspected hypersensitivity reaction develop.
Patients with severe lactic acidosis should not be treated with lactate-based peritoneal dialysis
solutions (See Contraindications). Patients with conditions known to increase the risk of lactic
acidosis [e.g., severe hypotension or sepsis that can be associated with acute renal failure, hepatic
failure, inborn errors of metabolism, and treatment with drugs such as nucleoside/nucleotide reverse
transcriptase inhibitors (NRTIs)] must be monitored for the occurrence of lactic acidosis before the
start of treatment and during treatment with lactate-based peritoneal dialysis solutions.
When prescribing the solution to be used for an individual patient, consideration should be given to
the potential interaction between the dialysis treatment and therapy directed at other existing
illnesses. Serum potassium levels should be monitored carefully in patients treated with cardiac
glycosides. For example, rapid potassium removal may create arrhythmias in cardiac patients using
digitalis or similar drugs; digitalis toxicity may be masked by hyperkalemia, hypermagnesemia, or
hypocalcemia. Correction of electrolytes by dialysis may precipitate signs and symptoms of digitalis
excess. Conversely, toxicity may occur at suboptimal dosages of digitalis if potassium is low or
calcium is high.
Diabetics require careful monitoring of insulin requirements and other treatments for hyperglycemia
during and following dialysis with dextrose containing solutions.
PRECAUTIONS
Reference ID: 3698977
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
General
Peritoneal-Dialysis Related
DIANEAL is intended for intraperitoneal administration only. Not for intravenous administration.
The following conditions may predispose to adverse reactions to peritoneal dialysis procedures:
abdominal conditions, including uncorrectable mechanical defects that prevent effective peritoneal
dialysis or increase the risk of infection, disruption of the peritoneal membrane and diaphragm by
surgery, congenital anomalies or trauma prior to complete healing, abdominal tumors, abdominal
wall infections, hernias, fecal fistula, colostomies or ileostomies, frequent episodes of diverticulitis,
inflammatory or ischemic bowel disease, large polycystic kidneys, or other conditions that
compromise the integrity of the abdominal wall, abdominal surface, or intra-abdominal cavity, such
as documented loss of peritoneal function or extensive adhesions that compromise peritoneal
function. Conditions that preclude normal nutrition, impaired respiratory function, recent aortic graft
placement, and potassium deficiency may also predispose to complications of peritoneal dialysis.
Aseptic technique must be employed throughout the peritoneal dialysis procedure to reduce the
possibility of infection.
Following use, the drained fluid should be inspected for the presence of fibrin or cloudiness, which
may indicate the presence of peritonitis.
If peritonitis occurs, the choice and dosage of antibiotics should be based upon the results of
identification and sensitivity studies of the isolated organism(s) when possible. Prior to identification
of the involved organism(s), broad-spectrum antibiotics may be indicated.
Overinfusion of peritoneal dialysis solution volume into the peritoneal cavity may be characterized by
abdominal distention, feeling of fullness and/or shortness of breath. Treatment of overinfusion is to
drain the peritoneal dialysis solution from the peritoneal cavity.
Need for Trained Physician
Treatment should be initiated and monitored under the supervision of a physician knowledgeable in
the management of patients with renal failure.
A patient’s volume status should be carefully monitored to avoid hyper- or hypovolemia and
potentially severe consequences including congestive heart failure, volume depletion and
hypovolemic shock. An accurate fluid balance record must be kept and the patient’s body weight
monitored. Excessive use of DIANEAL peritoneal dialysis solution with higher dextrose concentration
during a peritoneal dialysis treatment may result in significant removal of water from the patient (see
Dosage and Administration).
Significant losses of protein, amino acids, water-soluble vitamins and other medicines may occur
during peritoneal dialysis. The patient’s nutritional status should be monitored and replacement
therapy should be provided as necessary.
Information for Patients
Patients should be instructed not to use solutions if they are cloudy, discolored, contain visible
particulate matter, or if they show evidence of leaking containers (see Dosage and Administration).
Aseptic technique must be employed throughout the procedure.
An improper clamping sequence may result in infusion of air into the peritoneum (see Dosage and
Administration, Directions for Use).
To reduce possible discomfort during administration, patients should be instructed that solutions may
be warmed to 37°C (98°F) prior to use. Only dry heat should be used. It is best to warm solutions
Reference ID: 3698977
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
within the overwrap using a heating pad. To avoid contamination, solutions should not be immersed
in water for warming. Do not use a microwave oven to warm the solution (see Dosage and
Administration, Directions for Use).
Laboratory Tests
Serum Electrolytes
DIANEAL does not contain potassium. Evaluate serum potassium prior to administering potassium
chloride to the patient. In situations where there is a normal serum potassium level or hypokalemia,
addition of potassium chloride (up to a concentration of 4 mEq/L) to the solution may be necessary
to prevent severe hypokalemia. This should be made under careful evaluation of serum and total
body potassium, and only under the direction of a physician.
Fluid, hematology, blood chemistry, electrolyte concentrations, and bicarbonate should be monitored
periodically. If serum magnesium levels are low, magnesium supplements may be used.
Patients receiving DIANEAL solutions should have their calcium levels monitored for the
development of hypocalcemia or hypercalcemia. In these circumstances, adjustments to the dosage
of the phosphate binders, vitamin D analogs, and/or calcimimetics should be considered by the
physician. DIANEAL Low Calcium (2.5 mEq/L) Peritoneal Dialysis solution should be considered for
use in patients with hypercalcemia.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Studies to evaluate the carcinogenic or mutagenic potential of this product, or its potential to affect
fertility adversely, have not been performed.
Drug Interactions
No clinical drug interaction studies were performed. As with other dialysis solutions, blood
concentrations of dialyzable drugs may be reduced by dialysis. Dosage adjustment of concomitant
medications may be necessary. In patients using cardiac glycosides (digoxin and others), plasma
levels of calcium, potassium and magnesium must be carefully monitored (see Warnings).
Use in Specific Population
Pregnancy
Pregnancy Category C. DIANEAL is a peritoneal dialysis solution of electrolytes, lactate and
dextrose and is pharmacologically inactive. Animal reproduction studies have not been conducted
with DIANEAL dialysis solution. While there are no adequate and well controlled studies in pregnant
women, appropriate administration of DIANEAL with monitoring of fluid, electrolyte, acid-base and
glucose balance, is not expected to cause fetal harm, or affect reproductive capacity. Maintenance
of normal acid-base balance is important for fetal well being. Physicians should carefully consider
the potential risks and benefits for each specific patient before prescribing DIANEAL.
Nursing Mothers
DIANEAL is a dialysis solution of electrolytes, lactate and dextrose and is pharmacologically
inactive. The components of DIANEAL are excreted in human milk. Appropriate administration of
DIANEAL with monitoring of fluid, electrolyte, acid-base and glucose balance, is not expected to
harm a nursing infant. Physicians should carefully consider the potential risks and benefits for each
specific patient before prescribing DIANEAL.
Pediatric Use
Safety and effectiveness have been established based on published clinical data. No adequate and
well-controlled studies have been conducted with DIANEAL solutions in pediatric patients.
Geriatric Use
Safety and effectiveness have been established based on published clinical data.
Reference ID: 3698977
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
ADVERSE REACTIONS
The following adverse reactions have been identified during post approval use of DIANEAL.
Because these reactions are reported voluntarily from a population of uncertain size, it is not always
possible to reliably estimate their frequency or establish a causal relationship during drug exposure.
Adverse reactions are listed by MedDRA System Organ Class (SOC), then by Preferred Term in
order of severity.
INFECTIONS AND INFESTATIONS: Fungal peritonitis, Peritonitis bacterial, Catheter related
infection
METABOLISM AND NUTRITION DISORDERS: Hypovolemia, Hypervolemia, Fluid retention,
Hypokalemia, Hyponatremia, Dehydration, Hypochloremia
VASCULAR DISORDERS: Hypotension, Hypertension
RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS: Dyspnea
GASTROINTESTINAL DISORDERS: Sclerosing encapsulating peritonitis, Peritonitis, Peritoneal
cloudy effluent, Vomiting, Diarrhea, Nausea, Constipation, Abdominal pain, Abdominal distension,
Abdominal discomfort
SKIN AND SUBCUTANEOUS DISORDERS: Stevens-Johnson syndrome, Urticaria, Rash, (including
pruritic, erythematous and generalized), Pruritus
MUSCULOSKELETAL, CONNECTIVE TISSUE DISORDERS: Myalgia, Muscle spasms,
Musculoskeletal pain
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS: Generalized edema,
Pyrexia, Malaise, Infusion site pain, Catheter related complication
DRUG ABUSE AND DEPENDENCE
There has been no observed potential of drug abuse or dependence with DIANEAL solution.
OVERDOSAGE
There is a potential for overdose resulting in hypervolemia, hypovolemia, electrolyte disturbances or
hyperglycemia. Excessive use of DIANEAL peritoneal dialysis solution with 4.25% dextrose during a
peritoneal dialysis treatment can result in significant removal of water from the patient.
DOSAGE AND ADMINISTRATION
DIANEAL peritoneal dialysis solutions are intended for intraperitoneal administration only.
The mode of therapy, frequency of treatment, formulation, exchange volume, duration of dwell, and
length of dialysis should be selected by the physician responsible for and supervising the treatment
of the individual patient. DIANEAL should be administered at a rate that is comfortable for the
patient, generally over a period of 10-20 minutes for a single exchange.
Patients on continuous ambulatory peritoneal dialysis (CAPD) typically perform 4 cycles per day (24
hours). Patients on automated peritoneal dialysis (APD) typically perform 4-5 cycles at night and up
to 2 cycles during the day. The fill volume depends on body size, usually from 2.0 to 2.5 liters per
1.73m2 .
Reference ID: 3698977
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For current labeling information, please visit https://www.fda.gov/drugsatfda
To avoid the risk of severe dehydration and hypovolemia and to minimize the loss of protein, it is
advisable to select the peritoneal dialysis solution with the lowest level of osmolarity consistent with
the fluid removal requirements for that exchange. As the patient’s body weight becomes closer to the
ideal dry weight, lowering the dextrose concentration of DIANEAL is recommended. DIANEAL
4.25% dextrose-containing solution has the highest osmolarity of the DIANEAL solutions and using it
for all exchanges may cause dehydration.
Solutions that are cloudy, discolored, contain visible particulate matter, or show evidence of leakage
should not be used.
Following use, the drained fluid should be inspected for the presence of fibrin or cloudiness which
may indicate the presence of peritonitis.
For single use only. Discard unused portion.
It is recommended that patients being placed on peritoneal dialysis and/or their caretaker(s) should
be appropriately trained.
Addition of Potassium
Potassium is omitted from DIANEAL solutions because dialysis may be performed to correct
hyperkalemia. In situations where there is a normal serum potassium level or hypokalemia, the
addition of potassium chloride (up to a concentration of 4 mEq/L) may be indicated to prevent severe
hypokalemia. The decision to add potassium chloride should be made by the physician after careful
evaluation of serum potassium.
Addition of Insulin
Patients with insulin-dependent diabetes may require modification of insulin dosage following
initiation of treatment with DIANEAL. Appropriate monitoring of blood glucose should be performed
when initiating DIANEAL in diabetic patients and insulin dosage adjusted if needed (see Warnings).
Addition of Heparin
No human drug interaction studies with heparin were conducted. In vitro studies demonstrated no
evidence of incompatibility of heparin with DIANEAL.
Addition of Antibiotics
No formal clinical drug interaction studies have been performed. In vitro studies of the following
medications have demonstrated stability with DIANEAL: amphotericin B, ampicillin, cefazolin,
cefepime, cefotaxime, ceftazidime, ceftriaxone, ciprofloxacin, clindamycin, deferoxamine,
erythromycin, gentamicin, linezolid, mezlocillin, miconazole, moxifloxacin, nafcillin, ofloxacin,
penicillin G, piperacillin, sulfamethoxazole/trimethoprim, ticarcillin, tobramycin, and vancomycin.
However, aminoglycosides should not be mixed with penicillins due to chemical incompatibility.
Directions for Use
For complete CAPD and APD system preparation, see directions accompanying ancillary
equipment.
Aseptic technique must be used throughout the peritoneal dialysis procedure.
Warming
For patient comfort, DIANEAL can be warmed to 37°C (98°F). Only dry heat should be used. It is
best to warm solutions within the overwrap using a heating pad. Do not immerse DIANEAL in water
for warming. Do not use a microwave oven to warm DIANEAL.
To Open
Reference ID: 3698977
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For current labeling information, please visit https://www.fda.gov/drugsatfda
To open, tear the overwrap down at the slit and remove the solution container. Some opacity of the
plastic, due to moisture absorption during the sterilization process, may be observed. This does not
affect the solution quality or safety and may often leave a slight amount of moisture within the
overwrap. The opacity should diminish gradually.
Inspect for Container Integrity
Inspect the patient connector to ensure the pull ring is attached. Do not use if pull ring is not
attached to the connector. Inspect the DIANEAL container for signs of leakage and check for minute
leaks by squeezing the container firmly. If the container has frangible(s), inspect that they are
positioned correctly and are not broken. Do not use DIANEAL if the frangible(s) are broken or leaks
are suspected as sterility may be impaired.
For DIANEAL in UltraBag, inspect the tubing and drain container for presence of solution. Small
droplets are acceptable, but if solution flows past the frangible prior to use, do not use and discard
the units.
Adding Medications
Some drug additives may be incompatible with DIANEAL. See DOSAGE AND ADMINISTRATION
section for additional information. If the resealable rubber plug on the medication port is missing or
partly removed, do not use the product if medication is to be added.
1. Put on mask. Clean and/or disinfect hands.
2. Prepare medication port site using aseptic technique.
3. Using a syringe with a 1-inch long, 25- to 19-gauge needle, puncture the medication port and
inject additive.
4. Reposition container with container ports up and evacuate medication port by squeezing and
tapping it.
5. Mix solution and additive thoroughly.
Administration
1. Put on mask. Clean and/or disinfect hands.
2. Place DIANEAL on work surface.
3. For UltraBag system for manual exchange, uncoil tubing and drain bag. Ensure the patient
transfer set is closed. Break the connector (Y-set) frangible.
4. Remove pull ring from connector of solution container. Once the pull ring has been removed do
not reuse the solution or container.
5. Immediately attach the solution container to patient connector (transfer set) or appropriate
peritoneal dialysis set.
6. For Ambu-Flex, continue with therapy as instructed in user manual or directions accompanying
tubing sets for automated peritoneal dialysis.
7. For UltraBag, follow the below steps:
• Clamp solution line and then break frangible near solution bag. Hang solution container and
place the drainage container below the level of the abdomen.
• Open transfer set to drain the solution from abdomen. If drainage cannot be established,
contact your clinician. When drainage complete, close transfer set.
• Remove clamp from solution line and flush new solution to flow into the drainage container
for 5 seconds to prime the line. Clamp drain line after flush complete.
• Open transfer set to fill. When fill complete, close transfer set.
• Disconnect UltraBag from transfer set and apply MiniCap.
8. Upon completion of therapy, discard any unused portion.
HOW SUPPLIED
Reference ID: 3698977
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
DIANEAL peritoneal dialysis solutions are available in nominal size flexible containers as shown in
Tables 1-4.
All DIANEAL peritoneal dialysis solutions have overfills which are declared on container labeling.
Freezing of solution may occur at temperatures below 0°C (32°F). Allow to thaw naturally in ambient
conditions and thoroughly mix contents by shaking.
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is
recommended the product be stored at room temperature (25°C/77°F): brief exposure up to 40°C
(104°F) does not adversely affect the product.
Reference ID: 3698977
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 1. DIANEAL PD-2 Peritoneal Dialysis Solution (AMBU-FLEX CONTAINER)
Composition/100 mL
Ionic Concentration
(mEq/L)
How Supplied
(NaCl)
3 )
5 NaO
(CaCl
2 •6H2 O)
Fill
Container
SP
, U
SP
SP
USP (MgCl
e,
Volume
Size
Code
NDC
*Dextrose, Hydrous
Sodium Chloride, U
Sodium Lactate (C3 H
Calcium Chloride, U
2 •2H2 O)
Magnesium Chlorid
OSMOLARITY
(mOsmol/L) (calc)
pH
Sodium
Calcium
Magnesium
Chloride
Lactate
(mL)
(mL)
DIANEAL PD-2
Peritoneal Dialysis
Solution with 1.5%
Dextrose
AMBU-FLEX II
CONTAINER
1.5 g
538 mg
448 mg
25.7 mg 5.08 mg
346
5.2
(4.0 to 6.5)
132
3.5
0.5
96
40
1000
2000
3000
5000
6000
1000
3000
3000
6000
6000
L5B5163
L5B5166
L5B5169
L5B5193
L5B9710
0941-0411-05
0941-0411-06
0941-0411-04
0941-0411-07
0941-0411-11
DIANEAL PD-2
Peritoneal Dialysis
Solution with 2.5%
Dextrose
AMBU-FLEX II
CONTAINER
2.5 g
538 mg
448 mg
25.7 mg 5.08 mg
396
5.2
(4.0 to 6.5)
132
3.5
0.5
96
40
1000
2000
3000
5000
6000
1000
3000
3000
6000
6000
L5B5173
L5B5177
L5B5179
L5B5194
L5B9711
0941-0413-05
0941-0413-06
0941-0413-04
0941-0413-07
0941-0413-01
DIANEAL PD-2
Peritoneal Dialysis
Solution with
4.25% Dextrose
AMBU-FLEX II
CONTAINER
4.25 g
538 mg
448 mg
25.7 mg 5.08 mg
485
5.2
(4.0 to 6.5)
132
3.5
0.5
96
40
1000
2000
3000
5000
6000
1000
3000
3000
6000
6000
L5B5183
L5B5187
L5B5189
L5B5195
L5B9712
0941-0415-05
0941-0415-06
0941-0415-04
0941-0415-07
0941-0415-01
Reference ID: 3698977
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 2. DIANEAL Low Calcium (2.5 mEq/L) Peritoneal Dialysis Solution (AMBU-FLEX CONTAINER)
Composition/100 mL
Ionic Concentration
(mEq/L)
How Supplied
(NaCl)
3 )
5 NaO
(CaCl
SP (MgCl
Fill
Container
SP
U
SP
SP
e, U
Volume
Size
Code
NDC
*Dextrose, Hydrous,
Sodium Chloride, U
Sodium Lactate (C3 H
Calcium Chloride, U
2 •2H2 O)
Magnesium Chlorid
2 •6H2 O)
OSMOLARITY
(mOsmol/L) (calc)
pH
Sodium
Calcium
Magnesium
Chloride
Lactate
(mL)
(mL)
DIANEAL Low
Calcium (2.5 mEq/L)
Peritoneal Dialysis
Solution with 1.5%
Dextrose
AMBU-FLEX II
CONTAINER
1.5 g
538 mg 448 mg 18.3 mg 5.08 mg
344
5.2
(4.0 to 6.5)
132
2.5
0.5
95
40
2000
3000
5000
6000
3000
3000
6000
6000
L5B4825
L5B9901
L5B4826
L5B9770
0941-0409-06
0941-0409-05
0941-0409-07
0941-0409-01
DIANEAL Low
Calcium (2.5 mEq/L)
Peritoneal Dialysis
Solution with 2.5%
Dextrose
AMBU-FLEX II
CONTAINER
2.5 g
538 mg 448 mg 18.3 mg 5.08 mg
395
5.2
(4.0 to 6.5)
132
2.5
0.5
95
40
2000
3000
5000
6000
3000
3000
6000
6000
L5B9727
L5B9902
L5B5202
L5B9771
0941-0457-08
0941-0457-02
0941-0457-05
0941-0457-01
DIANEAL Low
Calcium (2.5 mEq/L)
Peritoneal Dialysis
Solution with 4.25%
Dextrose
AMBU-FLEX II
CONTAINER
4.25 g 538 mg 448 mg 18.3 mg 5.08 mg
483
5.2
(4.0 to 6.5)
132
2.5
0.5
95
40
2000
3000
5000
6000
3000
3000
6000
6000
L5B9747
L5B9903
L5B5203
L5B9772
0941-0459-08
0941-0459-02
0941-0459-05
0941-0459-01
Reference ID: 3698977
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 3. DIANEAL PD-2 Peritoneal Dialysis Solution (ULTRABAG CONTAINER)
Composition/100 mL
OSMOLARITY
(mOsmol/L) (calc)
pH
Ionic Concentration
(mEq/L)
How Supplied
*Dextrose, Hydrous, USP
Sodium Chloride, USP (NaCl)
Sodium Lactate (C3 H5 NaO3 )
Calcium Chloride, USP (CaCl2 •2H2 O)
Magnesium Chloride, USP (MgCl2 •6H2 O)
Sodium
Calcium
Magnesium
Chloride
Lactate
Fill
Volume
(mL)
Container
Size (mL)
Code
NDC
DIANEAL PD-2
Peritoneal Dialysis
Solution with
1.5% Dextrose
1.5 g
538 mg
448 mg
25.7 mg
5.08 mg
346
5.2
(4.0 to
6.5)
132
3.5
0.5
96
40
2000
2500
3000
2000
3000
5000
5B9866
5B9868
5B9857
0941-0426-52
0941-0426-53
0941-0426-55
DIANEAL PD-2
Peritoneal Dialysis
Solution with
2.5% Dextrose
2.5 g
538 mg
448 mg
25.7 mg
5.08 mg
396
5.2
(4.0 to
6.5)
132
3.5
0.5
96
40
2000
2500
3000
2000
3000
5000
5B9876
5B9878
5B9858
0941-0427-52
0941-0427-53
0941-0427-55
DIANEAL PD-2
Peritoneal Dialysis
Solution with
4.25% Dextrose
4.25 g
538 mg
448 mg
25.7 mg
5.08 mg
485
5.2
(4.0 to
6.5)
132
3.5
0.5
96
40
2000
2500
3000
2000
3000
5000
5B9896
5B9898
5B9859
0941-0429-52
0941-0429-53
0941-0429-55
Reference ID: 3698977
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 4. DIANEAL Low Calcium (2.5 mEq/L) Peritoneal Dialysis Solution (ULTRABAG CONTAINER)
Composition/100 mL
OSMOLARITY
(mOsmol/L) (calc)
pH
Ionic Concentration
(mEq/L)
How Supplied
*Dextrose, Hydrous, USP
Sodium Chloride, USP (NaCl)
Sodium Lactate (C3 H5 NaO3 )
Calcium Chloride, USP (CaCl2 •2H2 O)
Magnesium Chloride, USP (MgCl2 •6H2 O)
Sodium
Calcium
Magnesium
Chloride
Lactate
Fill
Volume
(mL)
Container
Size (mL)
Code
NDC
DIANEAL Low
Calcium (2.5 mEq/L)
Peritoneal Dialysis
Solution with 1.5%
Dextrose
1.5 g
538 mg 448 mg
18.3
mg
5.08
mg
344
5.2
(4.0 to 6.5)
132
2.5
0.5
95
40
1500
2000
2500
3000
2000
2000
3000
5000
5B9765
5B9766
5B9768
5B9757
0941-0424-51
0941-0424-52
0941-0424-53
0941-0424-55
DIANEAL Low
Calcium (2.5 mEq/L)
Peritoneal Dialysis
Solution with 2.5%
Dextrose
2.5 g
538 mg 448 mg
18.3
mg
5.08
mg
395
5.2
(4.0 to 6.5)
132
2.5
0.5
95
40
1500
2000
2500
3000
2000
2000
3000
5000
5B9775
5B9776
5B9778
5B9758
0941-0430-51
0941-0430-52
0941-0430-53
0941-0430-55
DIANEAL Low
Calcium (2.5 mEq/L)
Peritoneal Dialysis
Solution with 4.25%
Dextrose
4.25 g 538 mg 448 mg
18.3
mg
5.08
mg
483
5.2
(4.0 to 6.5)
132
2.5
0.5
95
40
1500
2000
2500
3000
2000
2000
3000
5000
5B9795
5B9796
5B9798
5B9759
0941-0433-51
0941-0433-52
0941-0433-53
0941-0433-55
Reference ID: 3698977
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Baxter, Dianeal, Ambu-Flex, UltraBag, and PL 146 are trademarks of Baxter International, Inc.
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
Printed in USA
02/2015
071972371
Reference ID: 3698977
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:46:56.266982
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020183s024lbl.pdf', 'application_number': 20163, 'submission_type': 'SUPPL ', 'submission_number': 25}
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12,283
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ACTHREL®
(corticorelin ovine triflutate for injection)
For intravenous injection only
DIAGNOSTIC USE ONLY
DESCRIPTION
ACTHREL® (corticorelin ovine triflutate for injection) is a sterile, nonpyrogenic, lyophilized white cake powder,
containing corticorelin ovine triflutate, a trifluoroacetate salt of a synthetic peptide that is used for the determination
of pituitary corticotroph responsiveness. Corticorelin ovine has an amino acid sequence identical to ovine
corticotropin-releasing hormone (oCRH). Corticorelin ovine is an analogue of the naturally occurring human CRH
(hCRH) peptide. Both peptides are potent stimulators of adrenocorticotropic hormone (ACTH) release from the
anterior pituitary. ACTH stimulates cortisol production from the adrenal cortex. The structural formula for
corticorelin ovine triflutate is described below:
Ser-Gin-Glu-Pro-Pro-Ile-Ser-Leu-Asp-Leu-Thr-Phe-His-Leu-Leu-Arg-Glu-Val-Leu-Glu-Met-Thr-Lys-Ala-Asp-
Gin-Leu-Ala-Gln-Gln-Ala-His-Ser-Asn-Arg-Lys-Leu-Leu-Asp-Ile-Ala-NH •xCF COOH
2
2
whereas x=4 - 8.
The empirical formula of corticorelin ovine is C
H
N O S with a molecular weight of 4670.35 Daltons.
205
339
59
63
ACTHREL® for injection is available in vials containing 100 mcg corticorelin ovine (as the trifluoroacetate),
0.88 mg ascorbic acid, 10 mg lactose, and 26 mg cysteine hydrochloride monohydrate. Trace amounts of chloride
ion may be present from the manufacturing process. The preparation is intended for intravenous administration.
CLINICAL PHARMACOLOGY
Pharmacodynamics: In normal subjects, intravenous administration of corticorelin results in a rapid and sustained
increase of plasma ACTH levels and a near parallel increase of plasma cortisol. In addition, intravenous
administration of corticorelin to normal subjects causes a concomitant and prolonged release of the related
proopiomelanocortin peptides β- and γ-lipotropins (β -and γ-LPH) and β-endorphin (β -END). A number of dose-
response studies have been performed on normal subjects using a range of corticorelin doses. In one study, doses of
corticorelin ranging from 0.001 to 30 mcg/kg body weight were administered to 29 healthy volunteers. Blood
samples were taken over a 2-hour period for determination of plasma ACTH and cortisol concentrations. There was
a direct dose-dependent relationship that was more pronounced for ACTH than for cortisol. The threshold dose was
0.03 mcg/kg, the half-maximal dose was 0.3-1.0 mcg/kg and the maximally effective dose was 3-10 mcg/kg.
Plasma ACTH levels in normal subjects increased 2 minutes after injection of corticorelin doses of ≥0.3 mcg/kg and
reached peak levels after 10-15 minutes. Plasma cortisol levels increased within 10 minutes and reached peak levels
at 30 to 60 minutes. As the dose of corticorelin was increased, the rises in plasma ACTH and cortisol were more
sustained, showing a biphasic response with a second lower peak at 2-3 hours after injection. Similar results were
found in another study using 0.3, 3.0, and 30 mcg/kg doses. The duration of mean plasma ACTH increase after
injection of 0.3, 3.0, and 30 mcg/kg was 4, 7, and 8 hours, respectively. The effect on plasma cortisol was similar,
but more prolonged. Because there are differences in basal levels and peak response levels following a.m. or p.m.
administration, it is recommended that subsequent evaluations in the same patient using the corticorelin stimulation
test be carried out at the same time of day as the original evaluation.
Baseline ACTH and cortisol levels are usually higher in the morning. Pooled ACTH values from normal unstressed
subjects (n=119) were 25 ± 7 pg/mL in the a.m. and 10 ± 3 in the p.m.; similar pooled cortisol values (n=170) were
11 ± 3 mcg/dL in the a.m. and 4 ± 2 mcg/dL in the p.m. The normal unstressed person has about seven to ten
Page 1 of 7
Reference ID: 3814083
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For current labeling information, please visit https://www.fda.gov/drugsatfda
secretory episodes of ACTH each day. Most of them occur in the early morning hours and are responsible for the
morning plasma cortisol surge. The following figure shows the daily circadian rhythm of ACTH and cortisol
secretions in a normal unstressed person. Insulin, plasma resin activity, prolactin, and growth hormone release are
not affected by corticorelin administration in humans. graph
Continuous 24-hour infusion of corticorelin (0.5, 1.0, and 3.0 mcg/kg/hr) increased plasma ACTH concentrations to
a plateau of 15-20 pg/mL by the third hour and urinary-free cortisol reaches 173 ± 43 mcg/dL by 24 hours,
comparable to those levels observed in patients with major depression, but less than levels noted in Cushing’s
disease. Continuous infusion did not abolish the circadian rhythm of plasma ACTH and cortisol, but did appear to
desensitize the corticotroph. Intermittent doses of corticorelin (25 mcg every 4 hours for 72 hours), however,
continued to elicit the expected ACTH and cortisol responses.
Intravenous administration of 1 mcg/kg corticorelin in combination with 10 pressor units intramuscular vasopressin
had a synergistic effect on ACTH and a less marked synergistic effect on cortisol secretion.
The basal and peak response levels of ACTH and cortisol to a 1 mcg/kg or 100 mcg dose of corticorelin
administered to normal volunteers in the morning and the evening are given below. These values were obtained by
combining the results from 9 clinical trials conducted in the a.m. and 4 clinical trials conducted in the p.m.
The following table is to be used only as a general guide.
Basal Concentrations and Peak Responses of ACTH and Cortisol in Normal Subjects after 1
mcg/kg or 100 mcg of ACTHREL®
Time of Day
No. of Subjects
ACTH Concentration mean
(range) pg/mL
Cortisol Concentration
mean (range) mcg/dL
Basal
Peak
Basal
Peak
a.m.
143
28 (16-65)
68 (39-114)
11 (8-13)
21 (17-25)
p.m.
70
9 (8-13)
30 (25-42)
4 (2-6)
16 (15-18)
Pharmacokinetics: Following a single intravenous injection of 1 mcg/kg of corticorelin to normal men, the
disappearance of immunoreactive corticorelin (IR-corticorelin) from plasma follows a biexponential decay curve.
Plasma half-lives for IR-corticorelin are 11.6 ± 1.5 minutes (mean ± SE) for the fast component and 73 ± 8 minutes
for the slow component. The mean volume of distribution for IR-corticorelin is 6.2 ± 0.5 L with an approximate
metabolic clearance rate of 95 ± 11 L/m2/day. Graded intravenous doses of corticorelin (0.01, 0.03, 0.1, 0.3, 1, 3, 10,
30 mcg/kg) produced a linear increase in plasma IR-corticorelin. Corticorelin does not appear to be bound
specifically by a circulating plasma protein.
Page 2 of 7
Reference ID: 3814083
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For current labeling information, please visit https://www.fda.gov/drugsatfda
INDICATIONS AND USAGE
ACTHREL® is indicated for use in differentiating pituitary and ectopic production of ACTH in patients with
ACTH-dependent Cushing’s syndrome.
Differential Diagnosis: There are two forms of Cushing’s syndrome:
a. ACTH-dependent (83%), in which hypercortisolism is due either to pituitary hypersecretion of ACTH
(Cushing’s disease) resulting from an adenoma (40%, usually microadenomas) or nonadenomatous hyperplasia,
possibly of hypothalamic origin (28%), or to hypercortisolism that is secondary to ectopic secretion of ACTH
(15%) and,
b. ACTH- independent (17%), in which hypercortisolism is due to autonomous cortisol secretion by an adrenal
tumor (9% adenomas, 8% carcinomas).
After the establishment of hypercortisolism consistent with the presence of Cushing’s syndrome, and following the
elimination of autonomous adrenal hyperfunction as its cause, the corticorelin test is used to aid in establishing the
source of excessive ACTH secretion.
The corticorelin stimulation test helps to differentiate between the etiologies of ACTH-dependent hypercortisolism
as follows:
1. High basal plasma ACTH plus high basal plasma cortisol (20 - 40 mcg/dL). ACTHREL® injection
(1 mcg/kg) results in:
a. Increased plasma ACTH levels
b. Increased plasma cortisol levels
Diagnosis: Cushing's disease (ACTH of pituitary origin)
2
High basal plasma ACTH (may be very high) plus high basal plasma cortisol (20 - 40 mcg/dL).
ACTHREL® injection (1 mcg/kg) results in:
a. Little or no response of plasma ACTH levels
b. Little or no response of plasma cortisol levels
Diagnosis: Ectopic ACTH syndrome
Test Methodology: To evaluate the status of the pituitary-adrenal axis in the differentiation of a pituitary source
from an ectopic source of excessive ACTH secretion, a corticorelin test procedure requires a minimum of five blood
samples.
Procedure
1. Venous blood samples should be drawn 15 minutes before and immediately prior to ACTHREL®
administration. The ACTH baseline is obtained by averaging the values of the two samples.
2. Administer ACTHREL® as an intravenous infusion over a 30 to 60- second interval at a dose of 1 mcg/kg body
weight. Higher doses are not recommended (see PRECAUTIONS and ADVERSE REACTIONS).
3. Draw venous blood samples at 15, 30, and 60 minutes after administration.
4. Blood samples should be handled as recommended by the laboratory that will determine their ACTH content. It
is extremely important to recognize that the reliability of the ACTHREL® test is directly related to the inter-
assay and intra-assay variability of the laboratory performing the assay.
Cortisol determinations may be performed on the same blood samples for the same time points as outlined above.
The blood sample handling precautions noted for ACTH should be followed for cortisol.
Interpretation of Test Results: The interpretation of the ACTH and cortisol responses following ACTHREL®
administration requires a knowledge of the clinical status of the individual patient, understanding of hypothalamic-
Page 3 of 7
Reference ID: 3814083
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pituitary-adrenal physiology, and familiarity with the normal hormonal ranges and the standards used by the
laboratory that performs the ACTH and cortisol assays.
Cushing’s Disease
The results of challenge with corticorelin injection have been reported in approximately 300 patients with Cushing’s
disease. Although the ACTH and cortisol responses were variable, a hyper-response to corticorelin was seen in a
majority of patients, despite high basal cortisol levels. This response pattern indicates an impairment of the negative
feedback of cortisol on the pituitary. Patients with pituitary-dependent Cushing’s disease tested with corticorelin do
not show the negative correlation between basal and stimulated levels of ACTH and cortisol that is found in normal
subjects. A positive correlation between basal ACTH levels and maximum ACTH increments after corticorelin
administration has been found in Cushing’s disease patients.
Ectopic ACTH Secretion
Patients with Cushing’s syndrome due to ectopic ACTH secretion (N=32) were found to have very high basal levels
of ACTH and cortisol, which were not further stimulated by corticorelin. However, there have been rare instances of
patients with ectopic sources of ACTH that have responded to the corticorelin test.
SUMMARY OF ACTH RESPONSES IN PATIENTS WITH HIGH BASAL CORTISOL
High ACTH Response
Low ACTH Response
High Basal ACTH
Cushing’s Disease
Ectopic ACTH Secretion
CUSHING’S DISEASE ACTH RESPONSES
(mean of 181 patients)
Basal ACTH 63 ± 72 pg/mL (mean ± SD)
Peak ACTH 189 ± 262 pg/mL (mean ± SD)
Mean of individual change from baseline + 227%
ECTOPIC ACTH SECRETION RESPONSES
(mean for 31 patients)
Basal ACTH 266 ± 464 pg/mL (mean ± SD)
Peak ACTH 276 ± 466 pg/mL (mean ± SD)
Mean of individual change from baseline + 15%
False negative responses to the corticorelin test in Cushing’s disease patients occur approximately 5 to 10% of the
time, which may lead the clinician to an incorrect diagnosis of ectopic production of ACTH at that frequency. (See
INDICATIONS AND USAGE, Differential Diagnosis).
CONTRAINDICATIONS
ACTHREL is contraindicated in patients with a history of a hypersensitivity reaction to ovine corticorelin or any of
its excipients.
PRECAUTIONS
General: The severity of adverse effects to a corticorelin injection appear to be dose-dependent. Dosages above
Page 4 of 7
Reference ID: 3814083
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1 mcg/kg are not recommended. While few adverse effects have been observed at the 1 mcg/kg or 100 mcg dose,
higher doses have been associated with transient tachycardia, decreased blood pressure, loss of consciousness, and
asystole (see ADVERSE REACTIONS). These symptoms can be substantially reduced by administering the drug
as a 30-second intravenous infusion instead of a bolus injection. At a dose of 200 mcg corticorelin, 4 of 60
volunteers and patients with disturbances of the hypothalamic-pituitary-adrenal (HPA) axis were reported to have
had decreased blood pressures. One patient had a severe hypotensive reaction with asystole. Three other patients had
an “absence-like” loss of consciousness lasting approximately 5 minutes. In subsequent investigations by the same
researchers over a 3-year period using 100 mcg of corticorelin, one patient in approximately 150 to 200 experienced
a severe drop in blood pressure and loss of sinus rhythm after receiving 55 mcg of corticorelin, which may have
been due to interaction with heparin (see PRECAUTIONS - Drug Interactions).
Hypersensitivity: Hypersensitivity reactions have been reported in patients receiving ACTHREL. Reactions
included urticaria, flushing of the face, neck and upper chest; dyspnea, wheezing, urticaria and angioedema
(involving tongue, lip and facial swelling). [see Adverse Reactions]. Should a hypersensitivity reaction occur,
discontinue ACTHREL, monitor and treat if indicated.
Drug Interactions: The plasma ACTH response to corticorelin injection is inhibited or blunted in normal subjects
pretreated with dexamethasone. The use of a heparin solution to maintain i.v. cannula patency during the corticorelin
test is not recommended. A possible interaction between corticorelin and heparin may have been responsible for a
major hypotensive reaction that occurred after corticorelin administration (see ADVERSE REACTIONS).
Carcinogenesis, Mutagenesis, Impairment of Fertility: Animal studies have not been conducted with corticorelin to
evaluate carcinogenic potential, mutagenicity, or effect on fertility.
Pregnancy: (Pregnancy Category C): Animal reproduction studies have not been conducted with corticorelin. It is
also not known whether corticorelin can cause fetal harm when administered to a pregnant woman or can affect
reproductive capacity. ACTHREL® should be given to a pregnant woman only if clearly needed.
Nursing Mothers: It is not known whether corticorelin is secreted in human milk. Because many drugs are excreted
in human milk, caution should be exercised when ACTHREL® is administered to a nursing woman.
PEDIATRIC USE
Only a few tests have been performed on children. Dosages were 1 mcg/kg body weight. Patient studies have
involved only children with multiple hypothalamic and/or pituitary hormone deficiencies, or tumors. Only two
studies with normal pediatric subjects have been conducted. No differences in response to the corticorelin test have
been reported in the children studied.
ADVERSE REACTIONS
Hypersensitivity reactions have been reported with 1 mcg/kg or 100 mcg/patient and include flushing of the face,
neck, and upper chest; dyspnea, wheezing, urticaria, and angioedema (involving tongue, lip and facial swelling).
Subjects have also reported an urge to take a deep breath, which occurs with a timing similar to, but less frequently
than, that of flushing. Higher doses (>3 mcg/kg) are associated with more prolonged flushing, tachycardia,
hypotension, dyspnea, and "chest compression" or tightness. In addition, at doses of >5 mcg/kg, significant increases
in heart rate and decreases in blood pressure were observed. The cardiovascular effects occurred 2-3 minutes after
injection and lasted for 30-60 minutes. The facial flushing was more prolonged, lasting up to 4 hours in some
subjects. All signs and symptoms could be reduced by administering the drug as a 30-second infusion instead of by
bolus injection.
Total doses of up to 200 mcg of corticorelin were administered as a bolus injection to 60 men and women, including
both healthy normal subjects and patients with endocrine disorders. In most cases, only minor adverse effects, such
as transient flushing and feelings of dyspnea, were noted. However, a few patients with disorders of the pituitary-
adrenal axis had major symptoms. One patient had a precipitous fall in blood pressure and pulse rate and developed
asystole, which required resuscitation. In two patients with Cushing’s disease and in one with secondary adrenal
insufficiency, an “absence-like” loss of consciousness occurred, which started within a few seconds after injection of
corticorelin and lasted from 10 seconds to 5 minutes. This was accompanied by a slight fall in blood pressure. One
Page 5 of 7
Reference ID: 3814083
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
patient with a well documented seizure diathesis experienced a grand mal epileptic seizure following ACTHREL®
administration. The patient had discontinued anti-convulsant therapy the day of the procedure. (See
PRECAUTIONS and Drug Interactions).
OVERDOSAGE
Symptoms of overdose include severe facial flushing, cardiovascular changes, and dyspnea. In the event of toxic
overdose (see ADVERSE REACTIONS), adverse effects should be treated symptomatically.
DOSAGE AND ADMINISTRATION
Dosage: A single intravenous dose of ACTHREL® at 1 mcg/kg is recommended for the testing of pituitary
corticotrophin function. A dose of 1 mcg/kg is the lowest dose that produces maximal cortisol responses and
significant (though apparently sub-maximal) ACTH responses. Doses above 1 mcg/kg are not recommended. (See
PRECAUTIONS and ADVERSE REACTIONS).
At a dose of 1 mcg/kg, the ACTH and cortisol responses to ACTHREL® are prolonged and remain elevated for up to
2 hours. The maximum increment in plasma ACTH occurs between 15 and 60 minutes after ACTHREL®
administration, whereas the maximum increment in plasma cortisol occurs between 30 and 120 minutes. In a clinical
study of 30 normal healthy men, the peak plasma ACTH and cortisol responses to ACTHREL® administration in the
early afternoon occurred at 42 ± 29 minutes and 65 ± 26 minutes (average ±SD), respectively. If a repeated
evaluation using the corticorelin stimulation test with ACTHREL® is needed, it is recommended that the
repeat test be carried out at the same time of day as the original test because there are differences in basal
levels and peak response levels following a.m. or p.m. administration to normal humans.
Administration: ACTHREL® is to be reconstituted aseptically with 2 mL of Sodium Chloride injection, USP (0.9%
sodium chloride), at the time of use by injecting 2 mL of the saline diluent into the lyophilized drug product cake.
To avoid bubble formation, DO NOT SHAKE the vial; instead, roll the vial to dissolve the product. The sterile
solution containing 50 mcg corticorelin/mL is then ready for injection by the intravenous route. The dosage to be
administered is determined by the patient’s weight (1 mcg corticorelin/kg). Some of the adverse effects can be
reduced by administering the drug as an infusion over 30 seconds instead of as a bolus injection.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration, whenever solution and container permit.
HOW SUPPLIED
ACTHREL® is supplied as a sterile, nonpyrogenic, lyophilized, white cake containing 100 mcg corticorelin ovine
(as the trifluoroacetate), 0.88 mg ascorbic acid, 10 mg lactose, and 26 mg cysteine hydrochloride monohydrate.
Trace amounts of chloride ion may be present from the manufacturing process. The package provides a single-dose,
rubber-capped, 5 mL, brown-glass vial (NDC 55566-0302-1) containing 100 mcg corticorelin ovine (as the
trifluoroacetate). ACTHREL® is stable in the lyophilized form when stored refrigerated at 2°C to 8°C (36°F to 46°F)
and protected from light. The reconstituted solution is stable up to 8 hours under refrigerated conditions. Discard
unused reconstituted solution.
Manufactured for:
Ferring Pharmaceuticals Inc.
Parsippany, NJ 07054
Made in Germany
Rx only
Page 6 of 7
Reference ID: 3814083
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Rev 09/2015
6011-05
Page 7 of 7
Reference ID: 3814083
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020162s010lbl.pdf', 'application_number': 20162, 'submission_type': 'SUPPL ', 'submission_number': 10}
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HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use VIDEX
safely and effectively. See full prescribing information for VIDEX.
VIDEX (didanosine, USP) pediatric powder for oral Solution
Initial U.S. Approval: 1991
WARNING: PANCREATITIS, LACTIC ACIDOSIS and
HEPATOMEGALY with STEATOSIS
See full prescribing information for complete boxed warning.
•
Fatal and nonfatal pancreatitis. VIDEX should be suspended in
patients with suspected pancreatitis and discontinued in patients
with confirmed pancreatitis. (5.1)
•
Lactic acidosis and severe hepatomegaly with steatosis, including
fatal cases. Fatal lactic acidosis has been reported in pregnant
women who received the combination of didanosine and
stavudine. (5.2)
---------------------------RECENT MAJOR CHANGES--------------------------
Dosage and Administration
Instructions for Reconstitution (2.4)
08/2014
---------------------------INDICATIONS AND USAGE---------------------------
VIDEX (didanosine, USP) is a nucleoside reverse transcriptase inhibitor for
use in combination with other antiretroviral agents for the treatment of human
immunodeficiency virus (HIV)-1 infection. (1)
------------------------DOSAGE AND ADMINISTRATION---------------------
•
Adult patients: Administered on an empty stomach at least 30 minutes
before or 2 hours after eating. Dosing is based on body weight. (2.1)
at least 60 kg
less than 60 kg
Preferred dosing
200 mg twice daily
125 mg twice daily
Dosing for patients whose
management requires once-
daily frequency
400 mg once daily
250 mg once daily
•
Pediatric patients (2 weeks old to 18 years old): Administered on an
empty stomach at least 30 minutes before or 2 hours after eating.
−
Between 2 weeks and 8 months old, dosing is 100 mg per m2 twice
daily.
−
For those greater than 8 months old, dosing is 120 mg per m2 twice
daily but not to exceed the adult dosing recommendation. (2.1)
•
Renal impairment: Dose reduction is recommended. (2.2)
•
Coadministration with tenofovir: Dose reduction is recommended.
Patients should be monitored closely for didanosine-associated adverse
reactions. (2.3, 7.1)
----------------------DOSAGE FORMS AND STRENGTHS--------------------
•
4-ounce glass bottle containing 2 g of VIDEX (3)
•
8-ounce glass bottle containing 4 g of VIDEX (3)
------------------------------CONTRAINDICATIONS-------------------------------
Coadministration with allopurinol or ribavirin is contraindicated. (4)
------------------------WARNINGS AND PRECAUTIONS----------------------
•
Pancreatitis: Suspension or discontinuation of didanosine may be
necessary. (5.1)
•
Lactic acidosis and severe hepatomegaly with steatosis: Suspend
didanosine in patients who develop clinical symptoms or signs with or
without laboratory findings. (5.2)
•
Hepatic toxicity: Interruption or discontinuation of didanosine must be
considered upon worsening of liver disease. (5.3)
•
Non-cirrhotic portal hypertension: Discontinue didanosine in patients
with evidence of non-cirrhotic portal hypertension. (5.4)
•
Patients may develop peripheral neuropathy (5.5), retinal changes and
optic neuritis (5.6), immune reconstitution syndrome (5.7), and
redistribution/accumulation of body fat (5.8).
-------------------------------ADVERSE REACTIONS-----------------------------
•
In adults, the most common adverse reactions (greater than 10%, all
grades) are diarrhea, peripheral neurologic symptoms/neuropathy,
abdominal pain, nausea, headache, rash, and vomiting. (6.1)
•
Adverse reactions in pediatric patients were consistent with those in
adults. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers
Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
--------------------------------DRUG INTERACTIONS-----------------------------
Coadministration of VIDEX can alter the concentration of other drugs and
other drugs may alter the concentration of didanosine. The potential drug-drug
interactions must be considered prior to and during therapy. (4, 7, 12.3)
------------------------USE IN SPECIFIC POPULATIONS----------------------
Pregnancy: Fatal lactic acidosis has been reported in pregnant women who
received both didanosine and stavudine with other agents. This combination
should be used with caution during pregnancy and only if the potential benefit
clearly outweighs the potential risk. (5.2, 8.1)
See 17 for PATIENT COUNSELING INFORMATION and Medication
Guide.
Revised: 08/2014
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: PANCREATITIS, LACTIC ACIDOSIS AND
HEPATOMEGALY WITH STEATOSIS
1
INDICATIONS AND USAGE
2
DOSAGE AND ADMINISTRATION
2.1
Recommended Dosage (Adult and Pediatric Patients)
2.2
Renal Impairment
2.3
Dosage Adjustment
2.4
Instructions for Reconstitution
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1
Pancreatitis
5.2
Lactic Acidosis/Severe Hepatomegaly with Steatosis
5.3
Hepatic Toxicity
5.4
Non-cirrhotic Portal Hypertension
5.5
Peripheral Neuropathy
5.6
Retinal Changes and Optic Neuritis
5.7
Immune Reconstitution Syndrome
5.8
Fat Redistribution
6
ADVERSE REACTIONS
6.1
Clinical Trials Experience
6.2
Postmarketing Experience
7
DRUG INTERACTIONS
7.1
Established Drug Interactions
7.2
Predicted Drug Interactions
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
8.3
Nursing Mothers
8.4
Pediatric Use
8.5
Geriatric Use
8.6
Renal Impairment
10
OVERDOSAGE
11
DESCRIPTION
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
12.3
Pharmacokinetics
12.4
Microbiology
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
13.2
Animal Toxicology and/or Pharmacology
14
CLINICAL STUDIES
14.1
Adult Patients
14.2
Pediatric Patients
16
HOW SUPPLIED/STORAGE AND HANDLING
17
PATIENT COUNSELING INFORMATION
* Sections or subsections omitted from the full prescribing information
are not listed.
Reference ID: 3607428
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
FULL PRESCRIBING INFORMATION
WARNING: PANCREATITIS, LACTIC ACIDOSIS and
HEPATOMEGALY with STEATOSIS
Fatal and nonfatal pancreatitis has occurred during therapy with VIDEX used
alone or in combination regimens in both treatment-naive and treatment-
experienced patients, regardless of degree of immunosuppression. VIDEX should be
suspended in patients with suspected pancreatitis and discontinued in patients with
confirmed pancreatitis [see Warnings and Precautions (5.1)].
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have
been reported with the use of nucleoside analogues alone or in combination,
including didanosine and other antiretrovirals. Fatal lactic acidosis has been
reported in pregnant women who received the combination of didanosine and
stavudine with other antiretroviral agents. The combination of didanosine and
stavudine should be used with caution during pregnancy and is recommended only
if the potential benefit clearly outweighs the potential risk [see Warnings and
Precautions (5.2)].
1
INDICATIONS AND USAGE
VIDEX® (didanosine, USP), also known as ddI, in combination with other antiretroviral agents
is indicated for the treatment of human immunodeficiency virus (HIV)-1 infection [see Clinical
Studies (14)].
2
DOSAGE AND ADMINISTRATION
VIDEX should be administered on an empty stomach, at least 30 minutes before or 2 hours after
eating.
2.1
Recommended Dosage (Adult and Pediatric Patients)
The preferred dosing frequency of VIDEX is twice daily because there is more evidence to
support the effectiveness of this dosing regimen. Once-daily dosing should be considered only
for patients whose management requires once-daily dosing of VIDEX [see Clinical Studies (14)].
The recommended adult total daily dose is based on body weight (kg) (see Table 1).
2
Reference ID: 3607428
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 1:
Recommended Dosage (Adult)
at least 60 kg
less than 60 kg
Preferred dosing
200 mg twice daily
125 mg twice daily
Dosing for patients whose management
requires once-daily frequency
400 mg once daily
250 mg once daily
Pediatric Patients (2 weeks old to 18 years old): The recommended dose of VIDEX
(didanosine) in pediatric patients between 2 weeks old and 8 months old is 100 mg per m2 twice
daily, and the recommended VIDEX dose for pediatric patients greater than 8 months old is
120 mg per m2 twice daily but not to exceed the adult dosing recommendation.
Dosing recommendations in patients less than 2 weeks of age cannot be made because the
pharmacokinetics of didanosine in these children are too variable to determine an appropriate
dose. There are no data on once-daily dosing of VIDEX in pediatric patients.
2.2
Renal Impairment
Adult Patients
In adult patients with impaired renal function, the dose of VIDEX should be adjusted to
compensate for the slower rate of elimination. The recommended doses and dosing intervals of
VIDEX in adult patients with renal insufficiency are presented in Table 2.
Table 2:
Recommended Dosage in Patients with Renal Impairment
Creatinine Clearance (mL/min)
Recommended VIDEX Dose by Patient Weight
at least 60 kg
less than 60 kg
at least 60
200 mg twice dailya
125 mg twice dailya
30-59
200 mg once daily
or 100 mg twice daily
150 mg once daily
or 75 mg twice daily
10-29
150 mg once daily
100 mg once daily
less than 10
100 mg once daily
75 mg once daily
a 400 mg once daily (at least 60 kg) or 250 mg once daily (less than 60 kg) for patients whose management requires
once-daily frequency of administration.
3
Reference ID: 3607428
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Pediatric Patients
Urinary excretion is also a major route of elimination of didanosine in pediatric patients,
therefore the clearance of didanosine may be altered in pediatric patients with renal impairment.
Although there are insufficient data to recommend a specific dose adjustment of VIDEX in this
patient population, a reduction in the dose should be considered (see Table 2).
Patients Requiring Continuous Ambulatory Peritoneal Dialysis (CAPD) or Hemodialysis
For patients requiring CAPD or hemodialysis, follow dosing recommendations for patients with
creatinine clearance of less than 10 mL per min, shown in Table 2. It is not necessary to
administer a supplemental dose of VIDEX following hemodialysis.
2.3
Dosage Adjustment
Concomitant Therapy with Tenofovir Disoproxil Fumarate
In patients who are also taking tenofovir disoproxil fumarate, a dose reduction of VIDEX to
250 mg (adults weighing at least 60 kg with creatinine clearance of at least 60 mL per min) or
200 mg (adults weighing less than 60 kg with creatinine clearance of at least 60 mL per min)
once daily is recommended. VIDEX and tenofovir disoproxil fumarate may be taken together in
the fasted state. Alternatively, if tenofovir disoproxil fumarate is taken with food, VIDEX should
be taken on an empty stomach (at least 30 minutes before food or 2 hours after food). The
appropriate dose of VIDEX coadministered with tenofovir disoproxil fumarate in patients with
creatinine clearance of less than 60 mL per min has not been established. ([See Drug Interactions
(7) and Clinical Pharmacology (12.3)]; see the complete prescribing information for VIDEX EC
(enteric-coated formulation of didanosine) for results of drug interaction studies of tenofovir
disoproxil fumarate with reduced doses of the enteric-coated formulation of didanosine.)
Hepatic Impairment
No dose adjustment is required in patients with hepatic impairment [see Warnings and
Precautions (5.3) and Clinical Pharmacology (12.3)].
4
Reference ID: 3607428
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2.4
Instructions for Reconstitution
Prior to dispensing, the pharmacist must reconstitute dry powder with Purified Water, USP, to an
initial concentration of 20 mg per mL and immediately mix the resulting solution with antacid to
a final concentration of 10 mg per mL as follows:
20 mg per mL Initial Solution
Reconstitute the product to 20 mg per mL by adding 100 mL or 200 mL of Purified Water, USP,
to the 2 g or 4 g of VIDEX powder, respectively, in the product bottle.
10 mg per mL Final Admixture
1. Immediately mix one part of the 20 mg per mL initial solution with one part of any
commercially available antacid that contains as active ingredients aluminum hydroxide
(400 mg per 5 mL), magnesium hydroxide (400 mg per 5 mL), and simethicone (40 mg per
5 mL) for a final dispensing concentration of 10 mg VIDEX per mL. For patient home use,
the admixture should be dispensed in appropriately sized, flint-glass or plastic (HDPE, PET,
or PETG) bottles with child-resistant closures.
2. Instruct the patient to shake the admixture thoroughly prior to use and to store the tightly
closed container in the refrigerator.
The bottles of powder should be stored at 59° F to 86° F (15° C to 30° C). The VIDEX
admixture may be stored up to 30 days in a refrigerator, 36° F to 46° F (2° C to 8° C). Discard
any unused portion after 30 days.
3
DOSAGE FORMS AND STRENGTHS
VIDEX (didanosine, USP) Pediatric Powder for Oral Solution is supplied in 4- and 8-ounce
glass bottles containing 2 g or 4 g of VIDEX, respectively.
4
CONTRAINDICATIONS
These recommendations are based on either drug interaction studies or observed clinical
toxicities.
5
Reference ID: 3607428
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Allopurinol: Coadministration of didanosine and allopurinol is contraindicated because systemic
exposures of didanosine are increased, which may increase didanosine-associated toxicity [see
Clinical Pharmacology (12.3)].
Ribavirin: Coadministration of didanosine and ribavirin is contraindicated because exposures of
the active metabolite of didanosine (dideoxyadenosine 5′-triphosphate) are increased. Fatal
hepatic
failure,
as
well
as
peripheral
neuropathy,
pancreatitis,
and
symptomatic
hyperlactatemia/lactic acidosis have been reported in patients receiving both didanosine and
ribavirin.
5
WARNINGS AND PRECAUTIONS
5.1
Pancreatitis
Fatal and nonfatal pancreatitis has occurred during therapy with VIDEX used alone or in
combination regimens in both treatment-naive and treatment-experienced patients,
regardless of degree of immunosuppression. VIDEX should be suspended in patients with
signs or symptoms of pancreatitis and discontinued in patients with confirmed pancreatitis.
Patients treated with VIDEX in combination with stavudine may be at increased risk for
pancreatitis.
When treatment with life-sustaining drugs known to cause pancreatic toxicity is required,
suspension of VIDEX (didanosine) therapy is recommended. In patients with risk factors for
pancreatitis, VIDEX should be used with extreme caution and only if clearly indicated. Patients
with advanced HIV-1 infection, especially the elderly, are at increased risk of pancreatitis and
should be followed closely. Patients with renal impairment may be at greater risk for pancreatitis
if treated without dose adjustment. The frequency of pancreatitis is dose related. [See Adverse
Reactions (6).]
5.2
Lactic Acidosis/Severe Hepatomegaly with Steatosis
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been
reported with the use of nucleoside analogues alone or in combination, including
didanosine and other antiretrovirals. A majority of these cases have been in women. Obesity
and prolonged nucleoside exposure may be risk factors. Fatal lactic acidosis has been reported in
pregnant women who received the combination of didanosine and stavudine with other
antiretroviral agents. The combination of didanosine and stavudine should be used with caution
6
Reference ID: 3607428
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
during pregnancy and is recommended only if the potential benefit clearly outweighs the
potential risk [see Use in Specific Populations (8.1)]. Particular caution should be exercised
when administering VIDEX to any patient with known risk factors for liver disease; however,
cases have also been reported in patients with no known risk factors. Treatment with VIDEX
should be suspended in any patient who develops clinical signs or symptoms with or without
laboratory findings consistent with symptomatic hyperlactatemia, lactic acidosis, or pronounced
hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked
transaminase elevations).
5.3
Hepatic Toxicity
The safety and efficacy of VIDEX have not been established in HIV-infected patients with
significant underlying liver disease. During combination antiretroviral therapy, patients with
preexisting liver dysfunction, including chronic active hepatitis, have an increased frequency of
liver function abnormalities, including severe and potentially fatal hepatic adverse events, and
should be monitored according to standard practice. If there is evidence of worsening liver
disease in such patients, interruption or discontinuation of treatment must be considered.
Hepatotoxicity and hepatic failure resulting in death were reported during postmarketing
surveillance in HIV-infected patients treated with hydroxyurea and other antiretroviral agents.
Fatal hepatic events were reported most often in patients treated with the combination of
hydroxyurea, didanosine, and stavudine. This combination should be avoided. [See Adverse
Reactions (6).]
5.4
Non-cirrhotic Portal Hypertension
Postmarketing cases of non-cirrhotic portal hypertension have been reported, including cases
leading to liver transplantation or death. Cases of didanosine-associated non-cirrhotic portal
hypertension were confirmed by liver biopsy in patients with no evidence of viral hepatitis.
Onset of signs and symptoms ranged from months to years after start of didanosine therapy.
Common presenting features included elevated liver enzymes, esophageal varices, hematemesis,
ascites, and splenomegaly.
Patients receiving VIDEX should be monitored for early signs of portal hypertension (eg,
thrombocytopenia and splenomegaly) during routine medical visits. Appropriate laboratory
testing including liver enzymes, serum bilirubin, albumin, complete blood count, and
7
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international normalized ratio (INR) and ultrasonography should be considered. VIDEX should
be discontinued in patients with evidence of non-cirrhotic portal hypertension.
5.5
Peripheral Neuropathy
Peripheral neuropathy, manifested by numbness, tingling, or pain in the hands or feet, has been
reported in patients receiving VIDEX therapy. Peripheral neuropathy has occurred more
frequently in patients with advanced HIV disease, in patients with a history of neuropathy, or in
patients being treated with neurotoxic drug therapy, including stavudine. Discontinuation of
VIDEX should be considered in patients who develop peripheral neuropathy. [See Adverse
Reactions (6).]
5.6
Retinal Changes and Optic Neuritis
Retinal changes and optic neuritis have been reported in adult and pediatric patients. Periodic
retinal examinations should be considered for patients receiving VIDEX [see Adverse Reactions
(6)].
5.7
Immune Reconstitution Syndrome
Immune reconstitution syndrome has been reported in patients treated with combination
antiretroviral therapy, including VIDEX. During the initial phase of combination antiretroviral
treatment, patients whose immune system responds may develop an inflammatory response to
indolent or residual opportunistic infections (such as Mycobacterium avium infection,
cytomegalovirus, Pneumocystis jiroveci pneumonia [PCP], or tuberculosis), which may
necessitate further evaluation and treatment.
Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome)
have also been reported to occur in the setting of immune reconstitution; however, the time to
onset is more variable, and can occur many months after initiation of treatment.
5.8
Fat Redistribution
Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement
(buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid
appearance” have been observed in patients receiving antiretroviral therapy. The mechanism and
long-term consequences of these events are currently unknown. A causal relationship has not
been established.
8
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6
ADVERSE REACTIONS
The following serious adverse reactions are described below and elsewhere in the labeling:
• Pancreatitis [see Boxed Warning, Warnings and Precautions (5.1)]
• Lactic acidosis/severe hepatomegaly with steatosis [see Boxed Warning, Warnings and
Precautions (5.2)]
• Hepatic toxicity [see Warnings and Precautions (5.3)]
• Non-cirrhotic portal hypertension [see Warnings and Precautions (5.4)]
• Peripheral neuropathy [see Warnings and Precautions (5.5)]
• Retinal changes and optic neuritis [see Warnings and Precautions (5.6)]
6.1
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates
observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials
of another drug and may not reflect the rates observed in practice.
Adults
Selected clinical adverse reactions that occurred in adult patients in clinical studies with VIDEX
are provided in Tables 3 and 4.
Table 3:
Selected Clinical Adverse Reactions from Monotherapy Studies
Percent of Patients*
ACTG 116A
ACTG 116B/117
Adverse Reactions
VIDEX
n=197
zidovudine
n=212
VIDEX
n=298
zidovudine
n=304
Diarrhea
19
15
28
21
Peripheral Neurologic
Symptoms/Neuropathy
Abdominal Pain
17
13
14
8
20
7
12
8
Rash/Pruritus
Pancreatitis
7
7
8
3
9
6
5
2
* The incidences reported included all severity grades and all reactions regardless of causality.
9
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Table 4:
Selected Clinical Adverse Reactions from Combination Studies
Percent of Patientsa,c
AI454-148b
START 2b
VIDEX +
zidovudine +
VIDEX +
zidovudine +
stavudine +
lamivudine +
stavudine +
lamivudine +
nelfinavir
nelfinavir
indinavir
indinavir
n=482
n=248
n=102
n=103
Adverse Reactions
Diarrhea
70
60
45
39
Nausea
28
40
53
67
Peripheral Neurologic
26
6
21
10
Symptoms/Neuropathy
Headache
21
30
46
37
Rash
13
16
30
18
Vomiting
12
14
30
35
Pancreatitis (see below)
1
*
less than 1
*
a Percentages based on treated subjects.
b Median duration of treatment 48 weeks.
c The incidences reported included all severity grades and all reactions regardless of causality.
* This event was not observed in this study arm.
Pancreatitis resulting in death was observed in one patient who received VIDEX (didanosine)
plus stavudine plus nelfinavir in Study AI454-148 and in one patient who received VIDEX plus
stavudine plus indinavir in the START 2 study. In addition, pancreatitis resulting in death was
observed in 2 of 68 patients who received VIDEX plus stavudine plus indinavir plus
hydroxyurea in an ACTG clinical trial [see Warnings and Precautions (5)].
The frequency of pancreatitis is dose related. In phase 3 studies, incidence ranged from 1% to
10% with doses higher than are currently recommended and from 1% to 7% with recommended
dose.
Selected laboratory abnormalities in clinical studies with VIDEX are shown in Tables 5-7.
Table 5:
Selected Laboratory Abnormalities from Monotherapy Studies
Percent of Patients
Parameter
ACTG 116A
ACTG 116B/117
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VIDEX
zidovudine
VIDEX
zidovudine
n=197
n=212
n=298
n=304
SGOT (AST) (greater than 5 x ULN)
9
4
7
6
SGPT (ALT) (greater than 5 x ULN)
9
6
6
6
Alkaline phosphatase (greater than 5 x ULN)
4
1
1
1
Amylase (at least 1.4 x ULN)
17
12
15
5
Uric acid (greater than 12 mg/dL)
3
1
2
1
ULN = upper limit of normal.
Table 6:
Selected Laboratory Abnormalities from Combination Studies
(Grades 3-4)
Percent of Patientsa
AI454-148b
START 2b
VIDEX +
zidovudine +
VIDEX +
zidovudine +
stavudine +
lamivudine +
stavudine +
lamivudine +
nelfinavir
nelfinavir
indinavir
indinavir
Parameter
n=482
n=248
n=102
n=103
Bilirubin (greater than 2.6 x ULN)
less than 1
less than 1
16
8
SGOT (AST) (greater than 5 x ULN)
3
2
7
7
SGPT (ALT) (greater than 5 x ULN)
3
3
8
5
GGT (greater than 5 x ULN)
NC
NC
5
2
Lipase (greater than 2 x ULN)
7
2
5
5
Amylase (greater than 2 x ULN)
NC
NC
8
2
ULN = upper limit of normal.
NC = Not Collected.
a Percentages based on treated subjects.
b Median duration of treatment 48 weeks.
11
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Table 7:
Selected Laboratory Abnormalities from Combination Studies (All
Grades)
Percent of Patientsa
AI454-148b
START 2b
Parameter
VIDEX +
stavudine +
nelfinavir
n=482
zidovudine +
lamivudine +
nelfinavir
n=248
VIDEX +
stavudine +
indinavir
n=102
zidovudine +
lamivudine +
indinavir
n=103
Bilirubin
7
3
68
55
SGOT (AST)
SGPT (ALT)
GGT
42
37
NC
23
24
NC
53
50
28
20
18
12
Lipase
Amylase
17
NC
11
NC
26
31
19
17
NC = Not Collected.
a Percentages based on treated subjects.
b Median duration of treatment 48 weeks.
Pediatric Patients
In clinical trials, 743 pediatric patients between 2 weeks and 18 years of age have been treated
with didanosine. Adverse reactions and laboratory abnormalities reported to occur in these
patients were generally consistent with the safety profile of didanosine in adults.
In pediatric phase 1 studies, pancreatitis occurred in 2 of 60 (3%) patients treated at entry doses
below 300 mg per m2 per day and in 5 of 38 (13%) patients treated at higher doses. In study
ACTG 152, pancreatitis occurred in none of the 281 pediatric patients who received didanosine
120 mg per m2 every 12 hours and in less than 1% of the 274 pediatric patients who received
didanosine 90 mg per m2 every 12 hours in combination with zidovudine [see Clinical Studies
(14)].
Retinal changes and optic neuritis have been reported in pediatric patients.
6.2
Postmarketing Experience
The following adverse reactions have been identified during postapproval use of didanosine.
Because they are reported voluntarily from a population of unknown size, it is not always
12
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possible to reliably estimate their frequency. These reactions have been chosen for inclusion due
to their seriousness, frequency of reporting, causal connection to VIDEX, or a combination of
these factors.
Blood and Lymphatic System Disorders – anemia, leukopenia, and thrombocytopenia.
Body as a Whole – alopecia, anaphylactoid reaction, asthenia, chills/fever, pain, and
redistribution/accumulation of body fat [see Warnings and Precautions (5.8)].
Digestive Disorders – anorexia, dyspepsia, and flatulence.
Exocrine Gland Disorders – pancreatitis (including fatal cases) [see Boxed Warning,
Warnings and Precautions (5.1)], sialadenitis, parotid gland enlargement, dry mouth, and
dry eyes.
Hepatobiliary Disorders – symptomatic hyperlactatemia/lactic acidosis and hepatic
steatosis [see Boxed Warning, Warnings and Precautions (5.2)]; non-cirrhotic portal
hypertension [see Warnings and Precautions (5.4)]; hepatitis and liver failure.
Metabolic Disorders – diabetes mellitus, hypoglycemia, and hyperglycemia.
Musculoskeletal Disorders – myalgia (with or without increases in creatine kinase),
rhabdomyolysis including acute renal failure and hemodialysis, arthralgia, and myopathy.
Ophthalmologic Disorders – retinal depigmentation and optic neuritis [see Warnings and
Precautions (5.6)].
Use with Stavudine- and Hydroxyurea-Based Regimens
When didanosine is used in combination with other agents with similar toxicities, the incidence
of these toxicities may be higher than when didanosine is used alone. Thus, patients treated with
VIDEX in combination with stavudine, with or without hydroxyurea, may be at increased risk
for pancreatitis and hepatotoxicity, which may be fatal, and severe peripheral neuropathy [see
Warnings and Precautions (5)]. The combination of VIDEX and hydroxyurea, with or without
stavudine, should be avoided.
13
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7
DRUG INTERACTIONS
7.1
Established Drug Interactions
Clinical recommendations based on the results of drug interaction studies are listed in Table 8.
Pharmacokinetic results of drug interaction studies are shown in Tables 12 and 13 [see
Contraindications (4), Clinical Pharmacology (12.3)].
Table 8:
Established Drug Interactions with VIDEX
Drug
Effect
Clinical Comment
ciprofloxacin
↓ ciprofloxacin concentration Administer VIDEX at least 2 hours after or 6 hours before
ciprofloxacin.
delavirdine
↓ delavirdine concentration
Administer VIDEX 1 hour after delavirdine.
ganciclovir
↑ didanosine concentration
If there is no suitable alternative to ganciclovir, then use in
combination with VIDEX with caution. Monitor for
didanosine-associated toxicity.
indinavir
↓ indinavir concentration
Administer VIDEX 1 hour after indinavir.
methadone
↓ didanosine concentration
Do not coadminister methadone with VIDEX pediatric
powder due to significant decreases in didanosine
concentrations. If coadministration of methadone and
didanosine is necessary, the recommended formulation of
didanosine is VIDEX EC. Patients should be closely
monitored for adequate clinical response when VIDEX EC
is coadministered with methadone, including monitoring
for changes in HIV RNA viral load.
nelfinavir
No interaction 1 hour after
Administer nelfinavir 1 hour after VIDEX.
didanosine
14
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Table 8:
Established Drug Interactions with VIDEX
Drug
Effect
Clinical Comment
tenofovir disoproxil
↑ didanosine concentration
A dose reduction of VIDEX to the following dosage once
fumarate
daily is recommended.a
•
250 mg (adults weighing at least 60 kg with creatinine
clearance of at least 60 mL/min)
•
200 mg (adults weighing less than 60 kg with
creatinine clearance of at least 60 mL/min)
VIDEX and tenofovir disoproxil fumarate may be taken
together in the fasted state. If tenofovir disoproxil
fumarate is taken with food, VIDEX should be taken on an
empty stomach (at least 30 minutes before food or 2 hours
after food). Patients should be monitored for didanosine
associated toxicities and clinical response.
↑ Indicates increase.
↓ Indicates decrease.
a The dosing recommendation for coadministration of VIDEX EC and tenofovir disoproxil fumarate with respect to
meal consumption differs from that of VIDEX. See the complete prescribing information for VIDEX EC.
Exposure to didanosine is increased when coadministered with tenofovir disoproxil fumarate
[see Clinical Pharmacology (12.3)]. Increased exposure may cause or worsen didanosine-related
clinical toxicities, including pancreatitis, symptomatic hyperlactatemia/lactic acidosis, and
peripheral neuropathy. Coadministration of tenofovir disoproxil fumarate with VIDEX should be
undertaken with caution, and patients should be monitored closely for didanosine-related
toxicities and clinical response. VIDEX should be suspended if signs or symptoms of
pancreatitis, symptomatic hyperlactatemia, or lactic acidosis develop [see Dosage and
Administration (2.3), Warnings and Precautions (5)]. Suppression of CD4 cell counts has been
observed in patients receiving tenofovir disoproxil fumarate with didanosine at a dose of 400 mg
daily.
15
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7.2
Predicted Drug Interactions
Predicted drug interactions with VIDEX are listed in Table 9.
Table 9:
Predicted Drug Interactions with VIDEX
Drug or Drug Class
Effect
Clinical Comment
Drugs that may cause pancreatic
↑ risk of pancreatitis
Use only with extreme cautiona
toxicity
b
Neurotoxic drugs
↑ risk of neuropathy
Use with caution
Antacids containing m
agnesium
↑ side effects associated with
Use caution with VIDEX Pediatric Powder for
or aluminum
antacid components
Oral Solution
Azole antifungals
↓ ketoconazole or itraconazole Administer drugs such as ketoconazole or
concentration
itraconazole at least 2 hours before VIDEX.
Quinolone antibiotics (see also
↓ quinolone concentration
Consult package insert of the quinolone.
ciprofloxacin in Table 8)
Tetracycline antibiotics
↓ antibiotic concentration
Consult package insert of the tetracycline.
↑ Indicates increase.
↓ Indicates decrease.
a Only if other drugs are not available and if clearly indicated. If treatment with life-sustaining drugs that cause
pancreatic toxicity is required, suspension of VIDEX is recommended [see Warnings and Precautions (5.1)].
b [See Warnings and Precautions (5.6).]
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Pregnancy Category B
Reproduction studies have been performed in rats and rabbits at doses up to 12 and 14.2 times
the estimated human exposure (based upon plasma levels), respectively, and have revealed no
evidence of impaired fertility or harm to the fetus due to didanosine. At approximately 12 times
the estimated human exposure, didanosine was slightly toxic to female rats and their pups during
mid and late lactation. These rats showed reduced food intake and body weight gains but the
physical and functional development of the offspring was not impaired and there were no major
changes in the F2 generation. A study in rats showed that didanosine and/or its metabolites are
16
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transferred to the fetus through the placenta. Animal reproduction studies are not always
predictive of human response.
There are no adequate and well-controlled studies of didanosine in pregnant women. Didanosine
should be used during pregnancy only if the potential benefit justifies the potential risk.
Fatal lactic acidosis has been reported in pregnant women who received the combination of
didanosine and stavudine with other antiretroviral agents. It is unclear if pregnancy augments the
risk of lactic acidosis/hepatic steatosis syndrome reported in nonpregnant individuals receiving
nucleoside analogues [see Warnings and Precautions (5.2)]. The combination of didanosine and
stavudine should be used with caution during pregnancy and is recommended only if the
potential benefit clearly outweighs the potential risk. Healthcare providers caring for HIV-
infected pregnant women receiving didanosine should be alert for early diagnosis of lactic
acidosis/hepatic steatosis syndrome.
Antiretroviral Pregnancy Registry
To monitor maternal-fetal outcomes of pregnant women exposed to didanosine and other
antiretroviral agents, an Antiretroviral Pregnancy Registry has been established. Physicians are
encouraged to register patients by calling 1-800-258-4263.
8.3
Nursing Mothers
The Centers for Disease Control and Prevention recommend that HIV-infected mothers not
breastfeed their infants to avoid risking postnatal transmission of HIV. A study in rats showed
that following oral administration, didanosine and/or its metabolites were excreted into the milk
of lactating rats. It is not known if didanosine is excreted in human milk. Because of both the
potential for HIV transmission and the potential for serious adverse reactions in nursing infants,
mothers should be instructed not to breastfeed if they are receiving didanosine.
8.4
Pediatric Use
Use of didanosine in pediatric patients from 2 weeks of age through adolescence is supported by
evidence from adequate and well-controlled studies of VIDEX in adult and pediatric patients
[see Dosage and Administration (2), Adverse Reactions (6.1), Clinical Pharmacology (12.3),
Clinical Studies (14)].
17
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8.5
Geriatric Use
In an Expanded Access Program for patients with advanced HIV infection, patients aged
65 years and older had a higher frequency of pancreatitis (10%) than younger patients (5%) [see
Warnings and Precautions (5.1)]. Clinical studies of didanosine did not include sufficient
numbers of subjects aged 65 years and over to determine whether they respond differently than
younger subjects. Didanosine is known to be substantially excreted by the kidney, and the risk of
toxic reactions to this drug may be greater in patients with impaired renal function. Because
elderly patients are more likely to have decreased renal function, care should be taken in dose
selection. In addition, renal function should be monitored and dosage adjustments should be
made accordingly [see Dosage and Administration (2.2)].
8.6
Renal Impairment
Patients with renal impairment (creatinine clearance of less than 60 mL per min) may be at
greater risk of toxicity from didanosine due to decreased drug clearance [see Clinical
Pharmacology (12.3)]. A dose reduction is recommended for these patients [see Dosage and
Administration (2)].
10
OVERDOSAGE
There is no known antidote for VIDEX (didanosine) overdosage. In phase 1 studies, in which
VIDEX was initially administered at doses ten times the currently recommended dose, toxicities
included: pancreatitis, peripheral neuropathy, diarrhea, hyperuricemia, and hepatic dysfunction.
Didanosine is not dialyzable by peritoneal dialysis, although there is some clearance by
hemodialysis [see Clinical Pharmacology (12.3)].
11
DESCRIPTION
VIDEX® is a brand name for didanosine, USP, a synthetic purine nucleoside analogue active
against HIV-1.
Didanosine is available as VIDEX, a Pediatric Powder for Oral Solution [see How
Supplied/Storage and Handling (16)] and as VIDEX EC Delayed-Release Capsules, containing
enteric-coated beadlets [consult prescribing information for VIDEX EC (didanosine)].
18
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The chemical name for didanosine is 2′,3′-dideoxyinosine. The structural formula is: structural formula
Didanosine is a white crystalline powder with the molecular formula C10H12N4O3 and a
molecular weight of 236.2. The aqueous solubility of didanosine at 25° C and pH of
approximately 6 is 27.3 mg per mL. Didanosine is unstable in acidic solutions. For example, at
pH less than 3 and 37° C, 10% of didanosine decomposes to hypoxanthine in less than 2 minutes.
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
Didanosine is an antiviral agent [see Microbiology (12.4)].
12.3
Pharmacokinetics
The pharmacokinetic parameters of didanosine are summarized in Table 10. Didanosine is
rapidly absorbed, with peak plasma concentrations generally observed from 0.25 to 1.50 hours
following oral dosing. Increases in plasma didanosine concentrations were dose proportional
over the range of 50 to 400 mg. Steady-state pharmacokinetic parameters did not differ
significantly from values obtained after a single dose. Binding of didanosine to plasma proteins
in vitro was low (less than 5%). Based on data from in vitro and animal studies, it is presumed
that the metabolism of didanosine in man occurs by the same pathways responsible for the
elimination of endogenous purines.
19
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Table 10:
Mean ± SD Pharmacokinetic Parameters for Didanosine in Adult and
Pediatric Patients
Pediatric Patientsb
8 months to
2 weeks to
Parameter
Adult Patientsa
n
19 years
n
4 months
n
Oral bioavailability (%)
42 ± 12
6
25 ± 20
46
ND
Apparent volume of
43.70 ± 8.90
6
28 ± 15
49
ND
distributionc (L/m2)
CSF-plasma ratiod
21 ± 0.03%e
5
46%
7
ND
(range 12-85%)
Systemic clearancec
2
526 ± 64.7
6
516 ± 184
49
ND
(mL/min/m )
Renal clearancef (mL/min/m2)
223 ± 85.0
6
240 ± 90
15
ND
Apparent oral clearanceg
1252 ± 154
6
2064 ± 736
48
1353 ± 759
41
(mL/min/m2)
Elimination half-lifef (h)
1.5 ± 0.4
6
0.8 ± 0.3
60
1.2 ± 0.3
21
Urinary recovery of
18 ± 8
6
18 ± 10
15
ND
didanosinef (%)
CSF = cerebrospinal fluid, ND = not determined.
a Parameter units for adults were converted to the same units in pediatric patients to facilitate comparisons among
populations: mean adult body weight = 70 kg and mean adult body surface area = 1.73 m2 .
b In 1-day old infants (n=10), the mean ± SD apparent oral clearance was 1523 ± 1176 mL/min/m2 and half-life was
2.0 ± 0.7 h.
c Following IV administration.
d Following IV administration in adults and IV or oral administration in pediatric patients.
e Mean ± SE.
f Following oral administration.
g Apparent oral clearance estimate was determined as the ratio of the mean systemic clearance and the mean oral
bioavailability estimate.
Effect of Food
Didanosine peak plasma concentrations (Cmax) and area under the plasma concentration time
curve (AUC) were decreased by approximately 55% when VIDEX tablets were administered up
to 2 hours after a meal. Administration of VIDEX tablets up to 30 minutes before a meal did not
result in any significant changes in bioavailability [see Dosage and Administration (2)]. VIDEX
should be taken on an empty stomach.
20
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Special Populations
Renal Insufficiency: Data from two studies in adults indicated that the apparent oral clearance of
didanosine decreased and the terminal elimination half-life increased as creatinine clearance
decreased (see Table 11). Following oral administration, didanosine was not detectable in
peritoneal dialysate fluid (n=6); recovery in hemodialysate (n=5) ranged from 0.6% to 7.4% of
the dose over a 3-4 hour dialysis period. The absolute bioavailability of didanosine was not
affected in patients requiring dialysis. [See Dosage and Administration (2.2).]
Table 11:
Mean ± SD Pharmacokinetic Parameters for Didanosine Following a
Single Oral Dose
Creatinine Clearance (mL/min)
Parameter
at least 90
n=12
60-90
n=6
30-59
n=6
10-29
n=3
Dialysis Patients
n=11
CLcr (mL/min)
CL/F (mL/min)
CLR (mL/min)
112 ± 22
2164 ± 638
458 ± 164
68 ± 8
1566 ± 833
247 ± 153
46 ± 8
1023 ± 378
100 ± 44
13 ± 5
628 ± 104
20 ± 8
ND
543 ± 174
less than 10
T½ (h)
1.42 ± 0.33
1.59 ± 0.13
1.75 ± 0.43
2.0 ± 0.3
4.1 ± 1.2
ND = not determined due to anuria.
CLcr = creatinine clearance.
CL/F = apparent oral clearance.
CLR = renal clearance.
Hepatic Impairment: The pharmacokinetics of didanosine have been studied in 12 non-HIV
infected subjects with moderate (n=8) to severe (n=4) hepatic impairment (Child-Pugh Class B
or C). Mean AUC and Cmax values following a single 400 mg dose of didanosine were
approximately 13% and 19% higher, respectively, in patients with hepatic impairment compared
to matched healthy subjects. No dose adjustment is needed, because a similar range and
distribution of AUC and Cmax values was observed for subjects with hepatic impairment and
matched healthy controls. [See Dosage and Administration (2.3).]
Pediatric Patients: The pharmacokinetics of didanosine have been evaluated in HIV-exposed
and HIV-infected pediatric patients from birth to adulthood. Overall, the pharmacokinetics of
didanosine in pediatric patients are similar to those of didanosine in adults. Didanosine plasma
concentrations appear to increase in proportion to oral doses ranging from 25 to 120 mg per m2
21
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in pediatric patients less than 5 months old and from 80 to 180 mg per m2 in children above 8
months old. For information on controlled clinical studies in pediatric patients, see Clinical
Studies (14.2), and Use in Specific Populations (8.4).
Geriatric Patients: Didanosine pharmacokinetics have not been studied in patients over 65 years
of age [see Use in Specific Populations (8.5)].
Gender: The effects of gender on didanosine pharmacokinetics have not been studied.
Drug Interactions
Tables 12 and 13 summarize the effects on AUC and Cmax, with a 95% confidence interval (CI)
when available, following coadministration of VIDEX (didanosine) with a variety of drugs.
Drug-drug interactions for VIDEX buffered tablets are applicable to the VIDEX pediatric
powder formulation and are noted in Tables 12 and 13. For clinical recommendations based on
drug interaction studies for drugs in bold font, see Dosage and Administration (2.3 for
Concomitant Therapy with Tenofovir Disoproxil Fumarate), Contraindications (4), and Drug
Interactions (7.1 and 7.2).
Table 12:
Results of Drug Interaction Studies with VIDEX: Effects of
Coadministered Drug on Didanosine Plasma AUC and Cmax Values
% Change of Didanosine
Pharmacokinetic Parametersa
AUC of
Cmax of
Didanosine
Didanosine
Drug
Didanosine Dosage
n
(95% CI)
(95% CI)
allopurinol,
renally impaired, 300 mg/day
200 mg single dose
2
↑ 312%
↑ 232%
healthy volunteer, 300 mg/day for
7 days
400 mg single dose
14
↑ 113%
↑ 69%
ciprofloxacin, 750 mg every 12 hours
for 3 days, 2 hours before didanosine
200 mg every 12 hours
for 3 days
8b
↓ 16%
↓ 28%
ganciclovir, 1000 mg every 8 hours,
2 hours after didanosine
200 mg every 12 hours
12
↑ 111%
NA
indinavir, 800 mg single dose,
simultaneous
200 mg single dose
16
↔
↔
1 hour before didanosine
200 mg single dose
16
↓ 17%
(-27, -7%)c
↓ 13%
(-28, 5%)c
ketoconazole, 200 mg/day for 4 days,
2 hours before didanosine
375 mg every 12 hours
for 4 days
12b
↔
↓ 12%
22
Reference ID: 3607428
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Table 12:
Results of Drug Interaction Studies with VIDEX: Effects of
Coadministered Drug on Didanosine Plasma AUC and Cmax Values
% Change of Didanosine
Pharmacokinetic Parametersa
AUC of
Cmax of
Didanosine
Didanosine
Drug
Didanosine Dosage
n
(95% CI)
(95% CI)
↔
↔
↑ Indicates increase.
↓ Indicates decrease.
↔ Indicates no change, or mean increase or decrease of less than 10%.
a The 95% confidence intervals for the percent change in the pharmacokinetic parameter are displayed.
b HIV-infected patients.
c 90% CI.
d Comparisons are made to a parallel control group not receiving methadone (n=10).
e Comparisons are made to historical controls (n=68, pooled from 3 studies) conducted in healthy subjects. The
number of subjects evaluated for AUC and Cmax is 15 and 16, respectively.
f For results of drug interaction studies between the enteric-coated formulation of didanosine (VIDEX EC) and
methadone, chronic maintenance dosef
tenofovir,g,h 300 mg once daily, 1 hour
after didanosine
loperamide, 4 mg every 6 hours for
1 day
metoclopramide, 10 mg single dose
ranitidine, 150 mg single dose, 2 hours
before didanosine
rifabutin, 300 or 600 mg/day for
12 days
ritonavir, 600 mg every 12 hours for
4 days
stavudine, 40 mg every 12 hours for
4 days
sulfamethoxazole, 1000 mg single dose
trimethoprim, 200 mg single dose
zidovudine, 200 mg every 8 hours for
3 days
200 mg single dose
400 mg single dose
250i mg or 400 mg once
daily for 7 days
300 mg single dose
300 mg single dose
375 mg single dose
167 mg or 250 mg every
12 hours for 12 days
200 mg every 12 hours
for 4 days
100 mg every 12 hours
for 4 days
200 mg single dose
200 mg single dose
200 mg every 12 hours
for 3 days
16d
15,16e
14
12b
12b
12b
11
12
10
8b
8b
6b
↓ 57%
↓ 29%
(-40, -16%)c
↑ 44%
(31, 59%)c
↔
↔
↑ 14%
↑ 13%
(-1, 27%)
↓ 13%
(0, 23%)
↔
↔
↔
↓ 66%
↓ 41%
(-54, -26%)c
↑ 28%
(11, 48%)c
↓ 23%
↑ 13%
↑ 13%
↑ 17%
(-4, 38%)
↓ 16%
(5, 26%)
↔
↔
↑ 17%
(-23, 77%)
23
Reference ID: 3607428
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Table 12:
Results of Drug Interaction Studies with VIDEX: Effects of
Coadministered Drug on Didanosine Plasma AUC and Cmax Values
% Change of Didanosine
Pharmacokinetic Parametersa
AUC of
Cmax of
Didanosine
Didanosine
Drug
Didanosine Dosage
n
(95% CI)
(95% CI)
methadone, see the complete prescribing information for VIDEX EC.
g Tenofovir disoproxil fumarate.
h For results of drug interaction studies between the enteric-coated formulation of didanosine (VIDEX EC) and
tenofovir disoproxil fumarate, see the complete prescribing information for VIDEX EC.
i Patients less than 60 kg with creatinine clearance of at least 60 mL/min.
NA = Not available.
Table 13:
Results of Drug Interaction Studies with VIDEX: Effects of
Didanosine on Coadministered Drug Plasma AUC and Cmax Values
% Change of Coadministered Drug
Pharmacokinetic Parametersa
Drug
Didanosine Dosage
n
AUC of
Coadministered
Drug
(95% CI)
Cmax of
Coadministered
Drug
(95% CI)
ciprofloxacin,
750 mg every 12 hours for 3 days,
2 hours before didanosine
200 mg every 12 hours for
3 days
8b
↓ 26%
↓ 16%
750 mg single dose
buffered placebo tablet
12
↓ 98%
↓ 93%
delavirdine, 400 mg single dose
simultaneous 1 hour before
didanosine
125 mg or 200 mg every
12 hours
125 mg or 200 mg every
12 hours
12b
12b
↓ 32%
↑ 20%
↓ 53%
↑ 18%
ganciclovir, 1000 mg every 8 hours,
2 hours after didanosine
200 mg every 12 hours
12b
↓ 21%
NA
indinavir, 800 mg single dose
simultaneous
200 mg single dose
16
↓ 84%
↓ 82%
1 hour before didanosine
200 mg single dose
16
↓ 11%
↓ 4%
ketoconazole, 200 mg/day for
4 days, 2 hours before didanosine
375 mg every 12 hours for
4 days
12b
↓ 14%
↓ 20%
nelfinavir, 750 mg single dose,
1 hour after didanosine
200 mg single dose
10b
↑ 12%
↔
dapsone, 100 mg single dose
200 mg every 12 hours for
6b
↔
↔
24
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Table 13:
Results of Drug Interaction Studies with VIDEX: Effects of
Didanosine on Coadministered Drug Plasma AUC and Cmax Values
% Change of Coadministered Drug
Pharmacokinetic Parametersa
AUC of
Cmax of
Coadministered
Coadministered
Drug
Drug
Drug
Didanosine Dosage
n
(95% CI)
(95% CI)
14 days
ranitidine, 150 mg single dose,
375 mg single dose
12b
↓ 16%
↔
2 hours before didanosine
ritonavir, 600 mg every 12 hours for 200 mg every 12 hours for
12
↔
↔
4 days
4 days
stavudine, 40 mg every 12 hours for 100 mg every 12 hours for
10b
↔
↑ 17%
4 days
4 days
sulfamethoxazole, 1000 mg single
↓ 11%
↓ 12%
200 mg single dose
8b
dose
(-17, -4%)
(-28, 8%)
d
tenofovir,c 300 mg once daily
250 mg or 400 mg once
14
↔
↔
1 hour after didanosine
daily for 7 days
↑ 10%
↓ 22%
trimethoprim, 200 mg single dose
200 mg single dose
8b
(-9, 34%)
(-59, 49%)
zidovudine, 200 mg every 8 hours
200 mg every 12 hours for
↓ 10%
↓ 16.5%
6b
for 3 days
3 days
(-27, 11%)
(-53, 47%)
↑ Indicates increase.
↓ Indicates decrease.
↔ Indicates no change, or mean increase or decrease of less than 10%.
a The 95% confidence intervals for the percent change in the pharmacokinetic parameter are displayed.
b HIV-infected patients.
c Tenofovir disoproxil fumarate.
d Patients less than 60 kg with creatinine clearance of at least 60 mL/min.
NA = Not available.
12.4
Microbiology
Mechanism of Action
Didanosine is a synthetic nucleoside analogue of the naturally occurring nucleoside
deoxyadenosine in which the 3′-hydroxyl group is replaced by hydrogen. Intracellularly,
didanosine is converted by cellular enzymes to the active metabolite, dideoxyadenosine
25
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5′-triphosphate. Dideoxyadenosine 5′-triphosphate inhibits the activity of HIV-1 reverse
transcriptase both by competing with the natural substrate, deoxyadenosine 5′-triphosphate, and
by its incorporation into viral DNA causing termination of viral DNA chain elongation.
Antiviral Activity in Cell Culture
The anti-HIV-1 activity of didanosine was evaluated in a variety of HIV-1 infected
lymphoblastic cell lines and monocyte/macrophage cell cultures. The concentration of drug
necessary to inhibit viral replication by 50% (EC50) ranged from 2.5 to 10 µM
(1 µM = 0.24 µg/mL) in lymphoblastic cell lines and 0.01 to 0.1 µM in monocyte/macrophage
cell cultures.
Resistance
HIV-1 isolates with reduced sensitivity to didanosine have been selected in cell culture and were
also obtained from patients treated with didanosine. Genetic analysis of isolates from didanosine
treated patients showed mutations in the reverse transcriptase gene that resulted in the amino acid
substitutions K65R, L74V, and M184V. The L74V substitution was most frequently observed in
clinical isolates. Phenotypic analysis of HIV-1 isolates from 60 patients (some with prior
zidovudine treatment) receiving 6 to 24 months of didanosine monotherapy showed that isolates
from 10 of 60 patients exhibited an average of a 10-fold decrease in susceptibility to didanosine
in cell culture compared to baseline isolates. Clinical isolates that exhibited a decrease in
didanosine susceptibility harbored one or more didanosine resistance-associated substitutions.
Cross-resistance
HIV-1 isolates from 2 of 39 patients receiving combination therapy for up to 2 years with
didanosine and zidovudine exhibited decreased susceptibility to didanosine, lamivudine,
stavudine, zalcitabine, and zidovudine in cell culture. These isolates harbored five substitutions
(A62V, V75I, F77L, F116Y, and Q151M) in the reverse transcriptase gene. In data from clinical
studies, the presence of thymidine analogue mutations (M41L, D67N, L210W, T215Y, K219Q)
has been shown to decrease the response to didanosine.
26
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13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
Lifetime carcinogenicity studies were conducted in mice and rats for 22 and 24 months,
respectively. In the mouse study, initial doses of 120, 800, and 1200 mg per kg per day for each
sex were lowered after 8 months to 120, 210, and 210 mg per kg per day for females and 120,
300, and 600 mg per kg per day for males. The two higher doses exceeded the maximally
tolerated dose in females and the high dose exceeded the maximally tolerated dose in males. The
low dose in females represented 0.68-fold maximum human exposure and the intermediate dose
in males represented 1.7-fold maximum human exposure based on relative AUC comparisons. In
the rat study, initial doses were 100, 250, and 1000 mg per kg per day, and the high dose was
lowered to 500 mg per kg per day after 18 months. The upper dose in male and female rats
represented 3-fold maximum human exposure.
Didanosine induced no significant increase in neoplastic lesions in mice or rats at maximally
tolerated doses.
Didanosine was positive in the following genetic toxicology assays: 1) the Escherichia coli tester
strain WP2 uvrA bacterial mutagenicity assay; 2) the L5178Y/TK+/- mouse lymphoma
mammalian cell gene mutation assay; 3) the in vitro chromosomal aberrations assay in cultured
human peripheral lymphocytes; 4) the in vitro chromosomal aberrations assay in Chinese
Hamster Lung cells; and 5) the BALB/c 3T3 in vitro transformation assay. No evidence of
mutagenicity was observed in an Ames Salmonella bacterial mutagenicity assay or in rat and
mouse in vivo micronucleus assays.
13.2
Animal Toxicology and/or Pharmacology
Evidence of a dose-limiting skeletal muscle toxicity has been observed in mice and rats (but not
in dogs) following long-term (greater than 90 days) dosing with didanosine at doses that were
approximately 1.2 to 12 times the estimated human exposure. The relationship of this finding to
the potential of VIDEX (didanosine) to cause myopathy in humans is unclear. However, human
myopathy has been associated with administration of VIDEX and other nucleoside analogues.
27
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14
CLINICAL STUDIES
14.1
Adult Patients
Combination Therapy
START 2 was a multicenter, randomized, open-label study comparing VIDEX (200 mg twice
daily)/stavudine/indinavir to zidovudine/lamivudine/indinavir in 205 treatment-naive patients.
Both regimens resulted in a similar magnitude of suppression of HIV-1 RNA levels and
increases in CD4 cell counts through 48 weeks.
Study AI454-148 was a randomized, open-label, multicenter study comparing treatment with
VIDEX (400 mg once daily) plus stavudine (40 mg twice daily) and nelfinavir (750 mg three
times daily) versus zidovudine (300 mg twice daily) plus lamivudine (150 mg twice daily) and
nelfinavir (750 mg three times daily) in 756 treatment-naive patients, with a median CD4 cell
count of 340 cells per mm3 (range 80 to 1568 cells per mm3) and a median plasma HIV-1 RNA
of 4.69 log10 copies per mL (range 2.6 to 5.9 log10 copies per mL) at baseline. Median CD4 cell
count increases at 48 weeks were 188 cells per mm 3 in both treatment groups. Treatment
response and outcomes through 48 weeks are shown in Figure 1 and Table 14. graph
28
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Table 14:
Outcomes of Randomized Treatment Through Week 48, AI454-148
Percent of Patients with HIV-1 RNA less than 400 copies/mL
(less than 50 copies/mL)
VIDEX/stavudine/nelfinavir
lamivudine/zidovudine/nelfinavir
Week 48 Status
n=503
n=253
Respondera
50* (34*)
59 (47)
Virologic failureb
36 (57)
32 (48)
Death or disease progression
less than 1 (less than 1)
1 (less than 1)
Discontinued due to adverse events
4 (2)
2 (less than 1)
Discontinued due to other reasonsc
6 (3)
4 (2)
Never initiated treatment
4 (4)
2 (2)
* p less than 0.05 for the differences between treatment groups, by Cochran-Mantel-Haenszel test.
a Patients achieved virologic response [two consecutive viral loads less than 400 (less than 50) copies/mL] and
maintained it to Week 48.
b Includes viral rebound and failing to achieve confirmed less than 400 (less than 50) copies/mL by Week 48.
c Includes lost to follow-up, noncompliance, withdrawal, and pregnancy.
Monotherapy
The efficacy of VIDEX was demonstrated in two randomized, double-blind studies comparing
VIDEX, given on a twice-daily schedule, to zidovudine, given three times daily, in 617 (ACTG
116A, conducted 1989-1992) and 913 (ACTG 116B/117, conducted 1989-1991) patients with
symptomatic HIV infection or AIDS who were treated for more than one year. In treatment-
naive patients (ACTG 116A), the rate of HIV disease progression or death was similar between
the treatment groups; mortality rates were 26% for patients receiving VIDEX and 21% for
patients receiving zidovudine. Of the patients who had received previous zidovudine treatment
(ACTG 116B/117), those treated with VIDEX had a lower rate of HIV disease progression or
death (32%) compared to those treated with zidovudine (41%); however, survival rates were
similar between the treatment groups.
Studies have demonstrated that the clinical benefit of monotherapy with antiretrovirals, including
VIDEX, was time limited.
14.2
Pediatric Patients
Efficacy in pediatric patients was demonstrated in a randomized, double-blind, controlled study
(ACTG 152, conducted 1991-1995) involving 831 patients 3 months to 18 years of age treated
29
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for more than 1.5 years with zidovudine (180 mg per m2 every 6 hours), VIDEX (120 mg per m2
every 12 hours), or zidovudine (120 mg per m2 every 6 hours) plus VIDEX (90 mg per m2 every
12 hours). Patients treated with VIDEX or VIDEX plus zidovudine had lower rates of HIV-1
disease progression or death compared with those treated with zidovudine alone.
16
HOW SUPPLIED/STORAGE AND HANDLING
VIDEX (didanosine, USP) Pediatric Powder for Oral Solution is supplied as shown in Table 15:
Table 15:
VIDEX Pediatric Powder for Oral Solution
NDC NO.
Packaging Information
Product Quantity
0087-6632-41
One, 4-ounce glass, bottle per carton
2 g/bottle
0087-6633-41
One, 8-ounce glass, bottle per carton
4 g/bottle
Storage
The bottles of powder should be stored at 59° F to 86° F (15° C to 30° C). The VIDEX
admixture may be stored up to 30 days in a refrigerator, 36° F to 46° F (2° C to 8° C). Discard
any unused portion after 30 days.
17
PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Pancreatitis
Advise patients that a serious toxicity of VIDEX, used alone and in combination regimens, is
pancreatitis, which may be fatal.
Peripheral Neuropathy
Advise patients that peripheral neuropathy, manifested by numbness, tingling, or pain in hands or
feet, may develop during therapy with VIDEX. Patients should be counseled that peripheral
neuropathy occurs with greatest frequency in patients with advanced HIV-1 disease or a history
of peripheral neuropathy, and that discontinuation of VIDEX may be required if toxicity
develops.
30
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Lactic Acidosis and Severe Hepatomegaly with Steatosis
Advise patients that lactic acidosis and severe hepatomegaly with steatosis, including fatal cases,
have been reported with the use of nucleoside analogues alone or in combination, including
didanosine and other antiretrovirals.
Hepatic Toxicity
Advise patients that hepatotoxicity including fatal hepatic adverse events were reported in
patients with preexisting liver dysfunction. The safety and efficacy of VIDEX have not been
established in HIV-infected patients with significant underlying liver disease.
Non-cirrhotic Portal Hypertension
Advise patients that non-cirrhotic portal hypertension has been reported in patients taking
VIDEX, including cases leading to liver transplantation or death.
Retinal Changes and Optic Neuritis
Advise patients that retinal changes and optic neuritis have been reported in adult and pediatric
patients, which may result in dry eyes and/or blurred vision. Advise patients to have regular eye
exams while taking VIDEX.
Fat Redistribution
Advise patients that redistribution or accumulation of body fat may occur in patients receiving
antiretroviral therapy and that the cause and long-term health effects of these conditions are not
known at this time.
Concomitant Therapy
Advise patients that when VIDEX is used in combination with other agents with similar
toxicities, the incidence of adverse events may be higher than when VIDEX is used alone. These
patients should be followed closely.
Patients should be cautioned about the use of medications or other substances, including alcohol,
which may exacerbate VIDEX toxicities.
31
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Information for Patients
VIDEX is not a cure for HIV-1 infection, and patients may continue to experience illnesses
associated with HIV-1 infection, including opportunistic infections. Therefore, patients should
remain under the care of a physician when using VIDEX.
Advise patients to avoid doing things that can spread HIV-1 infection to others.
• Do not share needles or other injection equipment.
• Do not share personal items that can have blood or body fluids on them, like toothbrushes
and razor blades.
• Do not have any kind of sex without protection. Always practice safer sex by using a
latex or polyurethane condom to lower the chance of sexual contact with semen, vaginal
secretions, or blood.
• Do not breastfeed. It is not known if VIDEX can be passed to your baby in your breast
milk and whether it could harm your baby. Also, mothers with HIV-1 should not
breastfeed because HIV-1 can be passed to the baby in breast milk.
Advise patients that the preferred dosing frequency of VIDEX is twice daily because there is
more evidence to support the effectiveness of this dosing frequency. Once-daily dosing should be
considered only for patients whose management requires once-daily dosing of VIDEX.
Advise patients to not miss a dose but if they do, patients should take VIDEX as soon as
possible. Patients should be told that if it is almost time for the next dose, they should skip the
missed dose and continue with the regular dosing schedule.
Advise patients to contact a poison control center or emergency room right away in case of an
overdose.
32
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Medication Guide
VIDEX® (VY-dex)
(didanosine, also known as ddI)
Pediatric Powder for Oral Solution
Read this Medication Guide before you start taking VIDEX and each time you get a
refill. There may be new information. This information does not take the place of
talking with your healthcare provider about your medical condition or your
treatment. You should stay under your healthcare provider’s care when taking
VIDEX.
What is the most important information I should know about VIDEX?
VIDEX may cause serious side effects, including:
1. Swelling of your pancreas (pancreatitis) that may cause death.
Pancreatitis can happen in people:
• who take VIDEX by itself, and in people who also take other antiviral
medicines along with VIDEX to treat their HIV-1 infection and
• who have never taken anti-HIV medicines before, and also in people who
have taken antiviral medicines to treat their HIV-1 infection.
People who take VIDEX with the medicine stavudine (ZERIT), and people with
kidney problems may have an increased risk for developing pancreatitis. People
who have advanced HIV-1 infection, especially the elderly, have an increased
risk of developing pancreatitis. Your dose of VIDEX may need to be decreased
by your healthcare provider, or your healthcare provider may need to hold or
stop your treatment with VIDEX if you develop pancreatitis.
Before you start taking VIDEX, tell your healthcare provider if you:
• have had pancreatitis
• have kidney problems
• drink alcoholic beverages
• take the medicine stavudine (ZERIT)
Call your healthcare provider right away if you develop:
33
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• stomach-area (abdomen) pain
• swelling of your stomach area
• nausea and vomiting
• fever
2. Build-up of acid in your blood (lactic acidosis). Lactic acidosis can happen
in some people who take VIDEX alone or with other antiviral medicines. Lactic
acidosis is a serious medical emergency that can lead to death. Death has
happened in pregnant women who take VIDEX and the medicine stavudine
(ZERIT), along with other antiviral medicines. The risk for lactic acidosis may be
higher if you:
• are pregnant
• are taking stavudine (ZERIT)
• have liver problems
• are overweight
• are taking HIV medicines for a long time
Lactic acidosis treatment usually requires hospitalization.
Lactic acidosis can be hard to identify early, because the symptoms could seem
like symptoms of other health problems. Call your healthcare provider right
away if you get the following symptoms which could be signs of lactic acidosis:
• feel very weak or tired
• have unusual (not normal) muscle pain
• have trouble breathing
• have stomach pain with nausea and vomiting
• feel cold, especially in your arms and legs
• feel dizzy or light-headed
• have a fast or irregular heartbeat
3. Severe liver problems. Severe liver problems can happen in people, including
pregnant women, who take VIDEX alone or with other antiviral medicines. In
some cases, these severe liver problems can lead to the need for you to have a
liver transplant, or cause death. Your liver may become large (hepatomegaly),
you may develop fat in your liver (steatosis), liver failure, or high blood pressure
in the large vein of your liver (portal hypertension). Your healthcare provider
should examine you and check your liver function while you are taking VIDEX.
34
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It is not known if VIDEX is safe and effective in people with HIV-infection who
also have liver disease.
Call your healthcare provider right away if you develop:
• yellowing of your skin or the white of your eyes (jaundice)
• dark urine
• pain on the right side of your stomach area (abdomen)
• swelling of your stomach area
• easy bruising or bleeding
• loss of appetite
• nausea or vomiting
• vomiting of blood
• dark-colored stools (bowel movements)
You may be more likely to develop severe liver problems if you:
• are a woman
• are pregnant
• are overweight
• have been treated for a long time with other medicines to treat HIV
What is VIDEX?
VIDEX is a prescription medicine used with other antiretroviral medicines to treat
human immunodeficiency virus type 1 (HIV-1) infection in children and adults.
VIDEX belongs to a class of drugs called nucleoside analogues.
When used with other HIV medicines, VIDEX may help:
• reduce the amount of HIV in your blood. This is called “viral load”.
• increase the number of white blood cells called CD4+ (T) cells in your blood,
which may help fight off other infections.
35
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Reducing the amount of HIV-1 and increasing the CD4+ (T) cells in your blood may
help improve your immune system. This may reduce your risk of death or getting
infections that can happen when your immune system is weak (opportunistic
infections).
VIDEX does not cure HIV-1 infection or AIDS. You must stay on continuous
HIV-1 therapy to control infection and decrease HIV-related illnesses.
Avoid doing things that can spread HIV-1 infection to others.
• Do not share or re-use needles or other injection equipment.
• Do not share personal items that can have blood or body fluids on them, like
toothbrushes and razor blades.
• Do not have any kind of sex without protection. Always practice safer sex by
using a latex or polyurethane condom to lower the chance of sexual contact
with any body fluids such as semen, vaginal secretions, or blood.
Ask your healthcare provider if you have any questions about how to prevent
passing HIV to other people.
Who should not take VIDEX?
Do not take VIDEX if you take:
• allopurinol (ZYLOPRIM, LOPURIN, ALOPRIM)
• ribavirin (COPEGUS, REBETOL, RIBASPHERE, RIBAVIRIN, VIRAZOLE)
What should I tell my healthcare provider before taking VIDEX?
Before you take VIDEX, tell your healthcare provider if you:
• have had pancreatitis
• have or had kidney problems
• have or had liver problems (such as hepatitis)
• have or had persistent numbness, tingling, or pain in the hands or feet
(neuropathy)
• drink alcoholic beverages
• have any other medical conditions
• are pregnant or plan to become pregnant. It is not known if VIDEX will harm
your unborn baby. Tell your healthcare provider right away if you become
pregnant while taking VIDEX. You and your healthcare provider will decide if
you should take VIDEX while you are pregnant.
36
Reference ID: 3607428
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Pregnancy Registry: There is a pregnancy registry for women who take
antiviral medicines during pregnancy. The purpose of the registry is to collect
information about the health of you and your baby. Talk to your healthcare
provider about how you can take part in this registry.
• are breastfeeding or plan to breastfeed. Do not breastfeed if you take
VIDEX. You should not breastfeed because of the risk of passing HIV to your
baby. It is not known if VIDEX passes into your breast milk. Talk to your
healthcare provider about the best way to feed your baby while taking
VIDEX.
Tell your healthcare provider about all the medicines you take, including
prescription and over-the-counter medicines, vitamins, and herbal supplements.
VIDEX may affect the way other medicines work, and other medicines may
affect how VIDEX works.
Especially tell your healthcare provider if you take:
• tenofovir disoproxil fumarate (VIREAD , ATRIPLA, COMPLERA, STRIBILD,
TRUVADA)
• hydroxyurea (DROXIA, HYDREA)
• delavirdine mesylate (RESCRIPTOR)
• ganciclovir (CYTOVENE, VALCYTE)
• indinavir (CRIXIVAN)
• methadone hydrochloride (DOLOPHINE HYDROCHLORIDE, METHADOSE)
• nelfinavir (VIRACEPT)
• antacids that contain magnesium or aluminum
• the
antifungal
medicines
ketoconazole
(NIZORAL)
and
itraconazole
(SPORANOX, ONMEL)
• a type of antibiotic called a “quinolone,” such as ciprofloxacin (CIPRO)
• an antibiotic that contains tetracycline
• stavudine (ZERIT)
Know the medicines you take. Keep a list of your medicines and show it to your
healthcare provider and pharmacist when you get a new medicine.
Ask your healthcare provider if you are not sure if you take one of the medicines
listed above.
How should I take VIDEX?
• Take VIDEX exactly as your healthcare provider tells you to take it.
• Your healthcare provider will tell you how much VIDEX to take and when to take
it.
37
Reference ID: 3607428
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For current labeling information, please visit https://www.fda.gov/drugsatfda
• Your healthcare provider may change your dose. Do not change your dose of
VIDEX without talking to your healthcare provider.
• Do not take VIDEX with food. Take VIDEX on an empty stomach at least 30
minutes before or 2 hours after you eat.
• VIDEX comes as a Powder for Oral Solution. Your pharmacist will give you a
bottle that contains VIDEX as a solution that has been mixed with acid-reducing
medicines (antacids).
• Shake the bottle well before taking each dose of VIDEX.
• Be sure to close the bottle tightly after each use.
• Try not to miss a dose of VIDEX, but if you do, take it as soon as possible. If it is
almost time for the next dose, skip the missed dose. Then continue your regular
dosing schedule.
• Some medicines should not be taken at the same time of day that you
take VIDEX. Check with your healthcare provider.
• If your kidneys are not working well, your healthcare provider will need to do
regular blood and urine tests to check how they are working while you take
VIDEX. Your healthcare provider may also lower your dose of VIDEX if your
kidneys are not working well.
• If you take too much VIDEX, call a poison control center or go to an
emergency room right away.
What are the possible side effects of VIDEX?
VIDEX can cause serious side effects.
• See “What is the most important information I should know about VIDEX?”
• Vision changes. Contact your healthcare provider if you have changes in
vision, such as dry eyes and/or blurred vision. You should have regular eye
exams while you take VIDEX.
• Nerve damage. Symptoms include numbness, tingling, or pain in your hands or
feet. These are common with VIDEX, but are more likely to happen in people
who have had these problems before, in people who take medicines that can
affect the nerves, including stavudine (ZERIT), and in people who have
advanced HIV disease. A child may not notice the symptoms. Ask your
healthcare provider about the signs and symptoms of nerve problems that you
should look for in your child during and after treatment with VIDEX.
• Changes in your immune system (immune reconstitution syndrome) can
happen when you start taking HIV-1 medicine. Your immune system may get
stronger and begin to fight infections that have been hidden in your body for a
long time. Tell your healthcare provider if you start having new symptoms after
starting to take HIV-1 medicine.
38
Reference ID: 3607428
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• Changes in body fat can happen in people who take HIV-1 medicines. These
changes may include increased amount of fat in the upper back and neck
(“buffalo hump”), breast, and around the main part of your body (trunk). Loss of
fat from the legs, arms, and face may also happen. The cause and long-term
health effects of these conditions are not known.
The most common side effects of VIDEX include:
• diarrhea
• stomach-area (abdomen) pain
• nausea
• vomiting
• headache
• rash
Tell your healthcare provider if you have any side effect that bothers you or that
does not go away.
These are not all the possible side effects of VIDEX. For more information, ask your
healthcare provider or pharmacist.
Call your doctor for medical advice about side effects. You may report side effects
to FDA at 1-800-FDA-1088.
How should I store VIDEX?
• Store VIDEX oral solution in a tightly closed container in the refrigerator
between 36° F to 46° F (2° C to 8° C) for up to 30 days.
• Safely throw away any unused VIDEX after 30 days.
Keep VIDEX and all medicines out of the reach of children.
General information about the safe and effective use of VIDEX
Medicines are sometimes prescribed for purposes other than those listed in a
Medication Guide. Do not use VIDEX for a condition for which it was not prescribed.
If you would like more information, talk with your healthcare provider. You can ask
your pharmacist or healthcare provider for information about VIDEX that is written
for
health
professionals.
For
more
information,
go
to
www.bms.com/products/Pages/home.aspx or call 1-800-321-1335.
39
Reference ID: 3607428
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
What are the ingredients in VIDEX?
Active ingredients: didanosine
Pediatric Oral Solution inactive ingredients: Purified Water, USP and an
antacid containing aluminum hydroxide (400 mg per 5 mL), magnesium hydroxide
(400 mg per 5 mL), and simethicone (40 mg per 5 mL).
This Medication Guide has been approved by the U.S. Food and Drug
Administration.
Bristol-Myers Squibb Company
Princeton, NJ 08543 USA
xxxxxx
August 2014
VIDEX and Zerit are registered trademarks of Bristol-Myers Squibb Company. All
other trademarks are the property of their respective owners.
40
Reference ID: 3607428
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For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:46:56.483538
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/020156s051lbl.pdf', 'application_number': 20156, 'submission_type': 'SUPPL ', 'submission_number': 51}
|
12,285
|
NDA 20-164/S-036
Page 1
Rx only
Rev. ---
508539D
SPINAL / EPIDURAL HEMATOMAS
When neuraxial anesthesia (epidural/spinal anesthesia) or spinal puncture is employed, patients anticoagulated or scheduled
to be anticoagulated with low molecular weight heparins or heparinoids for prevention of thromboembolic complications
are at risk of developing an epidural or spinal hematoma which can result in long-term or permanent paralysis.
The risk of these events is increased by the use of indwelling epidural catheters for administration of analgesia or by the
concomitant use of drugs affecting hemostasis such as non steroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors,
or other anticoagulants. The risk also appears to be increased by traumatic or repeated epidural or spinal puncture.
Patients should be frequently monitored for signs and symptoms of neurological impairment. If neurologic compromise is
noted, urgent treatment is necessary.
The physician should consider the potential benefit versus risk before neuraxial intervention in patients anticoagulated or to
be anticoagulated for thromboprophylaxis (see also WARNINGS, Hemorrhage, and PRECAUTIONS, Drug
Interactions).
DESCRIPTION
Lovenox Injection is a sterile solution containing enoxaparin sodium, a low molecular weight heparin.
Lovenox Injection is available in two concentrations:
1 100mg per mL of Water for Injection
-Prefilled Syringes
30 mg / 0.3 mL, 40mg / 0.4 mL
-Graduated Prefilled Syringes 60 mg / 0.6 mL, 80 mg/ 0.8 mL, 100 mg / 1 mL
-Ampules
30 mg / 0.3 mL
Lovenox injection 100 mg/mL Concentration contains 10 mg enoxaparin sodium (or approximate anti-Factor Xa activity
of 1000 IU [with reference to the W.H.O. First International Low Molecular Weight Heparin Reference Standard]) per 0.1
mL Water for Injection.
2 150 mg per mL of Water for Injection
-Graduated Prefilled Syringes 90 mg /0.6 mL, 120 mg / 0.8 mL, 150 mg / 1 mL
Lovenox Injection 150 mg/mL Concentration contains 15 mg enoxaparin sodium (or appropriate anti-Factor Xa activity
of 1500 IU [with reference to the W.H.O. First International Low Molecular Weight Heparin Reference Standard]) per 0.1
mL Water for Injection.
The solutions are preservative-free and intended for use only as a single-dose injection. (See DOSAGE AND
ADMINISTRATION and HOW SUPPLIED for dosage unit descriptions.) The pH of the injection is 5.5 to 7.5. Nitrogen
is used in the headspace to inhibit oxidation.
Enoxaparin is obtained by alkaline degradation of heparin benzyl ester derived from porcine intestinal mucosa. Its structure
is characterized by a 2-O-sulfo-4-enepyranosuronic acid group at the non-reducing end and a 2-N,6-O-disulfo-D-
glucosamine at the reducing end of the chain. The substance is the sodium salt. The average molecular weight is about 4500
daltons. The molecular weight distribution is:
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NDA 20-164/S-036
Page 2
<2000 daltons
≤20%
2000 to 8000 daltons
≥68%
>8000 daltons
≤18%
STRUCTURAL FORMULA
CLINICAL PHARMACOLOGY
Enoxaparin is a low molecular weight heparin which has antithrombotic properties. In humans, enoxaparin given at a dose
of 1.5 mg/kg subcutaneously (SC) is characterized by a higher ratio of anti-Factor Xa to anti-Factor IIa activity (mean±SD,
14.0±3.1) (based on areas under anti-Factor activity versus time curves) compared to the ratios observed for heparin
(mean±SD, 1.22±0.13). Increases of up to 1.8 times the control values were seen in the thrombin time (TT) and the
activated partial thromboplastin time (aPTT). Enoxaparin at a 1 mg/kg dose (100 mg / mL concentration), administered SC
every 12 hours to patients in a large clinical trial resulted in aPTT values of 45 seconds or less in the majority of patients (n
= 1607).
Pharmacodynamics (conducted using 100 mg / mL concentration): Maximum anti-Factor Xa and anti-thrombin (anti-
Factor IIa) activities occur 3 to 5 hours after SC injection of enoxaparin. Mean peak anti-Factor Xa activity was 0.16 IU/mL
(1.58 µg/mL) and 0.38 IU/mL (3.83 µg/mL) after the 20 mg and the 40 mg clinically tested SC doses, respectively. Mean
(n = 46) peak anti-Factor Xa activity was 1.1 IU/mL at steady state in patients with unstable angina receiving 1mg/kg SC
every 12 hours for 14 days. Mean absolute bioavailability of enoxaparin, given SC, based on anti-Factor Xa activity is 92%
in healthy volunteers. The volume of distribution of anti-Factor Xa activity is about 6 L. Following intravenous (i.v.)
dosing, the total body clearance of enoxaparin is 26 mL/min. After i.v. dosing of enoxaparin labeled with the gamma-
emitter, 99mTc, 40% of radioactivity and 8 to 20% of anti-Factor Xa activity were recovered in urine in 24 hours.
Elimination half-life based on anti-Factor Xa activity was 4.5 hours after SC administration. Following a 40 mg SC once a
day dose, significant anti-Factor Xa activity persists in plasma for about 12 hours.
Following SC dosing, the apparent clearance (CL/F) of enoxaparin is approximately 15 mL/min. Apparent clearance and
Amax derived from anti-Factor Xa values following single SC dosing (40 mg and 60 mg) were slightly higher in males than
in females. The source of the gender difference in these parameters has not been conclusively identified, however, body
weight may be a contributing factor.
Apparent clearance and Amax derived from anti-Factor Xa values following single and multiple SC dosing in elderly
subjects were close to those observed in young subjects. Following once a day SC dosing of 40 mg enoxaparin, the Day 10
mean area under anti-Factor Xa activity versus time curve (AUC) was approximately 15% greater than the mean Day 1
AUC value. In subjects with moderate renal impairment (creatinine clearance 30 to 80 mL/min), anti-Factor Xa CL/F
values were similar to those in healthy subjects. However, mean CL/F values of subjects with severe renal impairment
(creatinine clearance <30 mL/min), were approximately 30% lower than the mean CL/F value of control group subjects.
(See PRECAUTIONS.)
Although not studied clinically, the 150 mg/mL concentration of enoxaparin sodium is projected to result in anticoagulant
activities similar to those of 100 mg/mL and 200 mg/mL concentrations at the same enoxaparin dose. When a daily 1.5
mg/kg SC injection of enoxaparin sodium was given to 25 healthy male and female subjects using a 100 mg/ml or a 200
mg/mL concentration the following pharmacokinetic profiles were obtained (see table below):
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NDA 20-164/S-036
Page 3
Pharmacokinetic Parameters* After 5 Days of 1.5 mg/kg SC Once Daily Doses of
Enoxaparin Sodium Using 100 mg/mL or 200 mg/mL Concentrations
Concentration
Anti-Xa
Anti-IIa
Heptest
aPTT
Amax
(IU/mL or ∆
sec)
100 mg/mL
1.37 (±0.23)
0.23 (±0.05)
104.5 (±16.6)
19.3 (±4.7)
200 mg/mL
1.45 (±0.22)
0.26 (±0.05)
110.9 (±17.1)
22 (±6.7)
90% CI
102-110%
102-111%
tmax** (h)
100 mg/mL
3 (2-6)
4 (2-5)
2.5 (2-4.5)
3 (2-4.5)
200 mg/mL
3.5 (2-6)
4.5 (2.5-6)
3.3 (2-5)
3 (2-5)
AUC (ss)
(h*IU/mL or h*
∆ sec)
100 mg/mL
14.26 (±2.93)
1.54 (±0.61)
1321 (±219)
200 mg/mL
15.43 (±2.96)
1.77 (±0.67)
1401 (±227)
90% CI
105-112%
103-109%
*Means ± SD at Day 5 and 90% Confidence Interval (CI) of the ratio
**Median (range)
CLINICAL TRIALS
Prophylaxis of Deep Vein Thrombosis Following Abdominal Surgery in Patients at Risk for Thromboembolic
Complications: Abdominal surgery patients at risk include those who are over 40 years of age, obese, undergoing surgery
under general anesthesia lasting longer than 30 minutes or who have additional risk factors such as malignancy or a history
of deep vein thrombosis or pulmonary embolism.
In a double-blind, parallel group study of patients undergoing elective cancer surgery of the gastrointestinal, urological, or
gynecological tract, a total of 1116 patients were enrolled in the study, and 1115 patients treated. Patients ranged in age
from 32 to 97 years (mean age 67 years) with 52.7% men and 47.3% women. Patients were 98% Caucasian, 1.1% Black,
0.4% Oriental, 0.4% others. Lovenox Injection 40 mg SC, administered once a day, beginning 2 hours prior to surgery and
continuing for a maximum of 12 days after surgery, was comparable to heparin 5000 U every 8 hours SC in reducing the
risk of deep vein thrombosis (DVT). The efficacy data are provided below.
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NDA 20-164/S-036
Page 4
Efficacy of Lovenox Injection in the Prophylaxis of Deep Vein Thrombosis Following Abdominal Surgery
Dosing Regimen
Indication
Lovenox Inj.
40 mg q.d. SC
n (%)
Heparin
5000 U q8h SC
n (%)
All Treated Abdominal
Surgery Patients
555 (100)
560 (100)
Treatment Failures
Total VTE1 (%)
56 (10.1)
(95% CI2: 8 to 13)
63 (11.3)
(95% CI: 9 to 14)
DVT Only (%)
54 (9.7)
(95% CI: 7 to 12)
61 (10.9)
(95% CI: 8 to 13)
1 VTE = Venous thromboembolic events which included DVT, PE, and death considered to be thromboembolic in origin.
2 CI = Confidence Interval
In a second double-blind, parallel group study, Lovenox Injection 40 mg SC once a day was compared to heparin 5000 U
every 8 hours SC in patients undergoing colorectal surgery (one-third with cancer). A total of 1347 patients were
randomized in the study and all patients were treated. Patients ranged in age from 18 to 92 years (mean age 50.1 years)
with 54.2% men and 45.8% women. Treatment was initiated approximately 2 hours prior to surgery and continued for
approximately 7 to 10 days after surgery. The efficacy data are provided below.
Efficacy of Lovenox Injection in the Prophylaxis of Deep Vein Thrombosis Following Colorectal Surgery
Dosing Regimen
Indication
Lovenox Inj.
40 mg q.d. SC
n (%)
Heparin
5000 U q8h SC
n (%)
All Treated Colorectal Surgery
Patients
673 (100)
674 (100)
Treatment Failures
Total VTE1 (%)
48 (7.1)
(95% CI2: 5 to 9)
45 (6.7)
(95% CI: 5 to 9)
DVT Only (%)
47 (7.0)
(95% CI: 5 to 9)
44 (6.5)
(95% CI: 5 to 8)
1 VTE = Venous thromboembolic events which included DVT, PE, and death considered to be thromboembolic in origin.
2 CI = Confidence Interval
Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery: Lovenox Injection has been
shown to reduce the risk of post-operative deep vein thrombosis (DVT) following hip or knee replacement surgery.
In a double-blind study, Lovenox Injection 30 mg every 12 hours SC was compared to placebo in patients with hip
replacement. A total of 100 patients were randomized in the study and all patients were treated. Patients ranged in age from
41 to 84 years (mean age 67.1 years) with 45 % men and 55 % women. After hemostasis was established, treatment was
initiated 12 to 24 hours after surgery and was continued for 10 to 14 days after surgery. The efficacy data are provided
below.
Efficacy of Lovenox Injection in the Prophylaxis of Deep Vein Thrombosis Following Hip Replacement Surgery
Dosing Regimen
Indication
Lovenox Inj.
30 mg q12h SC
n (%)
Placebo
q12h SC
n (%)
All Treated Hip Replacement Patients
50 (100)
50 (100)
Treatment Failures
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NDA 20-164/S-036
Page 5
Total DVT (%)
5 (10)1
23 (46)
Proximal DVT (%)
1 (2)2
11 (22)
1 p value versus placebo = 0.0002
2 p value versus placebo = 0.0134
A double-blind, multicenter study compared three dosing regimens of Lovenox Injection in patients with hip replacement.
A total of 572 patients were randomized in the study and 568 patients were treated. Patients ranged in age from 31 to 88
years (mean age 64.7 years) with 63% men and 37% women. Patients were 93% Caucasian, 6% Black, <1% Oriental, 1%
others. Treatment was initiated within two days after surgery and was continued for 7 to 11 days after surgery. The efficacy
data are provided below.
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NDA 20-164/S-036
Page 6
Efficacy of Lovenox Injection in the Prophylaxis of Deep Vein Thrombosis Following Hip Replacement Surgery
Lovenox Dosing Regimen
Indication
10 mg q.d. SC
n (%)
30 mg q12h SC
n (%)
40 mg q.d. SC
n (%)
All Treated Hip
Replacement Patients
161 (100)
208 (100)
199 (100)
Treatment Failures
Total DVT (%)
40 (25)
22 (11)1
27 (14)
Proximal DVT (%)
17 (11)
8 (4)2
9 (5)
1 p value versus Lovenox 10 mg once a day = 0.0008
2 p value versus Lovenox 10 mg once a day = 0.0168
There was no significant difference between the 30 mg every 12 hours and 40 mg once a day regimens.
In a double-blind study, Lovenox Injection 30 mg every 12 hours SC was compared to placebo in patients undergoing knee
surgery. A total of 132 patients were randomized in the study and 131 patients were treated, of which 99 had total knee
replacement and 32 had either unicompartmental knee replacement or tibial osteotomy. The 99 patients with total knee
replacement ranged in age from 42 to 85 years (mean age 70.2 years) with 36.4% men and 63.6% women. After
hemostasis was established, treatment was initiated 12 to 24 hours after surgery and was continued up to 15 days after
surgery. The incidence of proximal and total DVT after surgery was significantly lower for enoxaparin compared to
placebo. The efficacy data are provided below.
Efficacy of Lovenox Injection in the Prophylaxis of Deep Vein Thrombosis Following Total Knee Replacement
Surgery
Dosing Regimen
Indication
Lovenox Inj.
30 mg q12h SC
n (%)
Placebo
q12h SC
n (%)
All Treated Total Knee
Replacement Patients
47 (100)
52 (100)
Treatment Failures
Total DVT (%)
5 (11)1
(95% CI2: 1 to 21)
32 (62)
(95% CI: 47 to 76)
Proximal DVT (%)
0 (0)3
(95% Upper CL4: 5)
7 (13)
(95% CI: 3 to 24)
1 p value versus placebo = 0.0001
2 CI = Confidence Interval
3 p value versus placebo = 0.013
4 CL = Confidence Limit
Additionally, in an open-label, parallel group, randomized clinical study, Lovenox Injection 30 mg every 12 hours SC in
patients undergoing elective knee replacement surgery was compared to heparin 5000 U every 8 hours SC. A total of 453
patients were randomized in the study and all were treated. Patients ranged in age from 38 to 90 years (mean age 68.5
years) with 43.7% men and 56.3% women. Patients were 92.5% Caucasian, 5.3% Black, 0.2% Oriental, 0.4% others.
Treatment was initiated after surgery and continued up to 14 days. The incidence of deep vein thrombosis was significantly
lower for enoxaparin compared to heparin.
Extended Prophylaxis of Deep Vein Thrombosis Following Hip Replacement Surgery: In a study of extended prophylaxis
for patients undergoing hip replacement surgery, patients were treated, while hospitalized, with enoxaparin 40 mg SC,
initiated up to 12 hours prior to surgery for the prophylaxis of post-operative DVT. At the end of the peri-operative period,
all patients underwent bilateral venography. In a double-blind design, those patients with no venous thromboembolic
disease were randomized to a post-discharge regimen of either enoxaparin 40 mg (n = 90) once a day SC or to placebo (n =
89) for 3 weeks. A total of 179 patients were randomized in the double-blind phase of the study and all patients were
treated. Patients ranged in age from 47 to 87 years (mean age 69.4 years) with 57 % men and 43 % women. In this
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NDA 20-164/S-036
Page 7
population of patients, the incidence of DVT during extended prophylaxis was significantly lower for enoxaparin compared
to placebo. The efficacy data are provided below.
Efficacy of Lovenox Injection in the Extended Prophylaxis of Deep Vein Thrombosis Following Hip Replacement
Surgery
Post-Discharge Dosing Regimen
Indication (Post-Discharge)
Lovenox Inj.
40 mg q.d. SC
n (%)
Placebo
q.d. SC
n (%)
All Treated Extended
Prophylaxis Patients
90 (100)
89 (100)
Treatment Failures
Total DVT (%)
6 (7)1
(95% CI2: 3 to 14)
18 (20)
(95% CI: 12 to 30)
Proximal DVT (%)
5 (6)3
(95% CI: 2 to 13)
7 (8)
(95% CI: 3 to 16)
1 p value versus placebo = 0.008
2 CI= Confidence Interval
3 p value versus placebo = 0.537
In a second study, patients undergoing hip replacement surgery were treated, while hospitalized, with Lovenox Injection 40
mg SC, initiated up to 12 hours prior to surgery. All patients were examined for clinical signs and symptoms of venous
thromboembolic (VTE) disease. In a double-blind design, patients without clinical signs and symptoms of VTE disease
were randomized to a post-discharge regimen of either Lovenox Injection 40 mg (n = 131) once a day SC or to placebo (n =
131) for 3 weeks. A total of 262 patients were randomized in the study double-blind phase and all patients were treated.
Patients ranged in age from 44 to 87 years (mean age 68.5 years) with 43.1 % men and 56.9 % women. Similar to the first
study the incidence of DVT during extended prophylaxis was significantly lower for Lovenox Injection compared to
placebo, with a statistically significant difference in both total DVT (Lovenox Injection 21 [16%] versus placebo 45 [34%];
p = 0.001) and proximal DVT (Lovenox Injection 8 [6%] versus placebo 28 [21%]; p = <0.001).
Prophylaxis of Deep Vein Thrombosis (DVT) In Medical Patients with Severely Restricted Mobility During Acute
Illness: In a double blind multicenter, parallel group study, Lovenox Injection 20 mg or 40 mg once a day SC was
compared to placebo in the prophylaxis of DVT in medical patients with severely restricted mobility during acute illness
(defined as walking distance of <10 meters for ≤3 days). This study included patients with heart failure (NYHA Class III or
IV); acute respiratory failure or complicated chronic respiratory insufficiency (not requiring ventilatory support): acute
infection (excluding septic shock); or acute rheumatic disorder [acute lumbar or sciatic pain, vertebral compression (due to
osteoporosis or tumor), acute arthritic episodes of the lower extremities]. A total of 1102 patients were enrolled in the
study, and 1073 patient treated. Patients ranged in age from 40 to 97 years (mean age 73 years) with equal proportions of
men and women. Treatment continued for a maximum of 14 days (median duration 7 days). When given at a dose of 40
mg once a day SC, Lovenox Injection significantly reduced the incidence of DVT as compared to placebo. The efficacy
data are provided below.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-164/S-036
Page 8
Efficacy of Lovenox Injection in the Prophylaxis of Deep Vein Thrombosis in Medical Patients With
Severely Restricted Mobility During Acute Illness
Dosing Regimen
Indication
Lovenox Inj.
20 mg q.d. SC
n (%)
Lovenox Inj.
40 mg q.d. SC
n (%)
Placebo
n (%)
All Treated Medical Patients
During Acute Illness
351(100)
360 (100)
362 (100)
Treatment Failure1
Total VTE2 (%)
43 (12.3)
16 (4.4)
43(11.9)
Total DVT (%)
43 (12.3)
(95% CI3 8.8 to 15.7)
16 (4.4)
(95% CI3 2.3 to 6.6 )
41 (11.3)
(95% CI3 8.1 to 14.6 )
Proximal DVT (%)
13 (3.7)
5 (1.4)
14 (3.9)
1 Treatment failures during therapy, between Days 1 and 14.
2 VTE = Venous thromboembolic events which included DVT, PE, and death considered to be thromboembolic in origin.
3 CI = Confidence Interval
At approximately 3 months following enrollment, the incidence of venous thromboembolism remained significantly lower
in the Lovenox Injection 40 mg treatment group versus the placebo treatment group.
Prophylaxis of Ischemic Complications in Unstable Angina and Non-Q-Wave Myocardial Infarction: In a
multicenter, double-blind, parallel group study, patients who recently experienced unstable angina or non-Q-wave
myocardial infarction were randomized to either Lovenox Injection 1 mg/kg every 12 hours SC or heparin i.v. bolus (5000
U) followed by a continuous infusion (adjusted to achieve an aPTT of 55 to 85 seconds). A total of 3171 patients were
enrolled in the study, and 3107 patients were treated. Patients ranged in age from 25-94 years (median age 64 years), with
33.4% of patients female and 66.6% male. Race was distributed as follows: 89.8% Caucasian, 4.8% Black, 2.0% Oriental,
and 3.5% other. All patients were also treated with aspirin 100 to 325 mg per day. Treatment was initiated within 24 hours
of the event and continued until clinical stabilization, revascularization procedures, or hospital discharge, with a maximal
duration of 8 days of therapy. The combined incidence of the triple endpoint of death, myocardial infarction, or recurrent
angina was lower for Lovenox Injection compared with heparin therapy at 14 days after initiation of treatment. The lower
incidence of the triple endpoint was sustained up to 30 days after initiation of treatment. These results were observed in an
analysis of both all-randomized and all-treated patients. The efficacy data are provided below.
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NDA 20-164/S-036
Page 9
Efficacy of Lovenox Injection in the Prophylaxis of Ischemic Complications in Unstable Angina and Non-Q-Wave
Myocardial Infarction
(Combined Endpoint of Death, Myocardial Infarction, or Recurrent Angina)
Dosing Regimen1
Indication
Lovenox Inj.
1 mg/kg q12h SC
n (%)
Heparin
aPTT Adjusted
i.v. Therapy
n (%)
Reduction
(%)
p Value
All Treated Unstable
Angina and Non-Q-Wave
MI Patients
1578 (100)
1529 (100)
Timepoint2
48 Hours
96 (6.1)
112 (7.3)
1.2
0.120
14 Days
261 (16.5)
303 (19.8)
3.3
0.017
30 Days
313 (19.8)
358 (23.4)
3.6
0.014
1 All patients were also treated with aspirin 100 to 325 mg per day.
2 Evaluation timepoints are after initiation of treatment. Therapy continued for up to 8 days (median duration of 2.6 days).
The combined incidence of death or myocardial infarction at all time points was lower for Lovenox Injection compared to
standard heparin therapy, but did not achieve statistical significance. The efficacy data are provided below.
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NDA 20-164/S-036
Page 10
Efficacy of Lovenox Injection in the Prophylaxis of Ischemic Complications in Unstable Angina and Non-Q-Wave
Myocardial Infarction
(Combined Endpoint of Death or Myocardial Infarction)
Dosing Regimen1
Indication
Lovenox Inj.
1 mg/kg q12h SC
n (%)
Heparin
aPTT Adjusted
i.v. Therapy
n (%)
Reduction
(%)
p Value
All Treated Unstable
Angina and Non-Q-Wave
MI Patients
1578 (100)
1529 (100)
Timepoint2
48 Hours
16 (1.0)
20 (1.3)
0.3
0.126
14 Days
76 (4.8)
93 (6.1)
1.3
0.115
30 Days
96 (6.1)
118 (7.7)
1.6
0.069
1 All patients were also treated with aspirin 100 to 325 mg per day.
2 Evaluation timepoints are after initiation of treatment. Therapy continued for up to 8 days (median duration of 2.6 days).
In a survey one year following treatment, with information available for 92% of enrolled patients, the combined incidence
of death, myocardial infarction, or recurrent angina remained lower for enoxaparin versus heparin (32.0% vs 35.7%)
Urgent revascularization procedures were performed less frequently in the Lovenox Injection group as compared to the
heparin group, 6.3% compared to 8.2% at 30 days (p = 0.047).
Treatment of Deep Vein Thrombosis With or Without Pulmonary Embolism (PE): In a multicenter, parallel group
study, 900 patients with acute lower extremity deep vein thrombosis (DVT) with or without (PE) were randomized to an
inpatient (hospital) treatment of either (i) Lovenox Injection 1.5 mg/kg once a day SC, (ii) Lovenox Injection 1mg/kg every
12 hours SC, or (iii) heparin i.v. bolus (5000 IU) followed by a continuous infusion (administered to achieve an aPTT of 55
to 85 seconds). A total of 900 patients were randomized in the study and all patients were treated. Patients ranged in age
from 18 to 92 years (mean age 60.7 years) with 54.7 % men and 45.3 % women. All patients also received warfarin
sodium (dose adjusted according to PT to achieve an International Normalization Ratio [INR] of 2.0 to 3.0), commencing
within 72 hours of initiation of Lovenox Injection or standard heparin therapy, and continuing for 90 days. Lovenox
Injection or standard heparin therapy was administered for a minimum of 5 days and until the targeted warfarin sodium
INR was achieved. Both Lovenox Injection regimens were equivalent to standard heparin therapy in reducing the risk of
recurrent venous thromboembolism (DVT and/or PE). The efficacy data are provided below.
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NDA 20-164/S-036
Page 11
Efficacy of Lovenox Injection in Treatment of Deep Vein Thrombosis
With or Without Pulmonary Embolism
Dosing Regimen1
Indication
Lovenox Inj.
1.5 mg/kg q.d. SC
n (%)
Lovenox Inj.
1 mg/kg q12h SC
n (%)
Heparin
APTT Adjusted
i.v. Therapy
n (%)
All Treated DVT Patients
with or without PE
298 (100)
312 (100)
290 (100)
Patient Outcome
Total VTE2 (%)
13 (4.4)3
9 (2.9) 3
12 (4.1)
DVT Only (%)
11 (3.7)
7 (2.2)
8 (2.8)
Proximal DVT (%)
9 (3.0)
6 (1.9)
7 (2.4)
PE (%)
2 (0.7)
2 (0.6)
4 (1.4)
1 All patients were also treated with warfarin sodium commencing within 72 hours of Lovenox Injection or standard heparin
therapy.
2 VTE = venous thromboembolic event (DVT and/or PE).
3 The 95% Confidence Intervals for the treatment differences for total VTE were:
Lovenox Injection once a day versus heparin (-3.0 to 3.5)
Lovenox Injection every 12 hours versus heparin (-4.2 to 1.7).
Similarly, in a multicenter, open-label, parallel group study, patients with acute proximal DVT were randomized to
Lovenox Injection or heparin. Patients who could not receive outpatient therapy were excluded from entering the study.
Outpatient exclusion criteria included the following: inability to receive outpatient heparin therapy because of associated
co-morbid conditions or potential for non-compliance and inability to attend follow-up visits as an outpatient because of
geographic inaccessibility. Eligible patients could be treated in the hospital, but ONLY Lovenox Injection patients were
permitted to go home on therapy (72%). A total of 501 patients were randomized in the study and all patients were treated.
Patients ranged in age from 19 to 96 years (mean age 57.8 years) with 60.5 % men and 39.5 % women. Patients were
randomized to either Lovenox Injection 1 mg/kg every 12 hours SC or heparin i.v. bolus (5000 IU) followed by a
continuous infusion administered to achieve an aPTT of 60 to 85 seconds (in-patient treatment). All patients also received
warfarin sodium as described in the previous study. Lovenox Injection or standard heparin therapy was administered for a
minimum of 5 days. Lovenox Injection was equivalent to standard heparin therapy in reducing the risk of recurrent venous
thromboembolism. The efficacy data are provided below.
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Page 12
Efficacy of Lovenox Injection in Treatment of Deep Vein Thrombosis
Dosing Regimen1
Indication
Lovenox Inj.
1 mg/kg q12h SC
n (%)
Heparin
aPTT Adjusted
i.v. Therapy
n (%)
All Treated DVT Patients
247 (100)
254 (100)
Patient Outcome
Total VTE2 (%)
13 (5.3) 3
17 (6.7)
DVT Only (%)
11 (4.5)
14 (5.5)
Proximal DVT (%)
10 (4.0)
12 (4.7)
PE (%)
2 (0.8)
3 (1.2)
1 All patients were also treated with warfarin sodium commencing on the evening of the second day of Lovenox Injection or
standard heparin therapy.
2 VTE = venous thromboembolic event (DVT and/or PE).3 The 95% Confidence Intervals for the treatment difference for
total VTE was: Lovenox Injection versus heparin (-5.6 to 2.7).
INDICATIONS AND USAGE
• Lovenox Injection is indicated for the prophylaxis of deep vein thrombosis, which may lead to pulmonary embolism:
• in patients undergoing abdominal surgery who are at risk for
thromboembolic complications;
• in patients undergoing hip replacement surgery, during and following
hospitalization;
• in patients undergoing knee replacement surgery;
• in medical patients who are at risk for thromboembolic complications
due to severely restricted mobility during acute illness.
• Lovenox Injection is indicated for the prophylaxis of ischemic complications of unstable angina and non-Q-wave
myocardial infarction, when concurrently administered with aspirin.
• Lovenox Injection is indicated for:
• the inpatient treatment of acute deep vein thrombosis with or
without pulmonary embolism, when administered in conjunction
with warfarin sodium;
• the outpatient treatment of acute deep vein thrombosis without
pulmonary embolism when administered in conjunction with warfarin
sodium.
See DOSAGE AND ADMINISTRATION: Adult Dosage for appropriate dosage regimens.
CONTRAINDICATIONS
Lovenox Injection is contraindicated in patients with active major bleeding, in patients with thrombocytopenia associated
with a positive in vitro test for anti-platelet antibody in the presence of enoxaparin sodium, or in patients with
hypersensitivity to enoxaparin sodium.
Patients with known hypersensitivity to heparin or pork products should not be treated with Lovenox Injection.
WARNINGS
Lovenox Injection is not intended for intramuscular administration.
Lovenox Injection cannot be used interchangeably (unit for unit) with heparin or other low molecular weight heparins as
they differ in manufacturing process, molecular weight distribution, anti-Xa and anti-IIa activities, units, and dosage. Each
of these medicines has its own instructions for use.
Lovenox Injection should be used with extreme caution in patients with a history of heparin-induced
thrombocytopenia.
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Page 13
Hemorrhage: Lovenox Injection, like other anticoagulants, should be used with extreme caution in conditions with
increased risk of hemorrhage, such as bacterial endocarditis, congenital or acquired bleeding disorders, active ulcerative
and angiodysplastic gastrointestinal disease, hemorrhagic stroke, or shortly after brain, spinal, or ophthalmological surgery,
or in patients treated concomitantly with platelet inhibitors.
Cases of epidural or spinal hematomas have been reported with the associated use of enoxaparin and spinal/epidural
anesthesia or spinal puncture resulting in long-term or permanent paralysis. The risk of these events is higher with
the use of post-operative indwelling epidural catheters or by the concomitant use of additional drugs affecting
hemostasis such as NSAIDs (see boxed WARNING; ADVERSE REACTIONS, Ongoing Safety Surveillance; and
PRECAUTIONS, Drug Interactions).
Major hemorrhages including retroperitoneal and intracranial bleeding have been reported. Some of these cases have been
fatal.
Bleeding can occur at any site during therapy with enoxaparin. An unexplained fall in hematocrit or blood pressure should
lead to a search for a bleeding site.
Thrombocytopenia: Thrombocytopenia can occur with the administration of Lovenox Injection.
Moderate thrombocytopenia (platelet counts between 100,000/mm3 and 50,000/mm3) occurred at a rate of 1.3% in patients
given Lovenox Injection, 1.2% in patients given heparin, and 0. 7% in patients given placebo in clinical trials.
Platelet counts less than 50,000/mm3 occurred at a rate of 0.1% in patients given Lovenox Injection, in 0.2% of patients
given heparin, and 0.4% of patients given placebo in the same trials.
Thrombocytopenia of any degree should be monitored closely. If the platelet count falls below 100,000/mm3, enoxaparin
should be discontinued. Cases of heparin-induced thrombocytopenia with thrombosis have also been observed in clinical
practice. Some of these cases were complicated by organ infarction, limb ischemia, or death.
PRECAUTIONS
General: Lovenox Injection should not be mixed with other injections or infusions.
Lovenox Injection should be used with care in patients with a bleeding diathesis, uncontrolled arterial hypertension or a
history of recent gastrointestinal ulceration, diabetic retinopathy, and hemorrhage. Elderly patients and patients with renal
insufficiency may show delayed elimination of enoxaparin. Enoxaparin should be used with care in these patients.
Adjustment of enoxaparin sodium dose may be considered for low weight (<45 kg) patients and/or for patients with severe
renal impairment (creatinine clearance <30mL/min).
If thromboembolic events occur despite enoxaparin prophylaxis, appropriate therapy should be initiated.
Laboratory Tests: Periodic complete blood counts, including platelet count, and stool occult blood tests are recommended
during the course of treatment with Lovenox Injection. When administered at recommended prophylaxis doses, routine
coagulation tests such as Prothrombin Time (PT) and Activated Partial Thromboplastin Time (aPTT) are relatively
insensitive measures of Lovenox Injection activity and, therefore, unsuitable for monitoring. Anti-Factor Xa may be used to
monitor the anticoagulant effect of Lovenox Injection in patients with significant renal impairment. If during Lovenox
Injection therapy abnormal coagulation parameters or bleeding should occur, anti-Factor Xa levels may be used to monitor
the anticoagulant effects of Lovenox Injection (see CLINICAL PHARMACOLOGY: Pharmacodynamics).
Drug Interactions: Unless really needed, agents which may enhance the risk of hemorrhage should be discontinued prior
to initiation of Lovenox Injection therapy. These agents include medications such as: anticoagulants, platelet inhibitors
including acetylsalicylic acid, salicylates, NSAIDs (including ketorolac tromethamine), dipyridamole, or sulfinpyrazone. If
co-administration is essential, conduct close clinical and laboratory monitoring (see PRECAUTIONS: Laboratory Tests).
Carcinogenesis, Mutagenesis, Impairment of Fertility: No long-term studies in animals have been performed to evaluate
the carcinogenic potential of enoxaparin. Enoxaparin was not mutagenic in in vitro tests, including the Ames test, mouse
lymphoma cell forward mutation test, and human lymphocyte chromosomal aberration test, and the in vivo rat bone marrow
chromosomal aberration test. Enoxaparin was found to have no effect on fertility or reproductive performance of male and
female rats at SC doses up to 20 mg/kg/day or 141 mg/m2/day. The maximum human dose in clinical trials was 2.0
mg/kg/day or 78 mg/m2/day (for an average body weight of 70 kg, height of 170 cm, and body surface area of 1.8 m2).
Pregnancy: Teratogenic Effects: Pregnancy Category B: Teratology studies have been conducted in pregnant rats and
rabbits at SC doses of enoxaparin up to 30 mg/kg/day or 211 mg/m2/day and 410 mg/m2/day, respectively. There was no
evidence of teratogenic effects or fetotoxicity due to enoxaparin. There are, however, no adequate and well-controlled
studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug
should be used during pregnancy only if clearly needed.
Non-teratogenic Effects: There have been a few spontaneous post-marketing reports of fetal death when pregnant women
received enoxaparin. Causality of the cases has not been determined. In one case, placental hemorrhage and detachment
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Page 14
were found in association with the fetal death. If enoxaparin is used during pregnancy, or if the patient becomes pregnant
while taking this drug, the patient should be apprised of the potential hazard to the fetus.
Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in
human milk, caution should be exercised when enoxaparin is administered to nursing women.
Pediatric Use: Safety and effectiveness of enoxaparin in pediatric patients have not been established.
Geriatric Use: Over 2800 patients, 65 years and older, have received enoxaparin sodium in pivotal clinical trials. The
efficacy of Lovenox Injection in the elderly (≥65 years) was similar to that seen in younger patients (<65 years). The
incidence of bleeding complications was similar between elderly and younger patients when 30 mg every 12 hours or 40
mg once a day doses of Lovenox Injection were employed. The incidence of bleeding complications was higher in elderly
patients as compared to younger patients when Lovenox Injection was administered at doses of 1.5 mg/kg once a day or 1
mg/kg every 12 hours. The risk of Lovenox Injection-associated bleeding increased with age. Serious adverse events
increased with age for patients receiving Lovenox Injection. Other clinical experience (including postmarketing
surveillance and literature reports) has not revealed additional differences in the safety of Lovenox Injection between
elderly and younger patients. Careful attention to dosing intervals and concomitant medications (especially antiplatelet
medications) is advised. Monitoring of geriatric patients with low body weight (<45 kg) and those predisposed to
decreased renal function should be considered. (see CLINICAL PHARMACOLOGY and General and Laboratory
Tests subsections of PRECAUTIONS)
ADVERSE REACTIONS
Hemorrhage: The incidence of major hemorrhagic complications during Lovenox Injection treatment has been low.
The following rates of major bleeding events have been reported during clinical trials with Lovenox Injection.
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Page 15
Major Bleeding Episodes Following Abdominal and Colorectal Surgery1
Dosing Regimen
Indications
Lovenox Inj.
40 mg q.d. SC
Heparin
5000 U q8h SC
Abdominal Surgery
n = 555
23 (4%)
n = 560
16 (3%)
Colorectal Surgery
n = 673
28 (4%)
n = 674
21 (3%)
1 Bleeding complications were considered major: (1) if the hemorrhage caused a significant clinical event, or (2) if
accompanied by a hemoglobin decrease ≥2g/dL or transfusion of 2 or more units of blood products. Retroperitoneal,
intraocular, and intracranial hemorrhages were always considered major.
Major Bleeding Episodes Following Hip or Knee Replacement Surgery1
Dosing Regimen
Indications
Lovenox Inj.
40 mg q.d. SC
Lovenox Inj.
30 mg q12h SC
Heparin
15,000 U/24h SC
Hip Replacement Surgery
Without Extended Prophylaxis2
n = 786
31 (4%)
n = 541
32 (6%)
Hip Replacement Surgery
With Extended Prophylaxis
Peri-operative Period3
n = 288
4 (2%)
Extended Prophylaxis Period4
n = 221
0 (0%)
Knee Replacement Surgery
Without Extended Prophylaxis2
n = 294
3 (1%)
n = 225
3 (1%)
1 Bleeding complications were considered major: (1) if the hemorrhage caused a significant clinical event, or (2) if
accompanied by a hemoglobin decrease ≥2g/dL or transfusion of 2 or more units of blood products. Retroperitoneal and
intracranial hemorrhages were always considered major. In the knee replacement surgery trials, intraocular hemorrhages
were also considered major hemorrhages.
2 Lovenox Injection 30 mg every 12 hours SC initiated 12 to 24 hours after surgery and continued for up to 14 days after
surgery.
3 Lovenox Injection 40 mg SC once a day initiated up to 12 hours prior to surgery and continued for up to 7 days after
surgery.
4 Lovenox Injection 40 mg SC once a day for up to 21 days after discharge.
NOTE: At no time point were the 40 mg once a day pre-operative and the 30 mg every 12 hours post-operative hip
replacement surgery prophylactic regimens compared in clinical trials.
Injection site hematomas during the extended prophylaxis period after hip replacement surgery occurred in 9% of the
Lovenox Injection patients versus 1.8% of the placebo patients.
Major Bleeding Episodes in Medical Patients With Severely Restricted Mobility During Acute Illness1
Dosing Regimen
Indications
Lovenox Inj.2
20 mg q.d. SC
Lovenox Inj.2
40 mg q.d. SC
Placebo2
Medical Patients During
Acute Illness
n = 351
1 (<1%)
n = 360
3 (<1%)
n = 362
2 (<1%)
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Page 16
1 Bleeding complications were considered major: (1) if the hemorrhage caused a significant clinical event, (2) if the
hemorrhage caused a decrease in hemoglobin of ≥2g/dL or transfusion of 2 or more units of blood products.
Retroperitoneal and intracranial hemorrhages were always considered major although none were reported during the trial.
2 The rates represent major bleeding on study medication up to 24 hours after last dose.
Major Bleeding Episodes in Unstable Angina and
Non-Q-Wave Myocardial Infarction
Dosing Regimen
Indication
Lovenox Inj.1
1 mg/kg q12h SC
Heparin1
aPTT Adjusted
i.v. Therapy
Unstable Angina and
Non-Q-Wave MI2,3
n = 1578
17 (1%)
n = 1529
18 (1%)
1 The rates represent major bleeding on study medication up to 12 hours after dose.
2 Aspirin therapy was administered concurrently (100 to 325 mg per day).
3 Bleeding complications were considered major: (1) if the hemorrhage caused a significant clinical event, or (2) if
accompanied by a hemoglobin decrease by ≥3g/dL or transfusion of 2 or more units of blood products. Intraocular,
retroperitoneal, and intracranial hemorrhages were always considered major.
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Page 17
Major Bleeding Episodes in Deep Vein Thrombosis
With or Without Pulmonary Embolism Treatment 1
Dosing Regimen2
Indication
Lovenox Inj.
1.5 mg/kg q.d. SC
Lovenox Inj.
1 mg/kg q12h SC
Heparin
aPTT Adjusted
i.v. Therapy
Treatment of DVT and PE
N = 298
5 (2%)
N = 559
9 (2%)
n = 554
9 (2%)
1 Bleeding complications were considered major: (1) if the hemorrhage caused a significant clinical event, or (2) if
accompanied by a hemoglobin decrease ≥2 g/dL or transfusion of 2 or more units of blood products. Retroperitoneal,
intraocular, and intracranial hemorrhages were always considered major.
2 All patients also received warfarin sodium (dose-adjusted according to PT to achieve an INR of 2.0 to 3.0) commencing
within 72 hours of Lovenox Injection or standard heparin therapy and continuing for up to 90 days.
Thrombocytopenia: see WARNINGS: Thrombocytopenia.
Elevations of Serum Aminotransferases: Asymptomatic increases in aspartate (AST [SGOT]) and alanine (ALT [SGPT])
aminotransferase levels greater than three times the upper limit of normal of the laboratory reference range have been
reported in up to 6.1% and 5.9% of patients, respectively, during treatment with Lovenox Injection. Similar significant
increases in aminotransferase levels have also been observed in patients and healthy volunteers treated with heparin and
other low molecular weight heparins. Such elevations are fully reversible and are rarely associated with increases in
bilirubin.
Since aminotransferase determinations are important in the differential diagnosis of myocardial infarction, liver disease,
and pulmonary emboli, elevations that might be caused by drugs like Lovenox Injection should be interpreted with caution.
Local Reactions: Mild local irritation, pain, hematoma, ecchymosis, and erythema may follow SC injection of Lovenox
Injection.
Other: Other adverse effects that were thought to be possibly or probably related to treatment with Lovenox Injection,
heparin, or placebo in clinical trials with patients undergoing hip or knee replacement surgery, abdominal or colorectal
surgery, or treatment for DVT and that occurred at a rate of at least 2% in the Lovenox Injection group, are provided below.
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Page 18
Adverse Events Occurring at ≥≥2% Incidence in Lovenox Injection Treated Patients1 Undergoing Abdominal or
Colorectal Surgery
Dosing Regimen
Lovenox Inj.
40 mg q.d. SC
n = 1228
Heparin
5000 U q8h SC
n = 1234
Adverse Event
Severe
Total
Severe
Total
Hemorrhage
<1%
7%
<1%
6%
Anemia
<1%
3%
<1%
3%
Ecchymosis
0%
3%
0%
3%
1 Excluding unrelated adverse events.
Adverse Events Occurring at ≥≥2% Incidence in Lovenox Injection Treated Patients1 Undergoing Hip or Knee
Replacement Surgery
Dosing Regimen
Lovenox Inj.
40 mg q.d. SC
Lovenox Inj.
30 mg q12h
SC
Heparin
15,000 U/24h
SC
Placebo
q12h SC
Peri-operative
Period
n = 288 2
Extended
Prophylaxis
Period
n = 131 3
n = 1080
n = 766
n = 115
Adverse Event
Severe Total
Severe Total
Severe Total
Severe Total
Severe Total
Fever
0%
8%
0%
0%
<1%
5%
<1%
4%
0%
3%
Hemorrhage
<1%
13%
0%
5%
<1%
4%
1%
4%
0%
3%
Nausea
<1%
3%
<1%
2%
0%
2%
Anemia
0%
16%
0%
<2%
<1%
2%
2%
5%
<1%
7%
Edema
<1%
2%
<1%
2%
0%
2%
Peripheral edema
0%
6%
0%
0%
<1%
3%
<1%
4%
0%
3%
1 Excluding unrelated adverse events.
2 Data represents Lovenox Injection 40 mg SC once a day initiated up to 12 hours prior to surgery in 288 hip replacement
surgery patients who received Lovenox Injection peri-operatively in an unblinded fashion in one clinical trial.
3 Data represents Lovenox Injection 40 mg SC once a day given in a blinded fashion as extended prophylaxis at the end of
the peri-operative period in 131 of the original 288 hip replacement surgery patients for up to 21 days in one clinical trial.
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Page 19
Adverse Events Occurring at ≥≥2% Incidence in Lovenox Injection Treated Medical Patients1 With Severely
Restricted Mobility During Acute Illness1
Dosing Regimen
Lovenox Inj.
40 mg q.d. SC
n = 360
Placebo
q.d. SC
n = 362
Adverse Event
%
%
Dyspnea
3.3
5.2
Thrombocytopenia
2.8
2.8
Confusion
2.2
1.1
Diarrhea
2.2
1.7
Nausea
2.5
1.7
1 Excluding unrelated and unlikely adverse events.
Adverse Events in Lovenox Injection Treated Patients With Unstable Angina or Non-Q-Wave Myocardial
Infarction: Non-hemorrhagic clinical events reported to be related to Lovenox Injection therapy occurred at an incidence
of ≤1%.
Non-major hemorrhagic episodes, primarily injection site ecchymoses and hematomas, were more frequently reported in
patients treated with SC Lovenox Injection than in patients treated with i.v. heparin.
Serious adverse events with Lovenox Injection or heparin in a clinical trial in patients with unstable angina or non-Q-wave
myocardial infarction that occurred at a rate of at least 0.5% in the Lovenox Injection group, are provided below
(irrespective of relationship to drug therapy).
Serious Adverse Events Occurring at ≥≥0.5% Incidence in Lovenox Injection Treated Patients With Unstable Angina
or Non-Q-Wave Myocardial Infarction
Dosing Regimen
Adverse Event
Lovenox Inj.
1 mg/kg q12h SC
n = 1578
n (%)
Heparin
aPTT Adjusted
i.v. Therapy
n = 1529
n (%)
Atrial fibrillation
11 (0.70)
3 (0.20)
Heart failure
15 (0.95)
11 (0.72)
Lung edema
11 (0.70)
11 (0.72)
Pneumonia
13 (0.82)
9 (0.59)
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NDA 20-164/S-036
Page 20
Adverse Events Occurring at ≥≥2% Incidence in Lovenox Injection Treated Patients1 Undergoing Treatment of Deep
Vein Thrombosis With or Without Pulmonary Embolism
Dosing Regimen
Lovenox Inj.
1.5 mg/kg q.d. SC
n = 298
Lovenox Inj.
1 mg/kg q12h SC
n = 559
Heparin
aPTT Adjusted
i.v. Therapy
n = 544
Adverse Event
Severe
Total
Severe
Total
Severe
Total
Injection Site
Hemorrhage
0%
5%
0%
3%
<1%
<1%
Injection Site Pain
0%
2%
0%
2%
0%
0%
Hematuria
0%
2%
0%
<1%
<1%
2%
1 Excluding unrelated adverse events.
Ongoing Safety Surveillance: Since 1993, there have been more than 68 reports of epidural or
spinal hematoma formation with concurrent use of enoxaparin and spinal/epidural anesthesia or
spinal puncture. The majority of patients had a post-operative indwelling epidural catheter
placed for analgesia or received additional drugs affecting hemostasis such as NSAIDs. Many of
the epidural or spinal hematomas caused neurologic injury, including long-term or permanent
paralysis. Because these events were reported voluntarily from a population of unknown size,
estimates of frequency cannot be made.
Other Ongoing Safety Surveillance Reports: local reactions at the injection site (i.e., skin necrosis, nodules,
inflammation, oozing), systemic allergic reactions (i.e., pruritus, urticaria, anaphylactoid reactions), vesiculobullous rash,
purpura, thrombocytosis, and thrombocytopenia with thrombosis (see WARNINGS, Thrombocytopenia). Very rare cases
of hyperlipidemia have been reported, with one case of hyperlipidemia, with marked hypertriglyceridemia, reported in a
diabetic pregnant woman; causality has not been determined.
OVERDOSAGE
Symptoms/Treatment: Accidental overdosage following administration of Lovenox Injection may lead to hemorrhagic
complications. Injected Lovenox Injection may be largely neutralized by the slow i.v. injection of protamine sulfate (1%
solution). The dose of protamine sulfate should be equal to the dose of Lovenox Injection injected: 1 mg protamine sulfate
should be administered to neutralize 1 mg Lovenox Injection. A second infusion of 0.5 mg protamine sulfate per 1 mg of
Lovenox Injection may be administered if the aPTT measured 2 to 4 hours after the first infusion remains prolonged.
However, even with higher doses of protamine, the aPTT may remain more prolonged than under normal conditions found
following administration of heparin. In all cases, the anti-Factor Xa activity is never completely neutralized (maximum
about 60%). Particular care should be taken to avoid overdosage with protamine sulfate. Administration of protamine
sulfate can cause severe hypotensive and anaphylactoid reactions. Because fatal reactions, often resembling anaphylaxis,
have been reported with protamine sulfate, it should be given only when resuscitation techniques and treatment of
anaphylactic shock are readily available. For additional information consult the labeling of Protamine Sulfate Injection,
USP, products.
A single SC dose of 46.4 mg/kg enoxaparin was lethal to rats. The symptoms of acute toxicity were ataxia, decreased
motility, dyspnea, cyanosis, and coma.
DOSAGE AND ADMINISTRATION
All patients should be evaluated for a bleeding disorder before administration of Lovenox Injection,
unless the medication is needed urgently. Since coagulation parameters are unsuitable for monitoring
Lovenox Injection activity, routine monitoring of coagulation parameters is not required (see
PRECAUTIONS, Laboratory Tests).
Note: Lovenox Injection is available in two concentrations:
1 100 mg/mL Concentration: 30 mg/0.3 mL ampules, 30 mg/0.3 mL and 40 mg/0.4 mL prefilled single-dose syringes,
60 mg/0.6 mL, 80 mg/0.8 mL, and 100 mg/1 mL prefilled, graduated, single-dose syringes.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-164/S-036
Page 21
2 150 mg/mL Concentration: 90 mg/0.6 mL, 120mg/0.8 mL, and 150 mg/1 mL prefilled, graduated, single-dose syringes.
Adult Dosage:
Abdominal Surgery: In patients undergoing abdominal surgery who are at risk for thromboembolic complications, the
recommended dose of Lovenox Injection is 40 mg once a day administered by SC injection with the initial dose given 2
hours prior to surgery. The usual duration of administration is 7 to 10 days; up to 12 days administration has been well
tolerated in clinical trials.
Hip or Knee Replacement Surgery: In patients undergoing hip or knee replacement surgery, the recommended dose of
Lovenox Injection is 30 mg every 12 hours administered by SC injection. Provided that hemostasis has been established,
the initial dose should be given 12 to 24 hours after surgery. For hip replacement surgery, a dose of 40 mg once a day SC,
given initially 12 (±3) hours prior to surgery, may be considered. Following the initial phase of thromboprophylaxis in hip
replacement surgery patients, continued prophylaxis with Lovenox Injection 40 mg once a day administered by SC
injection for 3 weeks is recommended. The usual duration of administration is 7 to 10 days; up to 14 days administration
has been well tolerated in clinical trials.
Medical Patients During Acute Illness: In medical patients at risk for thromboembolic complications due to severely
restricted mobility during acute illness, the recommended dose of Lovenox Injection in 40 mg once a day administered by
SC injection. The usual duration of administration is 6 to 11 days; up to 14 days of Lovenox injection has been well
tolerated in the controlled clinical trial.
Unstable Angina and Non-Q-Wave Myocardial Infarction: In patients with unstable angina or non-Q-
wave myocardial infarction, the recommended dose of Lovenox Injection is 1 mg/kg administered SC
every 12 hours in conjunction with oral aspirin therapy (100 to 325 mg once daily). Treatment with
Lovenox Injection should be prescribed for a minimum of 2 days and continued until clinical
stabilization. To minimize the risk of bleeding following vascular instrumentation during the treatment
of unstable angina, adhere precisely to the intervals recommended between Lovenox Injection doses.
The vascular access sheath for instrumentation should remain in place for 6 to 8 hours following a dose
of Lovenox Injection. The next scheduled dose should be given no sooner than 6 to 8 hours after
sheath removal. The site of the procedure should be observed for signs of bleeding or hematoma
formation. The usual duration of treatment is 2 to 8 days; up to 12.5 days of Lovenox injections have
been well tolerated in clinical trials.
Treatment of Deep Vein Thrombosis With or Without Pulmonary Embolism: In outpatient treatment, patients with acute
deep vein thrombosis without pulmonary embolism who can be treated at home, the recommended dose of Lovenox
Injection is 1 mg/kg every 12 hours administered SC. In inpatient (hospital) treatment, patients with acute deep vein
thrombosis with pulmonary embolism or patients with acute deep vein thrombosis without pulmonary embolism (who are
not candidates for outpatient treatment), the recommended dose of Lovenox Injection is 1 mg/kg every 12 hours
administered SC or 1.5 mg/kg once a day administered SC at the same time every day. In both outpatient and inpatient
(hospital) treatments, warfarin sodium therapy should be initiated when appropriate (usually within 72 hours of Lovenox
Injection). Lovenox Injection should be continued for a minimum of 5 days and until a therapeutic oral anticoagulant effect
has been achieved (International Normalization Ratio 2.0 to 3.0). The average duration of administration is 7 days; up to 17
days Lovenox Injection administration has been well tolerated in controlled clinical trials.
Administration: Enoxaparin injection is a clear, colorless to pale yellow sterile solution, and as with other parenteral drug
products, should be inspected visually for particulate matter and discoloration prior to administration.
When using Lovenox Injection ampules, to assure withdrawal of the appropriate volume of drug, the use of a tuberculin
syringe or equivalent is recommended.
Lovenox Injection is administered by SC injection. It must not be administered by intramuscular injection. Lovenox
Injection is intended for use under the guidance of a physician. Patients may self-inject only if their physician determines
that it is appropriate and with medical follow-up, as necessary. Proper training in subcutaneous injection technique (with or
without the assistance of an injection device) should be provided.
Subcutaneous Injection Technique: Patients should be lying down and Lovenox Injection administered
by deep SC injection. To avoid the loss of drug when using the 30 and 40 mg prefilled syringes, do not
expel the air bubble from the syringe before the injection. Administration should be alternated between
the left and right anterolateral and left and right posterolateral abdominal wall. The whole length of the
needle should be introduced into a skin fold held between the thumb and forefinger; the skin fold
should be held throughout the injection. To minimize bruising, do not rub the injection site after
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-164/S-036
Page 22
completion of the injection. An automatic injector, Lovenox EasyInjector™, is available for patients to
administer Lovenox Injection packaged in 30 mg and 40 mg prefilled syringes. Please see directions
accompanying the Lovenox EasyInjector™ automatic injection device.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-164/S-036
Page 23
HOW SUPPLIED
Lovenox® (enoxaparin sodium) Injection is available in two concentrations:
100 mg/mL Concentration
Dosage Unit / Strength1
Anti-Xa
Activity2
Package Size
(per carton)
Syringe Label
Color
NDC #
0075-
Ampules
30 mg / 0.3 mL
3000 IU
10 ampules
Medium Blue
0624-03
Prefilled Syringes3
30 mg / 0.3 mL
3000 IU
10 syringes
Medium Blue
0624-30
40 mg / 0.4 mL
4000 IU
10 syringes
Yellow
0620-40
Graduated Prefilled
Syringes 3
60 mg / 0.6 mL
6000 IU
10 syringes
Orange
0621-60
80 mg / 0.8 mL
8000 IU
10 syringes
Brown
0622-80
100 mg / 1 mL
10 000 IU
10 syringes
Black
0623-00
1 Strength represents the number of milligrams of enoxaparin sodium in Water for Injection. Lovenox Injection ampules,
30 and 40 mg prefilled syringes, and 60, 80, 100 mg graduated prefilled syringes each contain 10 mg enoxaparin
sodium per 0.1 mL Water for Injection.
2 Approximate anti-Factor Xa activity based on reference to the W.H.O. First International Low Molecular Weight Heparin
Reference Standard
3 Each Lovenox Injection syringe is affixed with a 27 gauge x 1/2 inch needle
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-164/S-036
Page 24
150 mg/mL Concentration
Dosage Unit / Strength1
Anti-Xa
Activity2
Package Size
(per carton)
Syringe Label
Color
NDC #
0075-
Graduated Prefilled
Syringes3
90 mg / 0.6 mL
9000 IU
10 syringes
Hot Pink
2909-01
120 mg / 0.8 mL
12 000 IU
10 syringes
Lavender
2912-01
150 mg / 1mL
15 000 IU
10 syringes
Navy Blue
2915-01
1 Strength represents the number of milligrams of enoxaparin sodium in Water for Injection. Lovenox Injection 90, 120,
and
150
mg
graduated
prefilled
syringes
contain
15 mg enoxaparin sodium per 0.1 mL Water for Injection.
2 Approximate anti-Factor Xa activity based on reference to the W.H.O. First International Low Molecular Weight Heparin
Reference Standard.
3 Each Lovenox Injection graduated prefilled syringe is affixed with a 27 gauge x 1/2 inch needle.
Store at Controlled Room Temperature, 15-25°C (59-77°F) [see USP].
Keep out of the reach of children.
Lovenox Injection prefilled and graduated prefilled syringes manufactured in France.
Lovenox Injection ampules manufactured in England.
Aventis Pharmaceuticals Products Inc.
COLLEGEVILLE, PA 19426
2000
IN-xxxxy
Rev. mm/yy
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:46:56.643916
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2000/20164S36lbl.pdf', 'application_number': 20164, 'submission_type': 'SUPPL ', 'submission_number': 37}
|
12,287
|
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to
use Lovenox safely and effectively. See full prescribing
information for Lovenox.
Lovenox® (enoxaparin sodium injection) for subcutaneous and
intravenous use
Initial U.S. Approval: 1993
WARNING: SPINAL/EPIDURAL HEMATOMA
See full prescribing information for complete boxed warning.
• Enoxaparin use in patients undergoing spinal/epidural
anesthesia or spinal puncture increases the risk of spinal or
epidural hematoma, which may cause long-term or
permanent paralysis (5.5)
• Risk is increased by:
o Indwelling epidural catheters for analgesia (5.5)
o Drugs affecting hemostasis [e.g., nonsteroidal anti-
inflammatory drugs, platelet inhibitors,
anticoagulants] (5.5, 7)
o Traumatic or repeated spinal or epidural puncture
(5.5)
-----------------------RECENT MAJOR CHANGES------------------
Indications and Usage (1.4),
5/2007
Dosage and Administration (2)
5/2007
ST-segment Elevation Myocardial Infarction
Warnings and Precautions (5.2)
5/2007
Percutaneous coronary revascularization procedures
------------------INDICATIONS AND USAGE-------------------
Lovenox is a low molecular weight heparin [LMWH] indicated
for:
•
Prophylaxis of deep vein thrombosis (DVT) in abdominal
surgery, hip replacement surgery, knee replacement surgery,
or medical patients with severely restricted mobility during
acute illness (1.1)
•
Inpatient treatment of acute DVT with or without pulmonary
embolism (1.2)
•
Outpatient treatment of acute DVT without pulmonary
embolism. (1.2)
•
Prophylaxis of ischemic complications of unstable angina and
non-Q-wave myocardial infarction [MI] (1.3)
•
Treatment of acute ST-segment elevation myocardial
infarction [STEMI] managed medically or with subsequent
percutaneous coronary intervention [PCI] (1.4)
-------------------DOSAGE AND ADMINISTRATION--------------
Indication
Standard Regimen
(2.1, 2.3)
Severe Renal
Impairment (2.2)
DVT prophylaxis in
abdominal surgery
40 mg SC once daily
30 mg SC once daily
DVT prophylaxis in
knee replacement
surgery
30 mg SC every 12
hours
30 mg SC once daily
DVT prophylaxis in hip
replacement surgery
30 mg SC every 12
hours or 40 mg SC
once daily
30 mg SC once daily
DVT prophylaxis in
medical patients
40 mg SC once daily
30 mg SC once daily
Inpatient treatment of
acute DVT with or
without pulmonary
embolism
1 mg/kg SC every 12
hours or 1.5 mg/kg SC
once daily (with
warfarin)
1 mg/kg SC once
daily
Outpatient treatment
acute DVT without
of
hours (with warfarin)
g SC once
daily
pulmonary embolism
1 mg/kg SC every 12
1 mg/k
Unstable angina and
g SC once
non-Q-wave MI
1 mg/kg SC every 12
hours (with aspirin)
1 mg/k
daily
Acute STEMI in
patients <75 years of
CI, see
1)]
hours with aspirin)
by
g SC once
daily
age
[For dosing in
subsequent P
Dosage and
Administration (2.
30 mg single IV bolus
plus a 1 mg/kg SC
dose followed by 1
mg/kg SC every 12
30-mg single IV
bolus plus a 1 mg/kg
SC dose followed
1 mg/k
Acute STEMI in
patients ≥75 years of
12 hours (no bolus)
daily (no bolus)
age
0.75 mg/kg SC every
1 mg/kg SC once
Do not use as intramuscular injection.
For subcutaneous use, do not mix with other injections or
fusions.
--------------------DOSAGE FORMS AND STRENGTHS--------
•
60 mg/0.6 mL, 80 mg/0.8
AINDICATIONS-----------------
i-platelet
)
oval
5.3)
arin or other LMWHs (5.6)
not
Multiple-dose formulations contain benzyl alcohol (5.8)
---
adverse reactions (>1%) were bleeding, anemia,
rombocytopenia, elevation of serum aminotransferase, diarrhea,
ADVERSE REACTIONS, contact
nofi-aventis at 1-800-633-1610 or FDA at 1-800-FDA-1088 or
ww.fda.gov/medwatch.
in
--
100 mg/mL concentration (3.1):
•
Prefilled syringes: 30 mg/0.3 mL, 40 mg/0.4 mL
Graduated prefilled syringes:
mL,100 mg/1 mL
•
Multiple-dose vial: 300 mg/3 mL
150 mg/mL concentration (3.2):
•
Graduated prefilled syringes: 120 mg/0.8 mL, 150 mg/1 mL
------------------------------CONTR
•
Active major bleeding (4.1)
Thrombocytopenia with a positive in vitro test for ant
•
antibody in the presence of enoxaparin sodium (4.2
Hypersensitivity to enoxaparin sodium (4.3)
•
•
Hypersensitivity to heparin or pork products (4.4)
-----------------------WARNINGS AND PRECAUTIONS----------
•
Use caution in conditions with increased risk of hemorrhage
(5.1)
•
Obtain hemostasis at the puncture site before sheath rem
after percutaneous coronary revascularisation (5.2)
•
Use caution with concomitant medical conditions (
•
Use caution in case of history of heparin-induced
thrombocytopenia (5.4)
•
Monitor thrombocytopenia of any degree closely (5.5)
•
Do not exchange with hep
•
Pregnant women with mechanical prosthetic heart valves
adequately studied (5.7)
•
•
Periodic blood counts recommended (5.9)
-----------------------------ADVERSE REACTIONS----------------
Most common
th
and nausea
To report SUSPECTED
sa
w
-----------------------------DRUG INTERACTIONS----
-
hich may enhance hemorrhage risk prior to
itiation of Lovenox or conduct close clinical and laboratory
--------------
Discontinue agents w
in
monitoring (5.9, 7).
1
----------------USE IN SPECIFIC POP
------
ULATIONS------------
patients with
•
Hepatic Impairment (8.8)
•
Low-weight patients: Observe for signs of bleeding (8.9)
•
Severe renal impairment: Adjust dose for
creatinine clearance <30 mL/min (2.2)
See 17 for PATIENT COUNSELING INFORMATION
Revised: [m/year]
WARNIN
1
INDIC
ction
)
2
NGTHS
on
4
5
ures
ty with Other Heparins
with Mechanical Prosthetic Heart
7
CTIONS
8
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
ical Prosthetic Heart Valves
ent
11
12
LOGY
13
OLOGY
lity
14
Acute
ardial
ections or subsections omitted from the full prescribing
ation are not listed
FULL PRESCRIBING INFORMATION: CONTENTS*
G - SPINAL / EPIDURAL HEMATOMAS
ATIONS AND USAGE
Prophylaxis of deep vein thrombosis in patients
1.1
undergoing surgery and in medical patients with
severely restricted mobility during acute illness
Treatment of acute deep vein thrombosis
1.2
1.3 Prophylaxis of ischemic complications of unstable
angina and non-Q-wave myocardial infar
1.4 Treatment of acute ST-segment Elevation Myocardial
Infarction (STEMI
DOSAGE AND ADMINISTRATION
2.1 Adult dosage
2.2 Renal impairment
2.3 Geriatric patients with acute STEMI
2.4 Administration
3
3.1 100-mg/mL concentrati
DOSAGE FORMS AND STRE
3.2 150-mg/mL concentration
CONTRAINDICATIONS
WARNINGS AND PRECAUTIONS
5.1 Increased risk of Hemorrhage
5.2 Percutaneous coronary revascularization proced
5.3 Use of Lovenox with Concomitant Medical Conditions
5.4 History of heparin-induced thrombocytopenia
5.5 Thrombocytopenia
Interchan
5.6
geabili
5.7 Pregnant Women
Valves
5.8 Benzyl alcohol
5.9 Laboratory tests
6
6.1 Clinical Studies
ADVERSE REACTIONS
6.2 Post-marketing experience
DRUG INTERA
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Patients with Mechan
8.7 Renal impairment
8.8 Hepatic impairm
8.9 Low-weight Patients
10
OVERDOSAGE
DESCRIPTION
CLINICAL PHARMACO
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
NONCLINICAL TOXIC
13.1 Carcinogenesis, Mutagenesis, Impairment of Ferti
13.2 Animal Toxicology
ICAL TRIALS EX
CLIN
PERIENCE
14.1 Prophylaxis of deep vein thrombosis following
abdominal surgery
14.2 Prophylaxis of deep vein thrombosis following Hip or
Knee Replacement surgery
Prophylaxis of deep vein thr
14.3
ombosis in Medical
Patients with Severely Restricted Mobility during
Illness
14.4 Treatment of acute deep vein thrombosis with or
without pulmonary embolism
14.5 Prophylaxis of ischemic complications in unstable
angina and non-Q-wave myocardial infarction
14.6 Treatment of acute ST-segment Elevation Myoc
Infarction (STEMI)
16 HOW SUPPLIED/STORAGE AND HANDLING
17
PATIENT COUSELING INFORMATION
*S
inform
2
1
2
FULL PRESCRIBING INFORMATION
WARNING: SPINAL / EPIDURAL HEMATOMAS
3
When neuraxial anesthesia (epidural/spinal anesthesia) or spinal puncture is employed,
4
patients anticoagulated or scheduled to be anticoagulated with low molecular weight
5
heparins or heparinoids for prevention of thromboembolic complications are at risk of
6
developing an epidural or spinal hematoma which can result in long-term or permanent
7
paralysis.
8
9
The risk of these events is increased by the use of indwelling epidural catheters for
10
administration of analgesia or by the concomitant use of drugs affecting hemostasis such as
11
non steroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, or other
12
anticoagulants. The risk also appears to be increased by traumatic or repeated epidural or
13
spinal puncture.
14
15
Monitor patients for signs and symptoms of neurological impairment. If neurologic
16
compromise is noted, urgent treatment is necessary.
17
18
Consider the potential benefit versus risk before neuraxial intervention in patients
19
anticoagulated or to be anticoagulated for thromboprophylaxis [see Warnings and
20
Precautions (5.1) and Drug Interactions (7)].
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
1 INDICATIONS AND USAGE
1.1 Prophylaxis of deep vein thrombosis
Lovenox is indicated for the prophylaxis of deep vein thrombosis, which may lead to pulmonary
embolism:
• in patients undergoing abdominal surgery who are at risk for thromboembolic
complications [see Clinical Trials Experience 14.1].
• in patients undergoing hip replacement surgery, during and following hospitalization.
• in patients undergoing knee replacement surgery.
• in medical patients who are at risk for thromboembolic complications due to severely
restricted mobility during acute illness.
1.2 Treatment of Acute Deep Vein Thrombosis
Lovenox is indicated for:
• the inpatient treatment of acute deep vein thrombosis with or without pulmonary
embolism, when administered in conjunction with warfarin sodium;
• the outpatient treatment of acute deep vein thrombosis without pulmonary embolism
when administered in conjunction with warfarin sodium.
1.3 Prophylaxis of Ischemic Complications of Unstable Angina and Non-Q-wave
Myocardial Infarction
Lovenox is indicated for the prophylaxis of ischemic complications of unstable angina and non-
Q-wave myocardial infarction, when concurrently administered with aspirin.
3
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
1.4 Treatment of acute ST- segment Elevation Myocardial Infarction (STEMI)
Lovenox has been shown to reduce the rate of the combined endpoint of recurrent myocardial
infarction or death in patients with acute STEMI receiving thrombolysis and being managed
medically or with Percutaneous Coronary Intervention (PCI).
2 DOSAGE AND ADMINISTRATION
All patients should be evaluated for a bleeding disorder before administration of Lovenox, unless
the medication is needed urgently. Since coagulation parameters are unsuitable for monitoring
Lovenox activity, routine monitoring of coagulation parameters is not required [see Warnings
and Precautions (5.9)].
For subcutaneous use, Lovenox should not be mixed with other injections or infusions. For
intravenous use (i.e., for treatment of acute STEMI), Lovenox can be mixed with normal saline
solution (0.9%) or 5% dextrose in water.
Lovenox is not intended for intramuscular administration.
2.1 Adult Dosage
Abdominal Surgery: In patients undergoing abdominal surgery who are at risk for
thromboembolic complications, the recommended dose of Lovenox is 40 mg once a day
administered by SC injection with the initial dose given 2 hours prior to surgery. The usual
duration of administration is 7 to 10 days; up to 12 days administration has been administered in
clinical trials.
65
66
67
68
69
70
Hip or Knee Replacement Surgery: In patients undergoing hip or knee replacement surgery, the
recommended dose of Lovenox is 30 mg every 12 hours administered by SC injection.
Provided that hemostasis has been established, the initial dose should be given 12 to 24 hours
after surgery. For hip replacement surgery, a dose of 40 mg once a day SC, given initially 12
(±3) hours prior to surgery, may be considered. Following the initial phase of
thromboprophylaxis in hip replacement surgery patients, it is recommended that continued
prophylaxis with Lovenox 40 mg once a day is administered by SC injection for 3 weeks. The
usual duration of administration is 7 to 10 days; up to 14 days administration has been
administered in clinical trials.
71
72
73
74
75
76
77
78
79
80
Medical Patients During Acute Illness: In medical patients at risk for thromboembolic
complications due to severely restricted mobility during acute illness, the recommended dose of
Lovenox is 40 mg once a day administered by SC injection. The usual duration of
administration is 6 to 11 days; up to 14 days of Lovenox has been administered in the controlled
clinical trial.
81
82
83
84
85
86
Treatment of Deep Vein Thrombosis With or Without Pulmonary Embolism: In outpatient
treatment, patients with acute deep vein thrombosis without pulmonary embolism who can be
87
88
4
treated at home, the recommended dose of Lovenox is 1 mg/kg every 12 hours administered
SC. In inpatient (hospital) treatment, patients with acute deep vein thrombosis with
pulmonary embolism or patients with acute deep vein thrombosis without pulmonary embolism
(who are not candidates for outpatient treatment), the recommended dose of Lovenox is 1 mg/kg
every 12 hours administered SC or 1.5 mg/kg once a day administered SC at the same time
every day. In both outpatient and inpatient (hospital) treatments, warfarin sodium therapy should
be initiated when appropriate (usually within 72 hours of Lovenox). Lovenox should be
continued for a minimum of 5 days and until a therapeutic oral anticoagulant effect has been
achieved (International Normalization Ratio 2.0 to 3.0). The average duration of administration
is 7 days; up to 17 days of Lovenox administration has been administered in controlled clinical
trials.
89
90
91
92
93
94
95
96
97
98
99
100
Unstable Angina and Non-Q-Wave Myocardial Infarction: In patients with unstable angina or
non-Q-wave myocardial infarction, the recommended dose of Lovenox is 1 mg/kg administered
SC every 12 hours in conjunction with oral aspirin therapy (100 to 325 mg once daily).
Treatment with Lovenox should be prescribed for a minimum of 2 days and continued until
clinical stabilization. The usual duration of treatment is 2 to 8 days; up to 12.5 days of Lovenox
has been administered in clinical trials. [See Warnings and Precautions (5.2) and Clinical Trials
Experience (14.5)].
101
102
103
104
105
106
107
108
Treatment of acute ST-segment Elevation Myocardial Infarction: In patients with acute ST-
segment Elevation Myocardial Infarction, the recommended dose of Lovenox is a single IV
bolus of 30 mg plus a 1 mg/kg SC dose followed by 1 mg/kg administered SC every 12 hours
(maximum 100 mg for the first two doses only, followed by 1 mg/kg dosing for the remaining
doses). Dosage adjustments are recommended in patients ≥75 years of age [see Dosage and
Administration (2.3)].
109
110
111
112
113
114
115
116
117
118
119
120
121
122
123
124
125
126
127
128
129
130
131
132
When administered in conjunction with a thrombolytic (fibrin-specific or non-fibrin specific),
Lovenox should be given between 15 minutes before and 30 minutes after the start of fibrinolytic
therapy. All patients should receive acetylsalicylic acid (ASA) as soon as they are identified as
having STEMI and maintained with 75 to 325 mg once daily unless contraindicated. In the
pivotal clinical study, the Lovenox treatment duration was 8 days or until hospital discharge,
whichever came first. An optimal duration of treatment is not known, but it is likely to be longer
than 8 days.
For patients managed with Percutaneous Coronary Intervention (PCI): If the last Lovenox SC
administration was given less than 8 hours before balloon inflation, no additional dosing is
needed. If the last Lovenox SC administration was given more than 8 hours before balloon
inflation, an IV bolus of 0.3 mg/kg of Lovenox should be administered [see Warnings and
Precautions (5.2)].
2.2 Renal Impairment
Although no dose adjustment is recommended in patients with moderate (creatinine clearance
30-50 mL/min) and mild (creatinine clearance 50-80 mL/min) renal impairment, all such patients
should be observed carefully for signs and symptoms of bleeding.
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The recommended prophylaxis and treatment dosage regimens for patients with severe renal
impairment (creatinine clearance <30 mL/min) are described in Table 1 [see Use in Specific
Populations (8.6) and Clinical Pharmacology (12.3)].
Table 1
Dosage Regimens for Patients with Severe Renal Impairment
(creatinine clearance <30mL/minute)
Indication
Dosage Regimen
Prophylaxis in abdominal surgery
30 mg administered SC once daily
Prophylaxis in hip or knee replacement surgery
30 mg administered SC once daily
Prophylaxis in medical patients during acute illness
30 mg administered SC once daily
Inpatient treatment of acute deep vein thrombosis with
or without pulmonary embolism, when administered in
conjunction with warfarin sodium
1 mg/kg administered SC once daily
Outpatient treatment of acute deep vein thrombosis
without pulmonary embolism, when administered in
conjunction with warfarin sodium
1 mg/kg administered SC once daily
Prophylaxis of ischemic complications of unstable
angina and non-Q-wave myocardial infarction, when
concurrently administered with aspirin
1 mg/kg administered SC once daily
Treatment of acute ST-segment Elevation Myocardial
Infarction in patients <75 years of age
30 mg single IV bolus plus a 1 mg/kg
SC dose followed by 1 mg/kg
administered SC once daily.
Treatment of acute ST-segment Elevation Myocardial
Infarction in geriatric patients ≥75 years of age
1 mg/kg administered SC once daily
(no initial bolus)
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2.3 Geriatric patients with acute ST-Elevation Myocardial Infarction
For treatment of acute ST-segment Elevation Myocardial Infarction in geriatric patients ≥75
years of age, do not use an initial IV bolus. Initiate dosing with 0.75 mg/kg SC every 12
hours (maximum 75 mg for the first two doses only, followed by 0.75 mg/kg dosing for the
remaining doses)[see Use in Specific Populations (8.5) and Clinical Pharmacology (12.3)].
No dose adjustment is necessary for other indications in geriatric patients unless kidney function
is impaired [see Dosage and Administration (2.2)].
2.4 Administration
Lovenox is a clear, colorless to pale yellow sterile solution, and as with other parenteral drug
products, should be inspected visually for particulate matter and discoloration prior to
administration.
The use of a tuberculin syringe or equivalent is recommended when using Lovenox multiple-
dose vials to assure withdrawal of the appropriate volume of drug.
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Lovenox must not be administered by intramuscular injection. Lovenox is intended for use
under the guidance of a physician.
For subcutaneous administration, patients may self-inject only if their physicians determine that
it is appropriate and with medical follow-up, as necessary. Proper training in subcutaneous
injection technique (with or without the assistance of an injection device) should be provided.
Subcutaneous Injection Technique: Patients should be lying down and Lovenox administered by
deep SC injection. To avoid the loss of drug when using the 30 and 40 mg prefilled syringes, do
not expel the air bubble from the syringe before the injection. Administration should be
alternated between the left and right anterolateral and left and right posterolateral abdominal
wall. The whole length of the needle should be introduced into a skin fold held between the
thumb and forefinger; the skin fold should be held throughout the injection. To minimize
bruising, do not rub the injection site after completion of the injection.
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Lovenox prefilled syringes and graduated prefilled syringes are available with a system that
shields the needle after injection.
1. Remove the needle shield by pulling it straight off the syringe (see Figure A). If adjusting the
dose is required, the dose adjustment must be done prior to injecting the prescribed dose to the
patient.
Figure A
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2. Inject using standard technique, pushing the plunger to the bottom of the syringe (see Figure
B).
Figure B
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3. Remove the syringe from the injection site keeping your finger on the plunger rod (see Figure
C).
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Figure C
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4. Orient the needle away from you and others, and activate the safety system by firmly
pushing the plunger rod. The protective sleeve will automatically cover the needle and an
audible “click” will be heard to confirm shield activation (see Figure D).
Figure D
197
5. Immediately dispose of the syringe in the nearest sharps container (see Figure E).
Figure E
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NOTE:
• The safety system can only be activated once the syringe has been emptied.
• Activation of the safety system must be done only after removing the needle from the
patient’s skin.
• Do not replace the needle shield after injection.
• The safety system should not be sterilized.
Activation of the safety system may cause minimal splatter of fluid. For optimal safety activate
the system while orienting it downwards away from yourself and others.
Intravenous (Bolus) Injection Technique: For intravenous injection, the multiple-dose vial should
be used. Lovenox should be administered through an intravenous line. Lovenox should not be
mixed or co-administered with other medications. To avoid the possible mixture of Lovenox
with other drugs, the intravenous access chosen should be flushed with a sufficient amount of
saline or dextrose solution prior to and following the intravenous bolus administration of
Lovenox to clear the port of drug. Lovenox may be safely administered with normal saline
solution (0.9%) or 5% dextrose in water.
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3 DOSAGE FORMS AND STRENGTHS
Lovenox is available in two concentrations:
3.1 100 mg per mL
-Prefilled Syringes
30 mg / 0.3 mL, 40 mg / 0.4 mL
-Graduated Prefilled Syringes 60 mg / 0.6 mL, 80 mg / 0.8 mL, 100 mg / 1 mL
-Multiple-Dose Vials
300 mg / 3 mL
3.2 150 mg per mL
-Graduated Prefilled Syringes 120 mg / 0.8 mL, 150 mg / 1 mL
4 CONTRAINDICATIONS
• Active major bleeding.
• Thrombocytopenia associated with a positive in vitro test for anti-platelet antibody in the
presence of enoxaparin sodium.
• Known hypersensitivity to enoxaparin sodium (e.g., pruritus, urticaria, anaphylactoid
reactions) [see Adverse Reactions (6.2)].
• Known hypersensitivity to heparin or pork products.
• Known hypersensitivity to benzyl alcohol (which is in only the multi-dose formulation of
Lovenox).
5 WARNINGS AND PRECAUTIONS
5.1 Increased Risk of Hemorrhage
Cases of epidural or spinal hematomas have been reported with the associated use of Lovenox
and spinal/epidural anesthesia or spinal puncture resulting in long-term or permanent paralysis.
The risk of these events is higher with the use of post-operative indwelling epidural catheters or
by the concomitant use of additional drugs affecting hemostasis such as NSAIDs [see boxed
Warning, Adverse Reactions (6.2) and Drug Interactions (7)].
Lovenox should be used with extreme caution in conditions with increased risk of hemorrhage,
such as bacterial endocarditis, congenital or acquired bleeding disorders, active ulcerative and
angiodysplastic gastrointestinal disease, hemorrhagic stroke, or shortly after brain, spinal, or
ophthalmological surgery, or in patients treated concomitantly with platelet inhibitors.
Major hemorrhages including retroperitoneal and intracranial bleeding have been reported.
Some of these cases have been fatal.
Bleeding can occur at any site during therapy with Lovenox. An unexplained fall in hematocrit
or blood pressure should lead to a search for a bleeding site.
5.2 Percutaneous coronary revascularization procedures
To minimize the risk of bleeding following the vascular instrumentation during the treatment of
unstable angina, non-Q-wave myocardial infarction and acute ST-segment elevation myocardial
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infarction, adhere precisely to the intervals recommended between Lovenox doses. It is
important to achieve hemostasis at the puncture site after PCI. In case a closure device is used,
the sheath can be removed immediately. If a manual compression method is used, sheath should
be removed 6 hours after the last IV/SC Lovenox. If the treatment with enoxaparin sodium is to
be continued, the next scheduled dose should be given no sooner than 6 to 8 hours after sheath
removal. The site of the procedure should be observed for signs of bleeding or hematoma
formation [see Dosage and Administration (2.1)].
5.3 Use of Lovenox with Concomitant Medical Conditions
Lovenox should be used with care in patients with a bleeding diathesis, uncontrolled arterial
hypertension or a history of recent gastrointestinal ulceration, diabetic retinopathy, and
hemorrhage.
5.4 History of Heparin-induced Thrombocytopenia
Lovenox should be used with extreme caution in patients with a history of heparin-induced
thrombocytopenia.
5.5 Thrombocytopenia
Thrombocytopenia can occur with the administration of Lovenox.
Moderate thrombocytopenia (platelet counts between 100,000/mm3 and 50,000/mm3) occurred at
a rate of 1.3% in patients given Lovenox, 1.2% in patients given heparin, and 0.7% in patients
given placebo in clinical trials.
Platelet counts less than 50,000/mm3 occurred at a rate of 0.1% in patients given Lovenox, in
0.2% of patients given heparin, and 0.4% of patients given placebo in the same trials.
Thrombocytopenia of any degree should be monitored closely. If the platelet count falls below
100,000/mm3, Lovenox should be discontinued. Cases of heparin-induced thrombocytopenia
with thrombosis have also been observed in clinical practice. Some of these cases were
complicated by organ infarction, limb ischemia, or death [see Warnings and Precautions (5.4)].
5.6 Interchangeability with Other Heparins
Lovenox cannot be used interchangeably (unit for unit) with heparin or other low molecular
weight heparins as they differ in manufacturing process, molecular weight distribution, anti-Xa
and anti-IIa activities, units, and dosage. Each of these medicines has its own instructions for
use.
5.7 Pregnant Women with Mechanical Prosthetic Heart Valves
The use of Lovenox for thromboprophylaxis in pregnant women with mechanical prosthetic
heart valves has not been adequately studied. In a clinical study of pregnant women with
mechanical prosthetic heart valves given enoxaparin (1 mg/kg twice daily) to reduce the risk of
thromboembolism, 2 of 8 women developed clots resulting in blockage of the valve and leading
to maternal and fetal death. Although a causal relationship has not been established these deaths
may have been due to therapeutic failure or inadequate anticoagulation. No patients in the
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heparin/warfarin group (0 of 4 women) died. There also have been isolated postmarketing
reports of valve thrombosis in pregnant women with mechanical prosthetic heart valves while
receiving enoxaparin for thromboprophylaxis. Women with mechanical prosthetic heart valves
may be at higher risk for thromboembolism during pregnancy, and, when pregnant, have a higher
rate of fetal loss from stillbirth, spontaneous abortion and premature delivery. Therefore,
frequent monitoring of peak and trough anti-Factor Xa levels, and adjusting of dosage may be
needed [see Use in Specific Populations (8.6)].
5.8 Benzyl Alcohol
Lovenox multiple-dose vials contain benzyl alcohol as a preservative. The administration of
medications containing benzyl alcohol as a preservative to premature neonates has been
associated with a fatal “Gasping Syndrome”. Because benzyl alcohol may cross the placenta,
Lovenox multiple-dose vials, preserved with benzyl alcohol, should be used with caution in
pregnant women and only if clearly needed [see Use in Specific Populations (8.1)].
5.9 Laboratory Tests
Periodic complete blood counts, including platelet count, and stool occult blood tests are
recommended during the course of treatment with Lovenox. When administered at
recommended prophylaxis doses, routine coagulation tests such as Prothrombin Time (PT) and
Activated Partial Thromboplastin Time (aPTT) are relatively insensitive measures of Lovenox
activity and, therefore, unsuitable for monitoring. Anti-Factor Xa may be used to monitor the
anticoagulant effect of Lovenox in patients with significant renal impairment. If during Lovenox
therapy abnormal coagulation parameters or bleeding should occur, anti-Factor Xa levels may be
used to monitor the anticoagulant effects of Lovenox [see Clinical Pharmacology (12.3)].
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
Because clinical studies are conducted under widely varying conditions, adverse reaction rates
observed in the clinical studies of a drug cannot be directly compared to rates in the clinical
studies of another drug and may not reflect the rates observed in practice.
Hemorrhage
The incidence of major hemorrhagic complications during Lovenox treatment has been low.
The following rates of major bleeding events have been reported during clinical trials with
Lovenox Injection [see Tables 2 to 7].
11
Table 2
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350
Major Bleeding Episodes Following Abdominal and Colorectal Surgery1
Dosing Regimen
Indications
Lovenox
40 mg q.d. SC
Heparin
5000 U q8h SC
Abdominal Surgery
n = 555
23 (4%)
n = 560
16 (3%)
Colorectal Surgery
n = 673
28 (4%)
n = 674
21 (3%)
1 Bleeding complications were considered major: (1) if the hemorrhage caused a significant
clinical event, or (2) if accompanied by a hemoglobin decrease ≥ 2 g/dL or transfusion of 2 or
more units of blood products. Retroperitoneal, intraocular, and intracranial hemorrhages were
always considered major.
351
352
353
354
355
356
357
Table 3
Major Bleeding Episodes Following Hip or Knee Replacement Surgery1
Dosing Regimen
Indications
Lovenox
40 mg q.d. SC
Lovenox
30 mg q12h SC
Heparin
15,000 U/24h SC
Hip Replacement Surgery
Without Extended Prophylaxis2
n = 786
31 (4%)
n = 541
32 (6%)
Hip Replacement Surgery
With Extended Prophylaxis
Peri-operative Period3
n = 288
4 (2%)
Extended Prophylaxis Period4
n = 221
0 (0%)
Knee Replacement Surgery
Without Extended Prophylaxis2
n = 294
3 (1%)
n = 225
3 (1%)
1 Bleeding complications were considered major: (1) if the hemorrhage caused a significant
clinical event, or (2) if accompanied by a hemoglobin decrease ≥ 2 g/dL or transfusion of 2 or
more units of blood products. Retroperitoneal and intracranial hemorrhages were always
considered major. In the knee replacement surgery trials, intraocular hemorrhages were also
considered major hemorrhages.
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359
360
361
362
363
364
365
366
367
368
2 Lovenox 30 mg every 12 hours SC initiated 12 to 24 hours after surgery and continued for up
to 14 days after surgery.
3 Lovenox 40 mg SC once a day initiated up to 12 hours prior to surgery and continued for up to
7 days after surgery.
4 Lovenox 40 mg SC once a day for up to 21 days after discharge.
12
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NOTE: At no time point were the 40 mg once a day pre-operative and the 30 mg every 12 hours
post-operative hip replacement surgery prophylactic regimens compared in clinical trials.
Injection site hematomas during the extended prophylaxis period after hip replacement surgery
occurred in 9% of the Lovenox patients versus 1.8% of the placebo patients.
Table 4
Major Bleeding Episodes in Medical Patients With Severely Restricted Mobility During
Acute Illness1
Dosing Regimen
Indications
Lovenox2
20 mg q.d. SC
Lovenox2
40 mg q.d. SC
Placebo2
Medical Patients During
Acute Illness
n = 351
1 (<1%)
n = 360
3 (<1%)
n = 362
2 (<1%)
1 Bleeding complications were considered major: (1) if the hemorrhage caused a significant
clinical event, (2) if the hemorrhage caused a decrease in hemoglobin of ≥ 2 g/dL or transfusion
of 2 or more units of blood products. Retroperitoneal and intracranial hemorrhages were always
considered major although none were reported during the trial.
377
378
379
380
381
382
383
384
385
2 The rates represent major bleeding on study medication up to 24 hours after last dose.
Table 5
Major Bleeding Episodes in Deep Vein Thrombosis With or Without Pulmonary Embolism
Treatment 1
Dosing Regimen2
Indication
Lovenox
1.5 mg/kg q.d. SC
Lovenox
1 mg/kg q12h SC
Heparin
aPTT Adjusted
IV Therapy
Treatment of DVT and PE
n = 298
5 (2%)
n = 559
9 (2%)
n = 554
9 (2%)
1 Bleeding complications were considered major: (1) if the hemorrhage caused a significant
clinical event, or (2) if accompanied by a hemoglobin decrease ≥ 2 g/dL or transfusion of 2 or
more units of blood products. Retroperitoneal, intraocular, and intracranial hemorrhages were
always considered major.
386
387
388
389
390
391
392
2 All patients also received warfarin sodium (dose-adjusted according to PT to achieve an INR of
2.0 to 3.0) commencing within 72 hours of Lovenox or standard heparin therapy and
continuing for up to 90 days.
13
Table 6
393
394
Major Bleeding Episodes in Unstable Angina and Non-Q-Wave Myocardial Infarction
Dosing Regimen
Indication
Lovenox1
1 mg/kg q12h SC
Heparin1
aPTT Adjusted
IV Therapy
Unstable Angina and
Non-Q-Wave MI2,3
n = 1578
17 (1%)
n = 1529
18 (1%)
1 The rates represent major bleeding on study medication up to 12 hours after dose.
395
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399
400
401
402
403
2 Aspirin therapy was administered concurrently (100 to 325 mg per day).
3 Bleeding complications were considered major: (1) if the hemorrhage caused a significant
clinical event, or (2) if accompanied by a hemoglobin decrease by ≥ 3 g/dL or transfusion of 2
or more units of blood products. Intraocular, retroperitoneal, and intracranial hemorrhages
were always considered major.
Table 7
Major Bleeding Episodes in acute ST-segment Elevation Myocardial Infarction
Dosing Regimen
Indication
Lovenox 1
Initial 30-mg IV bolus
followed by
1 mg/kg q12h SC
Heparin1
aPTT Adjusted
IV Therapy
acute ST-segment Elevation
Myocardial Infarction,
- Major bleeding (including
ICH) 2
- Intracranial hemorrhages
(ICH)
n = 10176
n (%)
211 (2.1)
84 (0.8)
n = 10151
n (%)
138 (1.4)
66 (0.7)
1The rates represent major bleeding (including ICH) up to 30 days
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405
406
407
408
409
410
411
412
413
414
415
2Bleedings were considered major if the hemorrhage caused a significant clinical event
associated with a hemoglobin decrease by ≥ 5 g/dL. ICH were always considered major.
Thrombocytopenia
[See Warnings and Precautions (5.5)]
Elevations of Serum Aminotransferases
Asymptomatic increases in aspartate (AST [SGOT]) and alanine (ALT [SGPT])
aminotransferase levels greater than three times the upper limit of normal of the laboratory
reference range have been reported in up to 6.1% and 5.9% of patients, respectively, during
treatment with Lovenox. Similar significant increases in aminotransferase levels have also been
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424
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434
observed in patients and healthy volunteers treated with heparin and other low molecular weight
heparins. Such elevations are fully reversible and are rarely associated with increases in
bilirubin.
Since aminotransferase determinations are important in the differential diagnosis of myocardial
infarction, liver disease, and pulmonary emboli, elevations that might be caused by drugs like
Lovenox should be interpreted with caution.
Local Reactions
Mild local irritation, pain, hematoma, ecchymosis, and erythema may follow SC injection of
Lovenox.
Other
Other adverse effects that were thought to be possibly or probably related to treatment with
Lovenox, heparin, or placebo in clinical trials with patients undergoing hip or knee replacement
surgery, abdominal or colorectal surgery, or treatment for DVT and that occurred at a rate of at
least 2% in the Lovenox group, are provided below [see Tables 8 to 11].
Table 8
Adverse Events Occurring at ≥2% Incidence in Lovenox-Treated Patients1 Undergoing
Abdominal or Colorectal Surgery
Dosing Regimen
Lovenox
40 mg q.d. SC
n = 1228
%
Heparin
5000 U q8h SC
n = 1234
%
Adverse Event
Severe
Total
Severe
Total
Hemorrhage
<1
7
<1
6
Anemia
<1
3
<1
3
Ecchymosis
0
3
0
3
1 Excluding unrelated adverse events.
435
15
Table 9
436
437
438
Adverse Events Occurring at ≥2% Incidence in Lovenox-Treated Patients1 Undergoing Hip
or Knee Replacement Surgery
Dosing Regimen
Lovenox
40 mg q.d. SC
Lovenox
30 mg q12h
SC
Heparin
15,000 U/24h
SC
Placebo
q12h SC
Peri-
operative
Period
n = 288 2
%
Extended
Prophylaxis
Period
n = 131 3
%
n = 1080
%
n = 766
%
n = 115
%
Adverse Event
Severe
Total
Severe
Total
Severe
Total
Severe Total
Severe
Total
Fever
0
8
0
0
<1
5
<1
4
0
3
Hemorrhage
<1
13
0
5
<1
4
1
4
0
3
Nausea
<1
3
<1%
2
0
2
Anemia
0
16
0
<2
<1
2
2
5
<1
7
Edema
<1
2
<1
2
0
2
Peripheral
edema
0
6
0
0
<1
3
<1
4
0
3
1 Excluding unrelated adverse events.
439
440
441
442
443
444
445
446
2 Data represents Lovenox 40 mg SC once a day initiated up to 12 hours prior to surgery in 288
hip replacement surgery patients who received Lovenox peri-operatively in an unblinded
fashion in one clinical trial.
3 Data represents Lovenox 40 mg SC once a day given in a blinded fashion as extended
prophylaxis at the end of the peri-operative period in 131 of the original 288 hip replacement
surgery patients for up to 21 days in one clinical trial.
16
Table 10
447
448
449
Adverse Events Occurring at ≥2% Incidence in Lovenox-Treated Medical Patients1 With
Severely Restricted Mobility During Acute Illness
Dosing Regimen
Adverse Event
Lovenox
40 mg q.d. SC
n = 360
%
Placebo
q.d. SC
n = 362
%
Dyspnea
3.3
5.2
Thrombocytopenia
2.8
2.8
Confusion
2.2
1.1
Diarrhea
2.2
1.7
Nausea
2.5
1.7
1 Excluding unrelated and unlikely adverse events.
450
451
452
453
454
Table 11
Adverse Events Occurring at ≥2% Incidence in Lovenox-Treated Patients1 Undergoing
Treatment of Deep Vein Thrombosis With or Without Pulmonary Embolism
Dosing Regimen
Lovenox
1.5 mg/kg q.d. SC
n = 298
%
Lovenox
1 mg/kg q12h SC
n = 559
%
Heparin
aPTT Adjusted
IV Therapy
n = 544
%
Adverse Event
Severe
Total
Severe
Total
Severe
Total
Injection Site
Hemorrhage
0
5
0
3
<1
<1
Injection Site Pain
0
2
0
2
0
0
Hematuria
0
2
0
<1
<1
2
1 Excluding unrelated adverse events.
455
456
457
458
459
460
461
462
463
464
Adverse Events in Lovenox-Treated Patients With Unstable Angina or Non-Q-
Wave Myocardial Infarction:
Non-hemorrhagic clinical events reported to be related to Lovenox therapy occurred at an
incidence of ≤1%.
Non-major hemorrhagic episodes, primarily injection site ecchymoses and hematomas, were
more frequently reported in patients treated with SC Lovenox than in patients treated with IV
heparin.
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466
467
468
469
470
471
Serious adverse events with Lovenox or heparin in a clinical trial in patients with unstable angina
or non-Q-wave myocardial infarction that occurred at a rate of at least 0.5% in the Lovenox
group are provided below (irrespective of relationship to drug therapy) [see Table 12].
Table 12
Serious Adverse Events Occurring at ≥0.5% Incidence in Lovenox-Treated Patients With
Unstable Angina or Non-Q-Wave Myocardial Infarction
Dosing Regimen
Adverse Event
Lovenox
1 mg/kg q12h SC
n = 1578
n (%)
Heparin
aPTT Adjusted
IV Therapy
n = 1529
n (%)
Atrial fibrillation
11 (0.70)
3 (0.20)
Heart failure
15 (0.95)
11 (0.72)
Lung edema
11 (0.70)
11 (0.72)
Pneumonia
13 (0.82)
9 (0.59)
472
473
474
475
476
477
478
479
480
481
482
483
484
485
486
487
488
489
490
491
492
493
494
495
496
Adverse Reactions in Lovenox-Treated Patients With acute ST-segment Elevation
Myocardial Infarction:
In a clinical trial in patients with acute ST-segment elevation myocardial infarction, the only
additional possibly related adverse reaction that occurred at a rate of at least 0.5% in the
Lovenox group was thrombocytopenia (1.5%)
6.2 Post-Marketing Experience
There have been reports of epidural or spinal hematoma formation with concurrent use of
Lovenox and spinal/epidural anesthesia or spinal puncture. The majority of patients had a post-
operative indwelling epidural catheter placed for analgesia or received additional drugs affecting
hemostasis such as NSAIDs. Many of the epidural or spinal hematomas caused neurologic
injury, including long-term or permanent paralysis.
Local reactions at the injection site (e.g., skin necrosis, nodules, inflammation, oozing), systemic
allergic reactions (e.g., pruritus, urticaria, anaphylactoid reactions), vesiculobullous rash, rare
cases of hypersensitivity cutaneous vasculitis, purpura, thrombocytosis, and thrombocytopenia
with thrombosis [see Warnings and Precautions (5.5)] have been reported. Very rare cases of
hyperlipidemia have also been reported, with one case of hyperlipidemia, with marked
hypertriglyceridemia, reported in a diabetic pregnant woman; causality has not been determined.
Because these reactions are reported voluntarily from a population of uncertain size, it is not
possible to estimate reliably their frequency or to establish a causal relationship to drug
exposure.
18
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7 DRUG INTERACTIONS
Unless really needed, agents which may enhance the risk of hemorrhage should be discontinued
prior to initiation of Lovenox therapy. These agents include medications such as: anticoagulants,
platelet inhibitors including acetylsalicylic acid, salicylates, NSAIDs (including ketorolac
tromethamine), dipyridamole, or sulfinpyrazone. If co-administration is essential, conduct close
clinical and laboratory monitoring [see Warnings and Precautions (5.9)].
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category B
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All pregnancies have a background risk of birth defects, loss, or other adverse outcome
regardless of drug exposure. The fetal risk summary below describes the potential of Lovenox to
increase the risk of developmental abnormalities above background risk.
Fetal Risk Summary
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Lovenox is not predicted to increase the risk of developmental abnormalities. Lovenox does not
cross the placenta, based on human and animal studies, and shows no evidence of teratogenic
effects or fetotoxicity.
Cases of “Gasping Syndrome” have occurred in premature infants when large amounts of benzyl
alcohol have been administered (99-405 mg/kg/day). The multiple-dose vial of Lovenox
contains 15 mg benzyl alcohol per 1 mL as a preservative [see Warnings and Precautions (5.8)].
Clinical Considerations
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It is not known if either dose adjustment or monitoring of anti-Xa activity of enoxaparin are
necessary during pregnancy.
Pregnancy alone confers an increased risk for thromboembolism that is even higher for women
with thromboembolic disease and certain high risk pregnancy conditions. While not adequately
studied, pregnant women with mechanical prosthetic heart valves may be at even higher risk for
thrombosis [see Warnings and Precautions (5.7) and Use in Specific Populations (8.6)].
Pregnant women with thromboembolic disease, including those with mechanical prosthetic heart
valves and those with inherited or acquired thrombophilias, have an increased risk of other
maternal complications and fetal loss regardless of the type of anticoagulant used.
All patients receiving anticoagulants such as enoxaparin, including pregnant women, are at risk
for bleeding. Pregnant women receiving enoxaparin should be carefully monitored for evidence
of bleeding or excessive anticoagulation. Consideration for use of a shorter acting anticoagulant
should be specifically addressed as delivery approaches [see Boxed Warning]. Hemorrhage can
occur at any site and may lead to death of mother and/or fetus. Pregnant women should be
apprised of the potential hazard to the fetus and the mother if enoxaparin is administered during
pregnancy.
19
Data
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•
Human Data - There are no adequate and well-controlled studies in pregnant women.
A retrospective study reviewed the records of 604 women who used enoxaparin during
pregnancy. A total of 624 pregnancies resulted in 693 live births. There were 72 hemorrhagic
events (11 serious) in 63 women. There were 14 cases of neonatal hemorrhage. Major
congenital anomalies in live births occurred at rates (2.5%) similar to background rates.
There have been postmarketing reports of fetal death when pregnant women received Lovenox.
Causality for these cases has not been determined. Insufficient data, the underlying disease, and
the possibility of inadequate anticoagulation complicate the evaluation of these cases.
A clinical study using enoxaparin in pregnant women with mechanical prosthetic heart valves
has been conducted [see Warnings and Precautions (5.7].
• Animal Data - Teratology studies have been conducted in pregnant rats and rabbits at SC
doses of enoxaparin up to 30 mg/kg/day or 211 mg/m2/day and 410 mg/m2/day,
respectively. There was no evidence of teratogenic effects or fetotoxicity due to
enoxaparin. Because animal reproduction studies are not always predictive of human
response, this drug should be used during pregnancy only if clearly needed.
8.3 Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted
in human milk, caution should be exercised when Lovenox is administered to nursing women.
8.4 Pediatric Use
Safety and effectiveness of Lovenox in pediatric patients have not been established.
8.5 Geriatric Use
Prevention of DVT in hip, knee and abdominal surgery; treatment of DVT, Prevention of
568
ischemic complications of unstable angina and non-Q-Wave myocardial infarction
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Over 2800 patients, 65 years and older, have received Lovenox in pivotal clinical trials. The
efficacy of Lovenox in the geriatric (≥65 years) was similar to that seen in younger patients (<65
years). The incidence of bleeding complications was similar between geriatric and younger
patients when 30 mg every 12 hours or 40 mg once a day doses of Lovenox were employed. The
incidence of bleeding complications was higher in geriatric patients as compared to younger
patients when Lovenox was administered at doses of 1.5 mg/kg once a day or 1 mg/kg every 12
hours. The risk of Lovenox -associated bleeding increased with age. Serious adverse events
increased with age for patients receiving Lovenox. Other clinical experience (including
postmarketing surveillance and literature reports) has not revealed additional differences in the
safety of Lovenox between geriatric and younger patients. Careful attention to dosing intervals
and concomitant medications (especially antiplatelet medications) is advised. Lovenox should
be used with care in geriatric patients who may show delayed elimination of enoxaparin.
Monitoring of geriatric patients with low body weight (<45 kg) and those predisposed to
20
decreased renal function should be considered [see Warnings and Precautions (5.9) and Clinical
Pharmacology (12.3)].
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Treatment of acute ST-segment Elevation Myocardial Infarction (STEMI)
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In the clinical study for treatment of acute STEMI, there was no evidence of difference in
efficacy between patients ≥75 years of age (n = 1241) and patients less than 75 years of age
(n=9015). Patients ≥75 years of age did not receive a 30 mg IV bolus prior to the normal dosage
regimen and had their SC dose adjusted to 0.75 mg/kg every 12 hours [see Dosage and
Administration (2.3)]. The incidence of bleeding complications was higher in patients ≥65 years
of age as compared to younger patients (<65 years).
8.6 Patients with Mechanical Prosthetic Heart Valves
The use of Lovenox has not been adequately studied for thromboprophylaxis in patients with
mechanical prosthetic heart valves and has not been adequately studied for long-term use in this
patient population. Isolated cases of prosthetic heart valve thrombosis have been reported in
patients with mechanical prosthetic heart valves who have received enoxaparin for
thromboprophylaxis. Some of these cases were pregnant women in whom thrombosis led to
maternal and fetal deaths. Insufficient data, the underlying disease and the possibility of
inadequate anticoagulation complicate the evaluation of these cases. Pregnant women with
mechanical prosthetic heart valves may be at higher risk for thromboembolism [see Warnings
and Precautions (5.7)].
8.7 Renal Impairment
In patients with renal impairment, there is an increase in exposure of enoxaparin sodium. All
such patients should be observed carefully for signs and symptoms of bleeding. Because
exposure of enoxaparin sodium is significantly increased in patients with severe renal
impairment (creatinine clearance <30 mL/min), a dosage adjustment is recommended for
therapeutic and prophylactic dosage ranges. No dosage adjustment is recommended in patients
with moderate (creatinine clearance 30-50 mL/min) and mild (creatinine clearance 50-80
mL/min) renal impairment [see Dosage and Administration (2.2) and Clinical Pharmacology
(12.3)].
8.8 Hepatic Impairment
The impact of hepatic impairment on enoxaparin’s exposure and antithrombotic effect has not
been investigated. Caution should be exercised when administering enoxaparin to patients with
hepatic impairment.
8.9 Low-Weight Patients
An increase in exposure of enoxaparin sodium with prophylactic dosages (non-weight adjusted)
has been observed in low-weight women (<45 kg) and low-weight men (<57 kg). All such
patients should be observed carefully for signs and symptoms of bleeding [see Clinical
Pharmacology (12.3)].
21
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663
10 OVERDOSAGE
Accidental overdosage following administration of Lovenox may lead to hemorrhagic
complications. Injected Lovenox may be largely neutralized by the slow IV injection of
protamine sulfate (1% solution). The dose of protamine sulfate should be equal to the dose of
Lovenox injected: 1 mg protamine sulfate should be administered to neutralize 1 mg Lovenox, if
enoxaparin sodium was administered in the previous 8 hours. An infusion of 0.5 mg protamine
per 1 mg of enoxaparin sodium may be administered if enoxaparin sodium was administered
greater than 8 hours previous to the protamine administration, or if it has been determined that a
second dose of protamine is required. The second infusion of 0.5 mg protamine sulfate per 1 mg
of Lovenox may be administered if the aPTT measured 2 to 4 hours after the first infusion
remains prolonged.
If at least 12 hours have elapsed since the last enoxaparin sodium injection, protamine
administration may not be required; however, even with higher doses of protamine, the aPTT
may remain more prolonged than following administration of heparin. In all cases, the anti-
Factor Xa activity is never completely neutralized (maximum about 60%). Particular care should
be taken to avoid overdosage with protamine sulfate. Administration of protamine sulfate can
cause severe hypotensive and anaphylactoid reactions. Because fatal reactions, often resembling
anaphylaxis, have been reported with protamine sulfate, it should be given only when
resuscitation techniques and treatment of anaphylactic shock are readily available. For
additional information consult the labeling of protamine sulfate injection products.
11 DESCRIPTION
Lovenox is a sterile aqueous solution containing enoxaparin sodium, a low molecular weight
heparin. The pH of the injection is 5.5 to 7.5.
Enoxaparin sodium is obtained by alkaline depolymerization of heparin benzyl ester derived
from porcine intestinal mucosa. Its structure is characterized by a 2-O-sulfo-4-enepyranosuronic
acid group at the non-reducing end and a 2-N,6-O-disulfo-D-glucosamine at the reducing end of
the chain. About 20% (ranging between 15% and 25%) of the enoxaparin structure contains an
1,6 anhydro derivative on the reducing end of the polysaccharide chain. The drug substance is
the sodium salt. The average molecular weight is about 4500 daltons. The molecular weight
distribution is:
<2000 daltons
≤20%
2000 to 8000 daltons ≥68%
>8000 daltons
≤18%
22
STRUCTURAL FORMULA
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681
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683
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690
691
692
693
694
695
668
673
674
675
*X = Percent of polysaccharide chain containing 1,6 anhydro derivative on the reducing end.
Lovenox 100 mg/mL Concentration contains 10 mg enoxaparin sodium (approximate anti-
Factor Xa activity of 1000 IU [with reference to the W.H.O. First International Low Molecular
Weight Heparin Reference Standard]) per 0.1 mL Water for Injection.
Lovenox 150 mg/mL Concentration contains 15 mg enoxaparin sodium (approximate anti-
Factor Xa activity of 1500 IU [with reference to the W.H.O. First International Low Molecular
Weight Heparin Reference Standard]) per 0.1 mL Water for Injection.
The Lovenox prefilled syringes and graduated prefilled syringes are preservative-free and
intended for use only as a single-dose injection. The multiple-dose vial contains 15 mg benzyl
alcohol per 1 mL as a preservative. [See Dosage and Administration (2) and How Supplied (18)
for dosage unit descriptions].
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Enoxaparin is a low molecular weight heparin which has antithrombotic properties.
X*= 15 to
25%
n= 0 to 20
R
100 - X
H
n =1 to 21
23
12.2 Pharmacodynamics
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703
704
705
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708
In humans, enoxaparin given at a dose of 1.5 mg/kg subcutaneously (SC) is characterized by a
higher ratio of anti-Factor Xa to anti-Factor IIa activity (mean ± SD, 14.0 ± 3.1) (based on areas
under anti-Factor activity versus time curves) compared to the ratios observed for heparin
(mean±SD, 1.22 ± 0.13). Increases of up to 1.8 times the control values were seen in the
thrombin time (TT) and the activated partial thromboplastin time (aPTT). Enoxaparin at a 1
mg/kg dose (100 mg / mL concentration), administered SC every 12 hours to patients in a large
clinical trial resulted in aPTT values of 45 seconds or less in the majority of patients (n = 1607).
A 30-mg IV bolus immediately followed by a 1 mg/kg SC administration resulted in aPTT post-
injection values of 50 seconds. The average aPTT prolongation value on Day 1 was about 16%
higher than on Day 4.
12.3 Pharmacokinetics
Absorption. Pharmacokinetic trials were conducted using the 100 mg/ml formulation. Maximum
anti-Factor Xa and anti-thrombin (anti-Factor IIa) activities occur 3 to 5 hours after SC injection
of enoxaparin. Mean peak anti-Factor Xa activity was 0.16 IU/mL (1.58 µg/mL) and 0.38
IU/mL (3.83µg/mL) after the 20 mg and the 40 mg clinically tested SC doses, respectively.
Mean (n = 46) peak anti-Factor Xa activity was 1.1 IU/mL at steady state in patients with
unstable angina receiving 1 mg/kg SC every 12 hours for 14 days. Mean absolute bioavailability
of enoxaparin, after 1.5 mg/kg given SC, based on anti-Factor Xa activity is approximately 100%
in healthy subjects.
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737
A 30 mg IV bolus immediately followed by a 1 mg/kg SC every 12 hours provided initial peak
anti-Factor Xa levels of 1.16 IU/mL (n=16) and average exposure corresponding to 84% of
steady-state levels. Steady state is achieved on the second day of treatment.
Enoxaparin pharmacokinetics appear to be linear over the recommended dosage ranges [see
Dosage and Administration (2)]. After repeated subcutaneous administration of 40 mg once
daily and 1.5 mg/kg once-daily regimens in healthy volunteers, the steady state is reached on day
2 with an average exposure ratio about 15% higher than after a single dose. Steady-state
enoxaparin activity levels are well predicted by single-dose pharmacokinetics. After repeated
subcutaneous administration of the 1 mg/kg twice daily regimen, the steady state is reached from
day 4 with mean exposure about 65% higher than after a single dose and mean peak and trough
levels of about 1.2 and 0.52 IU/mL, respectively. Based on enoxaparin sodium
pharmacokinetics, this difference in steady state is expected and within the therapeutic range.
Although not studied clinically, the 150 mg/mL concentration of enoxaparin sodium is projected
to result in anticoagulant activities similar to those of 100 mg/mL and 200 mg/mL concentrations
at the same enoxaparin dose. When a daily 1.5 mg/kg SC injection of enoxaparin sodium was
given to 25 healthy male and female subjects using a 100 mg/mL or a 200 mg/mL concentration
the following pharmacokinetic profiles were obtained [see Table 13]:
24
Table 13
738
Pharmacokinetic Parameters* After 5 Days of 1.5 mg/kg SC Once Daily Doses of
Enoxaparin Sodium Using 100 mg/mL or 200 mg/mL Concentrations
Concentration
Anti-Xa
Anti-IIa
Heptest
aPTT
Amax
(IU/mL or Δ
sec)
100 mg/mL
1.37 (±0.23)
0.23 (±0.05)
105 (±17)
19 (±5)
200 mg/mL
1.45 (±0.22)
0.26 (±0.05)
111 (±17)
22 (±7)
90% CI
102-110%
102-111%
tmax** (h)
100 mg/mL
3 (2-6)
4 (2-5)
2.5 (2-4.5)
3 (2-4.5)
200 mg/mL
3.5 (2-6)
4.5 (2.5-6)
3.3 (2-5)
3 (2-5)
AUC
(ss)
(h*IU/mL
or
h* Δ sec)
100 mg/mL
14.26 (±2.93)
1.54 (±0.61)
1321 (±219)
200 mg/mL
15.43 (±2.96)
1.77 (±0.67)
1401 (±227)
90% CI
105-112%
103-109%
*Means ± SD at Day 5 and 90% Confidence Interval (CI) of the ratio
**Median (range)
739
Distribution. The volume of distribution of anti-Factor Xa activity is about 4.3 L.
740
741
Elimination. Following intravenous (IV) dosing, the total body clearance of enoxaparin is 26
mL/min. After IV dosing of enoxaparin labeled with the gamma-emitter,
742
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745
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749
750
99mTc, 40% of
radioactivity and 8 to 20% of anti-Factor Xa activity were recovered in urine in 24 hours.
Elimination half-life based on anti-Factor Xa activity was 4.5 hours after a single SC dose to
about 7 hours after repeated dosing. Significant anti-Factor Xa activity persists in plasma for
about 12 hours following a 40 mg SC once a day dose.
Following SC dosing, the apparent clearance (CL/F) of enoxaparin is approximately 15 mL/min.
Metabolism. Enoxaparin sodium is primarily metabolized in the liver by desulfation and/or
depolymerization to lower molecular weight species with much reduced biological potency.
Renal clearance of active fragments represents about 10% of the administered dose and total
renal excretion of active and non-active fragments 40% of the dose.
751
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Special Populations
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Gender: Apparent clearance and Amax derived from anti-Factor Xa values following single SC
dosing (40 mg and 60 mg) were slightly higher in males than in females. The source of the
25
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gender difference in these parameters has not been conclusively identified; however, body
weight may be a contributing factor.
Geriatric: Apparent clearance and Amax derived from anti-Factor Xa values following single and
multiple SC dosing in geriatric subjects were close to those observed in young subjects.
Following once a day SC dosing of 40 mg enoxaparin, the Day 10 mean area under anti-Factor
Xa activity versus time curve (AUC) was approximately 15% greater than the mean Day 1 AUC
value. [see Dosage and Administration (2.3) and Use in Specific Populations (8.5)].
Renal Impairment: A linear relationship between anti-Factor Xa plasma clearance and creatinine
clearance at steady-state has been observed, which indicates decreased clearance of enoxaparin
sodium in patients with reduced renal function. Anti-Factor Xa exposure represented by AUC, at
steady-state, is marginally increased in mild (creatinine clearance 50–80 mL/min) and moderate
(creatinine clearance 30-50 mL/min) renal impairment after repeated subcutaneous 40 mg once-
daily doses. In patients with severe renal impairment (creatinine clearance <30 mL/min), the
AUC at steady state is significantly increased on average by 65% after repeated subcutaneous 40
mg once-daily doses [see Dosage and Administration (2.2) and Use in Specific Populations
(8.7)].
Hemodialysis: In a single study, elimination rate appeared similar but AUC was two-fold higher
than control population, after a single 0.25 or 0.5 mg/kg intravenous dose.
Hepatic Impairment: Studies with enoxaparin in patients with hepatic impairment have not been
conducted and the impact of hepatic impairment on the exposure to enoxaparin is unknown [see
Use in Specific Populations (8.8)].
Weight: After repeated subcutaneous 1.5 mg/kg once daily dosing, mean AUC of anti-Factor Xa
activity is marginally higher at steady-state in obese healthy volunteers (BMI 30-48 kg/m2)
compared to non-obese control subjects, while Amax is not increased.
When non-weight adjusted dosing was administered, it was found after a single-subcutaneous 40
mg dose, that anti-Factor Xa exposure is 52% higher in low-weight women (<45 kg) and 27%
higher in low-weight men (<57 kg) when compared to normal weight control subjects [see Use
in Specific Populations (8.9)].
Pharmacokinetic interaction: No pharmacokinetic interaction was observed between enoxaparin
and thrombolytics when administered concomitantly.
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803
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
No long-term studies in animals have been performed to evaluate the carcinogenic potential of
enoxaparin. Enoxaparin was not mutagenic in in vitro tests, including the Ames test, mouse
lymphoma cell forward mutation test, and human lymphocyte chromosomal aberration test, and
the in vivo rat bone marrow chromosomal aberration test. Enoxaparin was found to have no
effect on fertility or reproductive performance of male and female rats at SC doses up to 20
26
mg/kg/day or 141 mg/m2/day. The maximum human dose in clinical trials was 2.0 mg/kg/day or
78 mg/m
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828
2/day (for an average body weight of 70 kg, height of 170 cm, and body surface area of
1.8 m2).
13.2 Animal Toxicology
A single SC dose of 46.4 mg/kg enoxaparin was lethal to rats. The symptoms of acute toxicity
were ataxia, decreased motility, dyspnea, cyanosis, and coma.
14 CLINICAL TRIALS EXPERIENCE
14.1 Prophylaxis of Deep Vein Thrombosis (DVT) Following Abdominal Surgery in
Patients at Risk for Thromboembolic Complications
Abdominal surgery patients at risk include those who are over 40 years of age, obese,
undergoing surgery under general anesthesia lasting longer than 30 minutes or who have
additional risk factors such as malignancy or a history of DVT or pulmonary embolism.
In a double-blind, parallel group study of patients undergoing elective cancer surgery of the
gastrointestinal, urological, or gynecological tract, a total of 1116 patients were enrolled in the
study, and 1115 patients were treated. Patients ranged in age from 32 to 97 years (mean age 67
years) with 52.7% men and 47.3% women. Patients were 98% Caucasian, 1.1% Black, 0.4%
Asian and 0.4% others. Lovenox 40 mg SC, administered once a day, beginning 2 hours prior to
surgery and continuing for a maximum of 12 days after surgery, was comparable to heparin 5000
U every 8 hours SC in reducing the risk of DVT. The efficacy data are provided below [see
Table 14].
Table 14
Efficacy of Lovenox in the Prophylaxis of DVT Following Abdominal Surgery
Dosing Regimen
Indication
Lovenox
40 mg q.d. SC
n (%)
Heparin
5000 U q8h SC
n (%)
All Treated Abdominal
Surgery Patients
555 (100)
560 (100)
Treatment Failures
Total VTE1 (%)
56 (10.1)
63 (11.3)
(95% CI2: 8 to 13)
(95% CI: 9 to 14)
DVT Only (%)
54 (9.7)
(95% CI: 7 to 12)
61 (10.9)
(95% CI: 8 to 13)
1 VTE = Venous thromboembolic events which included DVT, PE, and death considered to be
thromboembolic in origin.
829
830
831
832
833
834
2 CI = Confidence Interval
In a second double-blind, parallel group study, Lovenox 40 mg SC once a day was compared to
heparin 5000 U every 8 hours SC in patients undergoing colorectal surgery (one-third with
27
cancer). A total of 1347 patients were randomized in the study and all patients were treated.
Patients ranged in age from 18 to 92 years (mean age 50.1 years) with 54.2% men and 45.8%
women. Treatment was initiated approximately 2 hours prior to surgery and continued for
approximately 7 to 10 days after surgery. The efficacy data are provided below [see Table 15].
835
836
837
838
839
840
841
842
Table 15
Efficacy of Lovenox in the Prophylaxis of Deep Vein Thrombosis Following Colorectal
Surgery
Dosing Regimen
Indication
Lovenox
40 mg q.d. SC
n (%)
Heparin
5000 U q8h SC
n (%)
All Treated Colorectal Surgery
Patients
673 (100)
674 (100)
Treatment Failures
Total VTE1 (%)
48 (7.1)
45 (6.7)
(95% CI2: 5 to 9)
(95% CI: 5 to 9)
DVT Only (%)
47 (7.0)
44 (6.5)
(95% CI: 5 to 9)
(95% CI: 5 to 8)
1 VTE = Venous thromboembolic events which included DVT, PE, and death considered to be
thromboembolic in origin.
843
844
845
846
847
848
849
850
851
852
853
854
855
856
857
2 CI = Confidence Interval
14.2 Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement
Surgery
Lovenox has been shown to reduce the risk of post-operative deep vein thrombosis (DVT)
following hip or knee replacement surgery.
In a double-blind study, Lovenox 30 mg every 12 hours SC was compared to placebo in patients
with hip replacement. A total of 100 patients were randomized in the study and all patients were
treated. Patients ranged in age from 41 to 84 years (mean age 67.1 years) with 45% men and
55% women. After hemostasis was established, treatment was initiated 12 to 24 hours after
surgery and was continued for 10 to 14 days after surgery. The efficacy data are provided below
[see Table 16].
28
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859
860
861
Table 16
Efficacy of Lovenox in the Prophylaxis of Deep Vein Thrombosis Following Hip
Replacement Surgery
Dosing Regimen
Indication
Lovenox
30 mg q12h SC
n (%)
Placebo
q12h SC
n (%)
All Treated Hip Replacement Patients
50 (100)
50 (100)
Treatment Failures
5 (10)1
Total DVT (%)
23 (46)
Proximal DVT (%)
1 (2)2
11 (22)
1 p value versus placebo = 0.0002
862
863
864
865
866
867
868
869
870
871
872
873
874
2 p value versus placebo = 0.0134
A double-blind, multicenter study compared three dosing regimens of Lovenox in patients with
hip replacement. A total of 572 patients were randomized in the study and 568 patients were
treated. Patients ranged in age from 31 to 88 years (mean age 64.7 years) with 63% men and
37% women. Patients were 93% Caucasian, 6% Black, <1% Asian, and 1% others. Treatment
was initiated within two days after surgery and was continued for 7 to 11 days after surgery. The
efficacy data are provided below [see Table 17].
Table 17
Efficacy of Lovenox in the Prophylaxis of Deep Vein Thrombosis Following Hip
Replacement Surgery
Dosing Regimen
Indication
10 mg q.d. SC
n (%)
30 mg q12h SC
n (%)
40 mg q.d. SC
n (%)
All Treated Hip
Replacement Patients
161 (100)
208 (100)
199 (100)
Treatment Failures
Total DVT (%)
22 (11)1
40 (25)
27 (14)
Proximal DVT (%)
17 (11)
8 (4)2
9 (5)
1 p value versus Lovenox 10 mg once a day = 0.0008
875
876
877
878
879
880
881
882
883
884
2 p value versus Lovenox 10 mg once a day = 0.0168
There was no significant difference between the 30 mg every 12 hours and 40 mg once a day
regimens. In a double-blind study, Lovenox 30 mg every 12 hours SC was compared to placebo
in patients undergoing knee replacement surgery. A total of 132 patients were randomized in the
study and 131 patients were treated, of which 99 had total knee replacement and 32 had either
unicompartmental knee replacement or tibial osteotomy. The 99 patients with total knee
replacement ranged in age from 42 to 85 years (mean age 70.2 years) with 36.4% men and
63.6% women. After hemostasis was established, treatment was initiated 12 to 24 hours after
29
surgery and was continued up to 15 days after surgery. The incidence of proximal and total DVT
after surgery was significantly lower for Lovenox compared to placebo. The efficacy data are
provided below [see Table 18].
885
886
887
888
889
890
891
Table 18
Efficacy of Lovenox in the Prophylaxis of Deep Vein Thrombosis Following Total Knee
Replacement Surgery
Dosing Regimen
Indication
Lovenox
30 mg q12h SC
n (%)
Placebo
q12h SC
n (%)
All Treated Total Knee
Replacement Patients
47 (100)
52 (100)
Treatment Failures
Total DVT (%)
5 (11)1
32 (62)
(95% CI2: 1 to 21)
(95% CI: 47 to 76)
0 (0)3
Proximal DVT (%)
7 (13)
(95% Upper CL4: 5)
(95% CI: 3 to 24)
1 p value versus placebo = 0.0001
892
893
894
895
896
897
898
899
900
901
902
903
904
905
906
907
908
909
910
911
912
913
914
915
2 CI = Confidence Interval
3 p value versus placebo = 0.013
4 CL = Confidence Limit
Additionally, in an open-label, parallel group, randomized clinical study, Lovenox 30 mg every
12 hours SC in patients undergoing elective knee replacement surgery was compared to heparin
5000 U every 8 hours SC. A total of 453 patients were randomized in the study and all were
treated. Patients ranged in age from 38 to 90 years (mean age 68.5 years) with 43.7% men and
56.3% women. Patients were 92.5% Caucasian, 5.3% Black, and 0.6% others. Treatment was
initiated after surgery and continued up to 14 days. The incidence of deep vein thrombosis was
significantly lower for Lovenox compared to heparin.
Extended Prophylaxis of Deep Vein Thrombosis Following Hip Replacement Surgery: In a study
of extended prophylaxis for patients undergoing hip replacement surgery, patients were treated,
while hospitalized, with Lovenox 40 mg SC, initiated up to 12 hours prior to surgery for the
prophylaxis of post-operative DVT. At the end of the peri-operative period, all patients
underwent bilateral venography. In a double-blind design, those patients with no venous
thromboembolic disease were randomized to a post-discharge regimen of either Lovenox 40 mg
(n = 90) once a day SC or to placebo (n = 89) for 3 weeks. A total of 179 patients were
randomized in the double-blind phase of the study and all patients were treated. Patients ranged
in age from 47 to 87 years (mean age 69.4 years) with 57% men and 43% women. In this
population of patients, the incidence of DVT during extended prophylaxis was significantly
lower for Lovenox compared to placebo. The efficacy data are provided below [see Table 19].
30
916
917
918
919
Table 19
Efficacy of Lovenox in the Extended Prophylaxis of Deep Vein Thrombosis Following Hip
Replacement Surgery
Post-Discharge Dosing Regimen
Indication (Post-Discharge)
Lovenox
40 mg q.d. SC
n (%)
Placebo
q.d. SC
n (%)
All Treated Extended
Prophylaxis Patients
90 (100)
89 (100)
Treatment Failures
Total DVT (%)
6 (7)1
18 (20)
(95% CI2: 3 to 14)
(95% CI: 12 to 30)
5 (6)3
Proximal DVT (%)
7 (8)
(95% CI: 2 to 13)
(95% CI: 3 to 16)
1 p value versus placebo = 0.008
920
921
922
923
924
925
926
927
928
929
930
931
932
933
934
935
936
937
938
939
940
941
942
943
944
945
946
947
2 CI= Confidence Interval
3 p value versus placebo = 0.537
In a second study, patients undergoing hip replacement surgery were treated, while hospitalized,
with Lovenox 40 mg SC, initiated up to 12 hours prior to surgery. All patients were examined
for clinical signs and symptoms of venous thromboembolic (VTE) disease. In a double-blind
design, patients without clinical signs and symptoms of VTE disease were randomized to a post-
discharge regimen of either Lovenox 40 mg (n = 131) once a day SC or to placebo (n = 131) for
3 weeks. A total of 262 patients were randomized in the study double-blind phase and all
patients were treated. Patients ranged in age from 44 to 87 years (mean age 68.5 years) with
43.1% men and 56.9% women. Similar to the first study the incidence of DVT during extended
prophylaxis was significantly lower for Lovenox compared to placebo, with a statistically
significant difference in both total DVT (Lovenox 21 [16%] versus placebo 45 [34%]; p = 0.001)
and proximal DVT (Lovenox 8 [6%] versus placebo 28 [21%]; p = <0.001).
14.3 Prophylaxis of Deep Vein Thrombosis (DVT) In Medical Patients with
Severely Restricted Mobility During Acute Illness
In a double blind multicenter, parallel group study, Lovenox 20 mg or 40 mg once a day SC was
compared to placebo in the prophylaxis of DVT in medical patients with severely restricted
mobility during acute illness (defined as walking distance of <10 meters for ≤3 days). This study
included patients with heart failure (NYHA Class III or IV); acute respiratory failure or
complicated chronic respiratory insufficiency (not requiring ventilatory support): acute infection
(excluding septic shock); or acute rheumatic disorder [acute lumbar or sciatic pain, vertebral
compression (due to osteoporosis or tumor), acute arthritic episodes of the lower extremities]. A
total of 1102 patients were enrolled in the study, and 1073 patients were treated. Patients ranged
in age from 40 to 97 years (mean age 73 years) with equal proportions of men and women.
Treatment continued for a maximum of 14 days (median duration 7 days). When given at a dose
31
of 40 mg once a day SC, Lovenox significantly reduced the incidence of DVT as compared to
placebo. The efficacy data are provided below [see Table 20].
948
949
950
951
952
953
Table 20
Efficacy of Lovenox in the Prophylaxis of Deep Vein Thrombosis in Medical Patients With
Severely Restricted Mobility During Acute Illness
Dosing Regimen
Lovenox
20 mg q.d. SC
n (%)
Lovenox
40 mg q.d. SC
n (%)
Placebo
Indication
n (%)
All Treated Medical Patients
During Acute Illness
351 (100)
360 (100)
362 (100)
Treatment Failure1
Total VTE2 (%)
43 (12.3)
16 (4.4)
43 (11.9)
Total DVT (%)
43 (12.3)
16 (4.4)
41 (11.3)
(95% CI3 8.8 to
15.7)
(95% CI3 2.3 to 6.6
)
(95% CI3 8.1 to 14.6
)
Proximal DVT (%)
13 (3.7)
5 (1.4)
14 (3.9)
1 Treatment failures during therapy, between Days 1 and 14.
954
955
956
957
958
959
960
961
962
963
964
965
966
967
968
969
970
971
972
973
974
975
976
2 VTE = Venous thromboembolic events which included DVT, PE, and death considered to be
thromboembolic in origin.
3 CI = Confidence Interval
At approximately 3 months following enrollment, the incidence of venous thromboembolism
remained significantly lower in the Lovenox 40 mg treatment group versus the placebo treatment
group.
14.4 Treatment of Deep Vein Thrombosis (DVT) with or without Pulmonary
Embolism (PE)
In a multicenter, parallel group study, 900 patients with acute lower extremity DVT with or
without PE were randomized to an inpatient (hospital) treatment of either (i) Lovenox 1.5 mg/kg
once a day SC, (ii) Lovenox 1 mg/kg every 12 hours SC, or (iii) heparin IV bolus (5000 IU)
followed by a continuous infusion (administered to achieve an aPTT of 55 to 85 seconds). A
total of 900 patients were randomized in the study and all patients were treated. Patients ranged
in age from 18 to 92 years (mean age 60.7 years) with 54.7% men and 45.3% women. All
patients also received warfarin sodium (dose adjusted according to PT to achieve an International
Normalization Ratio [INR] of 2.0 to 3.0), commencing within 72 hours of initiation of Lovenox
or standard heparin therapy, and continuing for 90 days. Lovenox or standard heparin therapy
was administered for a minimum of 5 days and until the targeted warfarin sodium INR was
achieved. Both Lovenox regimens were equivalent to standard heparin therapy in reducing the
risk of recurrent venous thromboembolism (DVT and/or PE). The efficacy data are provided
below [see Table 21].
32
977
978
979
980
Table 21
Efficacy of Lovenox in Treatment of Deep Vein Thrombosis
With or Without Pulmonary Embolism
Dosing Regimen1
Indication
Lovenox
1.5 mg/kg q.d. SC
n (%)
Lovenox
1 mg/kg q12h SC
n (%)
Heparin
aPTT Adjusted
IV Therapy
n (%)
All Treated DVT Patients
with or without PE
298 (100)
312 (100)
290 (100)
Patient Outcome
Total VTE2 (%)
13 (4.4)3
9 (2.9) 3
12 (4.1)
DVT Only (%)
11 (3.7)
7 (2.2)
8 (2.8)
Proximal DVT (%)
9 (3.0)
6 (1.9)
7 (2.4)
PE (%)
2 (0.7)
2 (0.6)
4 (1.4)
1 All patients were also treated with warfarin sodium commencing within 72 hours of Lovenox or
standard heparin therapy.
981
982
983
984
985
986
987
988
989
990
991
992
993
994
995
996
997
998
999
1000
1001
1002
2 VTE = venous thromboembolic event (DVT and/or PE).
3 The 95% Confidence Intervals for the treatment differences for total VTE were:
Lovenox once a day versus heparin (-3.0 to 3.5)
Lovenox every 12 hours versus heparin (-4.2 to 1.7).
Similarly, in a multicenter, open-label, parallel group study, patients with acute proximal DVT
were randomized to Lovenox or heparin. Patients who could not receive outpatient therapy were
excluded from entering the study. Outpatient exclusion criteria included the following: inability
to receive outpatient heparin therapy because of associated co-morbid conditions or potential for
non-compliance and inability to attend follow-up visits as an outpatient because of geographic
inaccessibility. Eligible patients could be treated in the hospital, but ONLY Lovenox patients
were permitted to go home on therapy (72%). A total of 501 patients were randomized in the
study and all patients were treated. Patients ranged in age from 19 to 96 years (mean age 57.8
years) with 60.5% men and 39.5% women. Patients were randomized to either Lovenox 1 mg/kg
every 12 hours SC or heparin IV bolus (5000 IU) followed by a continuous infusion
administered to achieve an aPTT of 60 to 85 seconds (in-patient treatment). All patients also
received warfarin sodium as described in the previous study. Lovenox or standard heparin
therapy was administered for a minimum of 5 days. Lovenox was equivalent to standard heparin
therapy in reducing the risk of recurrent venous thromboembolism. The efficacy data are
provided below [see Table 22].
33
1003
1004
1005
Table 22
Efficacy of Lovenox in Treatment of Deep Vein Thrombosis
Dosing Regimen1
Indication
Lovenox
1 mg/kg q12h SC
n (%)
Heparin
aPTT Adjusted
IV Therapy
n (%)
All Treated DVT Patients
247 (100)
254 (100)
Patient Outcome
Total VTE2 (%)
13 (5.3) 3
17 (6.7)
DVT Only (%)
11 (4.5)
14 (5.5)
Proximal DVT (%)
10 (4.0)
12 (4.7)
PE (%)
2 (0.8)
3 (1.2)
1 All patients were also treated with warfarin sodium commencing on the evening of the second
day of Lovenox or standard heparin therapy.
1006
1007
1008
1009
1010
1011
1012
1013
1014
1015
1016
1017
1018
1019
1020
1021
2 VTE = venous thromboembolic event (deep vein thrombosis [DVT] and/or pulmonary
embolism [PE]).
3 The 95% Confidence Intervals for the treatment difference for total VTE was: Lovenox versus
heparin
(- 5.6 to 2.7).
14.5 Prophylaxis of Ischemic Complications in Unstable Angina and Non-Q-Wave
Myocardial Infarction
In a multicenter, double-blind, parallel group study, patients who recently experienced unstable
angina or non-Q-wave myocardial infarction were randomized to either Lovenox 1 mg/kg every
12 hours SC or heparin IV bolus (5000 U) followed by a continuous infusion (adjusted to
achieve an aPTT of 55 to 85 seconds). A total of 3171 patients were enrolled in the study, and
3107 patients were treated. Patients ranged in age from 25-94 years (median age 64 years), with
33.4% of patients female and 66.6% male. Race was distributed as follows: 89.8% Caucasian,
4.8% Black, 2.0% Asian, and 3.5% other. All patients were also treated with aspirin 100 to 325
mg per day. Treatment was initiated within 24 hours of the event and continued until clinical
stabilization, revascularization procedures, or hospital discharge, with a maximal duration of 8
days of therapy. The combined incidence of the triple endpoint of death, myocardial infarction,
or recurrent angina was lower for Lovenox compared with heparin therapy at 14 days after
initiation of treatment. The lower incidence of the triple endpoint was sustained up to 30 days
after initiation of treatment. These results were observed in an analysis of both all-randomized
and all-treated patients. The efficacy data are provided below [see Table 23].
1022
1023
1024
1025
1026
1027
1028
1029
34
1030
1031
1032
1033
1034
Table 23
Efficacy of Lovenox in the Prophylaxis of Ischemic Complications in Unstable Angina and
Non-Q-Wave Myocardial Infarction
(Combined Endpoint of Death, Myocardial Infarction, or Recurrent Angina)
Dosing Regimen1
Indication
Lovenox
1mg/kg q12h SC
n (%)
Heparin
aPTT Adjusted
IV Therapy
n (%)
Reduction
(%)
p Value
All Treated Unstable
Angina and Non-Q-Wave
MI Patients
1578 (100)
1529 (100)
Timepoint2
48 Hours
96 (6.1)
112 (7.3)
1.2
0.120
14 Days
261 (16.5)
303 (19.8)
3.3
0.017
30 Days
313 (19.8)
358 (23.4)
3.6
0.014
1 All patients were also treated with aspirin 100 to 325 mg per day.
1035
1036
1037
1038
1039
1040
1041
1042
1043
1044
1045
1046
2 Evaluation timepoints are after initiation of treatment. Therapy continued for up to 8 days
(median duration of 2.6 days).
The combined incidence of death or myocardial infarction at all time points was lower for
Lovenox compared to standard heparin therapy, but did not achieve statistical significance. The
efficacy data are provided below [see Table 24].
Table 24
Efficacy of Lovenox in the Prophylaxis of Ischemic Complications in Unstable Angina and
Non-Q-Wave Myocardial Infarction
(Combined Endpoint of Death or Myocardial Infarction)
Dosing Regimen1
Indication
Lovenox
1 mg/kg q12h SC
n (%)
Heparin
aPTT Adjusted
IV Therapy
n (%)
Reduction
(%)
p Value
All Treated Unstable
Angina and Non-Q-Wave
MI Patients
1578 (100)
1529 (100)
Timepoint2
48 Hours
16 (1.0)
20 (1.3)
0.3
0.126
14 Days
76 (4.8)
93 (6.1)
1.3
0.115
30 Days
96 (6.1)
118 (7.7)
1.6
0.069
1 All patients were also treated with aspirin 100 to 325 mg per day.
1047
35
2 Evaluation timepoints are after initiation of treatment. Therapy continued for up to 8 days
(median duration of 2.6 days).
1048
1049
1050
1051
1052
1053
1054
1055
1056
1057
1058
1059
1060
1061
1062
1063
1064
1065
1066
1067
1068
1069
1070
1071
1072
1073
1074
1075
1076
1077
1078
1079
1080
1081
1082
1083
1084
1085
1086
1087
1088
1089
1090
1091
1092
In a survey one year following treatment, with information available for 92% of enrolled
patients, the combined incidence of death, myocardial infarction, or recurrent angina remained
lower for Lovenox versus heparin (32.0% vs 35.7%).
Urgent revascularization procedures were performed less frequently in the Lovenox group as
compared to the heparin group, 6.3% compared to 8.2% at 30 days (p = 0.047).
14.6 Treatment of acute ST-segment Elevation Myocardial Infarction (STEMI)
In a multicenter, double-blind, double-dummy, parallel group study, patients with STEMI who
were to be hospitalized within 6 hours of onset and were eligible to receive fibrinolytic therapy
were randomized in a 1:1 ratio to receive either Lovenox or unfractionated heparin.
Study medication was initiated between 15 minutes before and 30 minutes after the initiation of
fibrinolytic therapy. Unfractionated heparin was administered beginning with an IV bolus of 60
U/kg (maximum 4000 U) and followed with an infusion of 12 U/kg per hour (initial maximum
1000 U per hour) that was adjusted to maintain an aPTT of 1.5 to 2 times the control value. The
IV infusion was to be given for at least 48 hours. The enoxaparin dosing strategy was adjusted
according to the patient’s age and renal function. For patients younger than 75 years of age,
enoxaparin was given as a single 30-mg intravenous bolus plus a 1 mg/kg SC dose followed by
an SC injection of 1 mg/kg every 12 hours. For patients at least 75 years of age, the IV bolus
was not given and the SC dose was reduced to 0.75 mg/kg every 12 hours. For patients with
severe renal insufficiency (estimated creatinine clearance of less than 30 mL per minute), the
dose was to be modified to 1 mg/kg every 24 hours. The SC injections of enoxaparin were given
until hospital discharge or for a maximum of eight days (whichever came first). The mean
treatment duration for enoxaparin was 6.6 days. The mean treatment duration of unfractionated
heparin was 54 hours.
When percutaneous coronary intervention was performed during study medication period,
patients received antithrombotic support with blinded study drug. For patients on enoxaparin,
the PCI was to be performed on enoxaparin (no switch) using the regimen established in
previous studies, i.e. no additional dosing, if the last SC administration was less than 8 hours
before balloon inflation, IV bolus of 0.3 mg/kg enoxaparin if the last SC administration was
more than 8 hours before balloon inflation
All patients were treated with aspirin for a minimum of 30 days. Eighty percent of patients
received a fibrin-specific agent (19% tenecteplase, 5% reteplase and 55% alteplase) and 20%
received streptokinase.
Among 20,479 patients in the ITT population, the mean age was 60 years, and 76% were male.
Racial distribution was: 87% Caucasian, 9.8% Asian, 0.2% Black, and 2.8% other. Medical
history included previous MI (13%), hypertension (44%), diabetes (15%) and angiographic
evidence of CAD (5%). Concomitant medication included aspirin (95%), beta-blockers (86%),
36
ACE inhibitors (78%), statins (70%) and clopidogrel (27%). The MI at entry was anterior in
1093
43%, non-anterior in 56%, and both in 1%.
1094
1095
1096
1097
1098
1099
1100
1101
1102
1103
1104
1105
The primary efficacy end point was the composite of death from any cause or myocardial re-
infarction in the first 30 days after randomization. Total follow-up was one year.
The rate of the primary efficacy end point (death or myocardial re-infarction) was 9.9% in the
enoxaparin group, and 12.0% in the unfractionated heparin group, a 17% reduction in the relative
risk, (P=0.000003). [see Table 25]
Table 25
Efficacy of Lovenox Injection in the treatment of acute ST-segment Elevation Myocardial
Infarction
Enoxaparin
(N=10,256)
UFH
(N=10,223)
Relative Risk
(95% CI)
P Value
Outcome at 48 hours
n (%)
n (%)
Death or Myocardial Re-infarction
Death
Myocardial Re-infarction
Urgent Revascularization
Death or Myocardial Re-infarction or Urgent
Revascularization
478 (4.7)
383 (3.7)
102 (1.0)
74 (0.7)
548 (5.3)
531 (5.2)
390 (3.8)
156 (1.5)
96 (0.9)
622 (6.1)
0.90 (0.80 to 1.01)
0.98 (0.85 to 1.12)
0.65 (0.51 to 0.84)
0.77 (0.57 to 1.04)
0.88 (0.79 to 0.98)
0.08
0.76
<0.001
0.09
0.02
Outcome at 8 Days
Death or Myocardial Re-infarction
Death
Myocardial Re-infarction
Urgent Revascularization
Death or Myocardial Re-infarction or Urgent
Revascularization
740 (7.2)
559 (5.5)
204 (2.0)
145 (1.4)
874 (8.5)
954 (9.3)
605 (5.9)
379 (3.7)
247 (2.4)
1181 (11.6)
0.77 (0.71 to 0.85)
0.92 (0.82 to 1.03)
0.54 (0.45 to 0.63)
0.59 (0.48 to 0.72)
0.74 (0.68 to 0.80)
<0.001
0.15
<0.001
<0.001
<0.001
Outcome at 30 Days
Primary efficacy endpoint
(Death or Myocardial Re-infarction)
Death
Myocardial Re-infarction
Urgent Revascularization
Death or Myocardial Re-infarction or Urgent
Revascularization
1017 (9.9)
708 (6.9)
352 (3.4)
213 (2.1)
1199 (11.7)
1223 (12.0)
765 (7.5)
508 (5.0)
286 (2.8)
1479 (14.5)
0.83 (0.77 to 0.90)
0.000003
0.92 (0.84 to 1.02)
0.11
0.69 (0.60 to 0.79)
<0.001
0.74 (0.62 to 0.88)
<0.001
0.81 (0.75 to 0.87)
<0.001
Note: Urgent revascularization denotes episodes of recurrent myocardial ischemia (without infarction) leading to the
clinical decision to perform coronary revascularization during the same hospitalization. CI denotes confidence intervals.
1106
37
1107
1108
1109
1110
1111
1112
1113
1114
1115
The beneficial effect of enoxaparin on the primary end point was consistent across key
subgroups including age, gender, infarct location, history of diabetes, history of prior myocardial
infarction, fibrinolytic agent administered, and time to treatment with study drug (see Figure 1);
however, it is necessary to interpret such subgroup analyses with caution.
Figure 1. Relative Risks of and Absolute Event Rates for the Primary End Point at 30 Days in Various
Subgroups *
1116
1117
1118
1119
1120
1121
1122
1123
1124
1125
1126
1127
* The primary efficacy end point was the composite of death from any cause or myocardial re-infarction in the first
30 days. The overall treatment effect of enoxaparin as compared to the unfractionated heparin is shown at the
bottom of the figure. For each subgroup, the circle is proportional to the number and represents the point estimate of
the treatment effect and the horizontal lines represent the 95 percent confidence intervals. Fibrin-specific
fibrinolytic agents included alteplase, tenecteplase and reteplase. Time to treatment indicates the time from the
onset of symptoms to the administration of study drug (median, 3.2 hours).
The beneficial effect of enoxaparin on the primary end point observed during the first 30 days
was maintained over a 12 month follow-up period (see Figure 2).
38
Figure 2 - Kaplan-Meier plot - death or myocardial re-infarction at 30 days - ITT
population
1128
1129
1130
1131
1132
1133
1134
1135
1136
1137
1138
1139
1140
1141
1142
1143
1144
1145
1146
1147
1148
There is a trend in favor of enoxaparin during the first 48 hours, but most of the treatment
difference is attributed to a step increase in the event rate in the UFH group at 48 hours (seen in
Figure 2), an effect that is more striking when comparing the event rates just prior to and just
subsequent to actual times of discontinuation. These results provide evidence that UFH was
effective and that it would be better if used longer than 48 hours. There is a similar increase in
endpoint event rate when enoxaparin was discontinued, suggesting that it too was discontinued
too soon in this study.
The rates of major hemorrhages (defined as requiring 5 or more units of blood for transfusion, or
15% drop in hematocrit or clinically overt bleeding, including intracranial hemorrhage) at 30
days were 2.1% in the enoxaparin group and 1.4% in the unfractionated heparin group. The rates
of intracranial hemorrhage at 30 days were 0.8% in the enoxaparin group 0.7% in the
unfractionated heparin group. The 30-day rate of the composite endpoint of death, myocardial
re-infarction or ICH (a measure of net clinical benefit) was significantly lower in the enoxaparin
group (10.1%) as compared to the heparin group (12.2%).
39
16 HOW SUPPLIED/STORAGE AND HANDLING
1149
1150
Lovenox is available in two concentrations [see Tables 26 and 27]:
Table 26
100 mg/mL Concentration
Dosage Unit / Strength1
Anti-Xa
Activity2
Package Size
(per carton)
Label Color
NDC #
0075-
Prefilled Syringes3
30 mg / 0.3 mL
3000 IU
10 syringes
Medium Blue
0624-30
40 mg / 0.4 mL
4000 IU
10 syringes
Yellow
0620-40
Graduated Prefilled
Syringes3
60 mg / 0.6 mL
6000 IU
10 syringes
Orange
0621-60
80 mg / 0.8 mL
8000 IU
10 syringes
Brown
0622-80
100 mg / 1 mL
10,000 IU
10 syringes
Black
0623-00
Multiple-Dose Vial4
300 mg / 3 mL
30,000 IU
1 vial
Red
0626-03
1 Strength represents the number of milligrams of enoxaparin sodium in Water for Injection.
Lovenox 30 and 40 mg prefilled syringes, and 60, 80, and 100 mg graduated prefilled syringes
each contain 10 mg enoxaparin sodium per 0.1 mL Water for Injection.
1151
1152
1153
1154
1155
1156
1157
1158
2 Approximate anti-Factor Xa activity based on reference to the W.H.O. First International Low
Molecular Weight Heparin Reference Standard.
3 Each Lovenox syringe is affixed with a 27 gauge x 1/2 inch needle.
4 Each Lovenox multiple-dose vial contains 15 mg benzyl alcohol per 1 mL as a preservative.
Table 27
150 mg/mL Concentration
Dosage Unit / Strength1
Anti-Xa
Activity2
Package Size
(per carton)
Syringe
Label Color
NDC #
0075-
Graduated Prefilled
Syringes3
120 mg / 0.8 mL
12,000 IU
10 syringes
Purple
2912-01
150 mg / 1 mL
15,000 IU
10 syringes
Navy Blue
2915-01
1 Strength represents the number of milligrams of enoxaparin sodium in Water for Injection.
Lovenox 120 and 150 mg graduated prefilled syringes contain 15 mg enoxaparin sodium per
0.1 mL Water for Injection.
1159
1160
1161
1162
1163
1164
1165
2 Approximate anti-Factor Xa activity based on reference to the W.H.O. First International Low
Molecular Weight Heparin Reference Standard.
3 Each Lovenox graduated prefilled syringe is affixed with a 27 gauge x 1/2 inch needle.
40
1166
1167
1168
1169
1170
1171
1172
1173
1174
1175
1176
1177
1178
1179
1180
1181
1182
1183
1184
1185
1186
1187
1188
1189
1190
1191
1192
1193
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room
Temperature].
Do not store the multiple-dose vials for more than 28 days after the first use
Keep out of the reach of children.
17 PATIENT COUNSELING INFORMATION
Patients should be told that it may take them longer than usual to stop bleeding, that they may
bruise and/or bleed more easily when they are treated with Lovenox, and that they should report
any unusual bleeding or bruising to their physician [see Warnings and Precautions (5.1, 5.5)].
Patients should inform physicians and dentists that they are taking Lovenox and/or any other
product known to affect bleeding before any surgery is scheduled and before any new drug is
taken [see Warnings and Precautions (5.3)].
Patients should inform their physicians and dentists of all medications they are taking, including
those obtained without a prescription [see Drug Interactions (7)].
sanofi-aventis U.S. LLC
Bridgewater, NJ 08807
Multiple-dose vials are also manufactured by DSM Pharmaceuticals, Inc.
Greenville, NC 27835
Manufactured for:
sanofi-aventis U.S. LLC
Bridgewater, NJ 08807
41
|
custom-source
|
2025-02-12T13:46:56.875722
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/022138,020164s075lbl.pdf', 'application_number': 20164, 'submission_type': 'SUPPL ', 'submission_number': 75}
|
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NDA 20-164/S-055
Page 3
Rx only
Rev. XXXX
SPINAL / EPIDURAL HEMATOMAS
When neuraxial anesthesia (epidural/spinal anesthesia) or spinal puncture is employed, patients
anticoagulated or scheduled to be anticoagulated with low molecular weight heparins or heparinoids
for prevention of thromboembolic complications are at risk of developing an epidural or spinal
hematoma which can result in long-term or permanent paralysis.
The risk of these events is increased by the use of indwelling epidural catheters for administration of
analgesia or by the concomitant use of drugs affecting hemostasis such as non steroidal anti-
inflammatory drugs (NSAIDs), platelet inhibitors, or other anticoagulants. The risk also appears to be
increased by traumatic or repeated epidural or spinal puncture.
Patients should be frequently monitored for signs and symptoms of neurological impairment. If
neurologic compromise is noted, urgent treatment is necessary.
The physician should consider the potential benefit versus risk before neuraxial intervention in patients
anticoagulated or to be anticoagulated for thromboprophylaxis (see also WARNINGS, Hemorrhage,
and PRECAUTIONS, Drug Interactions).
DESCRIPTION
Lovenox Injection is a sterile aqueous solution containing enoxaparin sodium, a low molecular weight
heparin.
Lovenox Injection is available in two concentrations:
1. 100 mg per mL
-Prefilled Syringes
30 mg / 0.3 mL, 40 mg / 0.4 mL
-Graduated Prefilled Syringes
60 mg / 0.6 mL, 80 mg / 0.8 mL, 100 mg / 1 mL
-Multiple-Dose Vials
300 mg / 3.0 mL
Lovenox Injection 100 mg/mL Concentration contains 10 mg enoxaparin sodium (approximate anti-
Factor Xa activity of 1000 IU [with reference to the W.H.O. First International Low Molecular Weight
Heparin Reference Standard]) per 0.1 mL Water for Injection.
2. 150 mg per mL
-Graduated Prefilled Syringes
120 mg / 0.8 mL, 150 mg / 1 mL
Lovenox Injection 150 mg/mL Concentration contains 15 mg enoxaparin sodium (approximate anti-
Factor Xa activity of 1500 IU [with reference to the W.H.O. First International Low Molecular Weight
Heparin Reference Standard]) per 0.1 mL Water for Injection.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-164/S-055
Page 4
The Lovenox prefilled syringes and graduated prefilled syringes are preservative-free and intended for
use only as a single-dose injection. The multiple-dose vial contains 15 mg / 1.0 mL benzyl alcohol as a
preservative. (See DOSAGE AND ADMINISTRATION and HOW SUPPLIED for dosage unit
descriptions.) The pH of the injection is 5.5 to 7.5.
Enoxaparin sodium is obtained by alkaline depolymerization of heparin benzyl ester derived from
porcine intestinal mucosa. Its structure is characterized by a 2-O-sulfo-4-enepyranosuronic acid group
at the non-reducing end and a 2-N,6-O-disulfo-D-glucosamine at the reducing end of the chain. About
20% (ranging between 15% and 25%) of the enoxaparin structure contains an 1,6 anhydro derivative
on the reducing end of the polysaccharide chain. The drug substance is the sodium salt. The average
molecular weight is about 4500 daltons. The molecular weight distribution is:
<2000 daltons
≤20%
2000 to 8000 daltons ≥68%
>8000 daltons
≤18%
STRUCTURAL FORMULA
*X = Percent of polysaccharide chain containing 1,6 anhydro derivative on the reducing end.
CLINICAL PHARMACOLOGY
Enoxaparin is a low molecular weight heparin which has antithrombotic properties. In humans,
enoxaparin given at a dose of 1.5 mg/kg subcutaneously (SC) is characterized by a higher ratio of anti-
Factor Xa to anti-Factor IIa activity (mean±SD, 14.0±3.1) (based on areas under anti-Factor activity
versus time curves) compared to the ratios observed for heparin (mean±SD, 1.22±0.13). Increases of
X*= 15 to 25%
n= 0 to 20
R
100 - X
H
n =1 to 21
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-164/S-055
Page 5
up to 1.8 times the control values were seen in the thrombin time (TT) and the activated partial
thromboplastin time (aPTT). Enoxaparin at a 1 mg/kg dose (100 mg / mL concentration), administered
SC every 12 hours to patients in a large clinical trial resulted in aPTT values of 45 seconds or less in
the majority of patients (n = 1607).
Pharmacokinetics (conducted using 100 mg / mL concentration):
Absorption. Maximum anti-Factor Xa and anti-thrombin (anti-Factor IIa) activities occur 3 to 5 hours
after SC injection of enoxaparin. Mean peak anti-Factor Xa activity was 0.16 IU/mL (1.58 µg/mL) and
0.38 IU/mL (3.83 µg/mL) after the 20 mg and the 40 mg clinically tested SC doses, respectively. Mean
(n = 46) peak anti-Factor Xa activity was 1.1 IU/mL at steady state in patients with unstable angina
receiving 1 mg/kg SC every 12 hours for 14 days. Mean absolute bioavailability of enoxaparin, after
1.5 mg/kg given SC, based on anti-Factor Xa activity is approximately 100% in healthy volunteers.
Enoxaparin pharmacokinetics appear to be linear over the recommended dosage ranges (see Dosage
and Administration). After repeated subcutaneous administration of 40 mg once daily and 1.5 mg/kg
once-daily regimens in healthy volunteers, the steady state is reached on day 2 with an average
exposure ratio about 15% higher than after a single dose. Steady-state enoxaparin activity levels are
well predicted by single-dose pharmacokinetics. After repeated subcutaneous administration of the 1
mg/kg twice daily regimen, the steady state is reached from day 4 with mean exposure about 65%
higher than after a single dose and mean peak and trough levels of about 1.2 and 0.52 IU/mL,
respectively. Based on enoxaparin sodium pharmacokinetics, this difference in steady state is expected
and within the therapeutic range.
Although not studied clinically, the 150 mg/mL concentration of enoxaparin sodium is projected to
result in anticoagulant activities similar to those of 100 mg/mL and 200 mg/mL concentrations at the
same enoxaparin dose. When a daily 1.5 mg/kg SC injection of enoxaparin sodium was given to 25
healthy male and female subjects using a 100 mg/mL or a 200 mg/mL concentration the following
pharmacokinetic profiles were obtained (see table below):
Pharmacokinetic Parameters* After 5 Days of 1.5 mg/kg SC Once Daily Doses of
Enoxaparin Sodium Using 100 mg/mL or 200 mg/mL Concentrations
Concentration
Anti-Xa
Anti-IIa
Heptest
aPTT
Amax
(IU/mL or ∆ sec)
100 mg/mL
1.37 (±0.23)
0.23 (±0.05)
104.5 (±16.6)
19.3 (±4.7)
200 mg/mL
1.45 (±0.22)
0.26 (±0.05)
110.9 (±17.1)
22 (±6.7)
90% CI
102-110%
102-111%
tmax** (h)
100 mg/mL
3 (2-6)
4 (2-5)
2.5 (2-4.5)
3 (2-4.5)
200 mg/mL
3.5 (2-6)
4.5 (2.5-6)
3.3 (2-5)
3 (2-5)
AUC
(ss)
(h*IU/mL or h* ∆
sec)
100 mg/mL
14.26 (±2.93)
1.54 (±0.61)
1321 (±219)
200 mg/mL
15.43 (±2.96)
1.77 (±0.67)
1401 (±227)
90% CI
105-112%
103-109%
*Means ± SD at Day 5 and 90% Confidence Interval (CI) of the ratio
**Median (range)
Distribution. The volume of distribution of anti-Factor Xa activity is about 4.3 L.
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NDA 20-164/S-055
Page 6
Elimination. Following intravenous (i.v.) dosing, the total body clearance of enoxaparin is 26 mL/min.
After i.v. dosing of enoxaparin labeled with the gamma-emitter, 99mTc, 40% of radioactivity and 8 to
20% of anti-Factor Xa activity were recovered in urine in 24 hours. Elimination half-life based on anti-
Factor Xa activity was 4.5 hours after a single SC dose to about 7 hours after repeated dosing.
Following a 40 mg SC once a day dose, significant anti-Factor Xa activity persists in plasma for about
12 hours.
Following SC dosing, the apparent clearance (CL/F) of enoxaparin is approximately 15 mL/min.
Metabolism. Enoxaparin sodium is primarily metabolized in the liver by desulfation and/or
depolymerization to lower molecular weight species with much reduced biological potency. Renal
clearance of active fragments represents about 10% of the administered dose and total renal excretion
of active and non-active fragments 40% of the dose.
Special Populations
Gender: Apparent clearance and Amax derived from anti-Factor Xa values following single SC dosing
(40 mg and 60 mg) were slightly higher in males than in females. The source of the gender difference
in these parameters has not been conclusively identified, however, body weight may be a contributing
factor.
Geriatric: Apparent clearance and Amax derived from anti-Factor Xa values following single and
multiple SC dosing in elderly subjects were close to those observed in young subjects. Following once
a day SC dosing of 40 mg enoxaparin, the Day 10 mean area under anti-Factor Xa activity versus time
curve (AUC) was approximately 15% greater than the mean Day 1 AUC value. (See
PRECAUTIONS.)
Renal Impairment: A linear relationship between anti-Factor Xa plasma clearance and creatinine
clearance at steady-state has been observed, which indicates decreased clearance of enoxaparin sodium
in patients with reduced renal function. Anti-Factor Xa exposure represented by AUC, at steady-state,
is marginally increased in mild (creatinine clearance 50 –80 mL/min) and moderate (creatinine
clearance 30-50 mL/min) renal impairment after repeated subcutaneous 40 mg once daily doses. In
patients with severe renal impairment (creatinine clearance <30 mL/min), the AUC at steady state is
significantly increased on average by 65% after repeated subcutaneous 40-mg once-daily doses (see
PRECAUTIONS and DOSAGE AND ADMINISTRATION).
Weight: After repeated subcutaneous 1.5 mg/kg once daily dosing, mean AUC of anti-Factor Xa
activity is marginally higher at steady-state in obese healthy volunteers (BMI 30-48 kg/m2) compared
to non-obese control subjects, while Amax is not increased.
When non-weight adjusted dosing was administered, it was found after a single-subcutaneous 40-mg
dose, that anti-Factor Xa exposure is 52% higher in low-weight women (<45 kg) and 27% higher in
low-weight men (<57 kg) when compared to normal weight control subjects (see PRECAUTIONS).
Hemodialysis: In a single study, elimination rate appeared similar but AUC was two-fold higher than
control population, after a single 0.25 or 0.50 mg/kg intravenous dose.
CLINICAL TRIALS
Prophylaxis of Deep Vein Thrombosis Following Abdominal Surgery in Patients at Risk for
Thromboembolic Complications: Abdominal surgery patients at risk include those who are over 40
years of age, obese, undergoing surgery under general anesthesia lasting longer than 30 minutes or
who have additional risk factors such as malignancy or a history of deep vein thrombosis or pulmonary
embolism.
In a double-blind, parallel group study of patients undergoing elective cancer surgery of the
gastrointestinal, urological, or gynecological tract, a total of 1116 patients were enrolled in the study,
and 1115 patients were treated. Patients ranged in age from 32 to 97 years (mean age 67 years) with
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-164/S-055
Page 7
52.7% men and 47.3% women. Patients were 98% Caucasian, 1.1% Black, 0.4% Oriental, and 0.4%
others. Lovenox Injection 40 mg SC, administered once a day, beginning 2 hours prior to surgery and
continuing for a maximum of 12 days after surgery, was comparable to heparin 5000 U every 8 hours
SC in reducing the risk of deep vein thrombosis (DVT). The efficacy data are provided below.
EFFICACY OF LOVENOX INJECTION IN THE PROPHYLAXIS OF DEEP VEIN THROMBOSIS FOLLOWING ABDOMINAL
SURGERY
Dosing Regimen
Indication
Lovenox Inj.
40 mg q.d. SC
n (%)
Heparin
5000 U q8h SC
n (%)
All Treated Abdominal
Surgery Patients
555 (100)
560 (100)
Treatment Failures
Total VTE1 (%)
56 (10.1)
(95% CI2: 8 to 13)
63 (11.3)
(95% CI: 9 to 14)
DVT Only (%)
54 (9.7)
(95% CI: 7 to 12)
61 (10.9)
(95% CI: 8 to 13)
1 VTE = Venous thromboembolic events which included DVT, PE, and death considered to be thromboembolic in origin.
2 CI = Confidence Interval
In a second double-blind, parallel group study, Lovenox Injection 40 mg SC once a day was compared
to heparin 5000 U every 8 hours SC in patients undergoing colorectal surgery (one-third with cancer).
A total of 1347 patients were randomized in the study and all patients were treated. Patients ranged in
age from 18 to 92 years (mean age 50.1 years) with 54.2% men and 45.8% women. Treatment was
initiated approximately 2 hours prior to surgery and continued for approximately 7 to 10 days after
surgery. The efficacy data are provided below.
Efficacy of Lovenox Injection in the Prophylaxis of Deep Vein Thrombosis Following Colorectal Surgery
Dosing Regimen
Indication
Lovenox Inj.
40 mg q.d. SC
n (%)
Heparin
5000 U q8h SC
n (%)
All Treated Colorectal Surgery
Patients
673 (100)
674 (100)
Treatment Failures
Total VTE1 (%)
48 (7.1)
(95% CI2: 5 to 9)
45 (6.7)
(95% CI: 5 to 9)
DVT Only (%)
47 (7.0)
(95% CI: 5 to 9)
44 (6.5)
(95% CI: 5 to 8)
1 VTE = Venous thromboembolic events which included DVT, PE, and death considered to be thromboembolic in origin.
2 CI = Confidence Interval
Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery: Lovenox
Injection has been shown to reduce the risk of post-operative deep vein thrombosis (DVT) following
hip or knee replacement surgery.
In a double-blind study, Lovenox Injection 30 mg every 12 hours SC was compared to placebo in
patients with hip replacement. A total of 100 patients were randomized in the study and all patients
were treated. Patients ranged in age from 41 to 84 years (mean age 67.1 years) with 45% men and
This label may not be the latest approved by FDA.
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NDA 20-164/S-055
Page 8
55% women. After hemostasis was established, treatment was initiated 12 to 24 hours after surgery
and was continued for 10 to 14 days after surgery. The efficacy data are provided below.
Efficacy of Lovenox Injection in the Prophylaxis of Deep Vein Thrombosis Following Hip Replacement Surgery
Dosing Regimen
Indication
Lovenox Inj.
30 mg q12h SC
n (%)
Placebo
q12h SC
n (%)
All Treated Hip Replacement Patients
50 (100)
50 (100)
Treatment Failures
Total DVT (%)
5 (10)1
23 (46)
Proximal DVT (%)
1 (2)2
11 (22)
1 p value versus placebo = 0.0002
2 p value versus placebo = 0.0134
A double-blind, multicenter study compared three dosing regimens of Lovenox Injection in patients
with hip replacement. A total of 572 patients were randomized in the study and 568 patients were
treated. Patients ranged in age from 31 to 88 years (mean age 64.7 years) with 63% men and 37%
women. Patients were 93% Caucasian, 6% Black, <1% Oriental, and 1% others. Treatment was
initiated within two days after surgery and was continued for 7 to 11 days after surgery. The efficacy
data are provided below.
Efficacy of Lovenox Injection in the Prophylaxis of Deep Vein Thrombosis Following Hip Replacement Surgery
Dosing Regimen
Indication
10 mg q.d. SC
n (%)
30 mg q12h SC
n (%)
40 mg q.d. SC
n (%)
All Treated Hip
Replacement Patients
161 (100)
208 (100)
199 (100)
Treatment Failures
Total DVT (%)
40 (25)
22 (11)1
27 (14)
Proximal DVT (%)
17 (11)
8 (4)2
9 (5)
1 p value versus Lovenox 10 mg once a day = 0.0008
2 p value versus Lovenox 10 mg once a day = 0.0168
There was no significant difference between the 30 mg every 12 hours and 40 mg once a day regimens.
In a double-blind study, Lovenox Injection 30 mg every 12 hours SC was compared to placebo in
patients undergoing knee replacement surgery. A total of 132 patients were randomized in the study
and 131 patients were treated, of which 99 had total knee replacement and 32 had either
unicompartmental knee replacement or tibial osteotomy. The 99 patients with total knee replacement
ranged in age from 42 to 85 years (mean age 70.2 years) with 36.4% men and 63.6% women. After
hemostasis was established, treatment was initiated 12 to 24 hours after surgery and was continued up
to 15 days after surgery. The incidence of proximal and total DVT after surgery was significantly
lower for Lovenox Injection compared to placebo. The efficacy data are provided below.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-164/S-055
Page 9
Efficacy of Lovenox Injection in the Prophylaxis of Deep Vein Thrombosis Following Total Knee Replacement Surgery
Dosing Regimen
Indication
Lovenox Inj.
30 mg q12h SC
n (%)
Placebo
q12h SC
n (%)
All Treated Total Knee
Replacement Patients
47 (100)
52 (100)
Treatment Failures
Total DVT (%)
5 (11)1
(95% CI2: 1 to 21)
32 (62)
(95% CI: 47 to 76)
Proximal DVT (%)
0 (0)3
(95% Upper CL4: 5)
7 (13)
(95% CI: 3 to 24)
1 p value versus placebo = 0.0001
2 CI = Confidence Interval
3 p value versus placebo = 0.013
4 CL = Confidence Limit
Additionally, in an open-label, parallel group, randomized clinical study, Lovenox Injection 30 mg
every 12 hours SC in patients undergoing elective knee replacement surgery was compared to heparin
5000 U every 8 hours SC. A total of 453 patients were randomized in the study and all were treated.
Patients ranged in age from 38 to 90 years (mean age 68.5 years) with 43.7% men and 56.3% women.
Patients were 92.5% Caucasian, 5.3% Black, 0.2% Oriental, and 0.4% others. Treatment was initiated
after surgery and continued up to 14 days. The incidence of deep vein thrombosis was significantly
lower for Lovenox Injection compared to heparin.
Extended Prophylaxis of Deep Vein Thrombosis Following Hip Replacement Surgery: In a study of
extended prophylaxis for patients undergoing hip replacement surgery, patients were treated, while
hospitalized, with Lovenox Injection 40 mg SC, initiated up to 12 hours prior to surgery for the
prophylaxis of post-operative DVT. At the end of the peri-operative period, all patients underwent
bilateral venography. In a double-blind design, those patients with no venous thromboembolic disease
were randomized to a post-discharge regimen of either Lovenox Injection 40 mg (n = 90) once a day
SC or to placebo (n = 89) for 3 weeks. A total of 179 patients were randomized in the double-blind
phase of the study and all patients were treated. Patients ranged in age from 47 to 87 years (mean age
69.4 years) with 57% men and 43% women. In this population of patients, the incidence of DVT
during extended prophylaxis was significantly lower for Lovenox Injection compared to placebo. The
efficacy data are provided below.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-164/S-055
Page 10
Efficacy of Lovenox Injection in the Extended Prophylaxis of Deep Vein Thrombosis Following Hip Replacement
Surgery
Post-Discharge Dosing Regimen
Indication (Post-Discharge)
Lovenox Inj.
40 mg q.d. SC
n (%)
Placebo
q.d. SC
n (%)
All Treated Extended
Prophylaxis Patients
90 (100)
89 (100)
Treatment Failures
Total DVT (%)
6 (7)1
(95% CI2: 3 to 14)
18 (20)
(95% CI: 12 to 30)
Proximal DVT (%)
5 (6)3
(95% CI: 2 to 13)
7 (8)
(95% CI: 3 to 16)
1 p value versus placebo = 0.008
2 CI= Confidence Interval
3 p value versus placebo = 0.537
In a second study, patients undergoing hip replacement surgery were treated, while hospitalized, with
Lovenox Injection 40 mg SC, initiated up to 12 hours prior to surgery. All patients were examined for
clinical signs and symptoms of venous thromboembolic (VTE) disease. In a double-blind design,
patients without clinical signs and symptoms of VTE disease were randomized to a post-discharge
regimen of either Lovenox Injection 40 mg (n = 131) once a day SC or to placebo (n = 131) for 3
weeks. A total of 262 patients were randomized in the study double-blind phase and all patients were
treated. Patients ranged in age from 44 to 87 years (mean age 68.5 years) with 43.1% men and 56.9%
women. Similar to the first study the incidence of DVT during extended prophylaxis was significantly
lower for Lovenox Injection compared to placebo, with a statistically significant difference in both
total DVT (Lovenox Injection 21 [16%] versus placebo 45 [34%]; p = 0.001) and proximal DVT
(Lovenox Injection 8 [6%] versus placebo 28 [21%]; p = <0.001).
Prophylaxis of Deep Vein Thrombosis (DVT) In Medical Patients with Severely Restricted
Mobility During Acute Illness: In a double blind multicenter, parallel group study, Lovenox
Injection 20 mg or 40 mg once a day SC was compared to placebo in the prophylaxis of DVT in
medical patients with severely restricted mobility during acute illness (defined as walking distance of
<10 meters for ≤3 days). This study included patients with heart failure (NYHA Class III or IV); acute
respiratory failure or complicated chronic respiratory insufficiency (not requiring ventilatory support):
acute infection (excluding septic shock); or acute rheumatic disorder [acute lumbar or sciatic pain,
vertebral compression (due to osteoporosis or tumor), acute arthritic episodes of the lower extremities].
A total of 1102 patients were enrolled in the study, and 1073 patients were treated. Patients ranged in
age from 40 to 97 years (mean age 73 years) with equal proportions of men and women. Treatment
continued for a maximum of 14 days (median duration 7 days). When given at a dose of 40 mg once a
day SC, Lovenox Injection significantly reduced the incidence of DVT as compared to placebo. The
efficacy data are provided below.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-164/S-055
Page 11
Efficacy of Lovenox Injection in the Prophylaxis of Deep Vein Thrombosis in Medical Patients With Severely Restricted
Mobility During Acute Illness
Dosing Regimen
Indication
Lovenox Inj.
20 mg q.d. SC
n (%)
Lovenox Inj.
40 mg q.d. SC
n (%)
Placebo
n (%)
All Treated Medical Patients During
Acute Illness
351 (100)
360 (100)
362 (100)
Treatment Failure1
Total VTE2 (%)
43 (12.3)
16 (4.4)
43 (11.9)
Total DVT (%)
43 (12.3)
(95% CI3 8.8 to 15.7)
16 (4.4)
(95% CI3 2.3 to 6.6 )
41 (11.3)
(95% CI3 8.1 to 14.6 )
Proximal DVT (%)
13 (3.7)
5 (1.4)
14 (3.9)
1 Treatment failures during therapy, between Days 1 and 14.
2 VTE = Venous thromboembolic events which included DVT, PE, and death considered to be thromboembolic in origin.
3 CI = Confidence Interval
At approximately 3 months following enrollment, the incidence of venous thromboembolism remained
significantly lower in the Lovenox Injection 40 mg treatment group versus the placebo treatment
group.
Prophylaxis of Ischemic Complications in Unstable Angina and Non-Q-Wave Myocardial
Infarction: In a multicenter, double-blind, parallel group study, patients who recently experienced
unstable angina or non-Q-wave myocardial infarction were randomized to either Lovenox Injection 1
mg/kg every 12 hours SC or heparin i.v. bolus (5000 U) followed by a continuous infusion (adjusted to
achieve an aPTT of 55 to 85 seconds). A total of 3171 patients were enrolled in the study, and 3107
patients were treated. Patients ranged in age from 25-94 years (median age 64 years), with 33.4% of
patients female and 66.6% male. Race was distributed as follows: 89.8% Caucasian, 4.8% Black,
2.0% Oriental, and 3.5% other. All patients were also treated with aspirin 100 to 325 mg per day.
Treatment was initiated within 24 hours of the event and continued until clinical stabilization,
revascularization procedures, or hospital discharge, with a maximal duration of 8 days of therapy. The
combined incidence of the triple endpoint of death, myocardial infarction, or recurrent angina was
lower for Lovenox Injection compared with heparin therapy at 14 days after initiation of treatment.
The lower incidence of the triple endpoint was sustained up to 30 days after initiation of treatment.
These results were observed in an analysis of both all-randomized and all-treated patients. The
efficacy data are provided below.
This label may not be the latest approved by FDA.
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Efficacy of Lovenox Injection in the Prophylaxis of Ischemic Complications in Unstable Angina and Non-Q-Wave
Myocardial Infarction
(Combined Endpoint of Death, Myocardial Infarction, or Recurrent Angina)
Dosing Regimen1
Indication
Lovenox Inj.
1mg/kg q12h SC
n (%)
Heparin
aPTT Adjusted
i.v. Therapy
n (%)
Reduction
(%)
p Value
All Treated Unstable
Angina and Non-Q-Wave
MI Patients
1578 (100)
1529 (100)
Timepoint2
48 Hours
96 (6.1)
112 (7.3)
1.2
0.120
14 Days
261 (16.5)
303 (19.8)
3.3
0.017
30 Days
313 (19.8)
358 (23.4)
3.6
0.014
1 All patients were also treated with aspirin 100 to 325 mg per day.
2 Evaluation timepoints are after initiation of treatment. Therapy continued for up to 8 days (median duration of 2.6 days).
The combined incidence of death or myocardial infarction at all time points was lower for Lovenox
Injection compared to standard heparin therapy, but did not achieve statistical significance. The
efficacy data are provided below.
Efficacy of Lovenox Injection in the Prophylaxis of Ischemic Complications in Unstable Angina and Non-Q-Wave
Myocardial Infarction
(Combined Endpoint of Death or Myocardial Infarction)
Dosing Regimen1
Indication
Lovenox Inj.
1 mg/kg q12h SC
n (%)
Heparin
aPTT Adjusted
i.v. Therapy
n (%)
Reduction
(%)
p Value
All Treated Unstable
Angina and Non-Q-Wave
MI Patients
1578 (100)
1529 (100)
Timepoint2
48 Hours
16 (1.0)
20 (1.3)
0.3
0.126
14 Days
76 (4.8)
93 (6.1)
1.3
0.115
30 Days
96 (6.1)
118 (7.7)
1.6
0.069
1 All patients were also treated with aspirin 100 to 325 mg per day.
2 Evaluation timepoints are after initiation of treatment. Therapy continued for up to 8 days (median duration of 2.6 days).
In a survey one year following treatment, with information available for 92% of enrolled patients, the
combined incidence of death, myocardial infarction, or recurrent angina remained lower for Lovenox
Injection versus heparin (32.0% vs 35.7%).
Urgent revascularization procedures were performed less frequently in the Lovenox Injection group as
compared to the heparin group, 6.3% compared to 8.2% at 30 days (p = 0.047).
Treatment of Deep Vein Thrombosis (DVT) with or without Pulmonary Embolism (PE): In a
multicenter, parallel group study, 900 patients with acute lower extremity DVT with or without PE
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Page 13
were randomized to an inpatient (hospital) treatment of either (i) Lovenox Injection 1.5 mg/kg once a
day SC, (ii) Lovenox Injection 1 mg/kg every 12 hours SC, or (iii) heparin i.v. bolus (5000 IU)
followed by a continuous infusion (administered to achieve an aPTT of 55 to 85 seconds). A total of
900 patients were randomized in the study and all patients were treated. Patients ranged in age from
18 to 92 years (mean age 60.7 years) with 54.7% men and 45.3% women. All patients also received
warfarin sodium (dose adjusted according to PT to achieve an International Normalization Ratio [INR]
of 2.0 to 3.0), commencing within 72 hours of initiation of Lovenox Injection or standard heparin
therapy, and continuing for 90 days. Lovenox Injection or standard heparin therapy was administered
for a minimum of 5 days and until the targeted warfarin sodium INR was achieved. Both Lovenox
Injection regimens were equivalent to standard heparin therapy in reducing the risk of recurrent venous
thromboembolism (DVT and/or PE). The efficacy data are provided below.
Efficacy of Lovenox Injection in Treatment of Deep Vein Thrombosis
With or Without Pulmonary Embolism
Dosing Regimen1
Indication
Lovenox Inj.
1.5 mg/kg q.d. SC
n (%)
Lovenox Inj.
1 mg/kg q12h SC
n (%)
Heparin
aPTT Adjusted
i.v. Therapy
n (%)
All Treated DVT Patients
with or without PE
298 (100)
312 (100)
290 (100)
Patient Outcome
Total VTE2 (%)
13 (4.4)3
9 (2.9) 3
12 (4.1)
DVT Only (%)
11 (3.7)
7 (2.2)
8 (2.8)
Proximal DVT (%)
9 (3.0)
6 (1.9)
7 (2.4)
PE (%)
2 (0.7)
2 (0.6)
4 (1.4)
1 All patients were also treated with warfarin sodium commencing within 72 hours of Lovenox Injection or standard heparin
therapy.
2 VTE = venous thromboembolic event (DVT and/or PE).
3 The 95% Confidence Intervals for the treatment differences for total VTE were:
Lovenox Injection once a day versus heparin (-3.0 to 3.5)
Lovenox Injection every 12 hours versus heparin (-4.2 to 1.7).
Similarly, in a multicenter, open-label, parallel group study, patients with acute proximal DVT were
randomized to Lovenox Injection or heparin. Patients who could not receive outpatient therapy were
excluded from entering the study. Outpatient exclusion criteria included the following: inability to
receive outpatient heparin therapy because of associated co-morbid conditions or potential for non-
compliance and inability to attend follow-up visits as an outpatient because of geographic
inaccessibility. Eligible patients could be treated in the hospital, but ONLY Lovenox Injection
patients were permitted to go home on therapy (72%). A total of 501 patients were randomized in the
study and all patients were treated. Patients ranged in age from 19 to 96 years (mean age 57.8 years)
with 60.5% men and 39.5% women. Patients were randomized to either Lovenox Injection 1 mg/kg
every 12 hours SC or heparin i.v. bolus (5000 IU) followed by a continuous infusion administered to
achieve an aPTT of 60 to 85 seconds (in-patient treatment). All patients also received warfarin sodium
as described in the previous study. Lovenox Injection or standard heparin therapy was administered for
a minimum of 5 days. Lovenox Injection was equivalent to standard heparin therapy in reducing the
risk of recurrent venous thromboembolism. The efficacy data are provided below.
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Efficacy of Lovenox Injection in Treatment of Deep Vein Thrombosis
Dosing Regimen1
Indication
Lovenox Inj.
1 mg/kg q12h SC
n (%)
Heparin
aPTT Adjusted
i.v. Therapy
n (%)
All Treated DVT Patients
247 (100)
254 (100)
Patient Outcome
Total VTE2 (%)
13 (5.3) 3
17 (6.7)
DVT Only (%)
11 (4.5)
14 (5.5)
Proximal DVT (%)
10 (4.0)
12 (4.7)
PE (%)
2 (0.8)
3 (1.2)
1 All patients were also treated with warfarin sodium commencing on the evening of the second day of Lovenox Injection or
standard heparin therapy.
2 VTE = venous thromboembolic event (deep vein thrombosis [DVT] and/or pulmonary embolism [PE]).
3 The 95% Confidence Intervals for the treatment difference for total VTE was: Lovenox Injection versus heparin (-5.6 to
2.7).
INDICATIONS AND USAGE
•
Lovenox Injection is indicated for the prophylaxis of deep vein thrombosis, which may lead to
pulmonary embolism:
•
in patients undergoing abdominal surgery who are at risk for thromboembolic
complications;
•
in
patients
undergoing
hip
replacement
surgery,
during
and
following
hospitalization;
•
in patients undergoing knee replacement surgery;
•
in medical patients who are at risk for thromboembolic complications due to severely
restricted mobility during acute illness.
•
Lovenox Injection is indicated for the prophylaxis of ischemic complications of unstable angina
and non-Q-wave myocardial infarction, when concurrently administered with aspirin.
•
Lovenox Injection is indicated for:
•
the inpatient treatment of acute deep vein thrombosis with or without pulmonary
embolism, when administered in conjunction with warfarin sodium;
•
the outpatient treatment of acute deep vein thrombosis without pulmonary
embolism when administered in conjunction with warfarin sodium.
See DOSAGE AND ADMINISTRATION: Adult Dosage for appropriate dosage regimens.
CONTRAINDICATIONS
Lovenox Injection is contraindicated in patients with active major bleeding, in patients with
thrombocytopenia associated with a positive in vitro test for anti-platelet antibody in the presence of
enoxaparin sodium, or in patients with hypersensitivity to enoxaparin sodium.
Patients with known hypersensitivity to heparin or pork products should not be treated with Lovenox
Injection or any of its constituents.
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WARNINGS
Lovenox Injection is not intended for intramuscular administration.
Lovenox Injection cannot be used interchangeably (unit for unit) with heparin or other low molecular
weight heparins as they differ in manufacturing process, molecular weight distribution, anti-Xa and
anti-IIa activities, units, and dosage. Each of these medicines has its own instructions for use.
Lovenox Injection should be used with extreme caution in patients with a history of heparin-induced
thrombocytopenia.
Hemorrhage: Lovenox Injection, like other anticoagulants, should be used with extreme caution in
conditions with increased risk of hemorrhage, such as bacterial endocarditis, congenital or acquired
bleeding disorders, active ulcerative and angiodysplastic gastrointestinal disease, hemorrhagic stroke,
or shortly after brain, spinal, or ophthalmological surgery, or in patients treated concomitantly with
platelet inhibitors.
Cases of epidural or spinal hematomas have been reported with the associated use of Lovenox
Injection and spinal/epidural anesthesia or spinal puncture resulting in long-term or permanent
paralysis. The risk of these events is higher with the use of post-operative indwelling epidural
catheters or by the concomitant use of additional drugs affecting hemostasis such as NSAIDs (see
boxed WARNING; ADVERSE REACTIONS, Ongoing Safety Surveillance; and
PRECAUTIONS, Drug Interactions).
Major hemorrhages including retroperitoneal and intracranial bleeding have been reported. Some of
these cases have been fatal.
Bleeding can occur at any site during therapy with Lovenox Injection. An unexplained fall in
hematocrit or blood pressure should lead to a search for a bleeding site.
Thrombocytopenia: Thrombocytopenia can occur with the administration of Lovenox Injection.
Moderate thrombocytopenia (platelet counts between 100,000/mm3 and 50,000/mm3) occurred at a rate
of 1.3% in patients given Lovenox Injection, 1.2% in patients given heparin, and 0.7% in patients
given placebo in clinical trials.
Platelet counts less than 50,000/mm3 occurred at a rate of 0.1% in patients given Lovenox Injection, in
0.2% of patients given heparin, and 0.4% of patients given placebo in the same trials.
Thrombocytopenia of any degree should be monitored closely. If the platelet count falls below
100,000/mm3, Lovenox Injection should be discontinued. Cases of heparin-induced thrombocytopenia
with thrombosis have also been observed in clinical practice. Some of these cases were complicated by
organ infarction, limb ischemia, or death.
Pregnant Women with Mechanical Prosthetic Heart Valves: The use of Lovenox Injection for
thromboprophylaxis in pregnant women with mechanical prosthetic heart valves has not been
adequately studied. In a clinical study of pregnant women with mechanical prosthetic heart valves
given enoxaparin (1 mg/kg bid) to reduce the risk of thromboembolism, 2 of 8 women developed clots
resulting in blockage of the valve and leading to maternal and fetal death. Although a causal
relationship has not been established these deaths may have been due to therapeutic failure or
inadequate anticoagulation. No patients in the heparin/warfarin group (0 of 4 women) died. There also
have been isolated postmarketing reports of valve thrombosis in pregnant women with mechanical
prosthetic heart valves while receiving enoxaparin for thromboprophylaxis. Women with mechanical
prosthetic heart valves may be at higher risk for thromboembolism during pregnancy, and, when
pregnant, have a higher rate of fetal loss from stillbirth, spontaneous abortion and premature delivery.
Therefore, frequent monitoring of peak and trough anti-Factor Xa levels, and adjusting of dosage may
be needed.
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Miscellaneous: Lovenox multiple-dose vials contain benzyl alcohol as a preservative. The
administration of medications containing benzyl alcohol as a preservative to premature neonates has
been associated with a fatal “Gasping Syndrome”. Because benzyl alcohol may cross the placenta,
Lovenox multiple-dose vials, preserved with benzyl alcohol, should be used with caution in pregnant
women and only if clearly needed (see PRECAUTIONS, Pregnancy).
PRECAUTIONS
General: Lovenox Injection should not be mixed with other injections or infusions.
Lovenox Injection should be used with care in patients with a bleeding diathesis, uncontrolled arterial
hypertension or a history of recent gastrointestinal ulceration, diabetic retinopathy, and hemorrhage.
Lovenox Injection should be used with care in elderly patients who may show delayed elimination of
enoxaparin.
If thromboembolic events occur despite Lovenox Injection prophylaxis, appropriate therapy should be
initiated.
Mechanical Prosthetic Heart Valves: The use of Lovenox Injection has not been adequately studied
for thromboprophylaxis in patients with mechanical prosthetic heart valves and has not been
adequately studied for long-term use in this patient population. Isolated cases of prosthetic heart valve
thrombosis have been reported in patients with mechanical prosthetic heart valves who have received
enoxaparin for thromboprophylaxis. Some of these cases were pregnant women in whom thrombosis
led to maternal and fetal deaths. Insufficient data, the underlying disease and the possibility of
inadequate anticoagulation complicate the evaluation of these cases. Pregnant women with mechanical
prosthetic heart valves may be at higher risk for thromboembolism (see WARNINGS, Pregnant
Women with Mechanical Prosthetic Heart Valves).
Renal Impairment: In patients with renal impairment, there is an increase in exposure of enoxaparin
sodium. All such patients should be observed carefully for signs and symptoms of bleeding. Because
exposure of enoxaparin sodium is significantly increased in patients with severe renal impairment
(creatinine clearance <30 mL/min), a dosage adjustment is recommended for therapeutic and
prophylactic dosage ranges. No dosage adjustment is recommended in patients with moderate
(creatinine clearance 30-50 mL/min) and mild (creatinine clearance 50-80 mL/min) renal impairment.
(see
DOSAGE
AND
ADMINISTRATION
and
CLINICAL
PHARMACOLOGY,
Pharmacokinetics, Special Populations).
Low-Weight Patients: An increase in exposure of enoxaparin sodium with prophylactic dosages (non-
weight adjusted) has been observed in low-weight women (<45 kg) and low-weight men (<57 kg). All
such patients should be observed carefully for signs and symptoms of bleeding (see CLINICAL
PHARMACOLOGY, Pharmacokinetics, Special Populations).
Laboratory Tests: Periodic complete blood counts, including platelet count, and stool occult blood
tests are recommended during the course of treatment with Lovenox Injection. When administered at
recommended prophylaxis doses, routine coagulation tests such as Prothrombin Time (PT) and
Activated Partial Thromboplastin Time (aPTT) are relatively insensitive measures of Lovenox
Injection activity and, therefore, unsuitable for monitoring. Anti-Factor Xa may be used to monitor the
anticoagulant effect of Lovenox Injection in patients with significant renal impairment. If during
Lovenox Injection therapy abnormal coagulation parameters or bleeding should occur, anti-Factor Xa
levels may be used to monitor the anticoagulant effects of Lovenox Injection (see CLINICAL
PHARMACOLOGY: Pharmacokinetics).
Drug Interactions: Unless really needed, agents which may enhance the risk of hemorrhage should be
discontinued prior to initiation of Lovenox Injection therapy. These agents include medications such
as: anticoagulants, platelet inhibitors including acetylsalicylic acid, salicylates, NSAIDs (including
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Page 17
ketorolac tromethamine), dipyridamole, or sulfinpyrazone. If co-administration is essential, conduct
close clinical and laboratory monitoring (see PRECAUTIONS: Laboratory Tests).
Carcinogenesis, Mutagenesis, Impairment of Fertility: No long-term studies in animals have been
performed to evaluate the carcinogenic potential of enoxaparin. Enoxaparin was not mutagenic in in
vitro tests, including the Ames test, mouse lymphoma cell forward mutation test, and human
lymphocyte chromosomal aberration test, and the in vivo rat bone marrow chromosomal aberration
test. Enoxaparin was found to have no effect on fertility or reproductive performance of male and
female rats at SC doses up to 20 mg/kg/day or 141 mg/m2/day. The maximum human dose in clinical
trials was 2.0 mg/kg/day or 78 mg/m2/day (for an average body weight of 70 kg, height of 170 cm, and
body surface area of 1.8 m2).
Pregnancy: Pregnancy Category B:
All pregnancies have a background risk of birth defects, loss, or other adverse outcome regardless of
drug exposure. The fetal risk summary below describes Lovenox’s potential to increase the risk of
developmental abnormalities above background risk.
Fetal Risk Summary
Lovenox is not predicted to increase the risk of developmental abnormalities. Lovenox does not cross
the placenta, based on human and animal studies, and shows no evidence of teratogenic effects or
fetotoxicity.
Clinical Considerations
It is not known if dose adjustment or monitoring of anti-Xa activity of enoxaparin are necessary during
pregnancy.
Pregnancy alone confers an increased risk for thromboembolism, that is even higher for women with
thromboembolic disease and certain high risk pregnancy conditions. While not adequately studied,
pregnant women with mechanical prosthetic heart valves may be at even higher risk for thrombosis
(See WARNINGS, Pregnant Women with Mechanical Prosthetic Heart Valves and
PRECAUTIONS, Mechanical Prosthetic Heart Valves.) Pregnant women with thromboembolic
disease, including those with mechanical prosthetic heart valves, and those with inherited or acquired
thrombophilias, also have an increased risk of other maternal complications and fetal loss regardless of
the type of anticoagulant used.
All patients receiving anticoagulants such as enoxaparin, including pregnant women, are at risk for
bleeding. Pregnant women receiving enoxaparin should be carefully monitored for evidence of
bleeding or excessive anticoagulation. Consideration for use of a shorter acting anticoagulant should be
specifically addressed as delivery approaches (see BOXED WARNING, SPINAL/EPIDURAL
HEMATOMAS). Hemorrhage can occur at any site and may lead to death of mother and/or fetus.
Pregnant women should be apprised of the potential hazard to the fetus and the mother if enoxaparin is
administered during pregnancy.
Data
• Human Data - There are no adequate and well-controlled studies in pregnant women.
A retrospective study reviewed the records of 604 women who used enoxaparin during pregnancy.
A total of 624 pregnancies resulted in 693 live births. There were 72 hemorrhagic events (11
serious) in 63 women. There were 14 cases of neonatal hemorrhage. Major congenital anomalies
in live births occurred at rates (2.5%) similar to background rates.1
There have been postmarketing reports of fetal death when pregnant women received Lovenox
Injection. Causality for these cases has not been determined. Insufficient data, the underlying
disease, and the possibility of inadequate anticoagulation complicate the evaluation of these cases.
See WARNINGS: Pregnant Women with Mechanical Prosthetic Heart Valves for a clinical
study of pregnant women with mechanical prosthetic heart valves.
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• Animal Data - Teratology studies have been conducted in pregnant rats and rabbits at SC doses of
enoxaparin up to 30 mg/kg/day or 211 mg/m2/day and 410 mg/m2/day, respectively. There was no
evidence of teratogenic effects or fetotoxicity due to enoxaparin. Because animal reproduction
studies are not always predictive of human response, this drug should be used during pregnancy
only if clearly needed.
Cases of “Gasping Syndrome” have occurred in premature infants when large amounts of benzyl
alcohol have been administered (99-405 mg/kg/day). The multiple-dose vial of Lovenox solution
contains 15 mg / 1.0 mL benzyl alcohol as a preservative (see WARNINGS, Miscellaneous).
Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs
are excreted in human milk, caution should be exercised when Lovenox Injection is administered to
nursing women.
Pediatric Use: Safety and effectiveness of Lovenox Injection in pediatric patients have not been
established.
Geriatric Use: Over 2800 patients, 65 years and older, have received Lovenox Injection in pivotal
clinical trials. The efficacy of Lovenox Injection in the elderly (≥65 years) was similar to that seen in
younger patients (<65 years). The incidence of bleeding complications was similar between elderly
and younger patients when 30 mg every 12 hours or 40 mg once a day doses of Lovenox Injection
were employed. The incidence of bleeding complications was higher in elderly patients as compared
to younger patients when Lovenox Injection was administered at doses of 1.5 mg/kg once a day or 1
mg/kg every 12 hours. The risk of Lovenox Injection-associated bleeding increased with age. Serious
adverse events increased with age for patients receiving Lovenox Injection. Other clinical experience
(including postmarketing surveillance and literature reports) has not revealed additional differences in
the safety of Lovenox Injection between elderly and younger patients. Careful attention to dosing
intervals and concomitant medications (especially antiplatelet medications) is advised. Monitoring of
geriatric patients with low body weight (<45 kg) and those predisposed to decreased renal function
should be considered (see CLINICAL PHARMACOLOGY and General and Laboratory Tests
subsections of PRECAUTIONS).
ADVERSE REACTIONS
Hemorrhage: The incidence of major hemorrhagic complications during Lovenox Injection treatment
has been low.
The following rates of major bleeding events have been reported during clinical trials with Lovenox
Injection.
Major Bleeding Episodes Following Abdominal and Colorectal Surgery1
Dosing Regimen
Indications
Lovenox Inj.
40 mg q.d. SC
Heparin
5000 U q8h SC
Abdominal Surgery
n = 555
23 (4%)
n = 560
16 (3%)
Colorectal Surgery
n = 673
28 (4%)
n = 674
21 (3%)
1 Bleeding complications were considered major: (1) if the hemorrhage caused a significant clinical event, or (2) if
accompanied by a hemoglobin decrease ≥ 2 g/dL or transfusion of 2 or more units of blood products. Retroperitoneal,
intraocular, and intracranial hemorrhages were always considered major.
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Major Bleeding Episodes Following Hip or Knee Replacement Surgery1
Dosing Regimen
Indications
Lovenox Inj.
40 mg q.d. SC
Lovenox Inj.
30 mg q12h SC
Heparin
15,000 U/24h SC
Hip Replacement Surgery
Without Extended Prophylaxis2
n = 786
31 (4%)
n = 541
32 (6%)
Hip Replacement Surgery
With Extended Prophylaxis
Peri-operative Period3
n = 288
4 (2%)
Extended Prophylaxis Period4
n = 221
0 (0%)
Knee Replacement Surgery
Without Extended Prophylaxis2
n = 294
3 (1%)
n = 225
3 (1%)
1 Bleeding complications were considered major: (1) if the hemorrhage caused a significant clinical event, or (2) if
accompanied by a hemoglobin decrease ≥ 2 g/dL or transfusion of 2 or more units of blood products. Retroperitoneal and
intracranial hemorrhages were always considered major. In the knee replacement surgery trials, intraocular hemorrhages
were also considered major hemorrhages.
2 Lovenox Injection 30 mg every 12 hours SC initiated 12 to 24 hours after surgery and continued for up to 14 days after
surgery.
3 Lovenox Injection 40 mg SC once a day initiated up to 12 hours prior to surgery and continued for up to 7 days after
surgery.
4 Lovenox Injection 40 mg SC once a day for up to 21 days after discharge.
NOTE: At no time point were the 40 mg once a day pre-operative and the 30 mg every 12 hours post-
operative hip replacement surgery prophylactic regimens compared in clinical trials.
Injection site hematomas during the extended prophylaxis period after hip replacement surgery
occurred in 9% of the Lovenox Injection patients versus 1.8% of the placebo patients.
Major Bleeding Episodes in Medical Patients With Severely Restricted Mobility During Acute Illness1
Dosing Regimen
Indications
Lovenox Inj.2
20 mg q.d. SC
Lovenox Inj.2
40 mg q.d. SC
Placebo2
Medical Patients During Acute
Illness
n = 351
1 (<1%)
n = 360
3 (<1%)
n = 362
2 (<1%)
1 Bleeding complications were considered major: (1) if the hemorrhage caused a significant clinical event, (2) if the
hemorrhage caused a decrease in hemoglobin of ≥ 2 g/dL or transfusion of 2 or more units of blood products.
Retroperitoneal and intracranial hemorrhages were always considered major although none were reported during the trial.
2 The rates represent major bleeding on study medication up to 24 hours after last dose.
MAJOR BLEEDING EPISODES IN UNSTABLE ANGINA AND NON-Q-WAVE MYOCARDIAL INFARCTION
Dosing Regimen
Indication
Lovenox Inj.1
1 mg/kg q12h SC
Heparin1
aPTT Adjusted
i.v. Therapy
Unstable Angina and
Non-Q-Wave MI2,3
n = 1578
17 (1%)
n = 1529
18 (1%)
1 The rates represent major bleeding on study medication up to 12 hours after dose.
2 Aspirin therapy was administered concurrently (100 to 325 mg per day).
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3 Bleeding complications were considered major: (1) if the hemorrhage caused a significant clinical event, or (2) if
accompanied by a hemoglobin decrease by ≥ 3 g/dL or transfusion of 2 or more units of blood products. Intraocular,
retroperitoneal, and intracranial hemorrhages were always considered major.
Major Bleeding Episodes in Deep Vein Thrombosis With or Without Pulmonary Embolism Treatment 1
Dosing Regimen2
Indication
Lovenox Inj.
1.5 mg/kg q.d. SC
Lovenox Inj.
1 mg/kg q12h SC
Heparin
aPTT Adjusted
i.v. Therapy
Treatment of DVT and PE
n = 298
5 (2%)
n = 559
9 (2%)
n = 554
9 (2%)
1 Bleeding complications were considered major: (1) if the hemorrhage caused a significant clinical event, or (2) if
accompanied by a hemoglobin decrease ≥ 2 g/dL or transfusion of 2 or more units of blood products. Retroperitoneal,
intraocular, and intracranial hemorrhages were always considered major.
2 All patients also received warfarin sodium (dose-adjusted according to PT to achieve an INR of 2.0 to 3.0) commencing
within 72 hours of Lovenox Injection or standard heparin therapy and continuing for up to 90 days.
Thrombocytopenia: see WARNINGS: Thrombocytopenia.
Elevations of Serum Aminotransferases: Asymptomatic increases in aspartate (AST [SGOT]) and
alanine (ALT [SGPT]) aminotransferase levels greater than three times the upper limit of normal of the
laboratory reference range have been reported in up to 6.1% and 5.9% of patients, respectively, during
treatment with Lovenox Injection. Similar significant increases in aminotransferase levels have also
been observed in patients and healthy volunteers treated with heparin and other low molecular weight
heparins. Such elevations are fully reversible and are rarely associated with increases in bilirubin.
Since aminotransferase determinations are important in the differential diagnosis of myocardial
infarction, liver disease, and pulmonary emboli, elevations that might be caused by drugs like Lovenox
Injection should be interpreted with caution.
Local Reactions: Mild local irritation, pain, hematoma, ecchymosis, and erythema may follow SC
injection of Lovenox Injection.
Other: Other adverse effects that were thought to be possibly or probably related to treatment with
Lovenox Injection, heparin, or placebo in clinical trials with patients undergoing hip or knee
replacement surgery, abdominal or colorectal surgery, or treatment for DVT and that occurred at a rate
of at least 2% in the Lovenox Injection group, are provided below.
Adverse Events Occurring at ≥2% Incidence in Lovenox Injection Treated Patients1 Undergoing Abdominal or
Colorectal Surgery
Dosing Regimen
Lovenox Inj.
40 mg q.d. SC
n = 1228
Heparin
5000 U q8h SC
n = 1234
Adverse Event
Severe
Total
Severe
Total
Hemorrhage
<1%
7%
<1%
6%
Anemia
<1%
3%
<1%
3%
Ecchymosis
0%
3%
0%
3%
1 Excluding unrelated adverse events.
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Page 21
Adverse Events Occurring at ≥2% Incidence in Lovenox Injection Treated Patients1 Undergoing Hip or Knee
Replacement Surgery
Dosing Regimen
Lovenox Inj.
40 mg q.d. SC
Lovenox Inj.
30 mg q12h
SC
Heparin
15,000 U/24h
SC
Placebo
q12h SC
Peri-operative
Period
n = 288 2
Extended
Prophylaxis
Period
n = 131 3
n = 1080
n = 766
n = 115
Adverse Event
Severe Total
Severe Total
Severe Total
Severe Total
Severe Total
Fever
0%
8%
0%
0%
<1%
5%
<1%
4%
0%
3%
Hemorrhage
<1%
13%
0%
5%
<1%
4%
1%
4%
0%
3%
Nausea
<1%
3%
<1%
2%
0%
2%
Anemia
0%
16%
0%
<2%
<1%
2%
2%
5%
<1%
7%
Edema
<1%
2%
<1%
2%
0%
2%
Peripheral edema
0%
6%
0%
0%
<1%
3%
<1%
4%
0%
3%
1 Excluding unrelated adverse events.
2 Data represents Lovenox Injection 40 mg SC once a day initiated up to 12 hours prior to surgery in 288 hip replacement
surgery patients who received Lovenox Injection peri-operatively in an unblinded fashion in one clinical trial.
3 Data represents Lovenox Injection 40 mg SC once a day given in a blinded fashion as extended prophylaxis at the end of
the peri-operative period in 131 of the original 288 hip replacement surgery patients for up to 21 days in one clinical trial.
Adverse Events Occurring at ≥2% Incidence in Lovenox Injection Treated Medical Patients1 With Severely
Restricted Mobility During Acute Illness
Dosing Regimen
Adverse Event
Lovenox Inj.
40 mg q.d. SC
n = 360
%
Placebo
q.d. SC
n = 362
%
Dyspnea
3.3
5.2
Thrombocytopenia
2.8
2.8
Confusion
2.2
1.1
Diarrhea
2.2
1.7
Nausea
2.5
1.7
1 Excluding unrelated and unlikely adverse events.
Adverse Events in Lovenox Injection Treated Patients With Unstable Angina or Non-Q-Wave
Myocardial Infarction: Non-hemorrhagic clinical events reported to be related to Lovenox Injection
therapy occurred at an incidence of ≤1%.
Non-major hemorrhagic episodes, primarily injection site ecchymoses and hematomas, were more
frequently reported in patients treated with SC Lovenox Injection than in patients treated with i.v.
heparin.
Serious adverse events with Lovenox Injection or heparin in a clinical trial in patients with unstable
angina or non-Q-wave myocardial infarction that occurred at a rate of at least 0.5% in the Lovenox
Injection group, are provided below (irrespective of relationship to drug therapy).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-164/S-055
Page 22
Serious Adverse Events Occurring at ≥0.5% Incidence in Lovenox Injection Treated Patients With Unstable Angina
or Non-Q-Wave Myocardial Infarction
Dosing Regimen
Adverse Event
Lovenox Inj.
1 mg/kg q12h SC
n = 1578
n (%)
Heparin
aPTT Adjusted
i.v. Therapy
n = 1529
n (%)
Atrial fibrillation
11 (0.70)
3 (0.20)
Heart failure
15 (0.95)
11 (0.72)
Lung edema
11 (0.70)
11 (0.72)
Pneumonia
13 (0.82)
9 (0.59)
Adverse Events Occurring at ≥2% Incidence in Lovenox Injection Treated Patients1 Undergoing Treatment of Deep
Vein Thrombosis With or Without Pulmonary Embolism
Dosing Regimen
Lovenox Inj.
1.5 mg/kg q.d. SC
n = 298
Lovenox Inj.
1 mg/kg q12h SC
n = 559
Heparin
aPTT Adjusted
i.v. Therapy
n = 544
Adverse Event
Severe
Total
Severe
Total
Severe
Total
Injection Site Hemorrhage
0%
5%
0%
3%
<1%
<1%
Injection Site Pain
0%
2%
0%
2%
0%
0%
Hematuria
0%
2%
0%
<1%
<1%
2%
1 Excluding unrelated adverse events.
Ongoing Safety Surveillance: Since 1993, there have been over 80 reports of epidural or spinal
hematoma formation with concurrent use of Lovenox Injection and spinal/epidural anesthesia or
spinal puncture. The majority of patients had a post-operative indwelling epidural catheter
placed for analgesia or received additional drugs affecting hemostasis such as NSAIDs. Many of
the epidural or spinal hematomas caused neurologic injury, including long-term or permanent
paralysis. Because these events were reported voluntarily from a population of unknown size,
estimates of frequency cannot be made.
Other Ongoing Safety Surveillance Reports: local reactions at the injection site (i.e., skin necrosis,
nodules, inflammation, oozing), systemic allergic reactions (i.e., pruritus, urticaria, anaphylactoid
reactions), vesiculobullous rash, rare cases of hypersensitivity cutaneous vasculitis, purpura,
thrombocytosis, and thrombocytopenia with thrombosis (see WARNINGS, Thrombocytopenia).
Very rare cases of hyperlipidemia have been reported, with one case of hyperlipidemia, with marked
hypertriglyceridemia, reported in a diabetic pregnant woman; causality has not been determined.
OVERDOSAGE
Symptoms/Treatment: Accidental overdosage following administration of Lovenox Injection may
lead to hemorrhagic complications. Injected Lovenox Injection may be largely neutralized by the slow
i.v. injection of protamine sulfate (1% solution). The dose of protamine sulfate should be equal to the
dose of Lovenox Injection injected: 1 mg protamine sulfate should be administered to neutralize 1 mg
Lovenox Injection, if enoxaparin sodium was administered in the previous 8 hours. An infusion of 0.5
mg protamine per 1 mg of enoxaparin sodium may be administered if enoxaparin sodium was
administered greater than 8 hours previous to the protamine administration, or if it has been determined
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NDA 20-164/S-055
Page 23
that a second dose of protamine is required. The second infusion of 0.5 mg protamine sulfate per 1 mg
of Lovenox Injection may be administered if the aPTT measured 2 to 4 hours after the first infusion
remains prolonged.
After 12 hours of the enoxaparin sodium injection, protamine administration may not be required.
However, even with higher doses of protamine, the aPTT may remain more prolonged than under
normal conditions found following administration of heparin. In all cases, the anti-Factor Xa activity is
never completely neutralized (maximum about 60%). Particular care should be taken to avoid
overdosage with protamine sulfate. Administration of protamine sulfate can cause severe hypotensive
and anaphylactoid reactions. Because fatal reactions, often resembling anaphylaxis, have been reported
with protamine sulfate, it should be given only when resuscitation techniques and treatment of
anaphylactic shock are readily available. For additional information consult the labeling of Protamine
Sulfate Injection, USP, products.
A single SC dose of 46.4 mg/kg enoxaparin was lethal to rats. The symptoms of acute toxicity were
ataxia, decreased motility, dyspnea, cyanosis, and coma.
DOSAGE AND ADMINISTRATION
All patients should be evaluated for a bleeding disorder before administration of Lovenox Injection,
unless the medication is needed urgently. Since coagulation parameters are unsuitable for monitoring
Lovenox Injection activity, routine monitoring of coagulation parameters is not required (see
PRECAUTIONS, Laboratory Tests).
Note: Lovenox Injection is available in two concentrations:
1. 100 mg/mL Concentration: 30 mg / 0.3 mL and 40 mg / 0.4 mL prefilled single-dose syringes, 60
mg / 0.6 mL, 80 mg / 0.8 mL, and 100 mg / 1 mL prefilled, graduated, single-dose syringes, 300 mg /
3.0 mL multiple-dose vials.
2. 150 mg/mL Concentration: 120 mg / 0.8 mL and 150 mg / 1 mL prefilled, graduated, single-dose
syringes.
Adult Dosage:
Abdominal Surgery: In patients undergoing abdominal surgery who are at risk for thromboembolic
complications, the recommended dose of Lovenox Injection is 40 mg once a day administered by SC
injection with the initial dose given 2 hours prior to surgery. The usual duration of administration is 7
to 10 days; up to 12 days administration has been well tolerated in clinical trials.
Hip or Knee Replacement Surgery: In patients undergoing hip or knee replacement surgery, the
recommended dose of Lovenox Injection is 30 mg every 12 hours administered by SC injection.
Provided that hemostasis has been established, the initial dose should be given 12 to 24 hours after
surgery. For hip replacement surgery, a dose of 40 mg once a day SC, given initially 12 (±3) hours
prior to surgery, may be considered. Following the initial phase of thromboprophylaxis in hip
replacement surgery patients, continued prophylaxis with Lovenox Injection 40 mg once a day
administered by SC injection for 3 weeks is recommended. The usual duration of administration is 7
to 10 days; up to 14 days administration has been well tolerated in clinical trials.
Medical Patients During Acute Illness: In medical patients at risk for thromboembolic complications
due to severely restricted mobility during acute illness, the recommended dose of Lovenox Injection is
40 mg once a day administered by SC injection. The usual duration of administration is 6 to 11 days;
up to 14 days of Lovenox Injection has been well tolerated in the controlled clinical trial.
Unstable Angina and Non-Q-Wave Myocardial Infarction: In patients with unstable angina or non-Q-
wave myocardial infarction, the recommended dose of Lovenox Injection is 1 mg/kg administered SC
every 12 hours in conjunction with oral aspirin therapy (100 to 325 mg once daily). Treatment with
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-164/S-055
Page 24
Lovenox Injection should be prescribed for a minimum of 2 days and continued until clinical
stabilization. To minimize the risk of bleeding following vascular instrumentation during the treatment
of unstable angina, adhere precisely to the intervals recommended between Lovenox Injection doses.
The vascular access sheath for instrumentation should remain in place for 6 to 8 hours following a dose
of Lovenox Injection. The next scheduled dose should be given no sooner than 6 to 8 hours after
sheath removal. The site of the procedure should be observed for signs of bleeding or hematoma
formation. The usual duration of treatment is 2 to 8 days; up to 12.5 days of Lovenox Injection has
been well tolerated in clinical trials.
Treatment of Deep Vein Thrombosis With or Without Pulmonary Embolism: In outpatient treatment,
patients with acute deep vein thrombosis without pulmonary embolism who can be treated at home, the
recommended dose of Lovenox Injection is 1 mg/kg every 12 hours administered SC. In inpatient
(hospital) treatment, patients with acute deep vein thrombosis with pulmonary embolism or patients
with acute deep vein thrombosis without pulmonary embolism (who are not candidates for outpatient
treatment), the recommended dose of Lovenox Injection is 1 mg/kg every 12 hours administered SC
or 1.5 mg/kg once a day administered SC at the same time every day. In both outpatient and inpatient
(hospital) treatments, warfarin sodium therapy should be initiated when appropriate (usually within 72
hours of Lovenox Injection). Lovenox Injection should be continued for a minimum of 5 days and until
a therapeutic oral anticoagulant effect has been achieved (International Normalization Ratio 2.0 to 3.0).
The average duration of administration is 7 days; up to 17 days of Lovenox Injection administration
has been well tolerated in controlled clinical trials.
Renal Impairment: Although no dose adjustment is recommended in patients with moderate
(creatinine clearance 30-50 mL/min) and mild (creatinine clearance 50-80 mL/min) renal impairment,
all such patients should be observed carefully for signs and symptoms of bleeding.
The recommended prophylaxis and treatment dosage regimens for patients with severe renal
impairment (creatinine clearance <30 mL/min) are described in the following table (see CLINICAL
PHARMACOLOGY, Pharmacokinetics, Special Populations and PRECAUTIONS, Renal
Impairment).
Dosage Regimens for Patients with Severe Renal Impairment
(creatinine clearance <30mL/minute)
Indication
Dosage Regimen
Prophylaxis in abdominal surgery
30 mg administered SC once daily
Prophylaxis in hip or knee replacement surgery
30 mg administered SC once daily
Prophylaxis in medical patients during acute illness
30 mg administered SC once daily
Prophylaxis of ischemic complications of unstable angina and non-Q-
wave myocardial infarction, when concurrently administered with
aspirin
1 mg/kg administered SC once daily
Inpatient treatment of acute deep vein thrombosis with or without
pulmonary embolism, when administered in conjunction with warfarin
sodium
1 mg/kg administered SC once daily
Outpatient treatment of acute deep vein thrombosis without pulmonary
embolism, when administered in conjunction with warfarin sodium
1 mg/kg administered SC once daily
Administration: Lovenox Injection is a clear, colorless to pale yellow sterile solution, and as with
other parenteral drug products, should be inspected visually for particulate matter and discoloration
prior to administration.
The use of a tuberculin syringe or equivalent is recommended when using Lovenox multiple-dose vials
to assure withdrawal of the appropriate volume of drug.
Lovenox Injection is administered by SC injection. It must not be administered by intramuscular
injection. Lovenox Injection is intended for use under the guidance of a physician. Patients may self-
inject only if their physician determines that it is appropriate and with medical follow-up, as necessary.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-164/S-055
Page 25
Proper training in subcutaneous injection technique (with or without the assistance of an injection
device) should be provided.
Subcutaneous Injection Technique: Patients should be lying down and Lovenox Injection administered
by deep SC injection. To avoid the loss of drug when using the 30 and 40 mg prefilled syringes, do not
expel the air bubble from the syringe before the injection. Administration should be alternated between
the left and right anterolateral and left and right posterolateral abdominal wall. The whole length of the
needle should be introduced into a skin fold held between the thumb and forefinger; the skin fold
should be held throughout the injection. To minimize bruising, do not rub the injection site after
completion of the injection.
Lovenox Injection prefilled syringes and graduated prefilled syringes are available with a system that
shields the needle after injection.
• Remove the needle shield by pulling it straight off the syringe. If adjusting the dose is required,
the dose adjustment must be done prior to injecting the prescribed dose to the patient.
• Inject using standard technique, pushing the plunger to the bottom of the syringe.
• Remove the syringe from the injection site keeping your finger on the plunger rod.
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NDA 20-164/S-055
Page 26
• Orienting the needle away from you and others, activate the safety system by firmly pushing
the plunger rod. The protective sleeve will automatically cover the needle and an audible
“click” will be heard to confirm shield activation.
• Immediately dispose of the syringe in the nearest sharps container.
NOTE:
• The safety system can only be activated once the syringe has been emptied.
• Activation of the safety system must be done only after removing the needle from the patient’s
skin.
• Do not replace the needle shield after injection.
• The safety system should not be sterilized.
• Activation of the safety system may cause minimal splatter of fluid. For optimal safety activate
the system while orienting it downwards away from yourself and others.
HOW SUPPLIED
Lovenox® (enoxaparin sodium injection) is available in two concentrations:
100 mg/mL Concentration
Dosage Unit / Strength1
Anti-Xa
Activity2
Package Size
(per carton)
Label Color
NDC #
0075-
Prefilled Syringes3
30 mg / 0.3 mL
3000 IU
10 syringes
Medium Blue
0624-30
40 mg / 0.4 mL
4000 IU
10 syringes
Yellow
0620-40
Graduated Prefilled Syringes3
60 mg / 0.6 mL
6000 IU
10 syringes
Orange
0621-60
80 mg / 0.8 mL
8000 IU
10 syringes
Brown
0622-80
100 mg / 1 mL
10,000 IU
10 syringes
Black
0623-00
Multiple-Dose Vial4
300 mg / 3.0 mL
30,000 IU
1 vial
Red
0626-03
1 Strength represents the number of milligrams of enoxaparin sodium in Water for Injection. Lovenox Injection 30 and 40
mg prefilled syringes, and 60, 80, and 100 mg graduated prefilled syringes each contain 10 mg enoxaparin sodium per
0.1 mL Water for Injection.
2 Approximate anti-Factor Xa activity based on reference to the W.H.O. First International Low Molecular Weight Heparin
Reference Standard.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-164/S-055
Page 27
3 Each Lovenox Injection syringe is affixed with a 27 gauge x 1/2 inch needle.
4 Each Lovenox multiple-dose vial contains 15 mg / 1.0 mL of benzyl alcohol as a preservative.
150 mg/mL Concentration
Dosage Unit / Strength1
Anti-Xa
Activity2
Package Size
(per carton)
Syringe Label
Color
NDC #
0075-
Graduated Prefilled Syringes3
120 mg / 0.8 mL
12,000 IU
10 syringes
Purple
2912-01
150 mg / 1 mL
15,000 IU
10 syringes
Navy Blue
2915-01
1 Strength represents the number of milligrams of enoxaparin sodium in Water for Injection. Lovenox Injection 120 and
150 mg graduated prefilled syringes contain 15 mg enoxaparin sodium per 0.1 mL Water for Injection.
2 Approximate anti-Factor Xa activity based on reference to the W.H.O. First International Low Molecular Weight Heparin
Reference Standard.
3 Each Lovenox Injection graduated prefilled syringe is affixed with a 27 gauge x 1/2 inch needle.
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room
Temperature].
Keep out of the reach of children.
1 Lepercq J, Conard J, Borel-Derlon A, et al. Venous thromboembolism during pregnancy: a
retrospective study of enoxaparin safety in 624 pregnancies. Br J Obstet Gynec 2001; 108 (11): 1134-
40.
Lovenox Injection prefilled and graduated prefilled syringes manufactured by:
Aventis Pharma Specialties
94700 Maisons-Alfort
France
And
Aventis Pharma
Boulevard Industriel
76580 Le Trait
France
Lovenox multiple-dose vials manufactured by:
DSM Pharmaceuticals, Inc.
Greenville, NC 27835
Manufactured for:
Aventis Pharmaceuticals Inc.
Bridgewater, NJ 08807
©2004 Aventis Pharmaceuticals Inc.
Rev. XXXX
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
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|
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|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/20164s055lbl.pdf', 'application_number': 20164, 'submission_type': 'SUPPL ', 'submission_number': 55}
|
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HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use Lovenox
safely and effectively. See full prescribing information for Lovenox.
Lovenox (enoxaparin sodium injection) for subcutaneous and intravenous
use
Initial U.S. Approval: 1993
WARNING: SPINAL/EPIDURAL HEMATOMA
Epidural or spinal hematomas may occur in patients who are
anticoagulated with low molecular weight heparins (LMWH) or
heparinoids and are receiving neuraxial anesthesia or undergoing spinal
puncture. These hematomas may result in long-term or permanent
paralysis. Consider these risks when scheduling patients for spinal
procedures. Factors that can increase the risk of developing epidural or
spinal hematomas in these patients include:
• Use of indwelling epidural catheters
• Concomitant use of other drugs that affect hemostasis, such as
non-steroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors,
other anticoagulants
• A history of traumatic or repeated epidural or spinal punctures
• A history of spinal deformity or spinal surgery.
Monitor patients frequently for signs and symptoms of neurological
impairment. If neurological compromise is noted, urgent treatment is
necessary.
Consider the benefits and risks before neuraxial intervention in patients
anticoagulated or to be anticoagulated for thromboprophylaxis [see
Warnings and Precautions (5.1) and Drug Interactions (7)].
------------------RECENT MAJOR CHANGES------------------
Boxed Warning, Warnings and Precautions (5.1)
(12/2009)
------------------INDICATIONS AND USAGE-------------------
Lovenox is a low molecular weight heparin [LMWH] indicated for:
•
Prophylaxis of deep vein thrombosis (DVT) in abdominal surgery, hip
replacement surgery, knee replacement surgery, or medical patients with
severely restricted mobility during acute illness (1.1)
•
Inpatient treatment of acute DVT with or without pulmonary embolism
(1.2)
•
Outpatient treatment of acute DVT without pulmonary embolism. (1.2)
•
Prophylaxis of ischemic complications of unstable angina and non-Q
wave myocardial infarction [MI] (1.3)
•
Treatment of acute ST-segment elevation myocardial infarction [STEMI]
managed medically or with subsequent percutaneous coronary
intervention [PCI] (1.4)
-------------------DOSAGE AND ADMINISTRATION-------------
Indication
Standard Regimen (2.1, 2.3)
DVT prophylaxis in abdominal surgery
40 mg SC once daily up to 12
days
DVT prophylaxis in knee replacement
surgery
30 mg SC every 12 hours up to
14 days
DVT prophylaxis in hip replacement
surgery
30 mg SC every 12 hours or 40
mg SC once daily up to 14 days
DVT prophylaxis in medical patients
40 mg SC once daily up to 14
days
Inpatient treatment of acute DVT with or
without pulmonary embolism
1 mg/kg SC every 12 hours or
1.5 mg/kg SC once daily (with
warfarin) up to 17 days
Outpatient treatment of acute DVT
without pulmonary embolism
1 mg/kg SC every 12 hours
(with warfarin) up to 17 days
Unstable angina and non-Q-wave MI
1 mg/kg SC every 12 hours
(with aspirin) 2 to 8 days
Acute STEMI in patients <75 years of age
[For dosing in subsequent PCI, see
Dosage and Administration (2.1)]
30 mg single IV bolus plus a 1
mg/kg SC dose followed by 1
mg/kg SC every 12 hours at
least 8 days (with aspirin)
Acute STEMI in patients ≥75 years of age
0.75 mg/kg SC every 12 hours
(no bolus) at least 8 days (with
aspirin)
•
Adjust the dose for patients with severe renal impairment (2.2, 8.7)
----------------------DOSAGE FORMS AND STRENGTHS--------
100 mg/mL concentration (3.1):
•
Prefilled syringes: 30 mg/0.3 mL, 40 mg/0.4 mL
•
Graduated prefilled syringes: 60 mg/0.6 mL, 80 mg/0.8 mL,100 mg/1 mL
•
Multiple-dose vial: 300 mg/3 mL
150 mg/mL concentration (3.2):
•
Graduated prefilled syringes: 120 mg/0.8 mL, 150 mg/1 mL
------------------------------CONTRAINDICATIONS-----------------
•
Active major bleeding (4)
•
Thrombocytopenia with a positive in vitro test for anti-platelet antibody
in the presence of enoxaparin sodium (4)
•
Hypersensitivity to enoxaparin sodium (4)
•
Hypersensitivity to heparin or pork products (4)
•
Hypersensitivity to benzyl alcohol [for multi-dose formulation only] (4)
-----------------------WARNINGS AND PRECAUTIONS----------
•
Increased risk of hemorrhage: Use with caution in patients at risk (5.1)
•
Percutaneous coronary revascularization: Obtain hemostasis at the
puncture site before sheath removal (5.2)
•
Concomitant medical conditions: Use with caution in patients with
bleeding diathesis, uncontrolled arterial hypertension or history of recent
gastrointestinal ulceration, diabetic retinopathy, renal dysfunction, or
hemorrhage (5.3)
•
History of heparin-induced thrombocytopenia: Use with caution (5.4)
•
Thrombocytopenia: Monitor thrombocytopenia closely (5.5)
•
Interchangeability with other heparins: Do not exchange with heparin or
other LMWHs (5.6)
•
Pregnant women with mechanical prosthetic heart valves and their
fetuses, may be at increased risk and may need more frequent monitoring
and dosage adjustment (5.7)
-----------------------------ADVERSE REACTIONS-------------------
Most common adverse reactions (>1%) were bleeding, anemia,
thrombocytopenia, elevation of serum aminotransferase, diarrhea, and nausea
(6.1)
To report SUSPECTED ADVERSE REACTIONS, contact sanofi-aventis
at 1-800-633-1610 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
-----------------------------DRUG INTERACTIONS-------------------
Discontinue agents which may enhance hemorrhage risk prior to initiation of
Lovenox or conduct close clinical and laboratory monitoring (5.9, 7)
----------------------USE IN SPECIFIC POPULATIONS------------
•
Severe Renal Impairment: Adjust dose for patients with creatinine
clearance <30mL/min (2.2, 8.7)
•
Geriatric Patients: Monitor for increased risk of bleeding (8.5)
•
Patients with mechanical heart valves: Not adequately studied (8.6)
•
Hepatic Impairment: Use with caution. (8.8)
•
Low-Weight Patients: Observe for signs of bleeding (8.9)
See 17 for PATIENT COUNSELING INFORMATION
Revised: December, 2009
1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: SPINAL / EPIDURAL HEMATOMAS
1
INDICATIONS AND USAGE
1.1 Prophylaxis of Deep Vein Thrombosis
1.2 Treatment of Acute Deep Vein Thrombosis
1.3 Prophylaxis of Ischemic Complications of Unstable
Angina and Non-Q-Wave Myocardial Infarction
1.4 Treatment of Acute ST-Segment Elevation Myocardial
Infarction
2
DOSAGE AND ADMINISTRATION
2.1 Adult Dosage
2.2 Renal Impairment
2.3 Geriatric Patients with Acute ST-Segment Elevation
Myocardial Infarction
2.4 Administration
3
DOSAGE FORMS AND STRENGTHS
3.1 100 mg/mL Concentration
3.2 150 mg/mL Concentration
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1 Increased Risk of Hemorrhage
5.2 Percutaneous Coronary Revascularization Procedures
5.3 Use of Lovenox with Concomitant Medical Conditions
5.4 History of Heparin-Induced Thrombocytopenia
5.5 Thrombocytopenia
5.6 Interchangeability with Other Heparins
5.7 Pregnant Women with Mechanical Prosthetic Heart
Valves
5.8 Benzyl Alcohol
5.9 Laboratory Tests
6
ADVERSE REACTIONS
6.1 Clinical Trials Experience
6.2 Postmarketing Experience
7
DRUG INTERACTIONS
8
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Patients with Mechanical Prosthetic Heart Valves
8.7 Renal Impairment
8.8 Hepatic Impairment
8.9 Low-Weight Patients
10
OVERDOSAGE
11
DESCRIPTION
12
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
13.2 Animal Toxicology and/or Pharmacology
13.3 Reproductive and Developmental Toxicology
14 CLINICAL STUDIES
14.1 Prophylaxis of Deep Vein Thrombosis Following
Abdominal Surgery in Patients at Risk for
Thromboembolic Complications
14.2 Prophylaxis of Deep Vein Thrombosis Following Hip
or Knee Replacement Surgery
14.3 Prophylaxis of Deep Vein Thrombosis in Medical
Patients with Severely Restricted Mobility During
Acute Illness
14.4 Treatment of Deep Vein Thrombosis with or without
Pulmonary Embolism
14.5 Prophylaxis of Ischemic Complications in Unstable
Angina and Non-Q-Wave Myocardial Infarction
14.6 Treatment of Acute ST-Segment Elevation Myocardial
Infarction
16 HOW SUPPLIED/STORAGE AND HANDLING
17
PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing
information are not listed
2
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
FULL PRESCRIBING INFORMATION
WARNING: SPINAL/EPIDURAL HEMATOMAS
Epidural or spinal hematomas may occur in patients who are anticoagulated with low
molecular weight heparins (LMWH) or heparinoids and are receiving neuraxial anesthesia
or undergoing spinal puncture. These hematomas may result in long-term or permanent
paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that
can increase the risk of developing epidural or spinal hematomas in these patients include:
• Use of indwelling epidural catheters
• Concomitant use of other drugs that affect hemostasis, such as non-steroidal
anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants.
• A history of traumatic or repeated epidural or spinal punctures
• A history of spinal deformity or spinal surgery
Monitor patients frequently for signs and symptoms of neurological impairment. If
neurological compromise is noted, urgent treatment is necessary.
Consider the benefits and risks before neuraxial intervention in patients anticoagulated or
to be anticoagulated for thromboprophylaxis [see Warnings and Precautions (5.1) and Drug
Interactions (7)].
1 INDICATIONS AND USAGE
1.1 Prophylaxis of Deep Vein Thrombosis
Lovenox® is indicated for the prophylaxis of deep vein thrombosis (DVT), which may lead to
pulmonary embolism (PE):
• in patients undergoing abdominal surgery who are at risk for thromboembolic
complications [see Clinical Studies (14.1)].
• in patients undergoing hip replacement surgery, during and following hospitalization.
• in patients undergoing knee replacement surgery.
• in medical patients who are at risk for thromboembolic complications due to severely
restricted mobility during acute illness.
1.2 Treatment of Acute Deep Vein Thrombosis
Lovenox is indicated for:
• the inpatient treatment of acute deep vein thrombosis with or without pulmonary
embolism, when administered in conjunction with warfarin sodium.
• the outpatient treatment of acute deep vein thrombosis without pulmonary embolism
when administered in conjunction with warfarin sodium.
1.3 Prophylaxis of Ischemic Complications of Unstable Angina and Non-Q-Wave
Myocardial Infarction
Lovenox is indicated for the prophylaxis of ischemic complications of unstable angina and non
Q-wave myocardial infarction, when concurrently administered with aspirin.
3
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1.4 Treatment of Acute ST-Segment Elevation Myocardial Infarction
Lovenox, when administered concurrently with aspirin, has been shown to reduce the rate of the
combined endpoint of recurrent myocardial infarction or death in patients with acute ST-segment
elevation myocardial infarction (STEMI) receiving thrombolysis and being managed medically
or with percutaneous coronary intervention (PCI).
2 DOSAGE AND ADMINISTRATION
All patients should be evaluated for a bleeding disorder before administration of Lovenox, unless
the medication is needed urgently. Since coagulation parameters are unsuitable for monitoring
Lovenox activity, routine monitoring of coagulation parameters is not required [see Warnings
and Precautions (5.9)].
For subcutaneous use, Lovenox should not be mixed with other injections or infusions. For
intravenous use (i.e., for treatment of acute STEMI), Lovenox can be mixed with normal saline
solution (0.9%) or 5% dextrose in water.
Lovenox is not intended for intramuscular administration.
2.1 Adult Dosage
Abdominal Surgery: In patients undergoing abdominal surgery who are at risk for
thromboembolic complications, the recommended dose of Lovenox is 40 mg once a day
administered by SC injection with the initial dose given 2 hours prior to surgery. The usual
duration of administration is 7 to 10 days; up to 12 days administration has been administered in
clinical trials.
Hip or Knee Replacement Surgery: In patients undergoing hip or knee replacement surgery, the
recommended dose of Lovenox is 30 mg every 12 hours administered by SC injection.
Provided that hemostasis has been established, the initial dose should be given 12 to 24 hours
after surgery. For hip replacement surgery, a dose of 40 mg once a day SC, given initially 12
(±3) hours prior to surgery, may be considered. Following the initial phase of
thromboprophylaxis in hip replacement surgery patients, it is recommended that continued
prophylaxis with Lovenox 40 mg once a day be administered by SC injection for 3 weeks. The
usual duration of administration is 7 to 10 days; up to 14 days administration has been
administered in clinical trials.
Medical Patients During Acute Illness: In medical patients at risk for thromboembolic
complications due to severely restricted mobility during acute illness, the recommended dose of
Lovenox is 40 mg once a day administered by SC injection. The usual duration of
administration is 6 to 11 days; up to 14 days of Lovenox has been administered in the controlled
clinical trial.
Treatment of Deep Vein Thrombosis with or without Pulmonary Embolism: In outpatient
treatment, patients with acute deep vein thrombosis without pulmonary embolism who can be
4
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For current labeling information, please visit https://www.fda.gov/drugsatfda
treated at home, the recommended dose of Lovenox is 1 mg/kg every 12 hours administered
SC.
In inpatient (hospital) treatment, patients with acute deep vein thrombosis with
pulmonary embolism or patients with acute deep vein thrombosis without pulmonary embolism
(who are not candidates for outpatient treatment), the recommended dose of Lovenox is 1 mg/kg
every 12 hours administered SC or 1.5 mg/kg once a day administered SC at the same time
every day. In both outpatient and inpatient (hospital) treatments, warfarin sodium therapy should
be initiated when appropriate (usually within 72 hours of Lovenox). Lovenox should be
continued for a minimum of 5 days and until a therapeutic oral anticoagulant effect has been
achieved (International Normalization Ratio 2.0 to 3.0). The average duration of administration
is 7 days; up to 17 days of Lovenox administration has been administered in controlled clinical
trials.
Unstable Angina and Non-Q-Wave Myocardial Infarction: In patients with unstable angina or
non-Q-wave myocardial infarction, the recommended dose of Lovenox is 1 mg/kg administered
SC every 12 hours in conjunction with oral aspirin therapy (100 to 325 mg once daily).
Treatment with Lovenox should be prescribed for a minimum of 2 days and continued until
clinical stabilization. The usual duration of treatment is 2 to 8 days; up to 12.5 days of Lovenox
has been administered in clinical trials [see Warnings and Precautions (5.2) and Clinical Studies
(14.5)].
Treatment of Acute ST-Segment Elevation Myocardial Infarction: In patients with acute ST-
segment elevation myocardial infarction, the recommended dose of Lovenox is a single IV bolus
of 30 mg plus a 1 mg/kg SC dose followed by 1 mg/kg administered SC every 12 hours
(maximum 100 mg for the first two doses only, followed by 1 mg/kg dosing for the remaining
doses). Dosage adjustments are recommended in patients ≥75 years of age [see Dosage and
Administration (2.3)]. All patients should receive aspirin as soon as they are identified as having
STEMI and maintained with 75 to 325 mg once daily unless contraindicated.
When administered in conjunction with a thrombolytic (fibrin-specific or non-fibrin specific),
Lovenox should be given between 15 minutes before and 30 minutes after the start of fibrinolytic
therapy. In the pivotal clinical study, the Lovenox treatment duration was 8 days or until
hospital discharge, whichever came first. An optimal duration of treatment is not known, but it
is likely to be longer than 8 days.
For patients managed with percutaneous coronary intervention (PCI): If the last Lovenox SC
administration was given less than 8 hours before balloon inflation, no additional dosing is
needed. If the last Lovenox SC administration was given more than 8 hours before balloon
inflation, an IV bolus of 0.3 mg/kg of Lovenox should be administered [see Warnings and
Precautions (5.2)].
2.2 Renal Impairment
Although no dose adjustment is recommended in patients with moderate (creatinine clearance
30-50 mL/min) and mild (creatinine clearance 50-80 mL/min) renal impairment, all such patients
should be observed carefully for signs and symptoms of bleeding.
5
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
The recommended prophylaxis and treatment dosage regimens for patients with severe renal
impairment (creatinine clearance <30 mL/min) are described in Table 1 [see Use in Specific
Populations (8.6) and Clinical Pharmacology (12.3)].
Table 1
Dosage Regimens for Patients with Severe Renal Impairment
(creatinine clearance <30mL/minute)
Indication
Dosage Regimen
Prophylaxis in abdominal surgery
30 mg administered SC once daily
Prophylaxis in hip or knee replacement surgery
30 mg administered SC once daily
Prophylaxis in medical patients during acute illness
30 mg administered SC once daily
Inpatient treatment of acute deep vein thrombosis with
or without pulmonary embolism, when administered in
conjunction with warfarin sodium
1 mg/kg administered SC once daily
Outpatient treatment of acute deep vein thrombosis
without pulmonary embolism, when administered in
conjunction with warfarin sodium
1 mg/kg administered SC once daily
Prophylaxis of ischemic complications of unstable
angina and non-Q-wave myocardial infarction, when
concurrently administered with aspirin
1 mg/kg administered SC once daily
Treatment of acute ST-segment elevation myocardial
infarction in patients <75 years of age, when
administered in conjunction with aspirin
30 mg single IV bolus plus a 1 mg/kg
SC dose followed by 1 mg/kg
administered SC once daily.
Treatment of acute ST-segment elevation myocardial
infarction in geriatric patients ≥75 years of age, when
administered in conjunction with aspirin
1 mg/kg administered SC once daily
(no initial bolus)
2.3 Geriatric Patients with Acute ST-Segment Elevation Myocardial Infarction
For treatment of acute ST-segment elevation myocardial infarction in geriatric patients ≥75 years
of age, do not use an initial IV bolus. Initiate dosing with 0.75 mg/kg SC every 12 hours
(maximum 75 mg for the first two doses only, followed by 0.75 mg/kg dosing for the
remaining doses) [see Use in Specific Populations (8.5) and Clinical Pharmacology (12.3)].
No dose adjustment is necessary for other indications in geriatric patients unless kidney function
is impaired [see Dosage and Administration (2.2)].
2.4 Administration
Lovenox is a clear, colorless to pale yellow sterile solution, and as with other parenteral drug
products, should be inspected visually for particulate matter and discoloration prior to
administration.
The use of a tuberculin syringe or equivalent is recommended when using Lovenox multiple-
dose vials to assure withdrawal of the appropriate volume of drug.
6
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Lovenox must not be administered by intramuscular injection. Lovenox is intended for use
under the guidance of a physician.
For subcutaneous administration, patients may self-inject only if their physicians determine that
it is appropriate and with medical follow-up, as necessary. Proper training in subcutaneous
injection technique (with or without the assistance of an injection device) should be provided.
Subcutaneous Injection Technique: Patients should be lying down and Lovenox administered by
deep SC injection. To avoid the loss of drug when using the 30 and 40 mg prefilled syringes, do
not expel the air bubble from the syringe before the injection. Administration should be
alternated between the left and right anterolateral and left and right posterolateral abdominal
wall. The whole length of the needle should be introduced into a skin fold held between the
thumb and forefinger; the skin fold should be held throughout the injection. To minimize
bruising, do not rub the injection site after completion of the injection.
Lovenox prefilled syringes and graduated prefilled syringes are for single, one-time use only and
are available with a system that shields the needle after injection.
1. Remove the needle shield by pulling it straight off the syringe (see Figure A). If adjusting the
dose is required, the dose adjustment must be done prior to injecting the prescribed dose to the
patient.
Remove the needle shield by pulling it straight off the syringe
2. Inject using standard technique, pushing the plunger to the bottom of the syringe (see Figure
B).
Inject using standard technique, pushing the plunger to the bottom of the syringe
3. Remove the syringe from the injection site keeping your finger on the plunger rod (see Figure
C).
7
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Figure C Remove the syringe from the injection site keeping your finger on the plunger rod
4. Orient the needle away from you and others, and activate the safety system by firmly
pushing the plunger rod. The protective sleeve will automatically cover the needle and an
audible “click” will be heard to confirm shield activation (see Figure D).
Figure D Orient the needle away from you and others, and activate the safety system by firmly pushing the plunger rod
5. Immediately dispose of the syringe in the nearest sharps container (see Figure E).
Immediately dispose of the syringe in the nearest sharps container
NOTE:
• The safety system can only be activated once the syringe has been emptied.
• Activation of the safety system must be done only after removing the needle from the
patient’s skin.
• Do not replace the needle shield after injection.
• The safety system should not be sterilized.
Activation of the safety system may cause minimal splatter of fluid. For optimal safety activate
the system while orienting it downwards away from yourself and others.
Intravenous (Bolus) Injection Technique: For intravenous injection, the multiple-dose vial should
be used. Lovenox should be administered through an intravenous line. Lovenox should not be
mixed or co-administered with other medications. To avoid the possible mixture of Lovenox
with other drugs, the intravenous access chosen should be flushed with a sufficient amount of
saline or dextrose solution prior to and following the intravenous bolus administration of
Lovenox to clear the port of drug. Lovenox may be safely administered with normal saline
solution (0.9%) or 5% dextrose in water.
8
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
3 DOSAGE FORMS AND STRENGTHS
Lovenox is available in two concentrations:
3.1 100 mg/mL Concentration
-Prefilled Syringes
30 mg/0.3 mL, 40 mg/0.4 mL
-Graduated Prefilled Syringes 60 mg/0.6 mL, 80 mg/0.8 mL, 100 mg/1 mL
-Multiple-Dose Vials
300 mg/3 mL
3.2 150 mg/mL Concentration
-Graduated Prefilled Syringes 120 mg/0.8 mL, 150 mg/1 mL
4 CONTRAINDICATIONS
• Active major bleeding
• Thrombocytopenia associated with a positive in vitro test for anti-platelet antibody in the
presence of enoxaparin sodium
• Known
hypersensitivity
to
enoxaparin
sodium
(e.g.,
pruritus,
urticaria,
anaphylactic/anaphylactoid reactions) [see Adverse Reactions (6.2)]
• Known hypersensitivity to heparin or pork products
• Known hypersensitivity to benzyl alcohol (which is in only the multi-dose formulation of
Lovenox) [see Warnings and Precautions (5.8)]
5 WARNINGS AND PRECAUTIONS
5.1 Increased Risk of Hemorrhage
Cases of epidural or spinal hematomas have been reported with the associated use of Lovenox
and spinal/epidural anesthesia or spinal puncture resulting in long-term or permanent paralysis.
The risk of these events is higher with the use of post-operative indwelling epidural catheters,
with the concomitant use of additional drugs affecting hemostasis such as NSAIDs, with
traumatic or repeated epidural or spinal puncture, or in patients with a history of spinal surgery
or spinal deformity [see Boxed Warning, Adverse Reactions (6.2) and Drug Interactions (7)].
Lovenox should be used with extreme caution in conditions with increased risk of hemorrhage,
such as bacterial endocarditis, congenital or acquired bleeding disorders, active ulcerative and
angiodysplastic gastrointestinal disease, hemorrhagic stroke, or shortly after brain, spinal, or
ophthalmological surgery, or in patients treated concomitantly with platelet inhibitors.
Major hemorrhages including retroperitoneal and intracranial bleeding have been reported.
Some of these cases have been fatal.
Bleeding can occur at any site during therapy with Lovenox. An unexplained fall in hematocrit
or blood pressure should lead to a search for a bleeding site.
9
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5.2 Percutaneous Coronary Revascularization Procedures
To minimize the risk of bleeding following the vascular instrumentation during the treatment of
unstable angina, non-Q-wave myocardial infarction and acute ST-segment elevation myocardial
infarction, adhere precisely to the intervals recommended between Lovenox doses. It is
important to achieve hemostasis at the puncture site after PCI. In case a closure device is used,
the sheath can be removed immediately. If a manual compression method is used, sheath should
be removed 6 hours after the last IV/SC Lovenox. If the treatment with enoxaparin sodium is to
be continued, the next scheduled dose should be given no sooner than 6 to 8 hours after sheath
removal. The site of the procedure should be observed for signs of bleeding or hematoma
formation [see Dosage and Administration (2.1)].
5.3 Use of Lovenox with Concomitant Medical Conditions
Lovenox should be used with care in patients with a bleeding diathesis, uncontrolled arterial
hypertension or a history of recent gastrointestinal ulceration, diabetic retinopathy, renal
dysfunction and hemorrhage.
5.4 History of Heparin-Induced Thrombocytopenia
Lovenox should be used with extreme caution in patients with a history of heparin-induced
thrombocytopenia.
5.5 Thrombocytopenia
Thrombocytopenia can occur with the administration of Lovenox.
Moderate thrombocytopenia (platelet counts between 100,000/mm3 and 50,000/mm3) occurred at
a rate of 1.3% in patients given Lovenox, 1.2% in patients given heparin, and 0.7% in patients
given placebo in clinical trials.
Platelet counts less than 50,000/mm3 occurred at a rate of 0.1% in patients given Lovenox, in
0.2% of patients given heparin, and 0.4% of patients given placebo in the same trials.
Thrombocytopenia of any degree should be monitored closely. If the platelet count falls below
100,000/mm3, Lovenox should be discontinued. Cases of heparin-induced thrombocytopenia
with thrombosis have also been observed in clinical practice. Some of these cases were
complicated by organ infarction, limb ischemia, or death [see Warnings and Precautions (5.4)].
5.6 Interchangeability with Other Heparins
Lovenox cannot be used interchangeably (unit for unit) with heparin or other low molecular
weight heparins as they differ in manufacturing process, molecular weight distribution, anti-Xa
and anti-IIa activities, units, and dosage. Each of these medicines has its own instructions for
use.
10
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5.7 Pregnant Women with Mechanical Prosthetic Heart Valves
The use of Lovenox for thromboprophylaxis in pregnant women with mechanical prosthetic
heart valves has not been adequately studied. In a clinical study of pregnant women with
mechanical prosthetic heart valves given enoxaparin (1 mg/kg twice daily) to reduce the risk of
thromboembolism, 2 of 8 women developed clots resulting in blockage of the valve and leading
to maternal and fetal death. Although a causal relationship has not been established these deaths
may have been due to therapeutic failure or inadequate anticoagulation. No patients in the
heparin/warfarin group (0 of 4 women) died. There also have been isolated postmarketing
reports of valve thrombosis in pregnant women with mechanical prosthetic heart valves while
receiving enoxaparin for thromboprophylaxis. Women with mechanical prosthetic heart valves
may be at higher risk for thromboembolism during pregnancy, and, when pregnant, have a higher
rate of fetal loss from stillbirth, spontaneous abortion and premature delivery. Therefore,
frequent monitoring of peak and trough anti-Factor Xa levels, and adjusting of dosage may be
needed [see Use in Specific Populations (8.6)].
5.8 Benzyl Alcohol
Lovenox multiple-dose vials contain benzyl alcohol as a preservative. The administration of
medications containing benzyl alcohol as a preservative to premature neonates has been
associated with a fatal “gasping syndrome”. Because benzyl alcohol may cross the placenta,
Lovenox multiple-dose vials, preserved with benzyl alcohol, should be used with caution in
pregnant women and only if clearly needed [see Use in Specific Populations (8.1)].
5.9 Laboratory Tests
Periodic complete blood counts, including platelet count, and stool occult blood tests are
recommended during the course of treatment with Lovenox.
When administered at
recommended prophylaxis doses, routine coagulation tests such as Prothrombin Time (PT) and
Activated Partial Thromboplastin Time (aPTT) are relatively insensitive measures of Lovenox
activity and, therefore, unsuitable for monitoring. Anti-Factor Xa may be used to monitor the
anticoagulant effect of Lovenox in patients with significant renal impairment. If during Lovenox
therapy abnormal coagulation parameters or bleeding should occur, anti-Factor Xa levels may be
used to monitor the anticoagulant effects of Lovenox [see Clinical Pharmacology (12.3)].
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
The following serious adverse reactions are also discussed in other sections of the labeling:
• Spinal/epidural hematoma [see Boxed Warning and Warnings and Precautions (5.1)]
• Increased Risk of Hemorrhage [see Warnings and Precautions (5.1)]
• Thrombocytopenia [see Warnings and Precautions (5.5)]
Because clinical studies are conducted under widely varying conditions, adverse reaction rates
observed in the clinical studies of a drug cannot be directly compared to rates in the clinical
studies of another drug and may not reflect the rates observed in practice.
11
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For current labeling information, please visit https://www.fda.gov/drugsatfda
During clinical development for the approved indications, 15,918 patients were exposed to
enoxaparin sodium. These included 1,228 for prophylaxis of deep vein thrombosis following
abdominal surgery in patients at risk for thromboembolic complications, 1,368 for prophylaxis of
deep vein thrombosis following hip or knee replacement surgery, 711 for prophylaxis of deep
vein thrombosis in medical patients with severely restricted mobility during acute illness, 1,578
for prophylaxis of ischemic complications in unstable angina and non-Q-wave myocardial
infarction, 10,176 for treatment of acute ST-elevation myocardial infarction, and 857 for
treatment of deep vein thrombosis with or without pulmonary embolism. Enoxaparin sodium
doses in the clinical trials for prophylaxis of deep vein thrombosis following abdominal or hip or
knee replacement surgery or in medical patients with severely restricted mobility during acute
illness ranged from 40 mg SC once daily to 30 mg SC twice daily. In the clinical studies for
prophylaxis of ischemic complications of unstable angina and non-Q-wave myocardial infarction
doses were 1 mg/kg every 12 hours and in the clinical studies for treatment of acute ST-segment
elevation myocardial infarction enoxaparin sodium doses were a 30 mg IV bolus followed by 1
mg/kg every 12 hours SC.
Hemorrhage
The incidence of major hemorrhagic complications during Lovenox treatment has been low.
The following rates of major bleeding events have been reported during clinical trials with
Lovenox [see Tables 2 to 7].
Table 2
Major Bleeding Episodes Following Abdominal and Colorectal Surgery1
Indications
Dosing Regimen
Lovenox
40 mg q.d. SC
Heparin
5000 U q8h SC
Abdominal Surgery
n = 555
23 (4%)
n = 560
16 (3%)
Colorectal Surgery
n = 673
28 (4%)
n = 674
21 (3%)
1 Bleeding complications were considered major: (1) if the hemorrhage caused a significant
clinical event, or (2) if accompanied by a hemoglobin decrease ≥ 2 g/dL or transfusion of 2 or
more units of blood products. Retroperitoneal, intraocular, and intracranial hemorrhages were
always considered major.
Table 3
Major Bleeding Episodes Following Hip or Knee Replacement Surgery1
Indications
Dosing Regimen
Lovenox
40 mg q.d. SC
Lovenox
30 mg q12h SC
Heparin
15,000 U/24h SC
Hip Replacement Surgery
without Extended Prophylaxis2
n = 786
31 (4%)
n = 541
32 (6%)
Hip Replacement Surgery
12
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For current labeling information, please visit https://www.fda.gov/drugsatfda
with Extended Prophylaxis
Peri-operative Period3
Extended Prophylaxis Period4
n = 288
4 (2%)
n = 221
0 (0%)
Knee Replacement Surgery
without Extended Prophylaxis2
n = 294
3 (1%)
n = 225
3 (1%)
1 Bleeding complications were considered major: (1) if the hemorrhage caused a significant
clinical event, or (2) if accompanied by a hemoglobin decrease ≥ 2 g/dL or transfusion of 2 or
more units of blood products. Retroperitoneal and intracranial hemorrhages were always
considered major. In the knee replacement surgery trials, intraocular hemorrhages were also
considered major hemorrhages.
2 Lovenox 30 mg every 12 hours SC initiated 12 to 24 hours after surgery and continued for up
to 14 days after surgery
3 Lovenox 40 mg SC once a day initiated up to 12 hours prior to surgery and continued for up to
7 days after surgery
4 Lovenox 40 mg SC once a day for up to 21 days after discharge
NOTE: At no time point were the 40 mg once a day pre-operative and the 30 mg every 12 hours
post-operative hip replacement surgery prophylactic regimens compared in clinical trials.
Injection site hematomas during the extended prophylaxis period after hip replacement surgery
occurred in 9% of the Lovenox patients versus 1.8% of the placebo patients.
Table 4
Major Bleeding Episodes in Medical Patients with Severely Restricted Mobility During
Acute Illness1
Indications
Dosing Regimen
Lovenox2
20 mg q.d. SC
Lovenox2
40 mg q.d. SC
Placebo2
Medical Patients During
Acute Illness
n = 351
1 (<1%)
n = 360
3 (<1%)
n = 362
2 (<1%)
1 Bleeding complications were considered major: (1) if the hemorrhage caused a significant
clinical event, (2) if the hemorrhage caused a decrease in hemoglobin of ≥ 2 g/dL or transfusion
of 2 or more units of blood products. Retroperitoneal and intracranial hemorrhages were always
considered major although none were reported during the trial.
2 The rates represent major bleeding on study medication up to 24 hours after last dose.
Table 5
Major Bleeding Episodes in Deep Vein Thrombosis with or without Pulmonary Embolism
Treatment 1
Dosing Regimen2
Lovenox
Lovenox
Heparin
13
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Indication
1.5 mg/kg q.d. SC
1 mg/kg q12h SC
aPTT Adjusted
IV Therapy
Treatment of DVT and PE
n = 298
5 (2%)
n = 559
9 (2%)
n = 554
9 (2%)
1 Bleeding complications were considered major: (1) if the hemorrhage caused a significant
clinical event, or (2) if accompanied by a hemoglobin decrease ≥ 2 g/dL or transfusion of 2 or
more units of blood products. Retroperitoneal, intraocular, and intracranial hemorrhages were
always considered major.
2 All patients also received warfarin sodium (dose-adjusted according to PT to achieve an INR of
2.0 to 3.0) commencing within 72 hours of Lovenox or standard heparin therapy and
continuing for up to 90 days.
Table 6
Major Bleeding Episodes in Unstable Angina and Non-Q-Wave Myocardial Infarction
Indication
Dosing Regimen
Lovenox1
1 mg/kg q12h SC
Heparin1
aPTT Adjusted
IV Therapy
Unstable Angina and
Non-Q-Wave MI2,3
n = 1578
17 (1%)
n = 1529
18 (1%)
1 The rates represent major bleeding on study medication up to 12 hours after dose.
2 Aspirin therapy was administered concurrently (100 to 325 mg per day).
3 Bleeding complications were considered major: (1) if the hemorrhage caused a significant
clinical event, or (2) if accompanied by a hemoglobin decrease by ≥ 3 g/dL or transfusion of 2
or more units of blood products. Intraocular, retroperitoneal, and intracranial hemorrhages
were always considered major.
Table 7
Major Bleeding Episodes in Acute ST-Segment Elevation Myocardial Infarction
Indication
Dosing Regimen
Lovenox1
Initial 30 mg IV bolus
followed by
1 mg/kg q12h SC
Heparin1
aPTT Adjusted
IV Therapy
Acute ST-Segment Elevation
Myocardial Infarction
- Major bleeding (including
ICH) 2
- Intracranial hemorrhages
(ICH)
n = 10176
n (%)
211 (2.1)
84 (0.8)
n = 10151
n (%)
138 (1.4)
66 (0.7)
14
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1The rates represent major bleeding (including ICH) up to 30 days
2Bleedings were considered major if the hemorrhage caused a significant clinical event
associated with a hemoglobin decrease by ≥ 5 g/dL. ICH were always considered major.
Elevations of Serum Aminotransferases
Asymptomatic increases in aspartate (AST [SGOT]) and alanine (ALT [SGPT])
aminotransferase levels greater than three times the upper limit of normal of the laboratory
reference range have been reported in up to 6.1% and 5.9% of patients, respectively, during
treatment with Lovenox. Similar significant increases in aminotransferase levels have also been
observed in patients and healthy volunteers treated with heparin and other low molecular weight
heparins. Such elevations are fully reversible and are rarely associated with increases in
bilirubin.
Since aminotransferase determinations are important in the differential diagnosis of myocardial
infarction, liver disease, and pulmonary emboli, elevations that might be caused by drugs like
Lovenox should be interpreted with caution.
Local Reactions
Mild local irritation, pain, hematoma, ecchymosis, and erythema may follow SC injection of
Lovenox.
Adverse Reactions in Patients Receiving Lovenox for Prophylaxis or Treatment of
DVT, PE:
Other adverse reactions that were thought to be possibly or probably related to treatment with
Lovenox, heparin, or placebo in clinical trials with patients undergoing hip or knee replacement
surgery, abdominal or colorectal surgery, or treatment for DVT and that occurred at a rate of at
least 2% in the Lovenox group, are provided below [see Tables 8 to 11].
Table 8
Adverse Reactions Occurring at ≥2% Incidence in Lovenox-Treated Patients Undergoing
Abdominal or Colorectal Surgery
Adverse Reaction
Dosing Regimen
Lovenox
40 mg q.d. SC
n = 1228
%
Severe
Total
Heparin
5000 U q8h SC
n = 1234
%
Severe
Total
Hemorrhage
<1
7
<1
6
Anemia
<1
3
<1
3
Ecchymosis
0
3
0
3
15
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Table 9
Adverse Reactions Occurring at ≥2% Incidence in Lovenox-Treated Patients Undergoing
Hip or Knee Replacement Surgery
Dosing Regimen
Lovenox
Lovenox
Heparin
Placebo
40 mg q.d. SC
30 mg q12h
15,000 U/24h
q12h SC
SC
SC
Peri-operative
Extended
Period
Prophylaxis
Period
n = 288 1
n = 131 2
n = 1080
n = 766
n = 115
%
%
%
%
%
Adverse
Reaction
Severe Total
Severe Total
Severe Total
Severe Total Severe Total
Fever
0
8
0
0
<1
5
<1
4
0
3
Hemorrhage
<1
13
0
5
<1
4
1
4
0
3
Nausea
<1
3
<1
2
0
2
Anemia
0
16
0
<2
<1
2
2
5
<1
7
Edema
<1
2
<1
2
0
2
Peripheral
0
6
0
0
<1
3
<1
4
0
3
edema
1 Data represent Lovenox 40 mg SC once a day initiated up to 12 hours prior to surgery in 288
hip replacement surgery patients who received Lovenox peri-operatively in an unblinded
fashion in one clinical trial.
2 Data represent Lovenox 40 mg SC once a day given in a blinded fashion as extended
prophylaxis at the end of the peri-operative period in 131 of the original 288 hip replacement
surgery patients for up to 21 days in one clinical trial.
16
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 10
Adverse Reactions Occurring at ≥2% Incidence in Lovenox-Treated Medical Patients with
Severely Restricted Mobility During Acute Illness
Adverse Reaction
Dosing Regimen
Lovenox
40 mg q.d. SC
n = 360
%
Placebo
q.d. SC
n = 362
%
Dyspnea
3.3
5.2
Thrombocytopenia
2.8
2.8
Confusion
2.2
1.1
Diarrhea
2.2
1.7
Nausea
2.5
1.7
Table 11
Adverse Reactions Occurring at ≥2% Incidence in Lovenox-Treated Patients Undergoing
Treatment of Deep Vein Thrombosis with or without Pulmonary Embolism
Adverse Reaction
Dosing Regimen
Lovenox
1.5 mg/kg q.d. SC
n = 298
%
Severe
Total
Lovenox
1 mg/kg q12h SC
n = 559
%
Severe
Total
Heparin
aPTT Adjusted
IV Therapy
n = 544
%
Severe
Total
Injection Site
Hemorrhage
0
5
0
3
<1
<1
Injection Site Pain
0
2
0
2
0
0
Hematuria
0
2
0
<1
<1
2
Adverse Events in Lovenox-Treated Patients with Unstable Angina or Non-Q-
Wave Myocardial Infarction:
Non-hemorrhagic clinical events reported to be related to Lovenox therapy occurred at an
incidence of ≤1%.
Non-major hemorrhagic events, primarily injection site ecchymoses and hematomas, were more
frequently reported in patients treated with SC Lovenox than in patients treated with IV heparin.
Serious adverse events with Lovenox or heparin in a clinical trial in patients with unstable angina
or non-Q-wave myocardial infarction that occurred at a rate of at least 0.5% in the Lovenox
group are provided below [see Table 12].
17
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Table 12
Serious Adverse Events Occurring at ≥0.5% Incidence in Lovenox-Treated Patients with
Unstable Angina or Non-Q-Wave Myocardial Infarction
Adverse Event
Dosing Regimen
Lovenox
1 mg/kg q12h SC
n = 1578
n (%)
Heparin
aPTT Adjusted
IV Therapy
n = 1529
n (%)
Atrial fibrillation
11 (0.70)
3 (0.20)
Heart failure
15 (0.95)
11 (0.72)
Lung edema
11 (0.70)
11 (0.72)
Pneumonia
13 (0.82)
9 (0.59)
Adverse Reactions in Lovenox-Treated Patients with Acute ST-Segment Elevation
Myocardial Infarction:
In a clinical trial in patients with acute ST-segment elevation myocardial infarction, the only
adverse reaction that occurred at a rate of at least 0.5% in the Lovenox group was
thrombocytopenia (1.5%).
6.2 Postmarketing Experience
There have been reports of epidural or spinal hematoma formation with concurrent use of
Lovenox and spinal/epidural anesthesia or spinal puncture. The majority of patients had a post
operative indwelling epidural catheter placed for analgesia or received additional drugs affecting
hemostasis such as NSAIDs. Many of the epidural or spinal hematomas caused neurologic
injury, including long-term or permanent paralysis.
Local reactions at the injection site (e.g. nodules, inflammation, oozing), systemic allergic
reactions (e.g. pruritus, urticaria, anaphylactic/anaphylactoid reactions), vesiculobullous rash,
rare cases of hypersensitivity cutaneous vasculitis, purpura, skin necrosis (occurring at either the
injection site or distant from the injection site), thrombocytosis, and thrombocytopenia with
thrombosis [see Warnings and Precautions (5.5)] have been reported.
Cases of hyperkalemia have been reported. Most of these reports occurred in patients who also
had conditions that tend toward the development of hyperkalemia (e.g., renal dysfunction,
concomitant potassium-sparing drugs, administration of potassium, hematoma in body tissues).
Very rare cases of hyperlipidemia have also been reported, with one case of hyperlipidemia, with
marked hypertriglyceridemia, reported in a diabetic pregnant woman; causality has not been
determined.
18
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Because these reactions are reported voluntarily from a population of uncertain size, it is not
possible to estimate reliably their frequency or to establish a causal relationship to drug
exposure.
7 DRUG INTERACTIONS
Whenever possible, agents which may enhance the risk of hemorrhage should be discontinued
prior to initiation of Lovenox therapy. These agents include medications such as: anticoagulants,
platelet inhibitors including acetylsalicylic acid, salicylates, NSAIDs (including ketorolac
tromethamine), dipyridamole, or sulfinpyrazone. If co-administration is essential, conduct close
clinical and laboratory monitoring [see Warnings and Precautions (5.9)].
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category B
All pregnancies have a background risk of birth defect, loss, or other adverse outcome regardless
of drug exposure. The fetal risk summary below describes the potential of Lovenox to increase
the risk of developmental abnormalities above the background risk.
Fetal Risk Summary
Lovenox does not cross the placenta, and is not expected to result in fetal exposure to the drug.
Human data from a retrospective cohort study, which included 693 live births, suggest that
Lovenox does not increase the risk of major developmental abnormalities. Based on animal data,
enoxaparin is not predicted to increase the risk of major developmental abnormalities (see Data).
Clinical Considerations
Pregnancy alone confers an increased risk for thromboembolism that is even higher for women
with thromboembolic disease and certain high risk pregnancy conditions. While not adequately
studied, pregnant women with mechanical prosthetic heart valves may be at even higher risk for
thrombosis [see Warnings and Precautions (5.7) and Use in Specific Populations (8.6)].
Pregnant women with thromboembolic disease, including those with mechanical prosthetic heart
valves and those with inherited or acquired thrombophilias, have an increased risk of other
maternal complications and fetal loss regardless of the type of anticoagulant used.
All patients receiving anticoagulants, including pregnant women, are at risk for bleeding.
Pregnant women receiving enoxaparin should be carefully monitored for evidence of bleeding or
excessive anticoagulation. Consideration for use of a shorter acting anticoagulant should be
specifically addressed as delivery approaches [see Boxed Warning]. Hemorrhage can occur at
any site and may lead to death of mother and/or fetus. Pregnant women should be apprised of
the potential hazard to the fetus and the mother if enoxaparin is administered during pregnancy.
It is not known if monitoring of anti-Factor Xa activity and dose adjustment (by weight or anti-
Factor Xa activity) of Lovenox affect the safety and the efficacy of the drug during pregnancy.
19
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Cases of “gasping syndrome” have occurred in premature infants when large amounts of benzyl
alcohol have been administered (99-405 mg/kg/day). The multiple-dose vial of Lovenox
contains 15 mg benzyl alcohol per 1 mL as a preservative [see Warnings and Precautions (5.8)].
Data
•
Human Data - There are no adequate and well-controlled studies in pregnant women. A
retrospective study reviewed the records of 604 women who used enoxaparin during
pregnancy. A total of 624 pregnancies resulted in 693 live births. There were 72
hemorrhagic events (11 serious) in 63 women. There were 14 cases of neonatal
hemorrhage. Major congenital anomalies in live births occurred at rates (2.5%) similar to
background rates.
There have been postmarketing reports of fetal death when pregnant women received
Lovenox. Causality for these cases has not been determined. Insufficient data, the
underlying disease, and the possibility of inadequate anticoagulation complicate the
evaluation of these cases.
A clinical study using enoxaparin in pregnant women with mechanical prosthetic heart
valves has been conducted [see Warnings and Precautions (5.7)].
• Animal Data - Teratology studies have been conducted in pregnant rats and rabbits at SC
doses of enoxaparin up to 15 times the recommended human dose (by comparison with 2
mg/kg as the maximum recommended daily dose). There was no evidence of teratogenic
effects or fetotoxicity due to enoxaparin. Because animal reproduction studies are not
always predictive of human response, this drug should be used during pregnancy only if
clearly needed.
8.3 Nursing Mothers
It is not known whether Lovenox is excreted in human milk. Because many drugs are excreted
in human milk and because of the potential for serious adverse reactions in nursing infants from
Lovenox, a decision should be made whether to discontinue nursing or discontinue Lovenox,
taking into account the importance of Lovenox to the mother and the known benefits of nursing.
8.4 Pediatric Use
Safety and effectiveness of Lovenox in pediatric patients have not been established.
8.5 Geriatric Use
Prevention of Deep Vein Thrombosis in Hip, Knee and Abdominal Surgery; Treatment of Deep
Vein Thrombosis, Prevention of Ischemic Complications of Unstable Angina and Non-Q-wave
Myocardial Infarction
Over 2800 patients, 65 years and older, have received Lovenox in pivotal clinical trials. The
efficacy of Lovenox in the geriatric (≥65 years) was similar to that seen in younger patients (<65
20
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years). The incidence of bleeding complications was similar between geriatric and younger
patients when 30 mg every 12 hours or 40 mg once a day doses of Lovenox were employed. The
incidence of bleeding complications was higher in geriatric patients as compared to younger
patients when Lovenox was administered at doses of 1.5 mg/kg once a day or 1 mg/kg every 12
hours. The risk of Lovenox-associated bleeding increased with age. Serious adverse events
increased with age for patients receiving Lovenox. Other clinical experience (including
postmarketing surveillance and literature reports) has not revealed additional differences in the
safety of Lovenox between geriatric and younger patients. Careful attention to dosing intervals
and concomitant medications (especially antiplatelet medications) is advised. Lovenox should
be used with care in geriatric patients who may show delayed elimination of enoxaparin.
Monitoring of geriatric patients with low body weight (<45 kg) and those predisposed to
decreased renal function should be considered [see Warnings and Precautions (5.9) and Clinical
Pharmacology (12.3)].
Treatment of Acute ST-Segment Elevation Myocardial Infarction
In the clinical study for treatment of acute ST-segment elevation myocardial infarction, there was
no evidence of difference in efficacy between patients ≥75 years of age (n = 1241) and patients
less than 75 years of age (n=9015). Patients ≥75 years of age did not receive a 30 mg IV bolus
prior to the normal dosage regimen and had their SC dose adjusted to 0.75 mg/kg every 12 hours
[see Dosage and Administration (2.3)]. The incidence of bleeding complications was higher in
patients ≥65 years of age as compared to younger patients (<65 years).
8.6 Patients with Mechanical Prosthetic Heart Valves
The use of Lovenox has not been adequately studied for thromboprophylaxis in patients with
mechanical prosthetic heart valves and has not been adequately studied for long-term use in this
patient population. Isolated cases of prosthetic heart valve thrombosis have been reported in
patients with mechanical prosthetic heart valves who have received enoxaparin for
thromboprophylaxis. Some of these cases were pregnant women in whom thrombosis led to
maternal and fetal deaths. Insufficient data, the underlying disease and the possibility of
inadequate anticoagulation complicate the evaluation of these cases. Pregnant women with
mechanical prosthetic heart valves may be at higher risk for thromboembolism [see Warnings
and Precautions (5.7)].
8.7 Renal Impairment
In patients with renal impairment, there is an increase in exposure of enoxaparin sodium. All
such patients should be observed carefully for signs and symptoms of bleeding. Because
exposure of enoxaparin sodium is significantly increased in patients with severe renal
impairment (creatinine clearance <30 mL/min), a dosage adjustment is recommended for
therapeutic and prophylactic dosage ranges. No dosage adjustment is recommended in patients
with moderate (creatinine clearance 30-50 mL/min) and mild (creatinine clearance 50-80
mL/min) renal impairment [see Dosage and Administration (2.2) and Clinical Pharmacology
(12.3)]. In patients with renal failure, treatment with enoxaparin has been associated with the
development of hyperkalemia [see Adverse Reactions (6.2)].
21
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For current labeling information, please visit https://www.fda.gov/drugsatfda
8.8 Hepatic Impairment
The impact of hepatic impairment on enoxaparin’s exposure and antithrombotic effect has not
been investigated. Caution should be exercised when administering enoxaparin to patients with
hepatic impairment.
8.9 Low-Weight Patients
An increase in exposure of enoxaparin sodium with prophylactic dosages (non-weight adjusted)
has been observed in low-weight women (<45 kg) and low-weight men (<57 kg). All such
patients should be observed carefully for signs and symptoms of bleeding [see Clinical
Pharmacology (12.3)].
10 OVERDOSAGE
Accidental overdosage following administration of Lovenox may lead to hemorrhagic
complications. Injected Lovenox may be largely neutralized by the slow IV injection of
protamine sulfate (1% solution). The dose of protamine sulfate should be equal to the dose of
Lovenox injected: 1 mg protamine sulfate should be administered to neutralize 1 mg Lovenox, if
enoxaparin sodium was administered in the previous 8 hours. An infusion of 0.5 mg protamine
per 1 mg of enoxaparin sodium may be administered if enoxaparin sodium was administered
greater than 8 hours previous to the protamine administration, or if it has been determined that a
second dose of protamine is required. The second infusion of 0.5 mg protamine sulfate per 1 mg
of Lovenox may be administered if the aPTT measured 2 to 4 hours after the first infusion
remains prolonged.
If at least 12 hours have elapsed since the last enoxaparin sodium injection, protamine
administration may not be required; however, even with higher doses of protamine, the aPTT
may remain more prolonged than following administration of heparin. In all cases, the anti-
Factor Xa activity is never completely neutralized (maximum about 60%). Particular care should
be taken to avoid overdosage with protamine sulfate. Administration of protamine sulfate can
cause severe hypotensive and anaphylactoid reactions. Because fatal reactions, often resembling
anaphylaxis, have been reported with protamine sulfate, it should be given only when
resuscitation techniques and treatment of anaphylactic shock are readily available. For
additional information consult the labeling of protamine sulfate injection products.
11 DESCRIPTION
Lovenox is a sterile aqueous solution containing enoxaparin sodium, a low molecular weight
heparin. The pH of the injection is 5.5 to 7.5.
Enoxaparin sodium is obtained by alkaline depolymerization of heparin benzyl ester derived
from porcine intestinal mucosa. Its structure is characterized by a 2-O-sulfo-4-enepyranosuronic
acid group at the non-reducing end and a 2-N,6-O-disulfo-D-glucosamine at the reducing end of
the chain. About 20% (ranging between 15% and 25%) of the enoxaparin structure contains an
1,6 anhydro derivative on the reducing end of the polysaccharide chain. The drug substance is
22
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For current labeling information, please visit https://www.fda.gov/drugsatfda
the sodium salt. The average molecular weight is about 4500 daltons. The molecular weight
distribution is:
<2000 daltons
≤20%
2000 to 8000 daltons
≥68%
>8000 daltons
≤18%
STRUCTURAL FORMULA Structural Formula
R
X*= 15 to
25% Structural formula
n= 0 to 20
100 - X
H
n =1 to 21
*X = Percent of polysaccharide chain containing 1,6 anhydro derivative on the reducing end.
Lovenox 100 mg/mL Concentration contains 10 mg enoxaparin sodium (approximate anti-
Factor Xa activity of 1000 IU [with reference to the W.H.O. First International Low Molecular
Weight Heparin Reference Standard]) per 0.1 mL Water for Injection.
Lovenox 150 mg/mL Concentration contains 15 mg enoxaparin sodium (approximate anti-
Factor Xa activity of 1500 IU [with reference to the W.H.O. First International Low Molecular
Weight Heparin Reference Standard]) per 0.1 mL Water for Injection.
The Lovenox prefilled syringes and graduated prefilled syringes are preservative-free and
intended for use only as a single-dose injection. The multiple-dose vial contains 15 mg benzyl
alcohol per 1 mL as a preservative [see Dosage and Administration (2) and How Supplied (16)].
23
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For current labeling information, please visit https://www.fda.gov/drugsatfda
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Enoxaparin is a low molecular weight heparin which has antithrombotic properties.
12.2 Pharmacodynamics
In humans, enoxaparin given at a dose of 1.5 mg/kg subcutaneously (SC) is characterized by a
higher ratio of anti-Factor Xa to anti-Factor IIa activity (mean ± SD, 14.0 ± 3.1) (based on areas
under anti-Factor activity versus time curves) compared to the ratios observed for heparin
(mean±SD, 1.22 ± 0.13). Increases of up to 1.8 times the control values were seen in the
thrombin time (TT) and the activated partial thromboplastin time (aPTT). Enoxaparin at a 1
mg/kg dose (100 mg/mL concentration), administered SC every 12 hours to patients in a large
clinical trial resulted in aPTT values of 45 seconds or less in the majority of patients (n = 1607).
A 30 mg IV bolus immediately followed by a 1 mg/kg SC administration resulted in aPTT post-
injection values of 50 seconds. The average aPTT prolongation value on Day 1 was about 16%
higher than on Day 4.
12.3 Pharmacokinetics
Absorption: Pharmacokinetic trials were conducted using the 100 mg/mL formulation.
Maximum anti-Factor Xa and anti-thrombin (anti-Factor IIa) activities occur 3 to 5 hours after
SC injection of enoxaparin. Mean peak anti-Factor Xa activity was 0.16 IU/mL (1.58 mcg/mL)
and 0.38 IU/mL (3.83 mcg/mL) after the 20 mg and the 40 mg clinically tested SC doses,
respectively. Mean (n = 46) peak anti-Factor Xa activity was 1.1 IU/mL at steady state in
patients with unstable angina receiving 1 mg/kg SC every 12 hours for 14 days. Mean absolute
bioavailability of enoxaparin, after 1.5 mg/kg given SC, based on anti-Factor Xa activity is
approximately 100% in healthy subjects.
A 30 mg IV bolus immediately followed by a 1 mg/kg SC every 12 hours provided initial peak
anti-Factor Xa levels of 1.16 IU/mL (n=16) and average exposure corresponding to 84% of
steady-state levels. Steady state is achieved on the second day of treatment.
Enoxaparin pharmacokinetics appear to be linear over the recommended dosage ranges [see
Dosage and Administration (2)]. After repeated subcutaneous administration of 40 mg once
daily and 1.5 mg/kg once-daily regimens in healthy volunteers, the steady state is reached on day
2 with an average exposure ratio about 15% higher than after a single dose. Steady-state
enoxaparin activity levels are well predicted by single-dose pharmacokinetics. After repeated
subcutaneous administration of the 1 mg/kg twice daily regimen, the steady state is reached from
day 4 with mean exposure about 65% higher than after a single dose and mean peak and trough
levels of about 1.2 and 0.52 IU/mL, respectively.
Based on enoxaparin sodium
pharmacokinetics, this difference in steady state is expected and within the therapeutic range.
24
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Although not studied clinically, the 150 mg/mL concentration of enoxaparin sodium is projected
to result in anticoagulant activities similar to those of 100 mg/mL and 200 mg/mL concentrations
at the same enoxaparin dose. When a daily 1.5 mg/kg SC injection of enoxaparin sodium was
given to 25 healthy male and female subjects using a 100 mg/mL or a 200 mg/mL concentration
the following pharmacokinetic profiles were obtained [see Table 13].
Table 13
Pharmacokinetic Parameters* After 5 Days of 1.5 mg/kg SC Once Daily Doses of
Enoxaparin Sodium Using 100 mg/mL or 200 mg/mL Concentrations
Concentration
Anti-Xa
Anti-IIa
Heptest
aPTT
Amax
(IU/mL or Δ
sec)
100 mg/mL
1.37 (±0.23)
0.23 (±0.05)
105 (±17)
19 (±5)
200 mg/mL
1.45 (±0.22)
0.26 (±0.05)
111 (±17)
22 (±7)
90% CI
102-110%
102-111%
tmax** (h)
100 mg/mL
3 (2-6)
4 (2-5)
2.5 (2-4.5)
3 (2-4.5)
200 mg/mL
3.5 (2-6)
4.5 (2.5-6)
3.3 (2-5)
3 (2-5)
AUC
(ss)
(h*IU/mL
or
h* Δ sec)
100 mg/mL
14.26 (±2.93)
1.54 (±0.61)
1321 (±219)
200 mg/mL
15.43 (±2.96)
1.77 (±0.67)
1401 (±227)
90% CI
105-112%
103-109%
*Means ± SD at Day 5 and 90% Confidence Interval (CI) of the ratio
**Median (range)
Distribution: The volume of distribution of anti-Factor Xa activity is about 4.3 L.
Elimination: Following intravenous (IV) dosing, the total body clearance of enoxaparin is 26
mL/min. After IV dosing of enoxaparin labeled with the gamma-emitter, 99mTc, 40% of
radioactivity and 8 to 20% of anti-Factor Xa activity were recovered in urine in 24 hours.
Elimination half-life based on anti-Factor Xa activity was 4.5 hours after a single SC dose to
about 7 hours after repeated dosing. Significant anti-Factor Xa activity persists in plasma for
about 12 hours following a 40 mg SC once a day dose.
Following SC dosing, the apparent clearance (CL/F) of enoxaparin is approximately 15 mL/min.
Metabolism: Enoxaparin sodium is primarily metabolized in the liver by desulfation and/or
depolymerization to lower molecular weight species with much reduced biological potency.
25
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Renal clearance of active fragments represents about 10% of the administered dose and total
renal excretion of active and non-active fragments 40% of the dose.
Special Populations
Gender: Apparent clearance and Amax derived from anti-Factor Xa values following single SC
dosing (40 mg and 60 mg) were slightly higher in males than in females. The source of the
gender difference in these parameters has not been conclusively identified; however, body
weight may be a contributing factor.
Geriatric: Apparent clearance and Amax derived from anti-Factor Xa values following single and
multiple SC dosing in geriatric subjects were close to those observed in young subjects.
Following once a day SC dosing of 40 mg enoxaparin, the Day 10 mean area under anti-Factor
Xa activity versus time curve (AUC) was approximately 15% greater than the mean Day 1 AUC
value [see Dosage and Administration (2.3) and Use in Specific Populations (8.5)].
Renal Impairment: A linear relationship between anti-Factor Xa plasma clearance and creatinine
clearance at steady state has been observed, which indicates decreased clearance of enoxaparin
sodium in patients with reduced renal function. Anti-Factor Xa exposure represented by AUC, at
steady state, is marginally increased in mild (creatinine clearance 50–80 mL/min) and moderate
(creatinine clearance 30-50 mL/min) renal impairment after repeated subcutaneous 40 mg once-
daily doses. In patients with severe renal impairment (creatinine clearance <30 mL/min), the
AUC at steady state is significantly increased on average by 65% after repeated subcutaneous 40
mg once-daily doses [see Dosage and Administration (2.2) and Use in Specific Populations
(8.7)].
Hemodialysis: In a single study, elimination rate appeared similar but AUC was two-fold higher
than control population, after a single 0.25 or 0.5 mg/kg intravenous dose.
Hepatic Impairment: Studies with enoxaparin in patients with hepatic impairment have not been
conducted and the impact of hepatic impairment on the exposure to enoxaparin is unknown [see
Use in Specific Populations (8.8)].
Weight: After repeated subcutaneous 1.5 mg/kg once daily dosing, mean AUC of anti-Factor Xa
activity is marginally higher at steady state in obese healthy volunteers (BMI 30-48 kg/m2)
compared to non-obese control subjects, while Amax is not increased.
When non-weight adjusted dosing was administered, it was found after a single-subcutaneous 40
mg dose, that anti-Factor Xa exposure is 52% higher in low-weight women (<45 kg) and 27%
higher in low-weight men (<57 kg) when compared to normal weight control subjects [see Use
in Specific Populations (8.9)].
Pharmacokinetic interaction: No pharmacokinetic interaction was observed between enoxaparin
and thrombolytics when administered concomitantly.
26
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13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
No long-term studies in animals have been performed to evaluate the carcinogenic potential of
enoxaparin. Enoxaparin was not mutagenic in in vitro tests, including the Ames test, mouse
lymphoma cell forward mutation test, and human lymphocyte chromosomal aberration test, and
the in vivo rat bone marrow chromosomal aberration test. Enoxaparin was found to have no
effect on fertility or reproductive performance of male and female rats at SC doses up to 20
mg/kg/day or 141 mg/m2/day. The maximum human dose in clinical trials was 2.0 mg/kg/day or
78 mg/m2/day (for an average body weight of 70 kg, height of 170 cm, and body surface area of
1.8 m2).
13.2 Animal Toxicology and/or Pharmacology
A single SC dose of 46.4 mg/kg enoxaparin was lethal to rats. The symptoms of acute toxicity
were ataxia, decreased motility, dyspnea, cyanosis, and coma.
13.3 Reproductive and Developmental Toxicology
Teratology studies have been conducted in pregnant rats and rabbits at SC doses of enoxaparin
up to 30 mg/kg/day corresponding to 211 mg/m2/day and 410 mg/m2/day in rats and rabbits
respectively. There was no evidence of teratogenic effects or fetotoxicity due to enoxaparin.
14 CLINICAL STUDIES
14.1 Prophylaxis of Deep Vein Thrombosis Following Abdominal Surgery in
Patients at Risk for Thromboembolic Complications
Abdominal surgery patients at risk include those who are over 40 years of age, obese,
undergoing surgery under general anesthesia lasting longer than 30 minutes or who have
additional risk factors such as malignancy or a history of deep vein thrombosis (DVT) or
pulmonary embolism (PE).
In a double-blind, parallel group study of patients undergoing elective cancer surgery of the
gastrointestinal, urological, or gynecological tract, a total of 1116 patients were enrolled in the
study, and 1115 patients were treated. Patients ranged in age from 32 to 97 years (mean age 67
years) with 52.7% men and 47.3% women. Patients were 98% Caucasian, 1.1% Black, 0.4%
Asian and 0.4% others. Lovenox 40 mg SC, administered once a day, beginning 2 hours prior to
surgery and continuing for a maximum of 12 days after surgery, was comparable to heparin 5000
U every 8 hours SC in reducing the risk of DVT. The efficacy data are provided below [see
Table 14].
Table 14
Efficacy of Lovenox in the Prophylaxis of Deep Vein Thrombosis Following Abdominal
Surgery
Dosing Regimen
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Indication
n (%)
n (%)
All Treated Abdominal
Surgery Patients
555 (100)
560 (100)
Treatment Failures
Total VTE1 (%)
DVT Only (%)
56 (10.1)
(95% CI2: 8 to 13)
63 (11.3)
(95% CI: 9 to 14)
54 (9.7)
(95% CI: 7 to 12)
61 (10.9)
(95% CI: 8 to 13)
1 VTE = Venous thromboembolic events which included DVT, PE, and death considered to be
thromboembolic in origin
2 CI = Confidence Interval
In a second double-blind, parallel group study, Lovenox 40 mg SC once a day was compared to
heparin 5000 U every 8 hours SC in patients undergoing colorectal surgery (one-third with
cancer). A total of 1347 patients were randomized in the study and all patients were treated.
Patients ranged in age from 18 to 92 years (mean age 50.1 years) with 54.2% men and 45.8%
women. Treatment was initiated approximately 2 hours prior to surgery and continued for
approximately 7 to 10 days after surgery. The efficacy data are provided below [see Table 15].
Table 15
Efficacy of Lovenox in the Prophylaxis of Deep Vein Thrombosis Following Colorectal
Surgery
Indication
Dosing Regimen
Lovenox
40 mg q.d. SC
n (%)
Heparin
5000 U q8h SC
n (%)
All Treated Colorectal Surgery
Patients
673 (100)
674 (100)
Treatment Failures
Total VTE1 (%)
DVT Only (%)
48 (7.1)
(95% CI2: 5 to 9)
45 (6.7)
(95% CI: 5 to 9)
47 (7.0)
(95% CI: 5 to 9)
44 (6.5)
(95% CI: 5 to 8)
1 VTE = Venous thromboembolic events which included DVT, PE, and death considered to be
thromboembolic in origin
2 CI = Confidence Interval
14.2 Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement
Surgery
Lovenox has been shown to reduce the risk of post-operative deep vein thrombosis (DVT)
following hip or knee replacement surgery.
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In a double-blind study, Lovenox 30 mg every 12 hours SC was compared to placebo in patients
with hip replacement. A total of 100 patients were randomized in the study and all patients were
treated. Patients ranged in age from 41 to 84 years (mean age 67.1 years) with 45% men and
55% women. After hemostasis was established, treatment was initiated 12 to 24 hours after
surgery and was continued for 10 to 14 days after surgery. The efficacy data are provided below
[see Table 16].
Table 16
Efficacy of Lovenox in the Prophylaxis of Deep Vein Thrombosis Following Hip
Replacement Surgery
Indication
Dosing Regimen
Lovenox
30 mg q12h SC
n (%)
Placebo
q12h SC
n (%)
All Treated Hip Replacement Patients
50 (100)
50 (100)
Treatment Failures
Total DVT (%)
Proximal DVT (%)
5 (10)1
23 (46)
1 (2)2
11 (22)
1 p value versus placebo = 0.0002
2 p value versus placebo = 0.0134
A double-blind, multicenter study compared three dosing regimens of Lovenox in patients with
hip replacement. A total of 572 patients were randomized in the study and 568 patients were
treated. Patients ranged in age from 31 to 88 years (mean age 64.7 years) with 63% men and
37% women. Patients were 93% Caucasian, 6% Black, <1% Asian, and 1% others. Treatment
was initiated within two days after surgery and was continued for 7 to 11 days after surgery. The
efficacy data are provided below [see Table 17].
Table 17
Efficacy of Lovenox in the Prophylaxis of Deep Vein Thrombosis Following Hip
Replacement Surgery
Indication
Dosing Regimen
10 mg q.d. SC
n (%)
30 mg q12h SC
n (%)
40 mg q.d. SC
n (%)
All Treated Hip
Replacement Patients
161 (100)
208 (100)
199 (100)
Treatment Failures
Total DVT (%)
40 (25)
22 (11)1
27 (14)
Proximal DVT (%)
17 (11)
8 (4)2
9 (5)
1 p value versus Lovenox 10 mg once a day = 0.0008
2 p value versus Lovenox 10 mg once a day = 0.0168
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There was no significant difference between the 30 mg every 12 hours and 40 mg once a day
regimens. In a double-blind study, Lovenox 30 mg every 12 hours SC was compared to placebo
in patients undergoing knee replacement surgery. A total of 132 patients were randomized in the
study and 131 patients were treated, of which 99 had total knee replacement and 32 had either
unicompartmental knee replacement or tibial osteotomy. The 99 patients with total knee
replacement ranged in age from 42 to 85 years (mean age 70.2 years) with 36.4% men and
63.6% women. After hemostasis was established, treatment was initiated 12 to 24 hours after
surgery and was continued up to 15 days after surgery. The incidence of proximal and total DVT
after surgery was significantly lower for Lovenox compared to placebo. The efficacy data are
provided below [see Table 18].
Table 18
Efficacy of Lovenox in the Prophylaxis of Deep Vein Thrombosis Following Total Knee
Replacement Surgery
Indication
Dosing Regimen
Lovenox
30 mg q12h SC
n (%)
Placebo
q12h SC
n (%)
All Treated Total Knee
Replacement Patients
47 (100)
52 (100)
Treatment Failures
Total DVT (%)
5 (11)1
(95% CI2: 1 to 21)
32 (62)
(95% CI: 47 to 76)
Proximal DVT (%)
0 (0)3
(95% Upper CL4: 5)
7 (13)
(95% CI: 3 to 24)
1 p value versus placebo = 0.0001
2 CI = Confidence Interval
3 p value versus placebo = 0.013
4 CL = Confidence Limit
Additionally, in an open-label, parallel group, randomized clinical study, Lovenox 30 mg every
12 hours SC in patients undergoing elective knee replacement surgery was compared to heparin
5000 U every 8 hours SC. A total of 453 patients were randomized in the study and all were
treated. Patients ranged in age from 38 to 90 years (mean age 68.5 years) with 43.7% men and
56.3% women. Patients were 92.5% Caucasian, 5.3% Black, and 0.6% others. Treatment was
initiated after surgery and continued up to 14 days. The incidence of deep vein thrombosis was
significantly lower for Lovenox compared to heparin.
Extended Prophylaxis of Deep Vein Thrombosis Following Hip Replacement Surgery: In a study
of extended prophylaxis for patients undergoing hip replacement surgery, patients were treated,
while hospitalized, with Lovenox 40 mg SC, initiated up to 12 hours prior to surgery for the
prophylaxis of post-operative DVT. At the end of the peri-operative period, all patients
underwent bilateral venography.
In a double-blind design, those patients with no venous
thromboembolic disease were randomized to a post-discharge regimen of either Lovenox 40 mg
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(n = 90) once a day SC or to placebo (n = 89) for 3 weeks. A total of 179 patients were
randomized in the double-blind phase of the study and all patients were treated. Patients ranged
in age from 47 to 87 years (mean age 69.4 years) with 57% men and 43% women. In this
population of patients, the incidence of DVT during extended prophylaxis was significantly
lower for Lovenox compared to placebo. The efficacy data are provided below [see Table 19].
Table 19
Efficacy of Lovenox in the Extended Prophylaxis of Deep Vein Thrombosis Following Hip
Replacement Surgery
Indication (Post-Discharge)
Post-Discharge Dosing Regimen
Lovenox
40 mg q.d. SC
n (%)
Placebo
q.d. SC
n (%)
All Treated Extended
Prophylaxis Patients
90 (100)
89 (100)
Treatment Failures
Total DVT (%)
6 (7)1
(95% CI2: 3 to 14)
18 (20)
(95% CI: 12 to 30)
Proximal DVT (%)
5 (6)3
(95% CI: 2 to 13)
7 (8)
(95% CI: 3 to 16)
1 p value versus placebo = 0.008
2 CI= Confidence Interval
3 p value versus placebo = 0.537
In a second study, patients undergoing hip replacement surgery were treated, while hospitalized,
with Lovenox 40 mg SC, initiated up to 12 hours prior to surgery. All patients were examined
for clinical signs and symptoms of venous thromboembolic (VTE) disease. In a double-blind
design, patients without clinical signs and symptoms of VTE disease were randomized to a post-
discharge regimen of either Lovenox 40 mg (n = 131) once a day SC or to placebo (n = 131) for
3 weeks. A total of 262 patients were randomized in the study double-blind phase and all
patients were treated. Patients ranged in age from 44 to 87 years (mean age 68.5 years) with
43.1% men and 56.9% women. Similar to the first study the incidence of DVT during extended
prophylaxis was significantly lower for Lovenox compared to placebo, with a statistically
significant difference in both total DVT (Lovenox 21 [16%] versus placebo 45 [34%]; p = 0.001)
and proximal DVT (Lovenox 8 [6%] versus placebo 28 [21%]; p = <0.001).
14.3 Prophylaxis of Deep Vein Thrombosis in Medical Patients with Severely
Restricted Mobility During Acute Illness
In a double blind multicenter, parallel group study, Lovenox 20 mg or 40 mg once a day SC was
compared to placebo in the prophylaxis of deep vein thrombosis (DVT) in medical patients with
severely restricted mobility during acute illness (defined as walking distance of <10 meters for
≤3 days). This study included patients with heart failure (NYHA Class III or IV); acute
respiratory failure or complicated chronic respiratory insufficiency (not requiring ventilatory
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support): acute infection (excluding septic shock); or acute rheumatic disorder [acute lumbar or
sciatic pain, vertebral compression (due to osteoporosis or tumor), acute arthritic episodes of the
lower extremities]. A total of 1102 patients were enrolled in the study, and 1073 patients were
treated. Patients ranged in age from 40 to 97 years (mean age 73 years) with equal proportions
of men and women. Treatment continued for a maximum of 14 days (median duration 7 days).
When given at a dose of 40 mg once a day SC, Lovenox significantly reduced the incidence of
DVT as compared to placebo. The efficacy data are provided below [see Table 20].
Table 20
Efficacy of Lovenox in the Prophylaxis of Deep Vein Thrombosis in Medical Patients with
Severely Restricted Mobility During Acute Illness
Indication
Dosing Regimen
Lovenox
20 mg q.d. SC
n (%)
Lovenox
40 mg q.d. SC
n (%)
Placebo
n (%)
All Treated Medical
Patients During Acute
Illness
351 (100)
360 (100)
362 (100)
Treatment Failure1
Total VTE2 (%)
Total DVT (%)
Proximal DVT (%)
43 (12.3)
16 (4.4)
43 (11.9)
43 (12.3)
(95% CI3 8.8 to 15.7)
16 (4.4)
(95% CI3 2.3 to 6.6)
41 (11.3)
(95% CI3 8.1 to 14.6)
13 (3.7)
5 (1.4)
14 (3.9)
1 Treatment failures during therapy, between Days 1 and 14
2 VTE = Venous thromboembolic events which included DVT, PE, and death considered to be
thromboembolic in origin
3 CI = Confidence Interval
At approximately 3 months following enrollment, the incidence of venous thromboembolism
remained significantly lower in the Lovenox 40 mg treatment group versus the placebo treatment
group.
14.4 Treatment of Deep Vein Thrombosis with or without Pulmonary Embolism
In a multicenter, parallel group study, 900 patients with acute lower extremity deep vein
thrombosis (DVT) with or without pulmonary embolism (PE) were randomized to an inpatient
(hospital) treatment of either (i) Lovenox 1.5 mg/kg once a day SC, (ii) Lovenox 1 mg/kg every
12 hours SC, or (iii) heparin IV bolus (5000 IU) followed by a continuous infusion (administered
to achieve an aPTT of 55 to 85 seconds). A total of 900 patients were randomized in the study
and all patients were treated. Patients ranged in age from 18 to 92 years (mean age 60.7 years)
with 54.7% men and 45.3% women. All patients also received warfarin sodium (dose adjusted
according to PT to achieve an International Normalization Ratio [INR] of 2.0 to 3.0),
commencing within 72 hours of initiation of Lovenox or standard heparin therapy, and
continuing for 90 days. Lovenox or standard heparin therapy was administered for a minimum of
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5 days and until the targeted warfarin sodium INR was achieved. Both Lovenox regimens were
equivalent to standard heparin therapy in reducing the risk of recurrent venous thromboembolism
(DVT and/or PE). The efficacy data are provided below [see Table 21].
Table 21
Efficacy of Lovenox in Treatment of Deep Vein Thrombosis
with or without Pulmonary Embolism
Indication
Dosing Regimen1
Lovenox
1.5 mg/kg q.d. SC
n (%)
Lovenox
1 mg/kg q12h SC
n (%)
Heparin
aPTT Adjusted
IV Therapy
n (%)
All Treated DVT Patients
with or without PE
298 (100)
312 (100)
290 (100)
Patient Outcome
Total VTE2 (%)
DVT Only (%)
Proximal DVT (%)
PE (%)
13 (4.4)3
9 (2.9) 3
12 (4.1)
11 (3.7)
7 (2.2)
8 (2.8)
9 (3.0)
6 (1.9)
7 (2.4)
2 (0.7)
2 (0.6)
4 (1.4)
1 All patients were also treated with warfarin sodium commencing within 72 hours of Lovenox or
standard heparin therapy.
2 VTE = venous thromboembolic event (DVT and/or PE)
3 The 95% Confidence Intervals for the treatment differences for total VTE were:
Lovenox once a day versus heparin (-3.0 to 3.5)
Lovenox every 12 hours versus heparin (-4.2 to 1.7).
Similarly, in a multicenter, open-label, parallel group study, patients with acute proximal DVT
were randomized to Lovenox or heparin. Patients who could not receive outpatient therapy were
excluded from entering the study. Outpatient exclusion criteria included the following: inability
to receive outpatient heparin therapy because of associated co-morbid conditions or potential for
non-compliance and inability to attend follow-up visits as an outpatient because of geographic
inaccessibility. Eligible patients could be treated in the hospital, but ONLY Lovenox patients
were permitted to go home on therapy (72%). A total of 501 patients were randomized in the
study and all patients were treated. Patients ranged in age from 19 to 96 years (mean age 57.8
years) with 60.5% men and 39.5% women. Patients were randomized to either Lovenox 1 mg/kg
every 12 hours SC or heparin IV bolus (5000 IU) followed by a continuous infusion
administered to achieve an aPTT of 60 to 85 seconds (in-patient treatment). All patients also
received warfarin sodium as described in the previous study. Lovenox or standard heparin
therapy was administered for a minimum of 5 days. Lovenox was equivalent to standard heparin
therapy in reducing the risk of recurrent venous thromboembolism. The efficacy data are
provided below [see Table 22].
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Table 22
Efficacy of Lovenox in Treatment of Deep Vein Thrombosis
Indication
Dosing Regimen1
Lovenox
1 mg/kg q12h SC
n (%)
Heparin
aPTT Adjusted
IV Therapy
n (%)
All Treated DVT Patients
247 (100)
254 (100)
Patient Outcome
Total VTE2 (%)
DVT Only (%)
Proximal DVT (%)
PE (%)
13 (5.3) 3
17 (6.7)
11 (4.5)
14 (5.5)
10 (4.0)
12 (4.7)
2 (0.8)
3 (1.2)
1 All patients were also treated with warfarin sodium commencing on the evening of the second
day of Lovenox or standard heparin therapy.
2 VTE = venous thromboembolic event (deep vein thrombosis [DVT] and/or pulmonary
embolism [PE]).
3 The 95% Confidence Intervals for the treatment difference for total VTE was: Lovenox versus
heparin (- 5.6 to 2.7).
14.5 Prophylaxis of Ischemic Complications in Unstable Angina and Non-Q-Wave
Myocardial Infarction
In a multicenter, double-blind, parallel group study, patients who recently experienced unstable
angina or non-Q-wave myocardial infarction were randomized to either Lovenox 1 mg/kg every
12 hours SC or heparin IV bolus (5000 U) followed by a continuous infusion (adjusted to
achieve an aPTT of 55 to 85 seconds). A total of 3171 patients were enrolled in the study, and
3107 patients were treated. Patients ranged in age from 25-94 years (median age 64 years), with
33.4% of patients female and 66.6% male. Race was distributed as follows: 89.8% Caucasian,
4.8% Black, 2.0% Asian, and 3.5% other. All patients were also treated with aspirin 100 to 325
mg per day. Treatment was initiated within 24 hours of the event and continued until clinical
stabilization, revascularization procedures, or hospital discharge, with a maximal duration of 8
days of therapy. The combined incidence of the triple endpoint of death, myocardial infarction,
or recurrent angina was lower for Lovenox compared with heparin therapy at 14 days after
initiation of treatment. The lower incidence of the triple endpoint was sustained up to 30 days
after initiation of treatment. These results were observed in an analysis of both all-randomized
and all-treated patients. The efficacy data are provided below [see Table 23].
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Table 23
Efficacy of Lovenox in the Prophylaxis of Ischemic Complications in Unstable Angina and
Non-Q-Wave Myocardial Infarction
(Combined Endpoint of Death, Myocardial Infarction, or Recurrent Angina)
Indication
Dosing Regimen1
Reduction
(%)
p Value
Lovenox
1mg/kg q12h SC
n (%)
Heparin
aPTT Adjusted
IV Therapy
n (%)
All Treated Unstable
Angina and Non-Q-Wave
MI Patients
1578 (100)
1529 (100)
Timepoint2
48 Hours
96 (6.1)
112 (7.3)
1.2
0.120
14 Days
261 (16.5)
303 (19.8)
3.3
0.017
30 Days
313 (19.8)
358 (23.4)
3.6
0.014
1 All patients were also treated with aspirin 100 to 325 mg per day.
2 Evaluation timepoints are after initiation of treatment. Therapy continued for up to 8 days
(median duration of 2.6 days).
The combined incidence of death or myocardial infarction at all time points was lower for
Lovenox compared to standard heparin therapy, but did not achieve statistical significance. The
efficacy data are provided below [see Table 24].
Table 24
Efficacy of Lovenox in the Prophylaxis of Ischemic Complications in Unstable Angina and
Non-Q-Wave Myocardial Infarction
(Combined Endpoint of Death or Myocardial Infarction)
Indication
Dosing Regimen1
Reduction
(%)
p Value
Lovenox
1 mg/kg q12h SC
n (%)
Heparin
aPTT Adjusted
IV Therapy
n (%)
All Treated Unstable
Angina and Non-Q-Wave
MI Patients
1578 (100)
1529 (100)
Timepoint2
48 Hours
16 (1.0)
20 (1.3)
0.3
0.126
14 Days
76 (4.8)
93 (6.1)
1.3
0.115
30 Days
96 (6.1)
118 (7.7)
1.6
0.069
1 All patients were also treated with aspirin 100 to 325 mg per day.
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2 Evaluation timepoints are after initiation of treatment. Therapy continued for up to 8 days
(median duration of 2.6 days).
In a survey one year following treatment, with information available for 92% of enrolled
patients, the combined incidence of death, myocardial infarction, or recurrent angina remained
lower for Lovenox versus heparin (32.0% vs 35.7%).
Urgent revascularization procedures were performed less frequently in the Lovenox group as
compared to the heparin group, 6.3% compared to 8.2% at 30 days (p = 0.047).
14.6 Treatment of Acute ST-Segment Elevation Myocardial Infarction
In a multicenter, double-blind, double-dummy, parallel group study, patients with acute ST-
segment elevation myocardial infarction (STEMI) who were to be hospitalized within 6 hours of
onset and were eligible to receive fibrinolytic therapy were randomized in a 1:1 ratio to receive
either Lovenox or unfractionated heparin.
Study medication was initiated between 15 minutes before and 30 minutes after the initiation of
fibrinolytic therapy. Unfractionated heparin was administered beginning with an IV bolus of 60
U/kg (maximum 4000 U) and followed with an infusion of 12 U/kg per hour (initial maximum
1000 U per hour) that was adjusted to maintain an aPTT of 1.5 to 2 times the control value. The
IV infusion was to be given for at least 48 hours. The enoxaparin dosing strategy was adjusted
according to the patient’s age and renal function. For patients younger than 75 years of age,
enoxaparin was given as a single 30 mg intravenous bolus plus a 1 mg/kg SC dose followed by
an SC injection of 1 mg/kg every 12 hours. For patients at least 75 years of age, the IV bolus
was not given and the SC dose was reduced to 0.75 mg/kg every 12 hours. For patients with
severe renal insufficiency (estimated creatinine clearance of less than 30 mL per minute), the
dose was to be modified to 1 mg/kg every 24 hours. The SC injections of enoxaparin were given
until hospital discharge or for a maximum of eight days (whichever came first). The mean
treatment duration for enoxaparin was 6.6 days. The mean treatment duration of unfractionated
heparin was 54 hours.
When percutaneous coronary intervention was performed during study medication period,
patients received antithrombotic support with blinded study drug. For patients on enoxaparin,
the PCI was to be performed on enoxaparin (no switch) using the regimen established in
previous studies, i.e. no additional dosing, if the last SC administration was less than 8 hours
before balloon inflation, IV bolus of 0.3 mg/kg enoxaparin if the last SC administration was
more than 8 hours before balloon inflation.
All patients were treated with aspirin for a minimum of 30 days. Eighty percent of patients
received a fibrin-specific agent (19% tenecteplase, 5% reteplase and 55% alteplase) and 20%
received streptokinase.
Among 20,479 patients in the ITT population, the mean age was 60 years, and 76% were male.
Racial distribution was: 87% Caucasian, 9.8% Asian, 0.2% Black, and 2.8% other. Medical
history included previous MI (13%), hypertension (44%), diabetes (15%) and angiographic
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evidence of CAD (5%). Concomitant medication included aspirin (95%), beta-blockers (86%),
ACE inhibitors (78%), statins (70%) and clopidogrel (27%). The MI at entry was anterior in
43%, non-anterior in 56%, and both in 1%.
The primary efficacy end point was the composite of death from any cause or myocardial re-
infarction in the first 30 days after randomization. Total follow-up was one year.
The rate of the primary efficacy end point (death or myocardial re-infarction) was 9.9% in the
enoxaparin group, and 12.0% in the unfractionated heparin group, a 17% reduction in the relative
risk, (P=0.000003) [see Table 25].
Table 25
Efficacy of Lovenox in the Treatment of Acute ST-Segment Elevation Myocardial
Infarction
Enoxaparin
(N=10,256)
UFH
(N=10,223)
Relative Risk
(95% CI)
P Value
Outcome at 48 hours
n (%)
n (%)
Death or Myocardial Re-infarction
478 (4.7)
531 (5.2)
0.90 (0.80 to 1.01)
0.08
Death
383 (3.7)
390 (3.8)
0.98 (0.85 to 1.12)
0.76
Myocardial Re-infarction
102 (1.0)
156 (1.5)
0.65 (0.51 to 0.84)
<0.001
Urgent Revascularization
74 (0.7)
96 (0.9)
0.77 (0.57 to 1.04)
0.09
Death or Myocardial Re-infarction or Urgent
548 (5.3)
622 (6.1)
0.88 (0.79 to 0.98)
0.02
Revascularization
Outcome at 8 Days
Death or Myocardial Re-infarction
Death
Myocardial Re-infarction
Urgent Revascularization
Death or Myocardial Re-infarction or Urgent
Revascularization
740 (7.2)
559 (5.5)
204 (2.0)
145 (1.4)
874 (8.5)
954 (9.3)
605 (5.9)
379 (3.7)
247 (2.4)
1181 (11.6)
0.77 (0.71 to 0.85)
0.92 (0.82 to 1.03)
0.54 (0.45 to 0.63)
0.59 (0.48 to 0.72)
0.74 (0.68 to 0.80)
<0.001
0.15
<0.001
<0.001
<0.001
Outcome at 30 Days
Primary efficacy endpoint
(Death or Myocardial Re-infarction)
1017 (9.9)
1223 (12.0)
0.83 (0.77 to 0.90)
0.000003
Death
708 (6.9)
765 (7.5)
0.92 (0.84 to 1.02)
0.11
Myocardial Re-infarction
352 (3.4)
508 (5.0)
0.69 (0.60 to 0.79)
<0.001
Urgent Revascularization
213 (2.1)
286 (2.8)
0.74 (0.62 to 0.88)
<0.001
Death or Myocardial Re-infarction or Urgent
1199 (11.7)
1479 (14.5)
0.81 (0.75 to 0.87)
<0.001
Revascularization
Note: Urgent revascularization denotes episodes of recurrent myocardial ischemia (without infarction) leading to the
clinical decision to perform coronary revascularization during the same hospitalization. CI denotes confidence intervals.
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The beneficial effect of enoxaparin on the primary end point was consistent across key
subgroups including age, gender, infarct location, history of diabetes, history of prior myocardial
infarction, fibrinolytic agent administered, and time to treatment with study drug (see Figure 1);
however, it is necessary to interpret such subgroup analyses with caution.
Figure 1. Relative Risks of and Absolute Event Rates for the Primary End Point at 30 Days in Various
Subgroups * Relative Risks of and Absolute Event Rates for the Primary End Point at 30 Days in Various Subgroups
* The primary efficacy end point was the composite of death from any cause or myocardial re-infarction in the first
30 days. The overall treatment effect of enoxaparin as compared to the unfractionated heparin is shown at the
bottom of the figure. For each subgroup, the circle is proportional to the number and represents the point estimate of
the treatment effect and the horizontal lines represent the 95 percent confidence intervals. Fibrin-specific
fibrinolytic agents included alteplase, tenecteplase and reteplase. Time to treatment indicates the time from the
onset of symptoms to the administration of study drug (median, 3.2 hours).
The beneficial effect of enoxaparin on the primary end point observed during the first 30 days
was maintained over a 12 month follow-up period (see Figure 2).
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Figure 2 - Kaplan-Meier plot - death or myocardial re-infarction at 30 days - ITT population Kaplan-Meier plot - death or myocardial re-infarction at 30 days - ITT population
There is a trend in favor of enoxaparin during the first 48 hours, but most of the treatment
difference is attributed to a step increase in the event rate in the UFH group at 48 hours (seen in
Figure 2), an effect that is more striking when comparing the event rates just prior to and just
subsequent to actual times of discontinuation. These results provide evidence that UFH was
effective and that it would be better if used longer than 48 hours. There is a similar increase in
endpoint event rate when enoxaparin was discontinued, suggesting that it too was discontinued
too soon in this study.
The rates of major hemorrhages (defined as requiring 5 or more units of blood for transfusion, or
15% drop in hematocrit or clinically overt bleeding, including intracranial hemorrhage) at 30
days were 2.1% in the enoxaparin group and 1.4% in the unfractionated heparin group. The rates
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of intracranial hemorrhage at 30 days were 0.8% in the enoxaparin group 0.7% in the
unfractionated heparin group. The 30-day rate of the composite endpoint of death, myocardial
re-infarction or ICH (a measure of net clinical benefit) was significantly lower in the enoxaparin
group (10.1%) as compared to the heparin group (12.2%).
16 HOW SUPPLIED/STORAGE AND HANDLING
Lovenox is available in two concentrations [see Tables 26 and 27]:
Table 26
100 mg/mL Concentration
Dosage Unit / Strength1
Anti-Xa
Activity2
Package Size
(per carton)
Label Color
NDC #
0075-
Prefilled Syringes3
30 mg/0.3 mL
40 mg/0.4 mL
3000 IU
4000 IU
10 syringes
10 syringes
Medium Blue
Yellow
0624-30
0620-40
Graduated Prefilled
Syringes3
60 mg/0.6 mL
80 mg/0.8 mL
100 mg/1 mL
6000 IU
8000 IU
10,000 IU
10 syringes
10 syringes
10 syringes
Orange
Brown
Black
0621-60
0622-80
0623-00
Multiple-Dose Vial4
300 mg/3 mL
30,000 IU
1 vial
Red
0626-03
1 Strength represents the number of milligrams of enoxaparin sodium in Water for Injection.
Lovenox 30 and 40 mg prefilled syringes, and 60, 80, and 100 mg graduated prefilled syringes
each contain 10 mg enoxaparin sodium per 0.1 mL Water for Injection.
2 Approximate anti-Factor Xa activity based on reference to the W.H.O. First International Low
Molecular Weight Heparin Reference Standard.
3 Each Lovenox prefilled syringe is for single, one-time use only and is affixed with a 27 gauge x
1/2 inch needle.
4 Each Lovenox multiple-dose vial contains 15 mg benzyl alcohol per 1 mL as a preservative.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 27
150 mg/mL Concentration
Dosage Unit / Strength1
Anti-Xa
Activity2
Package Size
(per carton)
Syringe
Label Color
NDC #
0075-
Graduated Prefilled
Syringes3
120 mg / 0.8 mL
150 mg / 1 mL
12,000 IU
15,000 IU
10 syringes
10 syringes
Purple
Navy Blue
2912-01
2915-01
1 Strength represents the number of milligrams of enoxaparin sodium in Water for Injection.
Lovenox 120 and 150 mg graduated prefilled syringes contain 15 mg enoxaparin sodium per
0.1 mL Water for Injection.
2 Approximate anti-Factor Xa activity based on reference to the W.H.O. First International Low
Molecular Weight Heparin Reference Standard.
3 Each Lovenox graduated prefilled syringe is for single, one-time use only and is affixed with a
27 gauge x 1/2 inch needle.
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room
Temperature].
Do not store the multiple-dose vials for more than 28 days after the first use.
Keep out of the reach of children.
17 PATIENT COUNSELING INFORMATION
If patients have had neuraxial anesthesia or spinal puncture, and particularly, if they are taking
concomitant NSAIDs, platelet inhibitors, or other anticoagulants, they should be informed to
watch for signs and symptoms of spinal or epidural hematoma, such as tingling, numbness
(especially in the lower limbs) and muscular weakness. If any of these symptoms occur the
patient should contact his or her physician immediately.
Additionally, the use of aspirin and other NSAIDs may enhance the risk of hemorrhage. Their
use should be discontinued prior to enoxaparin therapy whenever possible; if co-administration is
essential, the patient’s clinical and laboratory status should be closely monitored [see Drug
Interactions (7)].
Patients should also be informed:
• of the instructions for injecting Lovenox if their therapy is to continue after discharge
from the hospitals.
• it may take them longer than usual to stop bleeding.
• they may bruise and/or bleed more easily when they are treated with Lovenox.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• they should report any unusual bleeding, bruising, or signs of thrombocytopenia (such as
a rash of dark red spots under the skin) to their physician [see Warnings and Precautions
(5.1, 5.5)].
• to tell their physicians and dentists they are taking Lovenox and/or any other product
known to affect bleeding before any surgery is scheduled and before any new drug is
taken [see Warnings and Precautions (5.3)].
• to tell their physicians and dentists of all medications they are taking, including those
obtained without a prescription, such as aspirin or other NSAIDs [see Drug Interactions
(7)].
sanofi-aventis U.S. LLC
Bridgewater, NJ 08807
Multiple-dose vials are also manufactured by DSM Pharmaceuticals, Inc.
Greenville, NC 27835
© 2009 sanofi-aventis U.S. LLC
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
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2025-02-12T13:46:57.403633
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020164s085lbl.pdf', 'application_number': 20164, 'submission_type': 'SUPPL ', 'submission_number': 85}
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HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
Lovenox safely and effectively. See full prescribing information
for Lovenox.
Lovenox® (enoxaparin sodium injection) for subcutaneous and
intravenous use
Initial U.S. Approval: 1993
WARNING: SPINAL/EPIDURAL HEMATOMA
See full prescribing information for complete boxed warning.
• Enoxaparin use in patients undergoing spinal/epidural
anesthesia or spinal puncture increases the risk of spinal or
epidural hematoma, which may cause long-term or
permanent paralysis (5.5)
• Risk is increased by:
o Indwelling epidural catheters for analgesia (5.5)
o Drugs affecting hemostasis [e.g., nonsteroidal anti
inflammatory drugs, platelet inhibitors, anticoagulants]
(5.5, 7)
o Traumatic or repeated spinal or epidural puncture (5.5)
------------------INDICATIONS AND USAGE-------------------
Lovenox is a low molecular weight heparin [LMWH] indicated for:
•
Prophylaxis of deep vein thrombosis (DVT) in abdominal
surgery, hip replacement surgery, knee replacement surgery, or
medical patients with severely restricted mobility during acute
illness (1.1)
•
Inpatient treatment of acute DVT with or without pulmonary
embolism (1.2)
•
Outpatient treatment of acute DVT without pulmonary
embolism. (1.2)
•
Prophylaxis of ischemic complications of unstable angina and
non-Q-wave myocardial infarction [MI] (1.3)
•
Treatment of acute ST-segment elevation myocardial infarction
[STEMI] managed medically or with subsequent percutaneous
coronary intervention [PCI] (1.4)
-------------------DOSAGE AND ADMINISTRATION-------------
Indication
Standard Regimen
(2.1, 2.3)
Severe Renal
Impairment (2.2)
DVT prophylaxis in
abdominal surgery
40 mg SC once
daily
30 mg SC once
daily
DVT prophylaxis in
knee replacement
surgery
30 mg SC every 12
hours
30 mg SC once
daily
DVT prophylaxis in
hip replacement
surgery
30 mg SC every 12
hours or 40 mg SC
once daily
30 mg SC once
daily
DVT prophylaxis in
medical patients
40 mg SC once
daily
30 mg SC once
daily
In patient treatment
of acute DVT with
or without
pulmonary
embolism
1 mg/kg SC every
12 hours or 1.5
mg/kg SC once
daily (with
warfarin)
1 mg/kg SC once
daily
Outpatient
treatment of acute
DVT without
pulmonary
embolism
1 mg/kg SC every
12 hours (with
warfarin)
1 mg/kg SC once
daily
Unstable angina
and non-Q-wave
MI
1 mg/kg SC every
12 hours (with
aspirin)
1 mg/kg SC once
daily
Acute STEMI in
patients <75 years
of age [For dosing
in subsequent PCI,
see Dosage and
Administration
(2.1)]
30-mg single IV
bolus plus a 1
mg/kg SC dose
followed by 1
mg/kg SC every 12
hours with aspirin)
30-mg single IV
bolus plus a 1
mg/kg SC dose
followed by 1
mg/kg SC once
daily
Acute STEMI in
0.75 mg/kg SC
1 mg/kg SC once
patients ≥75 years
of age
every 12 hours (no
bolus)
daily (no bolus)
Do not use as intramuscular injection.
For subcutaneous use, do not mix with other injections or infusions.
----------------------DOSAGE FORMS AND STRENGTHS--------
100 mg/mL concentration (3.1):
•
Prefilled syringes: 30 mg/0.3 mL, 40 mg/0.4 mL
•
Graduated prefilled syringes: 60 mg/0.6 mL, 80 mg/0.8 mL,100
mg/1 mL
•
Multiple-dose vial: 300 mg/3 mL
150 mg/mL con centration (3.2):
•
Graduated prefilled syringes: 120 m g/0.8 mL, 150 mg/1 mL
------------------------------CONTRAINDICATIONS-----------------
•
Active major bleeding (4)
•
Thrombocytopenia with a positive in vitro test for anti-platelet
antibody in the presence of enoxaparin sodium (4)
•
Hypersensitivity to enoxaparin sodium (4)
•
Hypersensitivity to heparin or pork product s (4)
-----------------------WARNINGS AND PRECAUTIO NS----------
•
Use caution in conditions with increased risk of hemorrhage
(5.1)
•
Obtain hemostasis at the puncture site before sheath removal
after percutaneous coronary revascularisation (5.2)
•
Use caution with concomitant medical conditions (5.3)
•
Use caution in case of history of heparin-induced
thrombocytopenia (5.4)
•
Monitor thrombocytopenia of any degree closely (5.5)
•
Do not exchange with heparin or other LMWHs (5.6)
•
Pregnant women with mechanical prosthetic heart valve s not
adequately studied (5.7)
•
Multiple-dose formulation s contain benzyl alcohol (5.8)
•
Periodic blood counts recommended (5.9)
-----------------------------ADVERSE REACTIONS-------------------
Most common adverse reactions (>1%) were bleeding, anemia,
thrombocytopenia, elevation of serum aminotransferase, diarrhea ,
and nausea
To report SUSPECTED ADVERSE REACTIONS, contact
sanofi-aventis at 1-800-633-1610 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
-----------------------------DRUG INTERACTIONS-------------------
Discontinue agents which may enhance hemorrhage risk prior to
initiation of Lovenox or conduct close clinical and laboratory
monitoring (5.9, 7).
----------------------USE IN SPECIFIC POPULATIONS------------
•
Severe renal impairment: Adjust dose for patients with creatinin e
clearance <30 mL/min (2.2)
•
Hepatic Impairment (8.8)
•
Low-weight patients: Observe for signs of bleeding (8.9)
See 17 for PATIENT COUNSELING INFORMATION
Revised: XXXX 2008
2
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
FULL PRESCRIBING INFORMATION: CONTENT S*
8.6 Patients with Mechan ical Prosthetic Heart Valves
8.7 Renal Impairment
WARNING: SPINAL / EPIDURAL HEMATOMAS
8.8 Hepatic Impair ment
1
INDICATIONS AND USAGE
8.9 Low-Weight P atients
1.1 Prophylaxis of Deep Vein Thrombosis
10
OVERDOSAGE
1.2 Treatment of Acute Deep Vein Thrombosis
11
DESCRIPTION
1.3 Prophylaxis of Ischemic Complications of Unstable
12 CLINICAL PHARMACOLOGY
Angina and Non-Q-W ave Myocardial Infarction
1.4 Treatment of acute ST-segment El evation Myocardial
12.1 Mechanism of Action
Infarction (STEMI )
12.2 Pharmacodynamics
2
DOSAGE AND ADMINISTRATION
12.3 Pharmacokinetics
2.1 Adult Dosage
13 NONCLINICAL TOXICO LOGY
2.2 Renal Impairment
13.1 Carcinogenesis, Mutagenesis, Impairment of Ferti lity
2.3 Geriatric patient s with acute ST-seg ment Elevation
13.2 Animal Toxicology
Myocardial Infarction
14 CLINICAL STUDIES
2.4 Administration
14.1 Prophylaxis of Deep Vein Thrombos is (DVT)
3
DOSAGE FORMS AND STREN GTHS
Following Abdominal Surgery in Patients at Risk for
3.1 100 mg/mL Concentr ation
Thromboembolic Complications
3.2 150 mg/mL Concentration
14.2 Prophylaxis of Deep Vein Thrombosis (DVT)Follow ing
4
CONTRAINDICATIONS
Hip or Knee Replacement Surgery
5
WARNINGS AND PRECAUTIONS
14.3 Prophylaxis of Deep V ein Thrombosis (DVT) in
5.1 Increased Risk of Hemorrhage
Medical Patients with Severely Restricted Mobility
5.2 Percutaneous Coronary Revascularization Proced ures
During Acute Illness
5.3 Use of Lovenox with Concomitant Medical Conditions
14.4 Treatment of Deep Vein Thrombosis (DVT) with or
5.4 History of Heparin-induced Thrombocyt openia
without Pulmonary Embolism (PE)
5.5 Thrombocytopenia
14.5 Prophylaxis of Ischemic Complications in Unstable
5.6 Interchangeability with Other Heparins
Angina and Non-Q-W ave Myocardial Infarction
5.7 Pregnant Women with Mechanical Prosthetic Heart
14.6 Treatment of acute ST-segment Elevation Myo cardial
Valves
Infarction (STEMI)
5.8 Benzyl Alcohol
16 HOW SUPPLIED/STORAGE AND HANDLING
5.9 Laboratory Tests
17 PATIENT COUNSELING INFORMATION
6
ADVERSE REACTIONS
6.1 Clinical Trials Experi ence
*Sections or subsections omitted from the full prescribing
6.2 Postmarketing Experience
information are not listed
7
DRUG INTERACTIONS
8
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
3
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
FULL PRESCRIBING INFORMATION
WARNING: SPINAL / EPIDURAL HEMATOMAS
When neuraxial anesthesia (epidural/spinal anesthesia) or spinal puncture is employed, patients
anticoagulated or scheduled to be anticoagulated with low molecular weight heparins or heparinoids for
prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma which
can result in long-term or permanent paralysis.
The risk of these events is increased by the use of indwelling epidural catheters for administration of
analgesia or by the concomitant use of drugs affecting hemostasis such as non steroidal anti-inflammatory
drugs (NSAIDs), platelet inhibitors, or other anticoagulants. The risk also appears to be increased by
traumatic or repeated epidural or spinal puncture.
Monitor patients for signs and symptoms of neurological impairment. If neurologic compromise is noted,
urgent treatment is necessary.
Consider the potential benefit versus risk before neuraxial intervention in patients anticoagulated or to be
anticoagulated for thromboprophylaxis [see Warnings and Precautions (5.1) and Drug Interactions (7)].
1 INDICATIONS AND USAGE
1.1 Prophylaxis of Deep Vein Thrombosis
Lovenox is indicated for the prophylaxis of deep vein thrombosis, which may lead to pulmonary
embolism:
• in patients undergoing abdominal surgery who are at risk for thromboembolic
complications [see Clinical Studies (14.1)].
• in patients undergoing hip replacement surgery, during and following hospitalization.
• in patients undergoing knee replacement surgery.
• in medical patients who are at risk for thromboembolic complications due to severely
restricted mobility during acute illness.
1.2 Treatment of Acute Deep Vein Thrombosis
Lovenox is indicated for:
• the inpatient treatment of acute deep vein thrombosis with or without pulmonary
embolism, when administered in conjunction with warfarin sodium;
• the outpatient treatment of acute deep vein thrombosis without pulmonary embolism
when administered in conjunction with warfarin sodium.
1.3 Prophylaxis of Ischemic Complications of Unstable Angina and Non-Q-Wave
Myocardial Infarction
Lovenox is indicated for the prophylaxis of ischemic complications of unstable angina and non
Q-wave myocardial infarction, when concurrently administered with aspirin.
1.4 Treatment of acute ST- segment Elevation Myocardial Infarction (STEMI)
2
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Lovenox has been shown to reduce the rate of the combined endpoint of recurrent myocardial
infarction or death in patients with acute STEMI receiving thrombolysis and being managed
medically or with Percutaneous Coronary Intervention (PCI).
2 DOSAGE AND ADMINISTRATION
All patients should be evaluated for a bleeding disorder before administration of Lovenox, unless
the medication is needed urgently. Since coagulation parameters are unsuitable for monitoring
Lovenox activity, routine monitoring of coagulation parameters is not required [see Warnings
and Precautions (5.9)].
For subcutaneous use, Lovenox should not be mixed with other injections or infusions. For
intravenous use (i.e., for treatment of acute STEMI), Lovenox can be mixed with normal saline
solution (0.9%) or 5% dextrose in water.
Lovenox is not intended for intramuscular administration.
2.1 Adult Dosage
Abdominal Surgery: In patients undergoing abdominal surgery who are at risk for
thromboembolic complications, the recommended dose of Lovenox is 40 mg once a day
administered by SC injection with the initial dose given 2 hours prior to surgery. The usual
duration of administration is 7 to 10 days; up to 12 days administration has been administered in
clinical trials.
Hip or Knee Replacement Surgery: In patients undergoing hip or knee replacement surgery, the
recommended dose of Lovenox is 30 mg every 12 hours administered by SC injection.
Provided that hemostasis has been established, the initial dose should be given 12 to 24 hours
after surgery. For hip replacement surgery, a dose of 40 mg once a day SC, given initially 12
(±3) hours prior to surgery, may be considered. Following the initial phase of
thromboprophylaxis in hip replacement surgery patients, it is recommended that continued
prophylaxis with Lovenox 40 mg once a day is administered by SC injection for 3 weeks. The
usual duration of administration is 7 to 10 days; up to 14 days administration has been
administered in clinical trials.
Medical Patients During Acute Illness: In medical patients at risk for thromboembolic
complications due to severely restricted mobility during acute illness, the recommended dose of
Lovenox is 40 mg once a day administered by SC injection. The usual duration of
administration is 6 to 11 days; up to 14 days of Lovenox has been administered in the controlled
clinical trial.
Treatment of Deep Vein Thrombosis With or Without Pulmonary Embolism: In outpatient
treatment, patients with acute deep vein thrombosis without pulmonary embolism who can be
treated at home, the recommended dose of Lovenox is 1 mg/kg every 12 hours administered
SC.
In inpatient (hospital) treatment, patients with acute deep vein thrombosis with
pulmonary embolism or patients with acute deep vein thrombosis without pulmonary embolism
(who are not candidates for outpatient treatment), the recommended dose of Lovenox is 1 mg/kg
every 12 hours administered SC or 1.5 mg/kg once a day administered SC at the same time
2
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
every day. In both outpatient and inpatient (hospital) treatments, warfarin sodium therapy should
be initiated when appropriate (usually within 72 hours of Lovenox). Lovenox should be
continued for a minimum of 5 days and until a therapeutic oral anticoagulant effect has been
achieved (International Normalization Ratio 2.0 to 3.0). The average duration of administration
is 7 days; up to 17 days of Lovenox administration has been administered in controlled clinical
trials.
Unstable Angina and Non-Q-Wave Myocardial Infarction: In patients with unstable angina or
non-Q-wave myocardial infarction, the recommended dose of Lovenox is 1 mg/kg administered
SC every 12 hours in conjunction with oral aspirin therapy (100 to 325 mg once daily).
Treatment with Lovenox should be prescribed for a minimum of 2 days and continued until
clinical stabilization. The usual duration of treatment is 2 to 8 days; up to 12.5 days of Lovenox
has been administered in clinical trials. [See Warnings and Precautions (5.2) and Clinical
Studies (14.5)].
Treatment of acute ST-segment Elevation Myocardial Infarction: In patients with acute ST-
segment Elevation Myocardial Infarction, the recommended dose of Lovenox is a single IV
bolus of 30 mg plus a 1 mg/kg SC dose followed by 1 mg/kg administered SC every 12 hours
(maximum 100 mg for the first two doses only, followed by 1 mg/kg dosing for the remaining
doses). Dosage adjustments are recommended in patients ≥75 years of age [see Dosage and
Administration (2.3)].
When administered in conjunction with a thrombolytic (fibrin-specific or non-fibrin specific),
Lovenox should be given between 15 minutes before and 30 minutes after the start of fibrinolytic
therapy. All patients should receive acetylsalicylic acid (ASA) as soon as they are identified as
having STEMI and maintained with 75 to 325 mg once daily unless contraindicated. In the
pivotal clinical study, the Lovenox treatment duration was 8 days or until hospital discharge,
whichever came first. An optimal duration of treatment is not known, but it is likely to be longer
than 8 days.
For patients managed with Percutaneous Coronary Intervention (PCI): If the last Lovenox SC
administration was given less than 8 hours before balloon inflation, no additional dosing is
needed. If the last Lovenox SC administration was given more than 8 hours before balloon
inflation, an IV bolus of 0.3 mg/kg of Lovenox should be administered [see Warnings and
Precautions (5.2)].
2.2 Renal Impairment
Although no dose adjustment is recommended in patients with moderate (creatinine clearance
30-50 mL/min) and mild (creatinine clearance 50-80 mL/min) renal impairment, all such patients
should be observed carefully for signs and symptoms of bleeding.
The recommended prophylaxis and treatment dosage regimens for patients with severe renal
impairment (creatinine clearance <30 mL/min) are described in Table 1 [see Use in Specific
Populations (8.6) and Clinical Pharmacology (12.3)].
3
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 1
Dosage Regimens for Patients with Severe Renal Impairment
(creatinine clearance <30mL/minute)
Indication
Dosage Regimen
Prophylaxis in abdominal surgery
30 mg administered SC once daily
Prophylaxis in hip or knee replacement surgery
30 mg administered SC once daily
Prophylaxis in medical patients during acute illness
30 mg administered SC once daily
Inpatient treatment of acute deep vein thrombosis with
or without pulmonary embolism, when administered in
conjunction with warfarin sodium
1 mg/kg administered SC once daily
Outpatient treatment of acute deep vein thrombosis
without pulmonary embolism, when administered in
conjunction with warfarin sodium
1 mg/kg administered SC once daily
Prophylaxis of ischemic complications of unstable
angina and non-Q-wave myocardial infarction, when
concurrently administered with aspirin
1 mg/kg administered SC once daily
Treatment of acute ST-segment Elevation Myocardial
Infarction in patients <75 years of age
30-mg single IV bolus plus a 1 mg/kg SC
dose followed by 1 mg/kg administered
SC once daily.
Treatment of acute ST-segment Elevation Myocardial
Infarction in geriatric patients ≥75 years of age
1 mg/kg administered SC once daily (no
initial bolus)
2.3 Geriatric patients with acute ST-segment Elevation Myocardial Infarction
For treatment of acute ST-segment Elevation Myocardial Infarction in geriatric patients ≥75 years of age,
do not use an initial IV bolus. Initiate dosing with 0.75 mg/kg SC every 12 hours (maximum 75 mg
for the first two doses only, followed by 0.75 mg/kg dosing for the remaining doses)[see Use in
Specific Populations (8.5) and Clinical Pharmacology (12.3)].
No dose adjustment is necessary for other indications in geriatric patients unless kidney function is
impaired [see Dosage and Administration (2.2)].
2.4 Administration
Lovenox is a clear, colorless to pale yellow sterile solution, and as with other parenteral drug
products, should be inspected visually for particulate matter and discoloration prior to
administration.
The use of a tuberculin syringe or equivalent is recommended when using Lovenox multiple-
dose vials to assure withdrawal of the appropriate volume of drug.
Lovenox must not be administered by intramuscular injection. Lovenox is intended for use
under the guidance of a physician.
For subcutaneous administration, patients may self-inject only if their physicians determine that
it is appropriate and with medical follow-up, as necessary. Proper training in subcutaneous
injection technique (with or without the assistance of an injection device) should be provided.
4
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Subcutaneous Injection Technique: Patients should be lying down and Lovenox administered by
deep SC injection. To avoid the loss of drug when using the 30 and 40 mg prefilled syringes, do
not expel the air bubble from the syringe before the injection. Administration should be
alternated between the left and right anterolateral and left and right posterolateral abdominal
wall. The whole length of the needle should be introduced into a skin fold held between the
thumb and forefinger; the skin fold should be held throughout the injection. To minimize
bruising, do not rub the injection site after completion of the injection.
Lovenox prefilled syringes and graduated prefilled syringes are available with a system that
shields the needle after injection.
1. Remove the needle shield by pulling it straight off the syringe (see Figure A). If adjusting the
dose is required, the dose adjustment must be done prior to injecting the prescribed dose to the
patient.
Usage Illustration
2. Inject using standard technique, pushing the plunger to the bottom of the syringe (see Figure
B).
Usage Illustration
3. Remove the syringe from the injection site keeping your finger on the plunger rod (see Figure
C).
Usage Illustration
4. Orient the needle away from you and others, and activate the safety system by firmly
pushing the plunger rod. The protective sleeve will automatically cover the needle and an
audible “click” will be heard to confirm shield activation (see Figure D).
5
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Figure D Usage Illustration
5. Immediately dispose of the syringe in the nearest sharps container (see Figure E).
Usage Illustration
NOTE:
• The safety system can only be activated once the syringe has been emptied.
• Activation of the safety system must be done only after removing the needle from the
patient’s skin.
• Do not replace the needle shield after injection.
• The safety system should not be sterilized.
Activation of the safety system may cause minimal splatter of fluid. For optimal safety activate
the system while orienting it downwards away from yourself and others.
Intravenous (Bolus) Injection Technique: For intravenous injection, the multiple-dose vial should
be used. Lovenox should be administered through an intravenous line. Lovenox should not be
mixed or co-administered with other medications. To avoid the possible mixture of Lovenox
with other drugs, the intravenous access chosen should be flushed with a sufficient amount of
saline or dextrose solution prior to and following the intravenous bolus administration of
Lovenox to clear the port of drug. Lovenox may be safely administered with normal saline
solution (0.9%) or 5% dextrose in water.
3 DOSAGE FORMS AND STRENGTHS
Lovenox is available in two concentrations:
3.1 100 mg/mL Concentration
-Prefilled Syringes
30 mg / 0.3 mL, 40 mg / 0.4 mL
-Graduated Prefilled Syringes 60 mg / 0.6 mL, 80 mg / 0.8 mL, 100 mg / 1 mL
-Multiple-Dose Vials
300 mg / 3 mL
3.2 150 mg/mL Concentration
-Graduated Prefilled Syringes 120 mg / 0.8 mL, 150 mg / 1 mL
6
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
4 CONTRAINDICATIONS
• Active major bleeding.
• Thrombocytopenia associated with a positive in vitro test for anti-platelet antibody in the
presence of enoxaparin sodium.
• Known
hypersensitivity
to
enoxaparin
sodium
(e.g.,
pruritus,
urticaria,
anaphylactic/anaphylactoid reactions) [see Adverse Reactions (6.2)].
• Known hypersensitivity to heparin or pork products.
• Known hypersensitivity to benzyl alcohol (which is in only the multi-dose formulation of
Lovenox).
5 WARNINGS AND PRECAUTIONS
5.1 Increased Risk of Hemorrhage
Cases of epidural or spinal hematomas have been reported with the associated use of Lovenox
and spinal/epidural anesthesia or spinal puncture resulting in long-term or permanent paralysis.
The risk of these events is higher with the use of post-operative indwelling epidural catheters or
by the concomitant use of additional drugs affecting hemostasis such as NSAIDs [see boxed
Warning, Adverse Reactions (6.2) and Drug Interactions (7)].
Lovenox should be used with extreme caution in conditions with increased risk of hemorrhage,
such as bacterial endocarditis, congenital or acquired bleeding disorders, active ulcerative and
angiodysplastic gastrointestinal disease, hemorrhagic stroke, or shortly after brain, spinal, or
ophthalmological surgery, or in patients treated concomitantly with platelet inhibitors.
Major hemorrhages including retroperitoneal and intracranial bleeding have been reported.
Some of these cases have been fatal.
Bleeding can occur at any site during therapy with Lovenox. An unexplained fall in hematocrit
or blood pressure should lead to a search for a bleeding site.
5.2 Percutaneous Coronary Revascularization Procedures
To minimize the risk of bleeding following the vascular instrumentation during the treatment of
unstable angina, non-Q-wave myocardial infarction and acute ST-segment elevation myocardial
infarction, adhere precisely to the intervals recommended between Lovenox doses. It is
important to achieve hemostasis at the puncture site after PCI. In case a closure device is used,
the sheath can be removed immediately. If a manual compression method is used, sheath should
be removed 6 hours after the last IV/SC Lovenox. If the treatment with enoxaparin sodium is to
be continued, the next scheduled dose should be given no sooner than 6 to 8 hours after sheath
removal. The site of the procedure should be observed for signs of bleeding or hematoma
formation [see Dosage and Administration (2.1)].
5.3 Use of Lovenox with Concomitant Medical Conditions
Lovenox should be used with care in patients with a bleeding diathesis, uncontrolled arterial
hypertension or a history of recent gastrointestinal ulceration, diabetic retinopathy, renal
dysfunction and hemorrhage.
7
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5.4 History of Heparin-induced Thrombocytopenia
Lovenox should be used with extreme caution in patients with a history of heparin-induced
thrombocytopenia.
5.5 Thrombocytopenia
Thrombocytopenia can occur with the administration of Lovenox.
3
Moderate thrombocytopenia (platelet counts between 100,000/mm3 and 50,000/mm ) occurred at
a rate of 1.3% in patients given Lovenox, 1.2% in patients given heparin, and 0.7% in patients
given placebo in clinical trials.
Platelet counts less than 50,000/mm3 occurred at a rate of 0.1% in patients given Lovenox, in
0.2% of patients given heparin, and 0.4% of patients given placebo in the same trials.
Thrombocytopenia of any degree should be monitored closely. If the platelet count falls below
100,000/mm3, Lovenox should be discontinued. Cases of heparin-induced thrombocytopenia
with thrombosis have also been observed in clinical practice. Some of these cases were
complicated by organ infarction, limb ischemia, or death [see Warnings and Precautions (5.4)].
5.6 Interchangeability with Other Heparins
Lovenox cannot be used interchangeably (unit for unit) with heparin or other low molecular
weight heparins as they differ in manufacturing process, molecular weight distribution, anti-Xa
and anti-IIa activities, units, and dosage. Each of these medicines has its own instructions for
use.
5.7 Pregnant Women with Mechanical Prosthetic Heart Valves
The use of Lovenox for thromboprophylaxis in pregnant women with mechanical prosthetic
heart valves has not been adequately studied. In a clinical study of pregnant women with
mechanical prosthetic heart valves given enoxaparin (1 mg/kg twice daily) to reduce the risk of
thromboembolism, 2 of 8 women developed clots resulting in blockage of the valve and leading
to maternal and fetal death. Although a causal relationship has not been established these deaths
may have been due to therapeutic failure or inadequate anticoagulation. No patients in the
heparin/warfarin group (0 of 4 women) died. There also have been isolated postmarketing
reports of valve thrombosis in pregnant women with mechanical prosthetic heart valves while
receiving enoxaparin for thromboprophylaxis. Women with mechanical prosthetic heart valves
may be at higher risk for thromboembolism during pregnancy, and, when pregnant, have a higher
rate of fetal loss from stillbirth, spontaneous abortion and premature delivery. Therefore,
frequent monitoring of peak and trough anti-Factor Xa levels, and adjusting of dosage may be
needed [see Use in Specific Populations (8.6)].
5.8 Benzyl Alcohol
Lovenox multiple-dose vials contain benzyl alcohol as a preservative. The administration of
medications containing benzyl alcohol as a preservative to premature neonates has been
associated with a fatal “Gasping Syndrome”. Because benzyl alcohol may cross the placenta,
8
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Lovenox multiple-dose vials, preserved with benzyl alcohol, should be used with caution in
pregnant women and only if clearly needed [see Use in Specific Populations (8.1)].
5.9 Laboratory Tests
Periodic complete blood counts, including platelet count, and stool occult blood tests are
recommended during the course of treatment with Lovenox.
When administered at
recommended prophylaxis doses, routine coagulation tests such as Prothrombin Time (PT) and
Activated Partial Thromboplastin Time (aPTT) are relatively insensitive measures of Lovenox
activity and, therefore, unsuitable for monitoring. Anti-Factor Xa may be used to monitor the
anticoagulant effect of Lovenox in patients with significant renal impairment. If during Lovenox
therapy abnormal coagulation parameters or bleeding should occur, anti-Factor Xa levels may be
used to monitor the anticoagulant effects of Lovenox [see Clinical Pharmacology (12.3)].
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
Because clinical studies are conducted under widely varying conditions, adverse reaction rates
observed in the clinical studies of a drug cannot be directly compared to rates in the clinical
studies of another drug and may not reflect the rates observed in practice.
Hemorrhage
The incidence of major hemorrhagic complications during Lovenox treatment has been low.
The following rates of major bleeding events have been reported during clinical trials with
Lovenox Injection [see Tables 2 to 7].
Table 2
Major Bleeding Episodes Following Abdominal and Colorectal Surgery1
Indications
Dosing Regimen
Lovenox
40 mg q.d. SC
Heparin
5000 U q8h SC
Abdominal Surgery
n = 555
23 (4%)
n = 560
16 (3%)
Colorectal Surgery
n = 673
28 (4%)
n = 674
21 (3%)
1 Bleeding complications were considered major: (1) if the hemorrhage caused a significant clinical event, or (2) if
accompanied by a hemoglobin decrease ≥ 2 g/dL or transfusion of 2 or more units of blood products.
Retroperitoneal, intraocular, and intracranial hemorrhages were always considered major.
9
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 3
Major Bleeding Episodes Following Hip or Knee Replacement Surgery1
Indications
Dosing Regimen
Lovenox
40 mg q.d. SC
Lovenox
30 mg q12h SC
Heparin
15,000 U/24h SC
Hip Replacement Surgery
Without Extended Prophylaxis2
n = 786
31 (4%)
n = 541
32 (6%)
Hip Replacement Surgery
With Extended Prophylaxis
Peri-operative Period3
Extended Prophylaxis Period4
n = 288
4 (2%)
n = 221
0 (0%)
Knee Replacement Surgery
Without Extended Prophylaxis2
n = 294
3 (1%)
n = 225
3 (1%)
1 Bleeding complications were considered major: (1) if the hemorrhage caused a significant clinical event, or (2) if
accompanied by a hemoglobin decrease ≥ 2 g/dL or transfusion of 2 or more units of blood products.
Retroperitoneal and intracranial hemorrhages were always considered major. In the knee replacement surgery
trials, intraocular hemorrhages were also considered major hemorrhages.
2 Lovenox 30 mg every 12 hours SC initiated 12 to 24 hours after surgery and continued for up to 14 days after
surgery.
3 Lovenox 40 mg SC once a day initiated up to 12 hours prior to surgery and continued for up to 7 days after
surgery.
4 Lovenox 40 mg SC once a day for up to 21 days after discharge.
NOTE: At no time point were the 40 mg once a day pre-operative and the 30 mg every 12 hours
post-operative hip replacement surgery prophylactic regimens compared in clinical trials.
Injection site hematomas during the extended prophylaxis period after hip replacement surgery
occurred in 9% of the Lovenox patients versus 1.8% of the placebo patients.
Table 4
Major Bleeding Episodes in Medical Patients With Severely Restricted Mobility During
Acute Illness1
Indications
Dosing Regimen
2
Lovenox
20 mg q.d. SC
2
Lovenox
40 mg q.d. SC
Placebo2
Medical Patients During
Acute Illness
n = 351
1 (<1%)
n = 360
3 (<1%)
n = 362
2 (<1%)
1 Bleeding complications were considered major: (1) if the hemorrhage caused a significant clinical event, (2) if the
hemorrhage caused a decrease in hemoglobin of ≥ 2 g/dL or transfusion of 2 or more units of blood products.
Retroperitoneal and intracranial hemorrhages were always considered major although none were reported during
the trial.
2 The rates represent major bleeding on study medication up to 24 hours after last dose.
10
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 5
Major Bleeding Episodes in Deep Vein Thrombosis With or Without Pulmonary Embolism
Treatment 1
Indication
Dosing Regimen2
Lovenox
1.5 mg/kg q.d. SC
Lovenox
1 mg/kg q12h SC
Heparin
aPTT Adjusted
IV Therapy
Treatment of DVT and PE
n = 298
5 (2%)
n = 559
9 (2%)
n = 554
9 (2%)
1 Bleeding complications were considered major: (1) if the hemorrhage caused a significant clinical event, or (2) if
accompanied by a hemoglobin decrease ≥ 2 g/dL or transfusion of 2 or more units of blood products.
Retroperitoneal, intraocular, and intracranial hemorrhages were always considered major.
2 All patients also received warfarin sodium (dose-adjusted according to PT to achieve an INR of 2.0 to 3.0)
commencing within 72 hours of Lovenox or standard heparin therapy and continuing for up to 90 days.
Table 6
Major Bleeding Episodes in Unstable Angina and Non-Q-Wave Myocardial Infarction
Indication
Dosing Regimen
1
Lovenox
1 mg/kg q12h SC
Heparin1
aPTT Adjusted
IV Therapy
Unstable Angina and
Non-Q-Wave MI2,3
n = 1578
17 (1%)
n = 1529
18 (1%)
1 The rates represent major bleeding on study medication up to 12 hours after dose.
2 Aspirin therapy was administered concurrently (100 to 325 mg per day).
3 Bleeding complications were considered major: (1) if the hemorrhage caused a significant clinical event, or (2) if
accompanied by a hemoglobin decrease by ≥ 3 g/dL or transfusion of 2 or more units of blood products.
Intraocular, retroperitoneal, and intracranial hemorrhages were always considered major.
Table 7
Major Bleeding Episodes in acute ST-segment Elevation Myocardial Infarction
Indication
Dosing Regimen
1
Lovenox
Initial 30-mg IV bolus
followed by
1 mg/kg q12h SC
Heparin1
aPTT Adjusted
IV Therapy
acute ST-segment Elevation
Myocardial Infarction,
n = 10176
n (%)
n = 10151
n (%)
11
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
- Major bleeding (including
ICH) 2
- Intracranial hemorrhages
(ICH)
211 (2.1)
84 (0.8)
138 (1.4)
66 (0.7)
1The rates represent major bleeding (including ICH) up to 30 days
2Bleedings were considered major if the hemorrhage caused a significant clinical event associated with a
hemoglobin decrease by ≥ 5 g/dL. ICH were always considered major.
Thrombocytopenia:
[See Warnings and Precautions (5.5)]
Elevations of Serum Aminotransferases
Asymptomatic increases in aspartate (AST [SGOT]) and alanine (ALT [SGPT])
aminotransferase levels greater than three times the upper limit of normal of the laboratory
reference range have been reported in up to 6.1% and 5.9% of patients, respectively, during
treatment with Lovenox. Similar significant increases in aminotransferase levels have also been
observed in patients and healthy volunteers treated with heparin and other low molecular weight
heparins. Such elevations are fully reversible and are rarely associated with increases in
bilirubin.
Since aminotransferase determinations are important in the differential diagnosis of myocardial
infarction, liver disease, and pulmonary emboli, elevations that might be caused by drugs like
Lovenox should be interpreted with caution.
Local Reactions
Mild local irritation, pain, hematoma, ecchymosis, and erythema may follow SC injection of
Lovenox.
Other
Other adverse effects that were thought to be possibly or probably related to treatment with
Lovenox, heparin, or placebo in clinical trials with patients undergoing hip or knee replacement
surgery, abdominal or colorectal surgery, or treatment for DVT and that occurred at a rate of at
least 2% in the Lovenox group, are provided below [see Tables 8 to 11].
12
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 8
Adverse Events Occurring at ≥2% Incidence in Lovenox-Treated Patients1 Undergoing
Abdominal or Colorectal Surgery
Adverse Event
Dosing Regimen
Lovenox
40 mg q.d. SC
n = 1228
%
Severe
Total
Heparin
5000 U q8h SC
n = 1234
%
Severe
Total
Hemorrhage
<1
7
<1
6
Anemia
<1
3
<1
3
Ecchymosis
0
3
0
3
1 Excluding unrelated adverse events.
Table 9
Adverse Events Occurring at ≥2% Incidence in Lovenox-Treated Patients1 Undergoing Hip
or Knee Replacement Surgery
Dosing Regimen
Lovenox
Lovenox
40 mg q.d. SC
Heparin
30 mg q12h
SC
Placebo
15,000 U/24h
q12h SC
SC
Peri-operative
Extended
Period
n = 288 2
%
Prophylaxis
Period
n = 131 3
%
n = 1080
%
n = 766
%
n = 115
%
Severe
Total
Severe
Total
Severe
Total
Severe
Total
Severe
Total
Adverse Event
Fever
0
8
0
0
<1
5
<1
4
0
3
Hemorrhage
<1
13
0
5
<1
4
1
4
0
3
Nausea
<1
3
<1
2
0
2
Anemia
0
16
0
<2
<1
2
2
5
<1
7
Edema
<1
2
<1
2
0
2
0
6
0
0
<1
3
<1
4
0
3
Peripheral
edema
1 Excluding unrelated adverse events.
2 Data represents Lovenox 40 mg SC once a day initiated up to 12 hours prior to surgery in 288 hip replacement
surgery patients who received Lovenox peri-operatively in an unblinded fashion in one clinical trial.
13
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
3 Data represents Lovenox 40 mg SC once a day given in a blinded fashion as extended prophylaxis at the end of the
peri-operative period in 131 of the original 288 hip replacement surgery patients for up to 21 days in one clinical
trial.
Table 10
Adverse Events Occurring at ≥2% Incidence in Lovenox-Treated Medical Patients1 With
Severely Restricted Mobility During Acute Illness
Adverse Event
Dosing Regimen
Lovenox
40 mg q.d. SC
n = 360
%
Placebo
q.d. SC
n = 362
%
Dyspnea
3.3
5.2
Thrombocytopenia
2.8
2.8
Confusion
2.2
1.1
Diarrhea
2.2
1.7
Nausea
2.5
1.7
1 Excluding unrelated and unlikely adverse events.
Table 11
Adverse Events Occurring at ≥2% Incidence in Lovenox-Treated Patients1 Undergoing
Treatment of Deep Vein Thrombosis With or Without Pulmonary Embolism
Adverse Event
Dosing Regimen
Lovenox
1.5 mg/kg q.d. SC
n = 298
%
Severe
Total
Lovenox
1 mg/kg q12h SC
n = 559
%
Severe
Total
Heparin
aPTT Adjusted
IV Therapy
n = 544
%
Severe
Total
Injection Site
Hemorrhage
0
5
0
3
<1
<1
Injection Site Pain
0
2
0
2
0
0
Hematuria
0
2
0
<1
<1
2
1 Excluding unrelated adverse events.
Adverse Events in Lovenox-Treated Patients With Unstable Angina or Non-Q-Wave
Myocardial Infarction:
Non-hemorrhagic clinical events reported to be related to Lovenox therapy occurred at an
incidence of ≤1%.
14
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Non-major hemorrhagic episodes, primarily injection site ecchymoses and hematomas, were
more frequently reported in patients treated with SC Lovenox than in patients treated with IV
heparin.
Serious adverse events with Lovenox or heparin in a clinical trial in patients with unstable angina
or non-Q-wave myocardial infarction that occurred at a rate of at least 0.5% in the Lovenox
group are provided below (irrespective of relationship to drug therapy) [see Table 12].
Table 12
Serious Adverse Events Occurring at ≥0.5% Incidence in Lovenox-Treated Patients With
Unstable Angina or Non-Q-Wave Myocardial Infarction
Adverse Event
Dosing Regimen
Lovenox
1 mg/kg q12h SC
n = 1578
n (%)
Heparin
aPTT Adjusted
IV Therapy
n = 1529
n (%)
Atrial fibrillation
11 (0.70)
3 (0.20)
Heart failure
15 (0.95)
11 (0.72)
Lung edema
11 (0.70)
11 (0.72)
Pneumonia
13 (0.82)
9 (0.59)
Adverse Reactions in Lovenox-Treated Patients With acute ST-segment Elevation Myocardial
Infarction:
In a clinical trial in patients with acute ST-segment elevation myocardial infarction, the only
additional possibly related adverse reaction that occurred at a rate of at least 0.5% in the
Lovenox group was thrombocytopenia (1.5%)
6.2 Postmarketing Experience
There have been reports of epidural or spinal hematoma formation with concurrent use of
Lovenox and spinal/epidural anesthesia or spinal puncture. The majority of patients had a post
operative indwelling epidural catheter placed for analgesia or received additional drugs affecting
hemostasis such as NSAIDs. Many of the epidural or spinal hematomas caused neurologic
injury, including long-term or permanent paralysis.
Local reactions at the injection site (e.g. nodules, inflammation, oozing), systemic allergic
reactions (e.g. pruritus, urticaria, anaphylactic/anaphylactoid reactions), vesiculobullous rash,
rare cases of hypersensitivity cutaneous vasculitis, purpura, skin necrosis (occurring at either the
injection site or distant from the injection site), thrombocytosis, and thrombocytopenia with
thrombosis [see Warnings and Precautions (5.5)] have been reported. Cases of hyperkalemia
have been reported. Most of these reports occurred in patients who also had conditions that tend
toward the development of hyperkalemia (e.g., renal dysfunction, concomitant potassium-sparing
15
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
drugs, administration of potassium, hematoma in body tissues).
Very rare cases of
hyperlipidemia have also been reported, with one case of hyperlipidemia, with marked
hypertriglyceridemia, reported in a diabetic pregnant woman; causality has not been determined.
Because these reactions are reported voluntarily from a population of uncertain size, it is not
possible to estimate reliably their frequency or to establish a causal relationship to drug
exposure.
7 DRUG INTERACTIONS
Unless really needed, agents which may enhance the risk of hemorrhage should be discontinued
prior to initiation of Lovenox therapy. These agents include medications such as: anticoagulants,
platelet inhibitors including acetylsalicylic acid, salicylates, NSAIDs (including ketorolac
tromethamine), dipyridamole, or sulfinpyrazone. If co-administration is essential, conduct close
clinical and laboratory monitoring [see Warnings and Precautions (5.9)].
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category B
All pregnancies have a background risk of birth defects, loss, or other adverse outcome
regardless of drug exposure. The fetal risk summary below describes the potential of Lovenox to
increase the risk of developmental abnormalities above background risk.
Fetal Risk Summary
Lovenox is not predicted to increase the risk of developmental abnormalities. Lovenox does not
cross the placenta, based on human and animal studies, and shows no evidence of teratogenic
effects or fetotoxicity.
Cases of “Gasping Syndrome” have occurred in premature infants when large amounts of benzyl
alcohol have been administered (99-405 mg/kg/day). The multiple-dose vial of Lovenox
contains 15 mg benzyl alcohol per 1 mL as a preservative [see Warnings and Precautions (5.8)].
Clinical Considerations
It is not known if either dose adjustment or monitoring of anti-Xa activity of enoxaparin are
necessary during pregnancy.
Pregnancy alone confers an increased risk for thromboembolism that is even higher for women
with thromboembolic disease and certain high risk pregnancy conditions. While not adequately
studied, pregnant women with mechanical prosthetic heart valves may be at even higher risk for
thrombosis [see Warnings and Precautions (5.7) and Use in Specific Populations (8.6)].
Pregnant women with thromboembolic disease, including those with mechanical prosthetic heart
valves and those with inherited or acquired thrombophilias, have an increased risk of other
maternal complications and fetal loss regardless of the type of anticoagulant used.
All patients receiving anticoagulants such as enoxaparin, including pregnant women, are at risk
for bleeding. Pregnant women receiving enoxaparin should be carefully monitored for evidence
16
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
of bleeding or excessive anticoagulation. Consideration for use of a shorter acting anticoagulant
should be specifically addressed as delivery approaches [see Boxed Warning]. Hemorrhage can
occur at any site and may lead to death of mother and/or fetus. Pregnant women should be
apprised of the potential hazard to the fetus and the mother if enoxaparin is administered during
pregnancy.
Data
•
Human Data - There are no adequate and well-controlled studies in pregnant women.
A retrospective study reviewed the records of 604 women who used enoxaparin during
pregnancy. A total of 624 pregnancies resulted in 693 live births. There were 72 hemorrhagic
events (11 serious) in 63 women. There were 14 cases of neonatal hemorrhage. Major
congenital anomalies in live births occurred at rates (2.5%) similar to background rates.
There have been postmarketing reports of fetal death when pregnant women received Lovenox.
Causality for these cases has not been determined. Insufficient data, the underlying disease, and
the possibility of inadequate anticoagulation complicate the evaluation of these cases.
A clinical study using enoxaparin in pregnant women with mechanical prosthetic heart valves
has been conducted [see Warnings and Precautions (5.7)].
• Animal Data - Teratology studies have been conducted in pregnant rats and rabbits at SC
doses of enoxaparin up to 30 mg/kg/day or 211 mg/m2/day and 410 mg/m2/day,
respectively. There was no evidence of teratogenic effects or fetotoxicity due to
enoxaparin. Because animal reproduction studies are not always predictive of human
response, this drug should be used during pregnancy only if clearly needed.
8.3 Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted
in human milk, caution should be exercised when Lovenox is administered to nursing women.
8.4 Pediatric Use
Safety and effectiveness of Lovenox in pediatric patients have not been established.
8.5 Geriatric Use
Prevention of DVT in hip, knee and abdominal surgery; Treatment of DVT, Prevention of
ischemic complications of unstable angina and non-Q-Wave myocardial infarction
Over 2800 patients, 65 years and older, have received Lovenox in pivotal clinical trials. The
efficacy of Lovenox in the geriatric (≥65 years) was similar to that seen in younger patients (<65
years). The incidence of bleeding complications was similar between geriatric and younger
patients when 30 mg every 12 hours or 40 mg once a day doses of Lovenox were employed. The
incidence of bleeding complications was higher in geriatric patients as compared to younger
patients when Lovenox was administered at doses of 1.5 mg/kg once a day or 1 mg/kg every 12
hours. The risk of Lovenox -associated bleeding increased with age. Serious adverse events
increased with age for patients receiving Lovenox. Other clinical experience (including
postmarketing surveillance and literature reports) has not revealed additional differences in the
safety of Lovenox between geriatric and younger patients. Careful attention to dosing intervals
17
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
and concomitant medications (especially antiplatelet medications) is advised. Lovenox should
be used with care in geriatric patients who may show delayed elimination of enoxaparin.
Monitoring of geriatric patients with low body weight (<45 kg) and those predisposed to
decreased renal function should be considered [see Warnings and Precautions (5.9) and Clinical
Pharmacology (12.3)].
Treatment of acute ST-segment Elevation Myocardial Infarction (STEMI)
In the clinical study for treatment of acute STEMI, there was no evidence of difference in
efficacy between patients ≥75 years of age (n = 1241) and patients less than 75 years of age
(n=9015). Patients ≥75 years of age did not receive a 30-mg IV bolus prior to the normal
dosage regimen and had their SC dose adjusted to 0.75 mg/kg every 12 hours [see Dosage and
Administration (2.3)]. The incidence of bleeding complications was higher in patients ≥65 years
of age as compared to younger patients (<65 years).
8.6 Patients with Mechanical Prosthetic Heart Valves
The use of Lovenox has not been adequately studied for thromboprophylaxis in patients with
mechanical prosthetic heart valves and has not been adequately studied for long-term use in this
patient population. Isolated cases of prosthetic heart valve thrombosis have been reported in
patients with mechanical prosthetic heart valves who have received enoxaparin for
thromboprophylaxis. Some of these cases were pregnant women in whom thrombosis led to
maternal and fetal deaths. Insufficient data, the underlying disease and the possibility of
inadequate anticoagulation complicate the evaluation of these cases. Pregnant women with
mechanical prosthetic heart valves may be at higher risk for thromboembolism [see Warnings
and Precautions (5.7)].
8.7 Renal Impairment
In patients with renal impairment, there is an increase in exposure of enoxaparin sodium. All
such patients should be observed carefully for signs and symptoms of bleeding. Because
exposure of enoxaparin sodium is significantly increased in patients with severe renal
impairment (creatinine clearance <30 mL/min), a dosage adjustment is recommended for
therapeutic and prophylactic dosage ranges. No dosage adjustment is recommended in patients
with moderate (creatinine clearance 30-50 mL/min) and mild (creatinine clearance 50-80
mL/min) renal impairment [see Dosage and Administration (2.2) and Clinical Pharmacology
(12.3)]. In patients with renal failure, treatment with enoxaparin has been associated with the
development of hyperkalemia [see Adverse Reactions (6.2)].
8.8 Hepatic Impairment
The impact of hepatic impairment on enoxaparin’s exposure and antithrombotic effect has not
been investigated. Caution should be exercised when administering enoxaparin to patients with
hepatic impairment.
8.9 Low-Weight Patients
An increase in exposure of enoxaparin sodium with prophylactic dosages (non-weight adjusted)
has been observed in low-weight women (<45 kg) and low-weight men (<57 kg). All such
18
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
patients should be observed carefully for signs and symptoms of bleeding [see Clinical
Pharmacology (12.3)].
10 OVERDOSAGE
Accidental overdosage following administration of Lovenox may lead to hemorrhagic
complications. Injected Lovenox may be largely neutralized by the slow IV injection of
protamine sulfate (1% solution). The dose of protamine sulfate should be equal to the dose of
Lovenox injected: 1 mg protamine sulfate should be administered to neutralize 1 mg Lovenox, if
enoxaparin sodium was administered in the previous 8 hours. An infusion of 0.5 mg protamine
per 1 mg of enoxaparin sodium may be administered if enoxaparin sodium was administered
greater than 8 hours previous to the protamine administration, or if it has been determined that a
second dose of protamine is required. The second infusion of 0.5 mg protamine sulfate per 1 mg
of Lovenox may be administered if the aPTT measured 2 to 4 hours after the first infusion
remains prolonged.
If at least 12 hours have elapsed since the last enoxaparin sodium injection, protamine
administration may not be required; however, even with higher doses of protamine, the aPTT
may remain more prolonged than following administration of heparin. In all cases, the anti-
Factor Xa activity is never completely neutralized (maximum about 60%). Particular care should
be taken to avoid overdosage with protamine sulfate. Administration of protamine sulfate can
cause severe hypotensive and anaphylactoid reactions. Because fatal reactions, often resembling
anaphylaxis, have been reported with protamine sulfate, it should be given only when
resuscitation techniques and treatment of anaphylactic shock are readily available. For
additional information consult the labeling of protamine sulfate injection products.
11 DESCRIPTION
Lovenox is a sterile aqueous solution containing enoxaparin sodium, a low molecular weight
heparin. The pH of the injection is 5.5 to 7.5.
Enoxaparin sodium is obtained by alkaline depolymerization of heparin benzyl ester derived
from porcine intestinal mucosa. Its structure is characterized by a 2-O-sulfo-4-enepyranosuronic
acid group at the non-reducing end and a 2-N,6-O-disulfo-D-glucosamine at the reducing end of
the chain. About 20% (ranging between 15% and 25%) of the enoxaparin structure contains an
1,6 anhydro derivative on the reducing end of the polysaccharide chain. The drug substance is
the sodium salt. The average molecular weight is about 4500 daltons. The molecular weight
distribution is:
<2000 daltons
≤20%
2000 to 8000 daltons ≥68%
>8000 daltons
≤18%
19
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STRUCTURAL FORMULA Chemical Structure
R
X*= 15 to
25% Chemcial Structure
n= 0 to 20
100 - X
H
n =1 to 21
*X = Percent of polysaccharide chain containing 1,6 anhydro derivative on the reducing end.
Lovenox 100 mg/mL Concentration contains 10 mg enoxaparin sodium (approximate anti-
Factor Xa activity of 1000 IU [with reference to the W.H.O. First International Low Molecular
Weight Heparin Reference Standard]) per 0.1 mL Water for Injection.
Lovenox 150 mg/mL Concentration contains 15 mg enoxaparin sodium (approximate anti-
Factor Xa activity of 1500 IU [with reference to the W.H.O. First International Low Molecular
Weight Heparin Reference Standard]) per 0.1 mL Water for Injection.
The Lovenox prefilled syringes and graduated prefilled syringes are preservative-free and
intended for use only as a single-dose injection. The multiple-dose vial contains 15 mg benzyl
alcohol per 1 mL as a preservative. [See Dosage and Administration (2) and How Supplied (16)
for dosage unit descriptions].
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Enoxaparin is a low molecular weight heparin which has antithrombotic properties.
20
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12.2 Pharmacodynamics
In humans, enoxaparin given at a dose of 1.5 mg/kg subcutaneously (SC) is characterized by a
higher ratio of anti-Factor Xa to anti-Factor IIa activity (mean ± SD, 14.0 ± 3.1) (based on areas
under anti-Factor activity versus time curves) compared to the ratios observed for heparin
(mean±SD, 1.22 ± 0.13). Increases of up to 1.8 times the control values were seen in the
thrombin time (TT) and the activated partial thromboplastin time (aPTT). Enoxaparin at a 1
mg/kg dose (100 mg / mL concentration), administered SC every 12 hours to patients in a large
clinical trial resulted in aPTT values of 45 seconds or less in the majority of patients (n = 1607).
A 30-mg IV bolus immediately followed by a 1 mg/kg SC administration resulted in aPTT post-
injection values of 50 seconds. The average aPTT prolongation value on Day 1 was about 16%
higher than on Day 4.
12.3 Pharmacokinetics
Absorption. Pharmacokinetic trials were conducted using the 100 mg/ml formulation. Maximum
anti-Factor Xa and anti-thrombin (anti-Factor IIa) activities occur 3 to 5 hours after SC injection
of enoxaparin. Mean peak anti-Factor Xa activity was 0.16 IU/mL (1.58 µg/mL) and 0.38
IU/mL (3.83µg/mL) after the 20 mg and the 40 mg clinically tested SC doses, respectively.
Mean (n = 46) peak anti-Factor Xa activity was 1.1 IU/mL at steady state in patients with
unstable angina receiving 1 mg/kg SC every 12 hours for 14 days. Mean absolute bioavailability
of enoxaparin, after 1.5 mg/kg given SC, based on anti-Factor Xa activity is approximately 100%
in healthy subjects.
A 30-mg IV bolus immediately followed by a 1 mg/kg SC every 12 hours provided initial peak
anti-Factor Xa levels of 1.16 IU/mL (n=16) and average exposure corresponding to 84% of
steady-state levels. Steady state is achieved on the second day of treatment.
Enoxaparin pharmacokinetics appear to be linear over the recommended dosage ranges [see
Dosage and Administration (2)]. After repeated subcutaneous administration of 40 mg once
daily and 1.5 mg/kg once-daily regimens in healthy volunteers, the steady state is reached on day
2 with an average exposure ratio about 15% higher than after a single dose. Steady-state
enoxaparin activity levels are well predicted by single-dose pharmacokinetics. After repeated
subcutaneous administration of the 1 mg/kg twice daily regimen, the steady state is reached from
day 4 with mean exposure about 65% higher than after a single dose and mean peak and trough
levels of about 1.2 and 0.52 IU/mL, respectively.
Based on enoxaparin sodium
pharmacokinetics, this difference in steady state is expected and within the therapeutic range.
Although not studied clinically, the 150 mg/mL concentration of enoxaparin sodium is projected
to result in anticoagulant activities similar to those of 100 mg/mL and 200 mg/mL concentrations
at the same enoxaparin dose. When a daily 1.5 mg/kg SC injection of enoxaparin sodium was
given to 25 healthy male and female subjects using a 100 mg/mL or a 200 mg/mL concentration
the following pharmacokinetic profiles were obtained [see Table 13]:
21
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Table 13
Pharmacokinetic Parameters* After 5 Days of 1.5 mg/kg SC Once Daily Doses of
Enoxaparin Sodium Using 100 mg/mL or 200 mg/mL Concentrations
Concentration
Anti-Xa
Anti-IIa
Heptest
aPTT
Amax
(IU/mL or Δ
sec)
100 mg/mL
1.37 (±0.23)
0.23 (±0.05)
105 (±17)
19 (±5)
200 mg/mL
1.45 (±0.22)
0.26 (±0.05)
111 (±17)
22 (±7)
90% CI
102-110%
102-111%
t
** (h)
max
100 mg/mL
3 (2-6)
4 (2-5)
2.5 (2-4.5)
3 (2-4.5)
200 mg/mL
3.5 (2-6)
4.5 (2.5-6)
3.3 (2-5)
3 (2-5)
AUC
(ss)
(h*IU/mL
or
h* Δ sec)
100 mg/mL
14.26 (±2.93)
1.54 (±0.61)
1321 (±219)
200 mg/mL
15.43 (±2.96)
1.77 (±0.67)
1401 (±227)
90% CI
105-112%
103-109%
*Means ± SD at Day 5 and 90% Confidence Interval (CI) of the ratio
**Median (range)
Distribution. The volume of distribution of anti-Factor Xa activity is about 4.3 L.
Elimination. Following intravenous (IV) dosing, the total body clearance of enoxaparin is 26
mL/min. After IV dosing of enoxaparin labeled with the gamma-emitter, 99mTc, 40% of
radioactivity and 8 to 20% of anti-Factor Xa activity were recovered in urine in 24 hours.
Elimination half-life based on anti-Factor Xa activity was 4.5 hours after a single SC dose to
about 7 hours after repeated dosing. Significant anti-Factor Xa activity persists in plasma for
about 12 hours following a 40 mg SC once a day dose.
Following SC dosing, the apparent clearance (CL/F) of enoxaparin is approximately 15 mL/min.
Metabolism. Enoxaparin sodium is primarily metabolized in the liver by desulfation and/or
depolymerization to lower molecular weight species with much reduced biological potency.
Renal clearance of active fragments represents about 10% of the administered dose and total
renal excretion of active and non-active fragments 40% of the dose.
Special Populations
Gender: Apparent clearance and Amax derived from anti-Factor Xa values following single SC
dosing (40 mg and 60 mg) were slightly higher in males than in females. The source of the
gender difference in these parameters has not been conclusively identified; however, body
weight may be a contributing factor.
22
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Geriatric: Apparent clearance and Amax derived from anti-Factor Xa values following single and
multiple SC dosing in geriatric subjects were close to those observed in young subjects.
Following once a day SC dosing of 40 mg enoxaparin, the Day 10 mean area under anti-Factor
Xa activity versus time curve (AUC) was approximately 15% greater than the mean Day 1 AUC
value. [see Dosage and Administration (2.3) and Use in Specific Populations (8.5)].
Renal Impairment: A linear relationship between anti-Factor Xa plasma clearance and creatinine
clearance at steady-state has been observed, which indicates decreased clearance of enoxaparin
sodium in patients with reduced renal function. Anti-Factor Xa exposure represented by AUC, at
steady-state, is marginally increased in mild (creatinine clearance 50–80 mL/min) and moderate
(creatinine clearance 30-50 mL/min) renal impairment after repeated subcutaneous 40 mg once-
daily doses. In patients with severe renal impairment (creatinine clearance <30 mL/min), the
AUC at steady state is significantly increased on average by 65% after repeated subcutaneous 40
mg once-daily doses [see Dosage and Administration (2.2) and Use in Specific Populations
(8.7)].
Hemodialysis: In a single study, elimination rate appeared similar but AUC was two-fold higher
than control population, after a single 0.25 or 0.5 mg/kg intravenous dose.
Hepatic Impairment: Studies with enoxaparin in patients with hepatic impairment have not been
conducted and the impact of hepatic impairment on the exposure to enoxaparin is unknown [see
Use in Specific Populations (8.8)].
Weight: After repeated subcutaneous 1.5 mg/kg once daily dosing, mean AUC of anti-Factor Xa
activity is marginally higher at steady-state in obese healthy volunteers (BMI 30-48 kg/m2)
compared to non-obese control subjects, while Amax is not increased.
When non-weight adjusted dosing was administered, it was found after a single-subcutaneous 40
mg dose, that anti-Factor Xa exposure is 52% higher in low-weight women (<45 kg) and 27%
higher in low-weight men (<57 kg) when compared to normal weight control subjects [see Use
in Specific Populations (8.9)].
Pharmacokinetic interaction: No pharmacokinetic interaction was observed between enoxaparin
and thrombolytics when administered concomitantly.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
No long-term studies in animals have been performed to evaluate the carcinogenic potential of
enoxaparin. Enoxaparin was not mutagenic in in vitro tests, including the Ames test, mouse
lymphoma cell forward mutation test, and human lymphocyte chromosomal aberration test, and
the in vivo rat bone marrow chromosomal aberration test. Enoxaparin was found to have no
effect on fertility or reproductive performance of male and female rats at SC doses up to 20
mg/kg/day or 141 mg/m2/day. The maximum human dose in clinical trials was 2.0 mg/kg/day or
23
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78 mg/m2/day (for an average body weight of 70 kg, height of 170 cm, and body surface area of
1.8 m2).
13.2 Animal Toxicology
A single SC dose of 46.4 mg/kg enoxaparin was lethal to rats. The symptoms of acute toxicity
were ataxia, decreased motility, dyspnea, cyanosis, and coma.
14 CLINICAL STUDIES
14.1 Prophylaxis of Deep Vein Thrombosis (DVT) Following Abdominal Surgery in Patients
at Risk for Thromboembolic Complications
Abdominal surgery patients at risk include those who are over 40 years of age, obese,
undergoing surgery under general anesthesia lasting longer than 30 minutes or who have
additional risk factors such as malignancy or a history of DVT or pulmonary embolism.
In a double-blind, parallel group study of patients undergoing elective cancer surgery of the
gastrointestinal, urological, or gynecological tract, a total of 1116 patients were enrolled in the
study, and 1115 patients were treated. Patients ranged in age from 32 to 97 years (mean age 67
years) with 52.7% men and 47.3% women. Patients were 98% Caucasian, 1.1% Black, 0.4%
Asian and 0.4% others. Lovenox 40 mg SC, administered once a day, beginning 2 hours prior to
surgery and continuing for a maximum of 12 days after surgery, was comparable to heparin 5000
U every 8 hours SC in reducing the risk of DVT. The efficacy data are provided below [see
Table 14].
Table 14
Efficacy of Lovenox in the Prophylaxis of DVT Following Abdominal Surgery
Indication
Dosing Regimen
Lovenox
40 mg q.d. SC
n (%)
Heparin
5000 U q8h SC
n (%)
All Treated Abdominal
Surgery Patients
555 (100)
560 (100)
Treatment Failures
Total VTE1 (%)
DVT Only (%)
56 (10.1)
(95% CI2: 8 to 13)
63 (11.3)
(95% CI: 9 to 14)
54 (9.7)
(95% CI: 7 to 12)
61 (10.9)
(95% CI: 8 to 13)
1 VTE = Venous thromboembolic events which included DVT, PE, and death considered to be thromboembolic in
origin.
2 CI = Confidence Interval
In a second double-blind, parallel group study, Lovenox 40 mg SC once a day was compared to
heparin 5000 U every 8 hours SC in patients undergoing colorectal surgery (one-third with
cancer). A total of 1347 patients were randomized in the study and all patients were treated.
Patients ranged in age from 18 to 92 years (mean age 50.1 years) with 54.2% men and 45.8%
24
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women. Treatment was initiated approximately 2 hours prior to surgery and continued for
approximately 7 to 10 days after surgery. The efficacy data are provided below [see Table 15].
Table 15
Efficacy of Lovenox in the Prophylaxis of Deep Vein Thrombosis Following Colorectal
Surgery
Indication
Dosing Regimen
Lovenox
40 mg q.d. SC
n (%)
Heparin
5000 U q8h SC
n (%)
All Treated Colorectal Surgery
Patients
673 (100)
674 (100)
Treatment Failures
Total VTE1 (%)
DVT Only (%)
48 (7.1)
(95% CI2: 5 to 9)
45 (6.7)
(95% CI: 5 to 9)
47 (7.0)
(95% CI: 5 to 9)
44 (6.5)
(95% CI: 5 to 8)
1 VTE = Venous thromboembolic events which included DVT, PE, and death considered to be thromboembolic in
origin.
2 CI = Confidence Interval
14.2 Prophylaxis of Deep Vein Thrombosis (DVT) Following Hip or Knee Replacement
Surgery
Lovenox has been shown to reduce the risk of post-operative deep vein thrombosis (DVT)
following hip or knee replacement surgery.
In a double-blind study, Lovenox 30 mg every 12 hours SC was compared to placebo in patients
with hip replacement. A total of 100 patients were randomized in the study and all patients were
treated. Patients ranged in age from 41 to 84 years (mean age 67.1 years) with 45% men and
55% women. After hemostasis was established, treatment was initiated 12 to 24 hours after
surgery and was continued for 10 to 14 days after surgery. The efficacy data are provided below
[see Table 16].
Table 16
Efficacy of Lovenox in the Prophylaxis of Deep Vein Thrombosis Following Hip
Replacement Surgery
Dosing Regimen
Lovenox
Placebo
30 mg q12h SC
q12h SC
n (%)
n (%)
All Treated Hip Replacement Patients
Indication
50 (100)
50 (100)
25
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Treatment Failures
Total DVT (%)
5 (10)1
23 (46)
Proximal DVT (%)
1 (2)2
11 (22)
1 p value versus placebo = 0.0002
2 p value versus placebo = 0.0134
A double-blind, multicenter study compared three dosing regimens of Lovenox in patients with
hip replacement. A total of 572 patients were randomized in the study and 568 patients were
treated. Patients ranged in age from 31 to 88 years (mean age 64.7 years) with 63% men and
37% women. Patients were 93% Caucasian, 6% Black, <1% Asian, and 1% others. Treatment
was initiated within two days after surgery and was continued for 7 to 11 days after surgery. The
efficacy data are provided below [see Table 17].
Table 17
Efficacy of Lovenox in the Prophylaxis of Deep Vein Thrombosis Following Hip
Replacement Surgery
Indication
Dosing Regimen
10 mg q.d. SC
n (%)
30 mg q12h SC
n (%)
40 mg q.d. SC
n (%)
All Treated Hip
Replacement Patients
161 (100)
208 (100)
199 (100)
Treatment Failures
Total DVT (%)
40 (25)
22 (11)1
27 (14)
Proximal DVT (%)
17 (11)
8 (4)2
9 (5)
1 p value versus Lovenox 10 mg once a day = 0.0008
2 p value versus Lovenox 10 mg once a day = 0.0168
There was no significant difference between the 30 mg every 12 hours and 40 mg once a day
regimens. In a double-blind study, Lovenox 30 mg every 12 hours SC was compared to placebo
in patients undergoing knee replacement surgery. A total of 132 patients were randomized in the
study and 131 patients were treated, of which 99 had total knee replacement and 32 had either
unicompartmental knee replacement or tibial osteotomy. The 99 patients with total knee
replacement ranged in age from 42 to 85 years (mean age 70.2 years) with 36.4% men and
63.6% women. After hemostasis was established, treatment was initiated 12 to 24 hours after
surgery and was continued up to 15 days after surgery. The incidence of proximal and total DVT
after surgery was significantly lower for Lovenox compared to placebo. The efficacy data are
provided below [see Table 18].
26
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Table 18
Efficacy of Lovenox in the Prophylaxis of Deep Vein Thrombosis Following Total Knee
Replacement Surgery
Indication
Dosing Regimen
Lovenox
30 mg q12h SC
n (%)
Placebo
q12h SC
n (%)
All Treated Total Knee
Replacement Patients
47 (100)
52 (100)
Treatment Failures
Total DVT (%)
5 (11)1
(95% CI2: 1 to 21)
32 (62)
(95% CI: 47 to 76)
Proximal DVT (%)
0 (0)3
4
(95% Upper CL : 5)
7 (13)
(95% CI: 3 to 24)
1 p value versus placebo = 0.0001
2 CI = Confidence Interval
3 p value versus placebo = 0.013
4 CL = Confidence Limit
Additionally, in an open-label, parallel group, randomized clinical study, Lovenox 30 mg every
12 hours SC in patients undergoing elective knee replacement surgery was compared to heparin
5000 U every 8 hours SC. A total of 453 patients were randomized in the study and all were
treated. Patients ranged in age from 38 to 90 years (mean age 68.5 years) with 43.7% men and
56.3% women. Patients were 92.5% Caucasian, 5.3% Black, and 0.6% others. Treatment was
initiated after surgery and continued up to 14 days. The incidence of deep vein thrombosis was
significantly lower for Lovenox compared to heparin.
Extended Prophylaxis of Deep Vein Thrombosis Following Hip Replacement Surgery: In a study
of extended prophylaxis for patients undergoing hip replacement surgery, patients were treated,
while hospitalized, with Lovenox 40 mg SC, initiated up to 12 hours prior to surgery for the
prophylaxis of post-operative DVT.
At the end of the peri-operative period, all patients
underwent bilateral venography.
In a double-blind design, those patients with no venous
thromboembolic disease were randomized to a post-discharge regimen of either Lovenox 40 mg
(n = 90) once a day SC or to placebo (n = 89) for 3 weeks. A total of 179 patients were
randomized in the double-blind phase of the study and all patients were treated. Patients ranged
in age from 47 to 87 years (mean age 69.4 years) with 57% men and 43% women. In this
population of patients, the incidence of DVT during extended prophylaxis was significantly
lower for Lovenox compared to placebo. The efficacy data are provided below [see Table 19].
27
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Table 19
Efficacy of Lovenox in the Extended Prophylaxis of Deep Vein Thrombosis Following Hip
Replacement Surgery
Indication (Post-Discharge)
Post-Discharge Dosing Regimen
Lovenox
40 mg q.d. SC
n (%)
Placebo
q.d. SC
n (%)
All Treated Extended
Prophylaxis Patients
90 (100)
89 (100)
Treatment Failures
Total DVT (%)
6 (7)1
(95% CI2: 3 to 14)
18 (20)
(95% CI: 12 to 30)
Proximal DVT (%)
5 (6)3
(95% CI: 2 to 13)
7 (8)
(95% CI: 3 to 16)
1 p value versus placebo = 0.008
2 CI= Confidence Interval
3 p value versus placebo = 0.537
In a second study, patients undergoing hip replacement surgery were treated, while hospitalized,
with Lovenox 40 mg SC, initiated up to 12 hours prior to surgery. All patients were examined
for clinical signs and symptoms of venous thromboembolic (VTE) disease. In a double-blind
design, patients without clinical signs and symptoms of VTE disease were randomized to a post-
discharge regimen of either Lovenox 40 mg (n = 131) once a day SC or to placebo (n = 131) for
3 weeks. A total of 262 patients were randomized in the study double-blind phase and all
patients were treated. Patients ranged in age from 44 to 87 years (mean age 68.5 years) with
43.1% men and 56.9% women. Similar to the first study the incidence of DVT during extended
prophylaxis was significantly lower for Lovenox compared to placebo, with a statistically
significant difference in both total DVT (Lovenox 21 [16%] versus placebo 45 [34%]; p = 0.001)
and proximal DVT (Lovenox 8 [6%] versus placebo 28 [21%]; p = <0.001).
14.3 Prophylaxis of Deep Vein Thrombosis (DVT) In Medical Patients with Severely
Restricted Mobility During Acute Illness
In a double blind multicenter, parallel group study, Lovenox 20 mg or 40 mg once a day SC was
compared to placebo in the prophylaxis of DVT in medical patients with severely restricted
mobility during acute illness (defined as walking distance of <10 meters for ≤3 days). This study
included patients with heart failure (NYHA Class III or IV); acute respiratory failure or
complicated chronic respiratory insufficiency (not requiring ventilatory support): acute infection
(excluding septic shock); or acute rheumatic disorder [acute lumbar or sciatic pain, vertebral
compression (due to osteoporosis or tumor), acute arthritic episodes of the lower extremities]. A
total of 1102 patients were enrolled in the study, and 1073 patients were treated. Patients ranged
in age from 40 to 97 years (mean age 73 years) with equal proportions of men and women.
Treatment continued for a maximum of 14 days (median duration 7 days). When given at a dose
of 40 mg once a day SC, Lovenox significantly reduced the incidence of DVT as compared to
placebo. The efficacy data are provided below [see Table 20].
28
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Table 20
Efficacy of Lovenox in the Prophylaxis of Deep Vein Thrombosis in Medical Patients With
Severely Restricted Mobility During Acute Illness
Indication
Dosing Regimen
Lovenox
20 mg q.d. SC
n (%)
Lovenox
40 mg q.d. SC
n (%)
Placebo
n (%)
All Treated Medical
Patients During Acute
Illness
351 (100)
360 (100)
362 (100)
Treatment Failure1
Total VTE2 (%)
Total DVT (%)
Proximal DVT (%)
43 (12.3)
16 (4.4)
43 (11.9)
43 (12.3)
(95% CI3 8.8 to 15.7)
16 (4.4)
(95% CI3 2.3 to 6.6)
41 (11.3)
(95% CI3 8.1 to 14.6)
13 (3.7)
5 (1.4)
14 (3.9)
1 Treatment failures during therapy, between Days 1 and 14.
2 VTE = Venous thromboembolic events which included DVT, PE, and death considered to be thromboembolic in
origin.
3 CI = Confidence Interval
At approximately 3 months following enrollment, the incidence of venous thromboembolism
remained significantly lower in the Lovenox 40 mg treatment group versus the placebo treatment
group.
14.4 Treatment of Deep Vein Thrombosis (DVT) with or without Pulmonary Embolism (PE)
In a multicenter, parallel group study, 900 patients with acute lower extremity DVT with or
without PE were randomized to an inpatient (hospital) treatment of either (i) Lovenox 1.5 mg/kg
once a day SC, (ii) Lovenox 1 mg/kg every 12 hours SC, or (iii) heparin IV bolus (5000 IU)
followed by a continuous infusion (administered to achieve an aPTT of 55 to 85 seconds). A
total of 900 patients were randomized in the study and all patients were treated. Patients ranged
in age from 18 to 92 years (mean age 60.7 years) with 54.7% men and 45.3% women. All
patients also received warfarin sodium (dose adjusted according to PT to achieve an International
Normalization Ratio [INR] of 2.0 to 3.0), commencing within 72 hours of initiation of Lovenox
or standard heparin therapy, and continuing for 90 days. Lovenox or standard heparin therapy
was administered for a minimum of 5 days and until the targeted warfarin sodium INR was
achieved. Both Lovenox regimens were equivalent to standard heparin therapy in reducing the
risk of recurrent venous thromboembolism (DVT and/or PE). The efficacy data are provided
below [see Table 21].
29
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Table 21
Efficacy of Lovenox in Treatment of Deep Vein Thrombosis
With or Without Pulmonary Embolism
Indication
Dosing Regimen1
Lovenox
1.5 mg/kg q.d. SC
n (%)
Lovenox
1 mg/kg q12h SC
n (%)
Heparin
aPTT Adjusted
IV Therapy
n (%)
All Treated DVT Patients
with or without PE
298 (100)
312 (100)
290 (100)
Patient Outcome
Total VTE2 (%)
DVT Only (%)
Proximal DVT (%)
PE (%)
13 (4.4)3
9 (2.9) 3
12 (4.1)
11 (3.7)
7 (2.2)
8 (2.8)
9 (3.0)
6 (1.9)
7 (2.4)
2 (0.7)
2 (0.6)
4 (1.4)
1 All patients were also treated with warfarin sodium commencing within 72 hours of Lovenox or standard heparin
therapy.
2 VTE = venous thromboembolic event (DVT and/or PE).
3 The 95% Confidence Intervals for the treatment differences for total VTE were:
Lovenox once a day versus heparin (-3.0 to 3.5)
Lovenox every 12 hours versus heparin (-4.2 to 1.7).
Similarly, in a multicenter, open-label, parallel group study, patients with acute proximal DVT
were randomized to Lovenox or heparin. Patients who could not receive outpatient therapy were
excluded from entering the study. Outpatient exclusion criteria included the following: inability
to receive outpatient heparin therapy because of associated co-morbid conditions or potential for
non-compliance and inability to attend follow-up visits as an outpatient because of geographic
inaccessibility. Eligible patients could be treated in the hospital, but ONLY Lovenox patients
were permitted to go home on therapy (72%). A total of 501 patients were randomized in the
study and all patients were treated. Patients ranged in age from 19 to 96 years (mean age 57.8
years) with 60.5% men and 39.5% women. Patients were randomized to either Lovenox 1 mg/kg
every 12 hours SC or heparin IV bolus (5000 IU) followed by a continuous infusion
administered to achieve an aPTT of 60 to 85 seconds (in-patient treatment). All patients also
received warfarin sodium as described in the previous study. Lovenox or standard heparin
therapy was administered for a minimum of 5 days. Lovenox was equivalent to standard heparin
therapy in reducing the risk of recurrent venous thromboembolism. The efficacy data are
provided below [see Table 22].
30
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Table 22
Efficacy of Lovenox in Treatment of Deep Vein Thrombosis
Indication
Dosing Regimen1
Lovenox
1 mg/kg q12h SC
n (%)
Heparin
aPTT Adjusted
IV Therapy
n (%)
All Treated DVT Patients
247 (100)
254 (100)
Patient Outcome
Total VTE2 (%)
DVT Only (%)
Proximal DVT (%)
PE (%)
13 (5.3) 3
17 (6.7)
11 (4.5)
14 (5.5)
10 (4.0)
12 (4.7)
2 (0.8)
3 (1.2)
1 All patients were also treated with warfarin sodium commencing on the evening of the second day of Lovenox or
standard heparin therapy.
2 VTE = venous thromboembolic event (deep vein thrombosis [DVT] and/or pulmonary embolism [PE]).
3 The 95% Confidence Intervals for the treatment difference for total VTE was: Lovenox versus heparin
(- 5.6 to 2.7).
14.5 Prophylaxis of Ischemic Complications in Unstable Angina and Non-Q-Wave Myocardial
Infarction
In a multicenter, double-blind, parallel group study, patients who recently experienced unstable
angina or non-Q-wave myocardial infarction were randomized to either Lovenox 1 mg/kg every
12 hours SC or heparin IV bolus (5000 U) followed by a continuous infusion (adjusted to
achieve an aPTT of 55 to 85 seconds). A total of 3171 patients were enrolled in the study, and
3107 patients were treated. Patients ranged in age from 25-94 years (median age 64 years), with
33.4% of patients female and 66.6% male. Race was distributed as follows: 89.8% Caucasian,
4.8% Black, 2.0% Asian, and 3.5% other. All patients were also treated with aspirin 100 to 325
mg per day. Treatment was initiated within 24 hours of the event and continued until clinical
stabilization, revascularization procedures, or hospital discharge, with a maximal duration of 8
days of therapy. The combined incidence of the triple endpoint of death, myocardial infarction,
or recurrent angina was lower for Lovenox compared with heparin therapy at 14 days after
initiation of treatment. The lower incidence of the triple endpoint was sustained up to 30 days
after initiation of treatment. These results were observed in an analysis of both all-randomized
and all-treated patients. The efficacy data are provided below [see Table 23].
31
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 23
Efficacy of Lovenox in the Prophylaxis of Ischemic Complications in Unstable Angina and
Non-Q-Wave Myocardial Infarction
(Combined Endpoint of Death, Myocardial Infarction, or Recurrent Angina)
Indication
Dosing Regimen1
Reduction
(%)
p Value
Lovenox
1mg/kg q12h SC
n (%)
Heparin
aPTT Adjusted
IV Therapy
n (%)
All Treated Unstable
Angina and Non-Q-Wave
MI Patients
1578 (100)
1529 (100)
Timepoint2
48 Hours
96 (6.1)
112 (7.3)
1.2
0.120
14 Days
261 (16.5)
303 (19.8)
3.3
0.017
30 Days
313 (19.8)
358 (23.4)
3.6
0.014
1 All patients were also treated with aspirin 100 to 325 mg per day.
2 Evaluation timepoints are after initiation of treatment. Therapy continued for up to 8 days (median duration of 2.6
days).
The combined incidence of death or myocardial infarction at all time points was lower for
Lovenox compared to standard heparin therapy, but did not achieve statistical significance. The
efficacy data are provided below [see Table 24].
Table 24
Efficacy of Lovenox in the Prophylaxis of Ischemic Complications in Unstable Angina and
Non-Q-Wave Myocardial Infarction
(Combined Endpoint of Death or Myocardial Infarction)
Indication
Dosing Regimen1
Reduction
(%)
p Value
Lovenox
1 mg/kg q12h SC
n (%)
Heparin
aPTT Adjusted
IV Therapy
n (%)
All Treated Unstable
Angina and Non-Q-Wave
MI Patients
1578 (100)
1529 (100)
Timepoint2
48 Hours
16 (1.0)
20 (1.3)
0.3
0.126
14 Days
76 (4.8)
93 (6.1)
1.3
0.115
30 Days
96 (6.1)
118 (7.7)
1.6
0.069
1 All patients were also treated with aspirin 100 to 325 mg per day.
32
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2 Evaluation timepoints are after initiation of treatment. Therapy continued for up to 8 days (median duration of 2.6
days).
In a survey one year following treatment, with information available for 92% of enrolled
patients, the combined incidence of death, myocardial infarction, or recurrent angina remained
lower for Lovenox versus heparin (32.0% vs 35.7%).
Urgent revascularization procedures were performed less frequently in the Lovenox group as
compared to the heparin group, 6.3% compared to 8.2% at 30 days (p = 0.047).
14.6 Treatment of acute ST-segment Elevation Myocardial Infarction (STEMI)
In a multicenter, double-blind, double-dummy, parallel group study, patients with STEMI who
were to be hospitalized within 6 hours of onset and were eligible to receive fibrinolytic therapy
were randomized in a 1:1 ratio to receive either Lovenox or unfractionated heparin.
Study medication was initiated between 15 minutes before and 30 minutes after the initiation of
fibrinolytic therapy. Unfractionated heparin was administered beginning with an IV bolus of 60
U/kg (maximum 4000 U) and followed with an infusion of 12 U/kg per hour (initial maximum
1000 U per hour) that was adjusted to maintain an aPTT of 1.5 to 2 times the control value. The
IV infusion was to be given for at least 48 hours. The enoxaparin dosing strategy was adjusted
according to the patient’s age and renal function. For patients younger than 75 years of age,
enoxaparin was given as a single 30-mg intravenous bolus plus a 1 mg/kg SC dose followed by
an SC injection of 1 mg/kg every 12 hours. For patients at least 75 years of age, the IV bolus
was not given and the SC dose was reduced to 0.75 mg/kg every 12 hours. For patients with
severe renal insufficiency (estimated creatinine clearance of less than 30 mL per minute), the
dose was to be modified to 1 mg/kg every 24 hours. The SC injections of enoxaparin were given
until hospital discharge or for a maximum of eight days (whichever came first). The mean
treatment duration for enoxaparin was 6.6 days. The mean treatment duration of unfractionated
heparin was 54 hours.
When percutaneous coronary intervention was performed during study medication period,
patients received antithrombotic support with blinded study drug. For patients on enoxaparin,
the PCI was to be performed on enoxaparin (no switch) using the regimen established in
previous studies, i.e. no additional dosing, if the last SC administration was less than 8 hours
before balloon inflation, IV bolus of 0.3 mg/kg enoxaparin if the last SC administration was
more than 8 hours before balloon inflation
All patients were treated with aspirin for a minimum of 30 days. Eighty percent of patients
received a fibrin-specific agent (19% tenecteplase, 5% reteplase and 55% alteplase) and 20%
received streptokinase.
Among 20,479 patients in the ITT population, the mean age was 60 years, and 76% were male.
Racial distribution was: 87% Caucasian, 9.8% Asian, 0.2% Black, and 2.8% other. Medical
history included previous MI (13%), hypertension (44%), diabetes (15%) and angiographic
evidence of CAD (5%). Concomitant medication included aspirin (95%), beta-blockers (86%),
ACE inhibitors (78%), statins (70%) and clopidogrel (27%). The MI at entry was anterior in
43%, non-anterior in 56%, and both in 1%.
33
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For current labeling information, please visit https://www.fda.gov/drugsatfda
The primary efficacy end point was the composite of death from any cause or myocardial re-
infarction in the first 30 days after randomization. Total follow-up was one year.
The rate of the primary efficacy end point (death or myocardial re-infarction) was 9.9% in the
enoxaparin group, and 12.0% in the unfractionated heparin group, a 17% reduction in the relative
risk, (P=0.000003). [see Table 25]
Table 25
Efficacy of Lovenox Injection in the treatment of acute ST-segment Elevation Myocardial
Infarction
Enoxaparin
UFH
Relative Risk
P Value
(N=10,256)
(N=10,223)
(95% CI)
Outcome at 48 hours
n (%)
n (%)
Death or Myocardial Re-infarction
478 (4.7)
531 (5.2)
0.90 (0.80 to 1.01)
0.08
Death
383 (3.7)
390 (3.8)
0.98 (0.85 to 1.12)
0.76
Myocardial Re-infarction
102 (1.0)
156 (1.5)
0.65 (0.51 to 0.84)
<0.001
Urgent Revascularization
74 (0.7)
96 (0.9)
0.77 (0.57 to 1.04)
0.09
Death or Myocardial Re-infarction or Urgent
548 (5.3)
622 (6.1)
0.88 (0.79 to 0.98)
0.02
Revascularization
Outcome at 8 Days
Death or Myocardial Re-infarction
740 (7.2)
954 (9.3)
0.77 (0.71 to 0.85)
<0.001
Death
559 (5.5)
605 (5.9)
0.92 (0.82 to 1.03)
0.15
Myocardial Re-infarction
204 (2.0)
379 (3.7)
0.54 (0.45 to 0.63)
<0.001
Urgent Revascularization
145 (1.4)
247 (2.4)
0.59 (0.48 to 0.72)
<0.001
Death or Myocardial Re-infarction or Urgent
874 (8.5)
1181 (11.6)
0.74 (0.68 to 0.80)
<0.001
Revascularization
Outcome at 30 Days
Primary efficacy endpoint
(Death or Myocardial Re-infarction)
1017 (9.9)
1223 (12.0)
0.83 (0.77 to 0.90)
0.000003
Death
708 (6.9)
765 (7.5)
0.92 (0.84 to 1.02)
0.11
Myocardial Re-infarction
352 (3.4)
508 (5.0)
0.69 (0.60 to 0.79)
<0.001
Urgent Revascularization
213 (2.1)
286 (2.8)
0.74 (0.62 to 0.88)
<0.001
Death or Myocardial Re-infarction or Urgent
1199 (11.7)
1479 (14.5)
0.81 (0.75 to 0.87)
<0.001
Revascularization
Note: Urgent revascularization denotes episodes of recurrent myocardial ischemia (without infarction) leading to the
clinical decision to perform coronary revascularization during the same hospitalization. CI denotes confidence intervals.
34
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For current labeling information, please visit https://www.fda.gov/drugsatfda
The beneficial effect of enoxaparin on the primary end point was consistent across key
subgroups including age, gender, infarct location, history of diabetes, history of prior myocardial
infarction, fibrinolytic agent administered, and time to treatment with study drug (see Figure 1);
however, it is necessary to interpret such subgroup analyses with caution.
Figure 1. Relative Risks of and Absolute Event Rates for the Primary End Point at 30 Days in Various
Subgroups * Relative Risk Chart
* The primary efficacy end point was the composite of death from any cause or myocardial re-infarction in the first
30 days. The overall treatment effect of enoxaparin as compared to the unfractionated heparin is shown at the
bottom of the figure. For each subgroup, the circle is proportional to the number and represents the point estimate of
the treatment effect and the horizontal lines represent the 95 percent confidence intervals. Fibrin-specific
fibrinolytic agents included alteplase, tenecteplase and reteplase. Time to treatment indicates the time from the
onset of symptoms to the administration of study drug (median, 3.2 hours).
35
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For current labeling information, please visit https://www.fda.gov/drugsatfda
The beneficial effect of enoxaparin on the primary end point observed during the first 30 days
was maintained over a 12 month follow-up period (see Figure 2).
Figure 2 - Kaplan-Meier plot - death or myocardial re-infarction at 30 days - ITT
Graph
There is a trend in favor of enoxaparin during the first 48 hours, but most of the treatment
difference is attributed to a step increase in the event rate in the UFH group at 48 hours (seen in
Figure 2), an effect that is more striking when comparing the event rates just prior to and just
subsequent to actual times of discontinuation. These results provide evidence that UFH was
effective and that it would be better if used longer than 48 hours. There is a similar increase in
endpoint event rate when enoxaparin was discontinued, suggesting that it too was discontinued
too soon in this study.
36
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For current labeling information, please visit https://www.fda.gov/drugsatfda
The rates of major hemorrhages (defined as requiring 5 or more units of blood for transfusion, or
15% drop in hematocrit or clinically overt bleeding, including intracranial hemorrhage) at 30
days were 2.1% in the enoxaparin group and 1.4% in the unfractionated heparin group. The rates
of intracranial hemorrhage at 30 days were 0.8% in the enoxaparin group 0.7% in the
unfractionated heparin group. The 30-day rate of the composite endpoint of death, myocardial
re-infarction or ICH (a measure of net clinical benefit) was significantly lower in the enoxaparin
group (10.1%) as compared to the heparin group (12.2%).
16 HOW SUPPLIED/STORAGE AND HANDLING
Lovenox is available in two concentrations [see Tables 26 and 27]:
Table 26
100 mg/mL Concentration
Dosage Unit / Strength1
Anti-Xa
Activity2
Package Size
(per carton)
Label Color
NDC #
0075-
Prefilled Syringes3
30 mg / 0.3 mL
40 mg / 0.4 mL
3000 IU
4000 IU
10 syringes
10 syringes
Medium Blue
Yellow
0624-30
0620-40
Graduated Prefilled
Syringes3
60 mg / 0.6 mL
80 mg / 0.8 mL
100 mg / 1 mL
6000 IU
8000 IU
10,000 IU
10 syringes
10 syringes
10 syringes
Orange
Brown
Black
0621-60
0622-80
0623-00
Multiple-Dose Vial4
300 mg / 3 mL
30,000 IU
1 vial
Red
0626-03
1 Strength represents the number of milligrams of enoxaparin sodium in Water for Injection. Lovenox 30 and 40 mg
prefilled syringes, and 60, 80, and 100 mg graduated prefilled syringes each contain 10 mg enoxaparin sodium
per 0.1 mL Water for Injection.
2 Approximate anti-Factor Xa activity based on reference to the W.H.O. First International Low Molecular Weight
Heparin Reference Standard.
3 Each Lovenox syringe is affixed with a 27 gauge x 1/2 inch needle.
4 Each Lovenox multiple-dose vial contains 15 mg benzyl alcohol per 1 mL as a preservative.
37
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 27
150 mg/mL Concentration
Dosage Unit / Strength1
Anti-Xa
Activity2
Package Size
(per carton)
Syringe
Label Color
NDC #
0075-
Graduated Prefilled
Syringes3
120 mg / 0.8 mL
150 mg / 1 mL
12,000 IU
15,000 IU
10 syringes
10 syringes
Purple
Navy Blue
2912-01
2915-01
1 Strength represents the number of milligrams of enoxaparin sodium in Water for Injection. Lovenox 120 and 150
mg graduated prefilled syringes contain 15 mg enoxaparin sodium per 0.1 mL Water for Injection.
2 Approximate anti-Factor Xa activity based on reference to the W.H.O. First International Low Molecular Weight
Heparin Reference Standard.
3 Each Lovenox graduated prefilled syringe is affixed with a 27 gauge x 1/2 inch needle.
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room
Temperature].
Do not store the multiple-dose vials for more than 28 days after the first use
Keep out of the reach of children.
17 PATIENT COUNSELING INFORMATION
Patients should be told that it may take them longer than usual to stop bleeding, that they may
bruise and/or bleed more easily when they are treated with Lovenox, and that they should report
any unusual bleeding or bruising to their physician [see Warnings and Precautions (5.1, 5.5)].
Patients should inform physicians and dentists that they are taking Lovenox and/or any other
product known to affect bleeding before any surgery is scheduled and before any new drug is
taken [see Warnings and Precautions (5.3)].
Patients should inform their physicians and dentists of all medications they are taking, including
those obtained without a prescription [see Drug Interactions (7)].
sanofi-aventis U.S. LLC
Bridgewater, NJ 08807
Multiple-dose vials are also manufactured by DSM Pharmaceuticals, Inc.
Greenville, NC 27835
© 2008 sanofi-aventis U.S. LLC
38
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For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:46:57.782709
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/020164s080lbl.pdf', 'application_number': 20164, 'submission_type': 'SUPPL ', 'submission_number': 80}
|
12,290
|
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use Lovenox
safely and effectively. See full prescribing information for Lovenox.
Lovenox (enoxaparin sodium injection) for subcutaneous and intravenous
use
Initial U.S. Approval: 1993
WARNING: SPINAL/EPIDURAL HEMATOMA
Epidural or spinal hematomas may occur in patients who are
anticoagulated with low molecular weight heparins (LMWH) or
heparinoids and are receiving neuraxial anesthesia or undergoing spinal
puncture. These hematomas may result in long-term or permanent
paralysis. Consider these risks when scheduling patients for spinal
procedures. Factors that can increase the risk of developing epidural or
spinal hematomas in these patients include:
• Use of indwelling epidural catheters
• Concomitant use of other drugs that affect hemostasis, such as
non-steroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors,
other anticoagulants
• A history of traumatic or repeated epidural or spinal punctures
• A history of spinal deformity or spinal surgery.
Monitor patients frequently for signs and symptoms of neurological
impairment. If neurological compromise is noted, urgent treatment is
necessary.
Consider the benefits and risks before neuraxial intervention in patients
anticoagulated or to be anticoagulated for thromboprophylaxis [see
Warnings and Precautions (5.1) and Drug Interactions (7)].
------------------RECENT MAJOR CHANGES------------------------
Administration (2.4)
(04/2011)
------------------INDICATIONS AND USAGE-------------------
Lovenox is a low molecular weight heparin [LMWH] indicated for:
•
Prophylaxis of deep vein thrombosis (DVT) in abdominal surgery, hip
replacement surgery, knee replacement surgery, or medical patients with
severely restricted mobility during acute illness (1.1)
•
Inpatient treatment of acute DVT with or without pulmonary embolism
(1.2)
•
Outpatient treatment of acute DVT without pulmonary embolism. (1.2)
•
Prophylaxis of ischemic complications of unstable angina and non-Q
wave myocardial infarction [MI] (1.3)
•
Treatment of acute ST-segment elevation myocardial infarction [STEMI]
managed medically or with subsequent percutaneous coronary
intervention [PCI] (1.4)
-------------------DOSAGE AND ADMINISTRATION-------------
Indication
Dose
DVT prophylaxis in abdominal surgery
40 mg SC once daily
DVT prophylaxis in knee replacement
surgery
30 mg SC every 12 hours
DVT prophylaxis in hip replacement
surgery
30 mg SC every 12 hours or 40
mg SC once daily
DVT prophylaxis in medical patients
40 mg SC once daily
Inpatient treatment of acute DVT with or
without pulmonary embolism
1 mg/kg SC every 12 hours or
1.5 mg/kg SC once daily *
Outpatient treatment of acute DVT
without pulmonary embolism
1 mg/kg SC every 12 hours*
Unstable angina and non-Q-wave MI
1 mg/kg SC every 12 hours
(with aspirin)
Acute STEMI in patients <75 years of age
[For dosing in subsequent PCI, see
Dosage and Administration (2.1)]
30 mg single IV bolus plus a 1
mg/kg SC dose followed by 1
mg/kg SC every 12 hours (with
aspirin)
Acute STEMI in patients ≥75 years of age
0.75 mg/kg SC every 12 hours
(no bolus) (with aspirin)
•
See recommended durations for Lovenox therapy (2.1)
•
*See recommendations regarding transitioning to warfarin therapy (2.1)
•
Adjust the dose for patients with severe renal impairment (2.2, 8.7)
----------------------DOSAGE FORMS AND STRENGTHS--------
100 mg/mL concentration (3.1):
•
Prefilled syringes: 30 mg/0.3 mL, 40 mg/0.4 mL
•
Graduated prefilled syringes: 60 mg/0.6 mL, 80 mg/0.8 mL,100 mg/1 mL
•
Multiple-dose vial: 300 mg/3 mL
150 mg/mL concentration (3.2):
•
Graduated prefilled syringes: 120 mg/0.8 mL, 150 mg/1 mL
------------------------------CONTRAINDICATIONS-----------------
•
Active major bleeding (4)
•
Thrombocytopenia with a positive in vitro test for anti-platelet antibody
in the presence of enoxaparin sodium (4)
•
Hypersensitivity to enoxaparin sodium (4)
•
Hypersensitivity to heparin or pork products (4)
•
Hypersensitivity to benzyl alcohol [for multi-dose formulation only] (4)
-----------------------WARNINGS AND PRECAUTIONS----------
•
Increased risk of hemorrhage: Use with caution in patients at risk (5.1)
•
Percutaneous coronary revascularization: Obtain hemostasis at the
puncture site before sheath removal (5.2)
•
Concomitant medical conditions: Use with caution in patients with
bleeding diathesis, uncontrolled arterial hypertension or history of recent
gastrointestinal ulceration, diabetic retinopathy, renal dysfunction, or
hemorrhage (5.3)
•
History of heparin-induced thrombocytopenia: Use with caution (5.4)
•
Thrombocytopenia: Monitor thrombocytopenia closely (5.5)
•
Interchangeability with other heparins: Do not exchange with heparin or
other LMWHs (5.6)
•
Pregnant women with mechanical prosthetic heart valves and their
fetuses, may be at increased risk and may need more frequent monitoring
and dosage adjustment (5.7)
-----------------------------ADVERSE REACTIONS-------------------
Most common adverse reactions (>1%) were bleeding, anemia,
thrombocytopenia, elevation of serum aminotransferase, diarrhea, and nausea
(6.1)
To report SUSPECTED ADVERSE REACTIONS, contact sanofi-aventis
at 1-800-633-1610 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
-----------------------------DRUG INTERACTIONS-------------------
Discontinue agents which may enhance hemorrhage risk prior to initiation of
Lovenox or conduct close clinical and laboratory monitoring (5.9, 7)
----------------------USE IN SPECIFIC POPULATIONS------------
•
Severe Renal Impairment: Adjust dose for patients with creatinine
clearance <30mL/min (2.2, 8.7)
•
Geriatric Patients: Monitor for increased risk of bleeding (8.5)
•
Patients with mechanical heart valves: Not adequately studied (8.6)
•
Hepatic Impairment: Use with caution. (8.8)
•
Low-Weight Patients: Observe for signs of bleeding (8.9)
See 17 for PATIENT COUNSELING INFORMATION
Revised: April, 2011
Page 1 of 42
Reference ID: 2935974
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: SPINAL / EPIDURAL HEMATOMAS
1
INDICATIONS AND USAGE
1.1 Prophylaxis of Deep Vein Thrombosis
1.2 Treatment of Acute Deep Vein Thrombosis
1.3 Prophylaxis of Ischemic Complications of Unstable
Angina and Non-Q-Wave Myocardial Infarction
1.4 Treatment of Acute ST-Segment Elevation Myocardial
Infarction
2
DOSAGE AND ADMINISTRATION
2.1 Adult Dosage
2.2 Renal Impairment
2.3 Geriatric Patients with Acute ST-Segment Elevation
Myocardial Infarction
2.4 Administration
3
DOSAGE FORMS AND STRENGTHS
3.1 100 mg/mL Concentration
3.2 150 mg/mL Concentration
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1 Increased Risk of Hemorrhage
5.2 Percutaneous Coronary Revascularization Procedures
5.3 Use of Lovenox with Concomitant Medical Conditions
5.4 History of Heparin-Induced Thrombocytopenia
5.5 Thrombocytopenia
5.6 Interchangeability with Other Heparins
5.7 Pregnant Women with Mechanical Prosthetic Heart
Valves
5.8 Benzyl Alcohol
5.9 Laboratory Tests
6
ADVERSE REACTIONS
6.1 Clinical Trials Experience
6.2 Postmarketing Experience
7
DRUG INTERACTIONS
8
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Patients with Mechanical Prosthetic Heart Valves
8.7 Renal Impairment
8.8 Hepatic Impairment
8.9 Low-Weight Patients
10
OVERDOSAGE
11
DESCRIPTION
12
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
13.2 Animal Toxicology and/or Pharmacology
13.3 Reproductive and Developmental Toxicology
14 CLINICAL STUDIES
14.1 Prophylaxis of Deep Vein Thrombosis Following
Abdominal Surgery in Patients at Risk for
Thromboembolic Complications
14.2 Prophylaxis of Deep Vein Thrombosis Following Hip
or Knee Replacement Surgery
14.3 Prophylaxis of Deep Vein Thrombosis in Medical
Patients with Severely Restricted Mobility During
Acute Illness
14.4 Treatment of Deep Vein Thrombosis with or without
Pulmonary Embolism
14.5 Prophylaxis of Ischemic Complications in Unstable
Angina and Non-Q-Wave Myocardial Infarction
14.6 Treatment of Acute ST-Segment Elevation Myocardial
Infarction
16 HOW SUPPLIED/STORAGE AND HANDLING
17
PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing
information are not listed
Page 2 of 42
Reference ID: 2935974
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
FULL PRESCRIBING INFORMATION
WARNING: SPINAL/EPIDURAL HEMATOMAS
Epidural or spinal hematomas may occur in patients who are anticoagulated with low
molecular weight heparins (LMWH) or heparinoids and are receiving neuraxial anesthesia
or undergoing spinal puncture. These hematomas may result in long-term or permanent
paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that
can increase the risk of developing epidural or spinal hematomas in these patients include:
• Use of indwelling epidural catheters
• Concomitant use of other drugs that affect hemostasis, such as non-steroidal
anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants.
• A history of traumatic or repeated epidural or spinal punctures
• A history of spinal deformity or spinal surgery
Monitor patients frequently for signs and symptoms of neurological impairment. If
neurological compromise is noted, urgent treatment is necessary.
Consider the benefits and risks before neuraxial intervention in patients anticoagulated or
to be anticoagulated for thromboprophylaxis [see Warnings and Precautions (5.1) and Drug
Interactions (7)].
1 INDICATIONS AND USAGE
1.1 Prophylaxis of Deep Vein Thrombosis
Lovenox® is indicated for the prophylaxis of deep vein thrombosis (DVT), which may lead to
pulmonary embolism (PE):
• in patients undergoing abdominal surgery who are at risk for thromboembolic
complications [see Clinical Studies (14.1)].
• in patients undergoing hip replacement surgery, during and following hospitalization.
• in patients undergoing knee replacement surgery.
• in medical patients who are at risk for thromboembolic complications due to severely
restricted mobility during acute illness.
1.2 Treatment of Acute Deep Vein Thrombosis
Lovenox is indicated for:
• the inpatient treatment of acute deep vein thrombosis with or without pulmonary
embolism, when administered in conjunction with warfarin sodium.
• the outpatient treatment of acute deep vein thrombosis without pulmonary embolism
when administered in conjunction with warfarin sodium.
1.3 Prophylaxis of Ischemic Complications of Unstable Angina and Non-Q-Wave
Myocardial Infarction
Lovenox is indicated for the prophylaxis of ischemic complications of unstable angina and non
Q-wave myocardial infarction, when concurrently administered with aspirin.
Reference ID: 2935974
Page 3 of 42
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1.4 Treatment of Acute ST-Segment Elevation Myocardial Infarction
Lovenox, when administered concurrently with aspirin, has been shown to reduce the rate of the
combined endpoint of recurrent myocardial infarction or death in patients with acute ST-segment
elevation myocardial infarction (STEMI) receiving thrombolysis and being managed medically
or with percutaneous coronary intervention (PCI).
2 DOSAGE AND ADMINISTRATION
All patients should be evaluated for a bleeding disorder before administration of Lovenox, unless
the medication is needed urgently. Since coagulation parameters are unsuitable for monitoring
Lovenox activity, routine monitoring of coagulation parameters is not required [see Warnings
and Precautions (5.9)].
For subcutaneous use, Lovenox should not be mixed with other injections or infusions. For
intravenous use (i.e., for treatment of acute STEMI), Lovenox can be mixed with normal saline
solution (0.9%) or 5% dextrose in water.
Lovenox is not intended for intramuscular administration.
2.1 Adult Dosage
Abdominal Surgery: In patients undergoing abdominal surgery who are at risk for
thromboembolic complications, the recommended dose of Lovenox is 40 mg once a day
administered by SC injection with the initial dose given 2 hours prior to surgery. The usual
duration of administration is 7 to 10 days; up to 12 days administration has been administered in
clinical trials.
Hip or Knee Replacement Surgery: In patients undergoing hip or knee replacement surgery, the
recommended dose of Lovenox is 30 mg every 12 hours administered by SC injection.
Provided that hemostasis has been established, the initial dose should be given 12 to 24 hours
after surgery. For hip replacement surgery, a dose of 40 mg once a day SC, given initially 12
(±3) hours prior to surgery, may be considered. Following the initial phase of
thromboprophylaxis in hip replacement surgery patients, it is recommended that continued
prophylaxis with Lovenox 40 mg once a day be administered by SC injection for 3 weeks. The
usual duration of administration is 7 to 10 days; up to 14 days administration has been
administered in clinical trials.
Medical Patients During Acute Illness: In medical patients at risk for thromboembolic
complications due to severely restricted mobility during acute illness, the recommended dose of
Lovenox is 40 mg once a day administered by SC injection. The usual duration of
administration is 6 to 11 days; up to 14 days of Lovenox has been administered in the controlled
clinical trial.
Treatment of Deep Vein Thrombosis with or without Pulmonary Embolism: In outpatient
treatment, patients with acute deep vein thrombosis without pulmonary embolism who can be
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treated at home, the recommended dose of Lovenox is 1 mg/kg every 12 hours administered
SC.
In inpatient (hospital) treatment, patients with acute deep vein thrombosis with
pulmonary embolism or patients with acute deep vein thrombosis without pulmonary embolism
(who are not candidates for outpatient treatment), the recommended dose of Lovenox is 1 mg/kg
every 12 hours administered SC or 1.5 mg/kg once a day administered SC at the same time
every day. In both outpatient and inpatient (hospital) treatments, warfarin sodium therapy should
be initiated when appropriate (usually within 72 hours of Lovenox). Lovenox should be
continued for a minimum of 5 days and until a therapeutic oral anticoagulant effect has been
achieved (International Normalization Ratio 2.0 to 3.0). The average duration of administration
is 7 days; up to 17 days of Lovenox administration has been administered in controlled clinical
trials.
Unstable Angina and Non-Q-Wave Myocardial Infarction: In patients with unstable angina or
non-Q-wave myocardial infarction, the recommended dose of Lovenox is 1 mg/kg administered
SC every 12 hours in conjunction with oral aspirin therapy (100 to 325 mg once daily).
Treatment with Lovenox should be prescribed for a minimum of 2 days and continued until
clinical stabilization. The usual duration of treatment is 2 to 8 days; up to 12.5 days of Lovenox
has been administered in clinical trials [see Warnings and Precautions (5.2) and Clinical Studies
(14.5)].
Treatment of Acute ST-Segment Elevation Myocardial Infarction: In patients with acute ST-
segment elevation myocardial infarction, the recommended dose of Lovenox is a single IV bolus
of 30 mg plus a 1 mg/kg SC dose followed by 1 mg/kg administered SC every 12 hours
(maximum 100 mg for the first two doses only, followed by 1 mg/kg dosing for the remaining
doses). Dosage adjustments are recommended in patients ≥75 years of age [see Dosage and
Administration (2.3)]. All patients should receive aspirin as soon as they are identified as having
STEMI and maintained with 75 to 325 mg once daily unless contraindicated.
When administered in conjunction with a thrombolytic (fibrin-specific or non-fibrin specific),
Lovenox should be given between 15 minutes before and 30 minutes after the start of fibrinolytic
therapy. In the pivotal clinical study, the Lovenox treatment duration was 8 days or until
hospital discharge, whichever came first. An optimal duration of treatment is not known, but it
is likely to be longer than 8 days.
For patients managed with percutaneous coronary intervention (PCI): If the last Lovenox SC
administration was given less than 8 hours before balloon inflation, no additional dosing is
needed. If the last Lovenox SC administration was given more than 8 hours before balloon
inflation, an IV bolus of 0.3 mg/kg of Lovenox should be administered [see Warnings and
Precautions (5.2)].
2.2 Renal Impairment
Although no dose adjustment is recommended in patients with moderate (creatinine clearance
30-50 mL/min) and mild (creatinine clearance 50-80 mL/min) renal impairment, all such patients
should be observed carefully for signs and symptoms of bleeding.
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The recommended prophylaxis and treatment dosage regimens for patients with severe renal
impairment (creatinine clearance <30 mL/min) are described in Table 1 [see Use in Specific
Populations (8.6) and Clinical Pharmacology (12.3)].
Table 1
Dosage Regimens for Patients with Severe Renal Impairment
(creatinine clearance <30mL/minute)
Indication
Dosage Regimen
Prophylaxis in abdominal surgery
30 mg administered SC once daily
Prophylaxis in hip or knee replacement surgery
30 mg administered SC once daily
Prophylaxis in medical patients during acute illness
30 mg administered SC once daily
Inpatient treatment of acute deep vein thrombosis with
or without pulmonary embolism, when administered in
conjunction with warfarin sodium
1 mg/kg administered SC once daily
Outpatient treatment of acute deep vein thrombosis
without pulmonary embolism, when administered in
conjunction with warfarin sodium
1 mg/kg administered SC once daily
Prophylaxis of ischemic complications of unstable
angina and non-Q-wave myocardial infarction, when
concurrently administered with aspirin
1 mg/kg administered SC once daily
Treatment of acute ST-segment elevation myocardial
infarction in patients <75 years of age, when
administered in conjunction with aspirin
30 mg single IV bolus plus a 1 mg/kg
SC dose followed by 1 mg/kg
administered SC once daily.
Treatment of acute ST-segment elevation myocardial
infarction in geriatric patients ≥75 years of age, when
administered in conjunction with aspirin
1 mg/kg administered SC once daily
(no initial bolus)
2.3 Geriatric Patients with Acute ST-Segment Elevation Myocardial Infarction
For treatment of acute ST-segment elevation myocardial infarction in geriatric patients ≥75 years
of age, do not use an initial IV bolus. Initiate dosing with 0.75 mg/kg SC every 12 hours
(maximum 75 mg for the first two doses only, followed by 0.75 mg/kg dosing for the
remaining doses) [see Use in Specific Populations (8.5) and Clinical Pharmacology (12.3)].
No dose adjustment is necessary for other indications in geriatric patients unless kidney function
is impaired [see Dosage and Administration (2.2)].
2.4 Administration
Lovenox is a clear, colorless to pale yellow sterile solution, and as with other parenteral drug
products, should be inspected visually for particulate matter and discoloration prior to
administration.
The use of a tuberculin syringe or equivalent is recommended when using Lovenox multiple-
dose vials to assure withdrawal of the appropriate volume of drug.
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Lovenox must not be administered by intramuscular injection. Lovenox is intended for use
under the guidance of a physician.
For subcutaneous administration, patients may self-inject only if their physicians determine that
it is appropriate and with medical follow-up, as necessary. Proper training in subcutaneous
injection technique (with or without the assistance of an injection device) should be provided.
Subcutaneous Injection Technique: Patients should be lying down and Lovenox administered by
deep SC injection. To avoid the loss of drug when using the 30 and 40 mg prefilled syringes, do
not expel the air bubble from the syringe before the injection. Administration should be
alternated between the left and right anterolateral and left and right posterolateral abdominal
wall. The whole length of the needle should be introduced into a skin fold held between the
thumb and forefinger; the skin fold should be held throughout the injection. To minimize
bruising, do not rub the injection site after completion of the injection.
Lovenox prefilled syringes and graduated prefilled syringes are for single, one-time use only and
are available with a system that shields the needle after injection.
Remove the prefilled syringe from the blister packaging by peeling at the arrow as directed on
the blister. Do not remove by pulling on the plunger as this may damage the syringe.
1. Remove the needle shield by pulling it straight off the syringe (see Figure A). If adjusting the
dose is required, the dose adjustment must be done prior to injecting the prescribed dose to the
patient.
usage illustration
2. Inject using standard technique, pushing the plunger to the bottom of the syringe (see Figure
B).
usage illustration
3. Remove the syringe from the injection site keeping your finger on the plunger rod (see Figure
C).
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Figure C usage illustration
4. Orient the needle away from you and others, and activate the safety system by firmly
pushing the plunger rod. The protective sleeve will automatically cover the needle and an
audible “click” will be heard to confirm shield activation (see Figure D).
Figure D usage illustration
5. Immediately dispose of the syringe in the nearest sharps container (see Figure E).
usage illustration
NOTE:
• The safety system can only be activated once the syringe has been emptied.
• Activation of the safety system must be done only after removing the needle from the
patient’s skin.
• Do not replace the needle shield after injection.
• The safety system should not be sterilized.
Activation of the safety system may cause minimal splatter of fluid. For optimal safety activate
the system while orienting it downwards away from yourself and others.
Intravenous (Bolus) Injection Technique: For intravenous injection, the multiple-dose vial should
be used. Lovenox should be administered through an intravenous line. Lovenox should not be
mixed or co-administered with other medications. To avoid the possible mixture of Lovenox
with other drugs, the intravenous access chosen should be flushed with a sufficient amount of
saline or dextrose solution prior to and following the intravenous bolus administration of
Lovenox to clear the port of drug. Lovenox may be safely administered with normal saline
solution (0.9%) or 5% dextrose in water.
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3 DOSAGE FORMS AND STRENGTHS
Lovenox is available in two concentrations:
3.1 100 mg/mL Concentration
-Prefilled Syringes
30 mg/0.3 mL, 40 mg/0.4 mL
-Graduated Prefilled Syringes 60 mg/0.6 mL, 80 mg/0.8 mL, 100 mg/1 mL
-Multiple-Dose Vials
300 mg/3 mL
3.2 150 mg/mL Concentration
-Graduated Prefilled Syringes 120 mg/0.8 mL, 150 mg/1 mL
4 CONTRAINDICATIONS
• Active major bleeding
• Thrombocytopenia associated with a positive in vitro test for anti-platelet antibody in the
presence of enoxaparin sodium
• Known
hypersensitivity
to
enoxaparin
sodium
(e.g.,
pruritus,
urticaria,
anaphylactic/anaphylactoid reactions) [see Adverse Reactions (6.2)]
• Known hypersensitivity to heparin or pork products
• Known hypersensitivity to benzyl alcohol (which is in only the multi-dose formulation of
Lovenox) [see Warnings and Precautions (5.8)]
5 WARNINGS AND PRECAUTIONS
5.1 Increased Risk of Hemorrhage
Cases of epidural or spinal hematomas have been reported with the associated use of Lovenox
and spinal/epidural anesthesia or spinal puncture resulting in long-term or permanent paralysis.
The risk of these events is higher with the use of post-operative indwelling epidural catheters,
with the concomitant use of additional drugs affecting hemostasis such as NSAIDs, with
traumatic or repeated epidural or spinal puncture, or in patients with a history of spinal surgery
or spinal deformity [see Boxed Warning, Adverse Reactions (6.2) and Drug Interactions (7)].
Lovenox should be used with extreme caution in conditions with increased risk of hemorrhage,
such as bacterial endocarditis, congenital or acquired bleeding disorders, active ulcerative and
angiodysplastic gastrointestinal disease, hemorrhagic stroke, or shortly after brain, spinal, or
ophthalmological surgery, or in patients treated concomitantly with platelet inhibitors.
Major hemorrhages including retroperitoneal and intracranial bleeding have been reported.
Some of these cases have been fatal.
Bleeding can occur at any site during therapy with Lovenox. An unexplained fall in hematocrit
or blood pressure should lead to a search for a bleeding site.
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5.2 Percutaneous Coronary Revascularization Procedures
To minimize the risk of bleeding following the vascular instrumentation during the treatment of
unstable angina, non-Q-wave myocardial infarction and acute ST-segment elevation myocardial
infarction, adhere precisely to the intervals recommended between Lovenox doses. It is
important to achieve hemostasis at the puncture site after PCI. In case a closure device is used,
the sheath can be removed immediately. If a manual compression method is used, sheath should
be removed 6 hours after the last IV/SC Lovenox. If the treatment with enoxaparin sodium is to
be continued, the next scheduled dose should be given no sooner than 6 to 8 hours after sheath
removal. The site of the procedure should be observed for signs of bleeding or hematoma
formation [see Dosage and Administration (2.1)].
5.3 Use of Lovenox with Concomitant Medical Conditions
Lovenox should be used with care in patients with a bleeding diathesis, uncontrolled arterial
hypertension or a history of recent gastrointestinal ulceration, diabetic retinopathy, renal
dysfunction and hemorrhage.
5.4 History of Heparin-Induced Thrombocytopenia
Lovenox should be used with extreme caution in patients with a history of heparin-induced
thrombocytopenia.
5.5 Thrombocytopenia
Thrombocytopenia can occur with the administration of Lovenox.
Moderate thrombocytopenia (platelet counts between 100,000/mm3 and 50,000/mm3) occurred at
a rate of 1.3% in patients given Lovenox, 1.2% in patients given heparin, and 0.7% in patients
given placebo in clinical trials.
Platelet counts less than 50,000/mm3 occurred at a rate of 0.1% in patients given Lovenox, in
0.2% of patients given heparin, and 0.4% of patients given placebo in the same trials.
Thrombocytopenia of any degree should be monitored closely. If the platelet count falls below
100,000/mm3, Lovenox should be discontinued. Cases of heparin-induced thrombocytopenia
with thrombosis have also been observed in clinical practice. Some of these cases were
complicated by organ infarction, limb ischemia, or death [see Warnings and Precautions (5.4)].
5.6 Interchangeability with Other Heparins
Lovenox cannot be used interchangeably (unit for unit) with heparin or other low molecular
weight heparins as they differ in manufacturing process, molecular weight distribution, anti-Xa
and anti-IIa activities, units, and dosage. Each of these medicines has its own instructions for
use.
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5.7 Pregnant Women with Mechanical Prosthetic Heart Valves
The use of Lovenox for thromboprophylaxis in pregnant women with mechanical prosthetic
heart valves has not been adequately studied. In a clinical study of pregnant women with
mechanical prosthetic heart valves given enoxaparin (1 mg/kg twice daily) to reduce the risk of
thromboembolism, 2 of 8 women developed clots resulting in blockage of the valve and leading
to maternal and fetal death. Although a causal relationship has not been established these deaths
may have been due to therapeutic failure or inadequate anticoagulation. No patients in the
heparin/warfarin group (0 of 4 women) died. There also have been isolated postmarketing
reports of valve thrombosis in pregnant women with mechanical prosthetic heart valves while
receiving enoxaparin for thromboprophylaxis. Women with mechanical prosthetic heart valves
may be at higher risk for thromboembolism during pregnancy, and, when pregnant, have a higher
rate of fetal loss from stillbirth, spontaneous abortion and premature delivery. Therefore,
frequent monitoring of peak and trough anti-Factor Xa levels, and adjusting of dosage may be
needed [see Use in Specific Populations (8.6)].
5.8 Benzyl Alcohol
Lovenox multiple-dose vials contain benzyl alcohol as a preservative. The administration of
medications containing benzyl alcohol as a preservative to premature neonates has been
associated with a fatal “gasping syndrome”. Because benzyl alcohol may cross the placenta,
Lovenox multiple-dose vials, preserved with benzyl alcohol, should be used with caution in
pregnant women and only if clearly needed [see Use in Specific Populations (8.1)].
5.9 Laboratory Tests
Periodic complete blood counts, including platelet count, and stool occult blood tests are
recommended during the course of treatment with Lovenox.
When administered at
recommended prophylaxis doses, routine coagulation tests such as Prothrombin Time (PT) and
Activated Partial Thromboplastin Time (aPTT) are relatively insensitive measures of Lovenox
activity and, therefore, unsuitable for monitoring. Anti-Factor Xa may be used to monitor the
anticoagulant effect of Lovenox in patients with significant renal impairment. If during Lovenox
therapy abnormal coagulation parameters or bleeding should occur, anti-Factor Xa levels may be
used to monitor the anticoagulant effects of Lovenox [see Clinical Pharmacology (12.3)].
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
The following serious adverse reactions are also discussed in other sections of the labeling:
• Spinal/epidural hematoma [see Boxed Warning and Warnings and Precautions (5.1)]
• Increased Risk of Hemorrhage [see Warnings and Precautions (5.1)]
• Thrombocytopenia [see Warnings and Precautions (5.5)]
Because clinical studies are conducted under widely varying conditions, adverse reaction rates
observed in the clinical studies of a drug cannot be directly compared to rates in the clinical
studies of another drug and may not reflect the rates observed in practice.
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During clinical development for the approved indications, 15,918 patients were exposed to
enoxaparin sodium. These included 1,228 for prophylaxis of deep vein thrombosis following
abdominal surgery in patients at risk for thromboembolic complications, 1,368 for prophylaxis of
deep vein thrombosis following hip or knee replacement surgery, 711 for prophylaxis of deep
vein thrombosis in medical patients with severely restricted mobility during acute illness, 1,578
for prophylaxis of ischemic complications in unstable angina and non-Q-wave myocardial
infarction, 10,176 for treatment of acute ST-elevation myocardial infarction, and 857 for
treatment of deep vein thrombosis with or without pulmonary embolism. Enoxaparin sodium
doses in the clinical trials for prophylaxis of deep vein thrombosis following abdominal or hip or
knee replacement surgery or in medical patients with severely restricted mobility during acute
illness ranged from 40 mg SC once daily to 30 mg SC twice daily. In the clinical studies for
prophylaxis of ischemic complications of unstable angina and non-Q-wave myocardial infarction
doses were 1 mg/kg every 12 hours and in the clinical studies for treatment of acute ST-segment
elevation myocardial infarction enoxaparin sodium doses were a 30 mg IV bolus followed by 1
mg/kg every 12 hours SC.
Hemorrhage
The incidence of major hemorrhagic complications during Lovenox treatment has been low.
The following rates of major bleeding events have been reported during clinical trials with
Lovenox [see Tables 2 to 7].
Table 2
Major Bleeding Episodes Following Abdominal and Colorectal Surgery1
Indications
Dosing Regimen
Lovenox
40 mg q.d. SC
Heparin
5000 U q8h SC
Abdominal Surgery
n = 555
23 (4%)
n = 560
16 (3%)
Colorectal Surgery
n = 673
28 (4%)
n = 674
21 (3%)
1 Bleeding complications were considered major: (1) if the hemorrhage caused a significant
clinical event, or (2) if accompanied by a hemoglobin decrease ≥ 2 g/dL or transfusion of 2 or
more units of blood products. Retroperitoneal, intraocular, and intracranial hemorrhages were
always considered major.
Table 3
Major Bleeding Episodes Following Hip or Knee Replacement Surgery1
Indications
Dosing Regimen
Lovenox
40 mg q.d. SC
Lovenox
30 mg q12h SC
Heparin
15,000 U/24h SC
Hip Replacement Surgery
without Extended Prophylaxis2
n = 786
31 (4%)
n = 541
32 (6%)
Hip Replacement Surgery
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with Extended Prophylaxis
Peri-operative Period3
n = 288
4 (2%)
Extended Prophylaxis Period4
n = 221
0 (0%)
Knee Replacement Surgery
n = 294
n = 225
without Extended Prophylaxis2
3 (1%)
3 (1%)
1 Bleeding complications were considered major: (1) if the hemorrhage caused a significant
clinical event, or (2) if accompanied by a hemoglobin decrease ≥ 2 g/dL or transfusion of 2 or
more units of blood products. Retroperitoneal and intracranial hemorrhages were always
considered major. In the knee replacement surgery trials, intraocular hemorrhages were also
considered major hemorrhages.
2 Lovenox 30 mg every 12 hours SC initiated 12 to 24 hours after surgery and continued for up
to 14 days after surgery
3 Lovenox 40 mg SC once a day initiated up to 12 hours prior to surgery and continued for up to
7 days after surgery
4 Lovenox 40 mg SC once a day for up to 21 days after discharge
NOTE: At no time point were the 40 mg once a day pre-operative and the 30 mg every 12 hours
post-operative hip replacement surgery prophylactic regimens compared in clinical trials.
Injection site hematomas during the extended prophylaxis period after hip replacement surgery
occurred in 9% of the Lovenox patients versus 1.8% of the placebo patients.
Table 4
Major Bleeding Episodes in Medical Patients with Severely Restricted Mobility During
Acute Illness1
Indications
Dosing Regimen
Lovenox2
20 mg q.d. SC
Lovenox2
40 mg q.d. SC
Placebo2
Medical Patients During
Acute Illness
n = 351
1 (<1%)
n = 360
3 (<1%)
n = 362
2 (<1%)
1 Bleeding complications were considered major: (1) if the hemorrhage caused a significant
clinical event, (2) if the hemorrhage caused a decrease in hemoglobin of ≥ 2 g/dL or transfusion
of 2 or more units of blood products. Retroperitoneal and intracranial hemorrhages were always
considered major although none were reported during the trial.
2 The rates represent major bleeding on study medication up to 24 hours after last dose.
Table 5
Major Bleeding Episodes in Deep Vein Thrombosis with or without Pulmonary Embolism
Treatment 1
Dosing Regimen2
Lovenox
Lovenox
Heparin
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Indication
1.5 mg/kg q.d. SC
1 mg/kg q12h SC
aPTT Adjusted
IV Therapy
Treatment of DVT and PE
n = 298
5 (2%)
n = 559
9 (2%)
n = 554
9 (2%)
1 Bleeding complications were considered major: (1) if the hemorrhage caused a significant
clinical event, or (2) if accompanied by a hemoglobin decrease ≥ 2 g/dL or transfusion of 2 or
more units of blood products. Retroperitoneal, intraocular, and intracranial hemorrhages were
always considered major.
2 All patients also received warfarin sodium (dose-adjusted according to PT to achieve an INR of
2.0 to 3.0) commencing within 72 hours of Lovenox or standard heparin therapy and
continuing for up to 90 days.
Table 6
Major Bleeding Episodes in Unstable Angina and Non-Q-Wave Myocardial Infarction
Indication
Dosing Regimen
Lovenox1
1 mg/kg q12h SC
Heparin1
aPTT Adjusted
IV Therapy
Unstable Angina and
Non-Q-Wave MI2,3
n = 1578
17 (1%)
n = 1529
18 (1%)
1 The rates represent major bleeding on study medication up to 12 hours after dose.
2 Aspirin therapy was administered concurrently (100 to 325 mg per day).
3 Bleeding complications were considered major: (1) if the hemorrhage caused a significant
clinical event, or (2) if accompanied by a hemoglobin decrease by ≥ 3 g/dL or transfusion of 2
or more units of blood products. Intraocular, retroperitoneal, and intracranial hemorrhages
were always considered major.
Table 7
Major Bleeding Episodes in Acute ST-Segment Elevation Myocardial Infarction
Indication
Dosing Regimen
Lovenox1
Initial 30 mg IV bolus
followed by
1 mg/kg q12h SC
Heparin1
aPTT Adjusted
IV Therapy
Acute ST-Segment Elevation
Myocardial Infarction
- Major bleeding (including
ICH) 2
- Intracranial hemorrhages
(ICH)
n = 10176
n (%)
211 (2.1)
84 (0.8)
n = 10151
n (%)
138 (1.4)
66 (0.7)
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1The rates represent major bleeding (including ICH) up to 30 days
2Bleedings were considered major if the hemorrhage caused a significant clinical event
associated with a hemoglobin decrease by ≥ 5 g/dL. ICH were always considered major.
Elevations of Serum Aminotransferases
Asymptomatic increases in aspartate (AST [SGOT]) and alanine (ALT [SGPT])
aminotransferase levels greater than three times the upper limit of normal of the laboratory
reference range have been reported in up to 6.1% and 5.9% of patients, respectively, during
treatment with Lovenox. Similar significant increases in aminotransferase levels have also been
observed in patients and healthy volunteers treated with heparin and other low molecular weight
heparins. Such elevations are fully reversible and are rarely associated with increases in
bilirubin.
Since aminotransferase determinations are important in the differential diagnosis of myocardial
infarction, liver disease, and pulmonary emboli, elevations that might be caused by drugs like
Lovenox should be interpreted with caution.
Local Reactions
Mild local irritation, pain, hematoma, ecchymosis, and erythema may follow SC injection of
Lovenox.
Adverse Reactions in Patients Receiving Lovenox for Prophylaxis or Treatment of
DVT, PE:
Other adverse reactions that were thought to be possibly or probably related to treatment with
Lovenox, heparin, or placebo in clinical trials with patients undergoing hip or knee replacement
surgery, abdominal or colorectal surgery, or treatment for DVT and that occurred at a rate of at
least 2% in the Lovenox group, are provided below [see Tables 8 to 11].
Table 8
Adverse Reactions Occurring at ≥2% Incidence in Lovenox-Treated Patients Undergoing
Abdominal or Colorectal Surgery
Adverse Reaction
Dosing Regimen
Lovenox
40 mg q.d. SC
n = 1228
%
Severe
Total
Heparin
5000 U q8h SC
n = 1234
%
Severe
Total
Hemorrhage
<1
7
<1
6
Anemia
<1
3
<1
3
Ecchymosis
0
3
0
3
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Table 9
Adverse Reactions Occurring at ≥2% Incidence in Lovenox-Treated Patients Undergoing
Hip or Knee Replacement Surgery
Dosing Regimen
Lovenox
Lovenox
Heparin
Placebo
40 mg q.d. SC
30 mg q12h
15,000 U/24h
q12h SC
SC
SC
Peri-operative
Extended
Period
Prophylaxis
Period
n = 288 1
n = 131 2
n = 1080
n = 766
n = 115
%
%
%
%
%
Adverse
Reaction
Severe Total
Severe Total
Severe Total
Severe Total Severe Total
Fever
0
8
0
0
<1
5
<1
4
0
3
Hemorrhage
<1
13
0
5
<1
4
1
4
0
3
Nausea
<1
3
<1
2
0
2
Anemia
0
16
0
<2
<1
2
2
5
<1
7
Edema
<1
2
<1
2
0
2
Peripheral
0
6
0
0
<1
3
<1
4
0
3
edema
1 Data represent Lovenox 40 mg SC once a day initiated up to 12 hours prior to surgery in 288
hip replacement surgery patients who received Lovenox peri-operatively in an unblinded
fashion in one clinical trial.
2 Data represent Lovenox 40 mg SC once a day given in a blinded fashion as extended
prophylaxis at the end of the peri-operative period in 131 of the original 288 hip replacement
surgery patients for up to 21 days in one clinical trial.
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Table 10
Adverse Reactions Occurring at ≥2% Incidence in Lovenox-Treated Medical Patients with
Severely Restricted Mobility During Acute Illness
Adverse Reaction
Dosing Regimen
Lovenox
40 mg q.d. SC
n = 360
%
Placebo
q.d. SC
n = 362
%
Dyspnea
3.3
5.2
Thrombocytopenia
2.8
2.8
Confusion
2.2
1.1
Diarrhea
2.2
1.7
Nausea
2.5
1.7
Table 11
Adverse Reactions Occurring at ≥2% Incidence in Lovenox-Treated Patients Undergoing
Treatment of Deep Vein Thrombosis with or without Pulmonary Embolism
Adverse Reaction
Dosing Regimen
Lovenox
1.5 mg/kg q.d. SC
n = 298
%
Severe
Total
Lovenox
1 mg/kg q12h SC
n = 559
%
Severe
Total
Heparin
aPTT Adjusted
IV Therapy
n = 544
%
Severe
Total
Injection Site
Hemorrhage
0
5
0
3
<1
<1
Injection Site Pain
0
2
0
2
0
0
Hematuria
0
2
0
<1
<1
2
Adverse Events in Lovenox-Treated Patients with Unstable Angina or Non-Q-
Wave Myocardial Infarction:
Non-hemorrhagic clinical events reported to be related to Lovenox therapy occurred at an
incidence of ≤1%.
Non-major hemorrhagic events, primarily injection site ecchymoses and hematomas, were more
frequently reported in patients treated with SC Lovenox than in patients treated with IV heparin.
Serious adverse events with Lovenox or heparin in a clinical trial in patients with unstable angina
or non-Q-wave myocardial infarction that occurred at a rate of at least 0.5% in the Lovenox
group are provided below [see Table 12].
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Table 12
Serious Adverse Events Occurring at ≥0.5% Incidence in Lovenox-Treated Patients with
Unstable Angina or Non-Q-Wave Myocardial Infarction
Adverse Event
Dosing Regimen
Lovenox
1 mg/kg q12h SC
n = 1578
n (%)
Heparin
aPTT Adjusted
IV Therapy
n = 1529
n (%)
Atrial fibrillation
11 (0.70)
3 (0.20)
Heart failure
15 (0.95)
11 (0.72)
Lung edema
11 (0.70)
11 (0.72)
Pneumonia
13 (0.82)
9 (0.59)
Adverse Reactions in Lovenox-Treated Patients with Acute ST-Segment Elevation
Myocardial Infarction:
In a clinical trial in patients with acute ST-segment elevation myocardial infarction, the only
adverse reaction that occurred at a rate of at least 0.5% in the Lovenox group was
thrombocytopenia (1.5%).
6.2 Postmarketing Experience
There have been reports of epidural or spinal hematoma formation with concurrent use of
Lovenox and spinal/epidural anesthesia or spinal puncture. The majority of patients had a post
operative indwelling epidural catheter placed for analgesia or received additional drugs affecting
hemostasis such as NSAIDs. Many of the epidural or spinal hematomas caused neurologic
injury, including long-term or permanent paralysis.
Local reactions at the injection site (e.g. nodules, inflammation, oozing), systemic allergic
reactions (e.g. pruritus, urticaria, anaphylactic/anaphylactoid reactions), vesiculobullous rash,
rare cases of hypersensitivity cutaneous vasculitis, purpura, skin necrosis (occurring at either the
injection site or distant from the injection site), thrombocytosis, and thrombocytopenia with
thrombosis [see Warnings and Precautions (5.5)] have been reported.
Cases of hyperkalemia have been reported. Most of these reports occurred in patients who also
had conditions that tend toward the development of hyperkalemia (e.g., renal dysfunction,
concomitant potassium-sparing drugs, administration of potassium, hematoma in body tissues).
Very rare cases of hyperlipidemia have also been reported, with one case of hyperlipidemia, with
marked hypertriglyceridemia, reported in a diabetic pregnant woman; causality has not been
determined.
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Because these reactions are reported voluntarily from a population of uncertain size, it is not
possible to estimate reliably their frequency or to establish a causal relationship to drug
exposure.
7 DRUG INTERACTIONS
Whenever possible, agents which may enhance the risk of hemorrhage should be discontinued
prior to initiation of Lovenox therapy. These agents include medications such as: anticoagulants,
platelet inhibitors including acetylsalicylic acid, salicylates, NSAIDs (including ketorolac
tromethamine), dipyridamole, or sulfinpyrazone. If co-administration is essential, conduct close
clinical and laboratory monitoring [see Warnings and Precautions (5.9)].
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category B
All pregnancies have a background risk of birth defect, loss, or other adverse outcome regardless
of drug exposure. The fetal risk summary below describes the potential of Lovenox to increase
the risk of developmental abnormalities above the background risk.
Fetal Risk Summary
Lovenox does not cross the placenta, and is not expected to result in fetal exposure to the drug.
Human data from a retrospective cohort study, which included 693 live births, suggest that
Lovenox does not increase the risk of major developmental abnormalities. Based on animal data,
enoxaparin is not predicted to increase the risk of major developmental abnormalities (see Data).
Clinical Considerations
Pregnancy alone confers an increased risk for thromboembolism that is even higher for women
with thromboembolic disease and certain high risk pregnancy conditions. While not adequately
studied, pregnant women with mechanical prosthetic heart valves may be at even higher risk for
thrombosis [see Warnings and Precautions (5.7) and Use in Specific Populations (8.6)].
Pregnant women with thromboembolic disease, including those with mechanical prosthetic heart
valves and those with inherited or acquired thrombophilias, have an increased risk of other
maternal complications and fetal loss regardless of the type of anticoagulant used.
All patients receiving anticoagulants, including pregnant women, are at risk for bleeding.
Pregnant women receiving enoxaparin should be carefully monitored for evidence of bleeding or
excessive anticoagulation. Consideration for use of a shorter acting anticoagulant should be
specifically addressed as delivery approaches [see Boxed Warning]. Hemorrhage can occur at
any site and may lead to death of mother and/or fetus. Pregnant women should be apprised of
the potential hazard to the fetus and the mother if enoxaparin is administered during pregnancy.
It is not known if monitoring of anti-Factor Xa activity and dose adjustment (by weight or anti-
Factor Xa activity) of Lovenox affect the safety and the efficacy of the drug during pregnancy.
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Cases of “gasping syndrome” have occurred in premature infants when large amounts of benzyl
alcohol have been administered (99-405 mg/kg/day). The multiple-dose vial of Lovenox
contains 15 mg benzyl alcohol per 1 mL as a preservative [see Warnings and Precautions (5.8)].
Data
•
Human Data - There are no adequate and well-controlled studies in pregnant women. A
retrospective study reviewed the records of 604 women who used enoxaparin during
pregnancy. A total of 624 pregnancies resulted in 693 live births. There were 72
hemorrhagic events (11 serious) in 63 women. There were 14 cases of neonatal
hemorrhage. Major congenital anomalies in live births occurred at rates (2.5%) similar to
background rates.
There have been postmarketing reports of fetal death when pregnant women received
Lovenox. Causality for these cases has not been determined. Insufficient data, the
underlying disease, and the possibility of inadequate anticoagulation complicate the
evaluation of these cases.
A clinical study using enoxaparin in pregnant women with mechanical prosthetic heart
valves has been conducted [see Warnings and Precautions (5.7)].
• Animal Data - Teratology studies have been conducted in pregnant rats and rabbits at SC
doses of enoxaparin up to 15 times the recommended human dose (by comparison with 2
mg/kg as the maximum recommended daily dose). There was no evidence of teratogenic
effects or fetotoxicity due to enoxaparin. Because animal reproduction studies are not
always predictive of human response, this drug should be used during pregnancy only if
clearly needed.
8.3 Nursing Mothers
It is not known whether Lovenox is excreted in human milk. Because many drugs are excreted
in human milk and because of the potential for serious adverse reactions in nursing infants from
Lovenox, a decision should be made whether to discontinue nursing or discontinue Lovenox,
taking into account the importance of Lovenox to the mother and the known benefits of nursing.
8.4 Pediatric Use
Safety and effectiveness of Lovenox in pediatric patients have not been established.
8.5 Geriatric Use
Prevention of Deep Vein Thrombosis in Hip, Knee and Abdominal Surgery; Treatment of Deep
Vein Thrombosis, Prevention of Ischemic Complications of Unstable Angina and Non-Q-wave
Myocardial Infarction
Over 2800 patients, 65 years and older, have received Lovenox in pivotal clinical trials. The
efficacy of Lovenox in the geriatric (≥65 years) was similar to that seen in younger patients (<65
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years). The incidence of bleeding complications was similar between geriatric and younger
patients when 30 mg every 12 hours or 40 mg once a day doses of Lovenox were employed. The
incidence of bleeding complications was higher in geriatric patients as compared to younger
patients when Lovenox was administered at doses of 1.5 mg/kg once a day or 1 mg/kg every 12
hours. The risk of Lovenox-associated bleeding increased with age. Serious adverse events
increased with age for patients receiving Lovenox. Other clinical experience (including
postmarketing surveillance and literature reports) has not revealed additional differences in the
safety of Lovenox between geriatric and younger patients. Careful attention to dosing intervals
and concomitant medications (especially antiplatelet medications) is advised. Lovenox should
be used with care in geriatric patients who may show delayed elimination of enoxaparin.
Monitoring of geriatric patients with low body weight (<45 kg) and those predisposed to
decreased renal function should be considered [see Warnings and Precautions (5.9) and Clinical
Pharmacology (12.3)].
Treatment of Acute ST-Segment Elevation Myocardial Infarction
In the clinical study for treatment of acute ST-segment elevation myocardial infarction, there was
no evidence of difference in efficacy between patients ≥75 years of age (n = 1241) and patients
less than 75 years of age (n=9015). Patients ≥75 years of age did not receive a 30 mg IV bolus
prior to the normal dosage regimen and had their SC dose adjusted to 0.75 mg/kg every 12 hours
[see Dosage and Administration (2.3)]. The incidence of bleeding complications was higher in
patients ≥65 years of age as compared to younger patients (<65 years).
8.6 Patients with Mechanical Prosthetic Heart Valves
The use of Lovenox has not been adequately studied for thromboprophylaxis in patients with
mechanical prosthetic heart valves and has not been adequately studied for long-term use in this
patient population. Isolated cases of prosthetic heart valve thrombosis have been reported in
patients with mechanical prosthetic heart valves who have received enoxaparin for
thromboprophylaxis. Some of these cases were pregnant women in whom thrombosis led to
maternal and fetal deaths. Insufficient data, the underlying disease and the possibility of
inadequate anticoagulation complicate the evaluation of these cases. Pregnant women with
mechanical prosthetic heart valves may be at higher risk for thromboembolism [see Warnings
and Precautions (5.7)].
8.7 Renal Impairment
In patients with renal impairment, there is an increase in exposure of enoxaparin sodium. All
such patients should be observed carefully for signs and symptoms of bleeding. Because
exposure of enoxaparin sodium is significantly increased in patients with severe renal
impairment (creatinine clearance <30 mL/min), a dosage adjustment is recommended for
therapeutic and prophylactic dosage ranges. No dosage adjustment is recommended in patients
with moderate (creatinine clearance 30-50 mL/min) and mild (creatinine clearance 50-80
mL/min) renal impairment [see Dosage and Administration (2.2) and Clinical Pharmacology
(12.3)]. In patients with renal failure, treatment with enoxaparin has been associated with the
development of hyperkalemia [see Adverse Reactions (6.2)].
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8.8 Hepatic Impairment
The impact of hepatic impairment on enoxaparin’s exposure and antithrombotic effect has not
been investigated. Caution should be exercised when administering enoxaparin to patients with
hepatic impairment.
8.9 Low-Weight Patients
An increase in exposure of enoxaparin sodium with prophylactic dosages (non-weight adjusted)
has been observed in low-weight women (<45 kg) and low-weight men (<57 kg). All such
patients should be observed carefully for signs and symptoms of bleeding [see Clinical
Pharmacology (12.3)].
10 OVERDOSAGE
Accidental overdosage following administration of Lovenox may lead to hemorrhagic
complications. Injected Lovenox may be largely neutralized by the slow IV injection of
protamine sulfate (1% solution). The dose of protamine sulfate should be equal to the dose of
Lovenox injected: 1 mg protamine sulfate should be administered to neutralize 1 mg Lovenox, if
enoxaparin sodium was administered in the previous 8 hours. An infusion of 0.5 mg protamine
per 1 mg of enoxaparin sodium may be administered if enoxaparin sodium was administered
greater than 8 hours previous to the protamine administration, or if it has been determined that a
second dose of protamine is required. The second infusion of 0.5 mg protamine sulfate per 1 mg
of Lovenox may be administered if the aPTT measured 2 to 4 hours after the first infusion
remains prolonged.
If at least 12 hours have elapsed since the last enoxaparin sodium injection, protamine
administration may not be required; however, even with higher doses of protamine, the aPTT
may remain more prolonged than following administration of heparin. In all cases, the anti-
Factor Xa activity is never completely neutralized (maximum about 60%). Particular care should
be taken to avoid overdosage with protamine sulfate. Administration of protamine sulfate can
cause severe hypotensive and anaphylactoid reactions. Because fatal reactions, often resembling
anaphylaxis, have been reported with protamine sulfate, it should be given only when
resuscitation techniques and treatment of anaphylactic shock are readily available. For
additional information consult the labeling of protamine sulfate injection products.
11 DESCRIPTION
Lovenox is a sterile aqueous solution containing enoxaparin sodium, a low molecular weight
heparin. The pH of the injection is 5.5 to 7.5.
Enoxaparin sodium is obtained by alkaline depolymerization of heparin benzyl ester derived
from porcine intestinal mucosa. Its structure is characterized by a 2-O-sulfo-4-enepyranosuronic
acid group at the non-reducing end and a 2-N,6-O-disulfo-D-glucosamine at the reducing end of
the chain. About 20% (ranging between 15% and 25%) of the enoxaparin structure contains an
1,6 anhydro derivative on the reducing end of the polysaccharide chain. The drug substance is
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s
t
r
u
c
t
u
r
a
l
f
o
r
m
u
la
the sodium salt. The average molecular weight is about 4500 daltons. The molecular weight
distribution is:
<2000 daltons
≤20%
2000 to 8000 daltons
≥68%
>8000 daltons
≤18%
STRUCTURAL FORMULA structural formula
*X = Percent of polysaccharide chain containing 1,6 anhydro derivative on the reducing end.
Lovenox 100 mg/mL Concentration contains 10 mg enoxaparin sodium (approximate anti-
Factor Xa activity of 1000 IU [with reference to the W.H.O. First International Low Molecular
Weight Heparin Reference Standard]) per 0.1 mL Water for Injection.
Lovenox 150 mg/mL Concentration contains 15 mg enoxaparin sodium (approximate anti-
Factor Xa activity of 1500 IU [with reference to the W.H.O. First International Low Molecular
Weight Heparin Reference Standard]) per 0.1 mL Water for Injection.
The Lovenox prefilled syringes and graduated prefilled syringes are preservative-free and
intended for use only as a single-dose injection. The multiple-dose vial contains 15 mg benzyl
alcohol per 1 mL as a preservative [see Dosage and Administration (2) and How Supplied (16)].
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12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Enoxaparin is a low molecular weight heparin which has antithrombotic properties.
12.2 Pharmacodynamics
In humans, enoxaparin given at a dose of 1.5 mg/kg subcutaneously (SC) is characterized by a
higher ratio of anti-Factor Xa to anti-Factor IIa activity (mean ± SD, 14.0 ± 3.1) (based on areas
under anti-Factor activity versus time curves) compared to the ratios observed for heparin
(mean±SD, 1.22 ± 0.13). Increases of up to 1.8 times the control values were seen in the
thrombin time (TT) and the activated partial thromboplastin time (aPTT). Enoxaparin at a 1
mg/kg dose (100 mg/mL concentration), administered SC every 12 hours to patients in a large
clinical trial resulted in aPTT values of 45 seconds or less in the majority of patients (n = 1607).
A 30 mg IV bolus immediately followed by a 1 mg/kg SC administration resulted in aPTT post-
injection values of 50 seconds. The average aPTT prolongation value on Day 1 was about 16%
higher than on Day 4.
12.3 Pharmacokinetics
Absorption: Pharmacokinetic trials were conducted using the 100 mg/mL formulation.
Maximum anti-Factor Xa and anti-thrombin (anti-Factor IIa) activities occur 3 to 5 hours after
SC injection of enoxaparin. Mean peak anti-Factor Xa activity was 0.16 IU/mL (1.58 mcg/mL)
and 0.38 IU/mL (3.83 mcg/mL) after the 20 mg and the 40 mg clinically tested SC doses,
respectively. Mean (n = 46) peak anti-Factor Xa activity was 1.1 IU/mL at steady state in
patients with unstable angina receiving 1 mg/kg SC every 12 hours for 14 days. Mean absolute
bioavailability of enoxaparin, after 1.5 mg/kg given SC, based on anti-Factor Xa activity is
approximately 100% in healthy subjects.
A 30 mg IV bolus immediately followed by a 1 mg/kg SC every 12 hours provided initial peak
anti-Factor Xa levels of 1.16 IU/mL (n=16) and average exposure corresponding to 84% of
steady-state levels. Steady state is achieved on the second day of treatment.
Enoxaparin pharmacokinetics appear to be linear over the recommended dosage ranges [see
Dosage and Administration (2)]. After repeated subcutaneous administration of 40 mg once
daily and 1.5 mg/kg once-daily regimens in healthy volunteers, the steady state is reached on day
2 with an average exposure ratio about 15% higher than after a single dose. Steady-state
enoxaparin activity levels are well predicted by single-dose pharmacokinetics. After repeated
subcutaneous administration of the 1 mg/kg twice daily regimen, the steady state is reached from
day 4 with mean exposure about 65% higher than after a single dose and mean peak and trough
levels of about 1.2 and 0.52 IU/mL, respectively.
Based on enoxaparin sodium
pharmacokinetics, this difference in steady state is expected and within the therapeutic range.
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Although not studied clinically, the 150 mg/mL concentration of enoxaparin sodium is projected
to result in anticoagulant activities similar to those of 100 mg/mL and 200 mg/mL concentrations
at the same enoxaparin dose. When a daily 1.5 mg/kg SC injection of enoxaparin sodium was
given to 25 healthy male and female subjects using a 100 mg/mL or a 200 mg/mL concentration
the following pharmacokinetic profiles were obtained [see Table 13].
Table 13
Pharmacokinetic Parameters* After 5 Days of 1.5 mg/kg SC Once Daily Doses of
Enoxaparin Sodium Using 100 mg/mL or 200 mg/mL Concentrations
Concentration
Anti-Xa
Anti-IIa
Heptest
aPTT
Amax
(IU/mL or Δ
sec)
100 mg/mL
1.37 (±0.23)
0.23 (±0.05)
105 (±17)
19 (±5)
200 mg/mL
1.45 (±0.22)
0.26 (±0.05)
111 (±17)
22 (±7)
90% CI
102-110%
102-111%
tmax** (h)
100 mg/mL
3 (2-6)
4 (2-5)
2.5 (2-4.5)
3 (2-4.5)
200 mg/mL
3.5 (2-6)
4.5 (2.5-6)
3.3 (2-5)
3 (2-5)
AUC
(ss)
(h*IU/mL
or
h* Δ sec)
100 mg/mL
14.26 (±2.93)
1.54 (±0.61)
1321 (±219)
200 mg/mL
15.43 (±2.96)
1.77 (±0.67)
1401 (±227)
90% CI
105-112%
103-109%
*Means ± SD at Day 5 and 90% Confidence Interval (CI) of the ratio
**Median (range)
Distribution: The volume of distribution of anti-Factor Xa activity is about 4.3 L.
Elimination: Following intravenous (IV) dosing, the total body clearance of enoxaparin is 26
mL/min. After IV dosing of enoxaparin labeled with the gamma-emitter, 99mTc, 40% of
radioactivity and 8 to 20% of anti-Factor Xa activity were recovered in urine in 24 hours.
Elimination half-life based on anti-Factor Xa activity was 4.5 hours after a single SC dose to
about 7 hours after repeated dosing. Significant anti-Factor Xa activity persists in plasma for
about 12 hours following a 40 mg SC once a day dose.
Following SC dosing, the apparent clearance (CL/F) of enoxaparin is approximately 15 mL/min.
Metabolism: Enoxaparin sodium is primarily metabolized in the liver by desulfation and/or
depolymerization to lower molecular weight species with much reduced biological potency.
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Renal clearance of active fragments represents about 10% of the administered dose and total
renal excretion of active and non-active fragments 40% of the dose.
Special Populations
Gender: Apparent clearance and Amax derived from anti-Factor Xa values following single SC
dosing (40 mg and 60 mg) were slightly higher in males than in females. The source of the
gender difference in these parameters has not been conclusively identified; however, body
weight may be a contributing factor.
Geriatric: Apparent clearance and Amax derived from anti-Factor Xa values following single and
multiple SC dosing in geriatric subjects were close to those observed in young subjects.
Following once a day SC dosing of 40 mg enoxaparin, the Day 10 mean area under anti-Factor
Xa activity versus time curve (AUC) was approximately 15% greater than the mean Day 1 AUC
value [see Dosage and Administration (2.3) and Use in Specific Populations (8.5)].
Renal Impairment: A linear relationship between anti-Factor Xa plasma clearance and creatinine
clearance at steady state has been observed, which indicates decreased clearance of enoxaparin
sodium in patients with reduced renal function. Anti-Factor Xa exposure represented by AUC, at
steady state, is marginally increased in mild (creatinine clearance 50–80 mL/min) and moderate
(creatinine clearance 30-50 mL/min) renal impairment after repeated subcutaneous 40 mg once-
daily doses. In patients with severe renal impairment (creatinine clearance <30 mL/min), the
AUC at steady state is significantly increased on average by 65% after repeated subcutaneous 40
mg once-daily doses [see Dosage and Administration (2.2) and Use in Specific Populations
(8.7)].
Hemodialysis: In a single study, elimination rate appeared similar but AUC was two-fold higher
than control population, after a single 0.25 or 0.5 mg/kg intravenous dose.
Hepatic Impairment: Studies with enoxaparin in patients with hepatic impairment have not been
conducted and the impact of hepatic impairment on the exposure to enoxaparin is unknown [see
Use in Specific Populations (8.8)].
Weight: After repeated subcutaneous 1.5 mg/kg once daily dosing, mean AUC of anti-Factor Xa
activity is marginally higher at steady state in obese healthy volunteers (BMI 30-48 kg/m2)
compared to non-obese control subjects, while Amax is not increased.
When non-weight adjusted dosing was administered, it was found after a single-subcutaneous 40
mg dose, that anti-Factor Xa exposure is 52% higher in low-weight women (<45 kg) and 27%
higher in low-weight men (<57 kg) when compared to normal weight control subjects [see Use
in Specific Populations (8.9)].
Pharmacokinetic interaction: No pharmacokinetic interaction was observed between enoxaparin
and thrombolytics when administered concomitantly.
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Dosing Regimen
Lovenox
Heparin
40 mg q.d. SC
5000 U q8h SC
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
No long-term studies in animals have been performed to evaluate the carcinogenic potential of
enoxaparin. Enoxaparin was not mutagenic in in vitro tests, including the Ames test, mouse
lymphoma cell forward mutation test, and human lymphocyte chromosomal aberration test, and
the in vivo rat bone marrow chromosomal aberration test. Enoxaparin was found to have no
effect on fertility or reproductive performance of male and female rats at SC doses up to 20
mg/kg/day or 141 mg/m2/day. The maximum human dose in clinical trials was 2.0 mg/kg/day or
78 mg/m2/day (for an average body weight of 70 kg, height of 170 cm, and body surface area of
1.8 m2).
13.2 Animal Toxicology and/or Pharmacology
A single SC dose of 46.4 mg/kg enoxaparin was lethal to rats. The symptoms of acute toxicity
were ataxia, decreased motility, dyspnea, cyanosis, and coma.
13.3 Reproductive and Developmental Toxicology
Teratology studies have been conducted in pregnant rats and rabbits at SC doses of enoxaparin
up to 30 mg/kg/day corresponding to 211 mg/m2/day and 410 mg/m2/day in rats and rabbits
respectively. There was no evidence of teratogenic effects or fetotoxicity due to enoxaparin.
14 CLINICAL STUDIES
14.1 Prophylaxis of Deep Vein Thrombosis Following Abdominal Surgery in
Patients at Risk for Thromboembolic Complications
Abdominal surgery patients at risk include those who are over 40 years of age, obese,
undergoing surgery under general anesthesia lasting longer than 30 minutes or who have
additional risk factors such as malignancy or a history of deep vein thrombosis (DVT) or
pulmonary embolism (PE).
In a double-blind, parallel group study of patients undergoing elective cancer surgery of the
gastrointestinal, urological, or gynecological tract, a total of 1116 patients were enrolled in the
study, and 1115 patients were treated. Patients ranged in age from 32 to 97 years (mean age 67
years) with 52.7% men and 47.3% women. Patients were 98% Caucasian, 1.1% Black, 0.4%
Asian and 0.4% others. Lovenox 40 mg SC, administered once a day, beginning 2 hours prior to
surgery and continuing for a maximum of 12 days after surgery, was comparable to heparin 5000
U every 8 hours SC in reducing the risk of DVT. The efficacy data are provided below [see
Table 14].
Table 14
Efficacy of Lovenox in the Prophylaxis of Deep Vein Thrombosis Following Abdominal
Surgery
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Indication
n (%)
n (%)
All Treated Abdominal
Surgery Patients
555 (100)
560 (100)
Treatment Failures
Total VTE1 (%)
DVT Only (%)
56 (10.1)
(95% CI2: 8 to 13)
63 (11.3)
(95% CI: 9 to 14)
54 (9.7)
(95% CI: 7 to 12)
61 (10.9)
(95% CI: 8 to 13)
1 VTE = Venous thromboembolic events which included DVT, PE, and death considered to be
thromboembolic in origin
2 CI = Confidence Interval
In a second double-blind, parallel group study, Lovenox 40 mg SC once a day was compared to
heparin 5000 U every 8 hours SC in patients undergoing colorectal surgery (one-third with
cancer). A total of 1347 patients were randomized in the study and all patients were treated.
Patients ranged in age from 18 to 92 years (mean age 50.1 years) with 54.2% men and 45.8%
women. Treatment was initiated approximately 2 hours prior to surgery and continued for
approximately 7 to 10 days after surgery. The efficacy data are provided below [see Table 15].
Table 15
Efficacy of Lovenox in the Prophylaxis of Deep Vein Thrombosis Following Colorectal
Surgery
Indication
Dosing Regimen
Lovenox
40 mg q.d. SC
n (%)
Heparin
5000 U q8h SC
n (%)
All Treated Colorectal Surgery
Patients
673 (100)
674 (100)
Treatment Failures
Total VTE1 (%)
DVT Only (%)
48 (7.1)
(95% CI2: 5 to 9)
45 (6.7)
(95% CI: 5 to 9)
47 (7.0)
(95% CI: 5 to 9)
44 (6.5)
(95% CI: 5 to 8)
1 VTE = Venous thromboembolic events which included DVT, PE, and death considered to be
thromboembolic in origin
2 CI = Confidence Interval
14.2 Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement
Surgery
Lovenox has been shown to reduce the risk of post-operative deep vein thrombosis (DVT)
following hip or knee replacement surgery.
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In a double-blind study, Lovenox 30 mg every 12 hours SC was compared to placebo in patients
with hip replacement. A total of 100 patients were randomized in the study and all patients were
treated. Patients ranged in age from 41 to 84 years (mean age 67.1 years) with 45% men and
55% women. After hemostasis was established, treatment was initiated 12 to 24 hours after
surgery and was continued for 10 to 14 days after surgery. The efficacy data are provided below
[see Table 16].
Table 16
Efficacy of Lovenox in the Prophylaxis of Deep Vein Thrombosis Following Hip
Replacement Surgery
Indication
Dosing Regimen
Lovenox
30 mg q12h SC
n (%)
Placebo
q12h SC
n (%)
All Treated Hip Replacement Patients
50 (100)
50 (100)
Treatment Failures
Total DVT (%)
Proximal DVT (%)
5 (10)1
23 (46)
1 (2)2
11 (22)
1 p value versus placebo = 0.0002
2 p value versus placebo = 0.0134
A double-blind, multicenter study compared three dosing regimens of Lovenox in patients with
hip replacement. A total of 572 patients were randomized in the study and 568 patients were
treated. Patients ranged in age from 31 to 88 years (mean age 64.7 years) with 63% men and
37% women. Patients were 93% Caucasian, 6% Black, <1% Asian, and 1% others. Treatment
was initiated within two days after surgery and was continued for 7 to 11 days after surgery. The
efficacy data are provided below [see Table 17].
Table 17
Efficacy of Lovenox in the Prophylaxis of Deep Vein Thrombosis Following Hip
Replacement Surgery
Indication
Dosing Regimen
10 mg q.d. SC
n (%)
30 mg q12h SC
n (%)
40 mg q.d. SC
n (%)
All Treated Hip
Replacement Patients
161 (100)
208 (100)
199 (100)
Treatment Failures
Total DVT (%)
40 (25)
22 (11)1
27 (14)
Proximal DVT (%)
17 (11)
8 (4)2
9 (5)
1 p value versus Lovenox 10 mg once a day = 0.0008
2 p value versus Lovenox 10 mg once a day = 0.0168
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There was no significant difference between the 30 mg every 12 hours and 40 mg once a day
regimens. In a double-blind study, Lovenox 30 mg every 12 hours SC was compared to placebo
in patients undergoing knee replacement surgery. A total of 132 patients were randomized in the
study and 131 patients were treated, of which 99 had total knee replacement and 32 had either
unicompartmental knee replacement or tibial osteotomy. The 99 patients with total knee
replacement ranged in age from 42 to 85 years (mean age 70.2 years) with 36.4% men and
63.6% women. After hemostasis was established, treatment was initiated 12 to 24 hours after
surgery and was continued up to 15 days after surgery. The incidence of proximal and total DVT
after surgery was significantly lower for Lovenox compared to placebo. The efficacy data are
provided below [see Table 18].
Table 18
Efficacy of Lovenox in the Prophylaxis of Deep Vein Thrombosis Following Total Knee
Replacement Surgery
Indication
Dosing Regimen
Lovenox
30 mg q12h SC
n (%)
Placebo
q12h SC
n (%)
All Treated Total Knee
Replacement Patients
47 (100)
52 (100)
Treatment Failures
Total DVT (%)
5 (11)1
(95% CI2: 1 to 21)
32 (62)
(95% CI: 47 to 76)
Proximal DVT (%)
0 (0)3
(95% Upper CL4: 5)
7 (13)
(95% CI: 3 to 24)
1 p value versus placebo = 0.0001
2 CI = Confidence Interval
3 p value versus placebo = 0.013
4 CL = Confidence Limit
Additionally, in an open-label, parallel group, randomized clinical study, Lovenox 30 mg every
12 hours SC in patients undergoing elective knee replacement surgery was compared to heparin
5000 U every 8 hours SC. A total of 453 patients were randomized in the study and all were
treated. Patients ranged in age from 38 to 90 years (mean age 68.5 years) with 43.7% men and
56.3% women. Patients were 92.5% Caucasian, 5.3% Black, and 0.6% others. Treatment was
initiated after surgery and continued up to 14 days. The incidence of deep vein thrombosis was
significantly lower for Lovenox compared to heparin.
Extended Prophylaxis of Deep Vein Thrombosis Following Hip Replacement Surgery: In a study
of extended prophylaxis for patients undergoing hip replacement surgery, patients were treated,
while hospitalized, with Lovenox 40 mg SC, initiated up to 12 hours prior to surgery for the
prophylaxis of post-operative DVT. At the end of the peri-operative period, all patients
underwent bilateral venography.
In a double-blind design, those patients with no venous
thromboembolic disease were randomized to a post-discharge regimen of either Lovenox 40 mg
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(n = 90) once a day SC or to placebo (n = 89) for 3 weeks. A total of 179 patients were
randomized in the double-blind phase of the study and all patients were treated. Patients ranged
in age from 47 to 87 years (mean age 69.4 years) with 57% men and 43% women. In this
population of patients, the incidence of DVT during extended prophylaxis was significantly
lower for Lovenox compared to placebo. The efficacy data are provided below [see Table 19].
Table 19
Efficacy of Lovenox in the Extended Prophylaxis of Deep Vein Thrombosis Following Hip
Replacement Surgery
Indication (Post-Discharge)
Post-Discharge Dosing Regimen
Lovenox
40 mg q.d. SC
n (%)
Placebo
q.d. SC
n (%)
All Treated Extended
Prophylaxis Patients
90 (100)
89 (100)
Treatment Failures
Total DVT (%)
6 (7)1
(95% CI2: 3 to 14)
18 (20)
(95% CI: 12 to 30)
Proximal DVT (%)
5 (6)3
(95% CI: 2 to 13)
7 (8)
(95% CI: 3 to 16)
1 p value versus placebo = 0.008
2 CI= Confidence Interval
3 p value versus placebo = 0.537
In a second study, patients undergoing hip replacement surgery were treated, while hospitalized,
with Lovenox 40 mg SC, initiated up to 12 hours prior to surgery. All patients were examined
for clinical signs and symptoms of venous thromboembolic (VTE) disease. In a double-blind
design, patients without clinical signs and symptoms of VTE disease were randomized to a post-
discharge regimen of either Lovenox 40 mg (n = 131) once a day SC or to placebo (n = 131) for
3 weeks. A total of 262 patients were randomized in the study double-blind phase and all
patients were treated. Patients ranged in age from 44 to 87 years (mean age 68.5 years) with
43.1% men and 56.9% women. Similar to the first study the incidence of DVT during extended
prophylaxis was significantly lower for Lovenox compared to placebo, with a statistically
significant difference in both total DVT (Lovenox 21 [16%] versus placebo 45 [34%]; p = 0.001)
and proximal DVT (Lovenox 8 [6%] versus placebo 28 [21%]; p = <0.001).
14.3 Prophylaxis of Deep Vein Thrombosis in Medical Patients with Severely
Restricted Mobility During Acute Illness
In a double blind multicenter, parallel group study, Lovenox 20 mg or 40 mg once a day SC was
compared to placebo in the prophylaxis of deep vein thrombosis (DVT) in medical patients with
severely restricted mobility during acute illness (defined as walking distance of <10 meters for
≤3 days). This study included patients with heart failure (NYHA Class III or IV); acute
respiratory failure or complicated chronic respiratory insufficiency (not requiring ventilatory
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support): acute infection (excluding septic shock); or acute rheumatic disorder [acute lumbar or
sciatic pain, vertebral compression (due to osteoporosis or tumor), acute arthritic episodes of the
lower extremities]. A total of 1102 patients were enrolled in the study, and 1073 patients were
treated. Patients ranged in age from 40 to 97 years (mean age 73 years) with equal proportions
of men and women. Treatment continued for a maximum of 14 days (median duration 7 days).
When given at a dose of 40 mg once a day SC, Lovenox significantly reduced the incidence of
DVT as compared to placebo. The efficacy data are provided below [see Table 20].
Table 20
Efficacy of Lovenox in the Prophylaxis of Deep Vein Thrombosis in Medical Patients with
Severely Restricted Mobility During Acute Illness
Indication
Dosing Regimen
Lovenox
20 mg q.d. SC
n (%)
Lovenox
40 mg q.d. SC
n (%)
Placebo
n (%)
All Treated Medical
Patients During Acute
Illness
351 (100)
360 (100)
362 (100)
Treatment Failure1
Total VTE2 (%)
Total DVT (%)
Proximal DVT (%)
43 (12.3)
16 (4.4)
43 (11.9)
43 (12.3)
(95% CI3 8.8 to 15.7)
16 (4.4)
(95% CI3 2.3 to 6.6)
41 (11.3)
(95% CI3 8.1 to 14.6)
13 (3.7)
5 (1.4)
14 (3.9)
1 Treatment failures during therapy, between Days 1 and 14
2 VTE = Venous thromboembolic events which included DVT, PE, and death considered to be
thromboembolic in origin
3 CI = Confidence Interval
At approximately 3 months following enrollment, the incidence of venous thromboembolism
remained significantly lower in the Lovenox 40 mg treatment group versus the placebo treatment
group.
14.4 Treatment of Deep Vein Thrombosis with or without Pulmonary Embolism
In a multicenter, parallel group study, 900 patients with acute lower extremity deep vein
thrombosis (DVT) with or without pulmonary embolism (PE) were randomized to an inpatient
(hospital) treatment of either (i) Lovenox 1.5 mg/kg once a day SC, (ii) Lovenox 1 mg/kg every
12 hours SC, or (iii) heparin IV bolus (5000 IU) followed by a continuous infusion (administered
to achieve an aPTT of 55 to 85 seconds). A total of 900 patients were randomized in the study
and all patients were treated. Patients ranged in age from 18 to 92 years (mean age 60.7 years)
with 54.7% men and 45.3% women. All patients also received warfarin sodium (dose adjusted
according to PT to achieve an International Normalization Ratio [INR] of 2.0 to 3.0),
commencing within 72 hours of initiation of Lovenox or standard heparin therapy, and
continuing for 90 days. Lovenox or standard heparin therapy was administered for a minimum of
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5 days and until the targeted warfarin sodium INR was achieved. Both Lovenox regimens were
equivalent to standard heparin therapy in reducing the risk of recurrent venous thromboembolism
(DVT and/or PE). The efficacy data are provided below [see Table 21].
Table 21
Efficacy of Lovenox in Treatment of Deep Vein Thrombosis
with or without Pulmonary Embolism
Indication
Dosing Regimen1
Lovenox
1.5 mg/kg q.d. SC
n (%)
Lovenox
1 mg/kg q12h SC
n (%)
Heparin
aPTT Adjusted
IV Therapy
n (%)
All Treated DVT Patients
with or without PE
298 (100)
312 (100)
290 (100)
Patient Outcome
Total VTE2 (%)
DVT Only (%)
Proximal DVT (%)
PE (%)
13 (4.4)3
9 (2.9) 3
12 (4.1)
11 (3.7)
7 (2.2)
8 (2.8)
9 (3.0)
6 (1.9)
7 (2.4)
2 (0.7)
2 (0.6)
4 (1.4)
1 All patients were also treated with warfarin sodium commencing within 72 hours of Lovenox or
standard heparin therapy.
2 VTE = venous thromboembolic event (DVT and/or PE)
3 The 95% Confidence Intervals for the treatment differences for total VTE were:
Lovenox once a day versus heparin (-3.0 to 3.5)
Lovenox every 12 hours versus heparin (-4.2 to 1.7).
Similarly, in a multicenter, open-label, parallel group study, patients with acute proximal DVT
were randomized to Lovenox or heparin. Patients who could not receive outpatient therapy were
excluded from entering the study. Outpatient exclusion criteria included the following: inability
to receive outpatient heparin therapy because of associated co-morbid conditions or potential for
non-compliance and inability to attend follow-up visits as an outpatient because of geographic
inaccessibility. Eligible patients could be treated in the hospital, but ONLY Lovenox patients
were permitted to go home on therapy (72%). A total of 501 patients were randomized in the
study and all patients were treated. Patients ranged in age from 19 to 96 years (mean age 57.8
years) with 60.5% men and 39.5% women. Patients were randomized to either Lovenox 1 mg/kg
every 12 hours SC or heparin IV bolus (5000 IU) followed by a continuous infusion
administered to achieve an aPTT of 60 to 85 seconds (in-patient treatment). All patients also
received warfarin sodium as described in the previous study. Lovenox or standard heparin
therapy was administered for a minimum of 5 days. Lovenox was equivalent to standard heparin
therapy in reducing the risk of recurrent venous thromboembolism. The efficacy data are
provided below [see Table 22].
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Table 22
Efficacy of Lovenox in Treatment of Deep Vein Thrombosis
Indication
Dosing Regimen1
Lovenox
1 mg/kg q12h SC
n (%)
Heparin
aPTT Adjusted
IV Therapy
n (%)
All Treated DVT Patients
247 (100)
254 (100)
Patient Outcome
Total VTE2 (%)
DVT Only (%)
Proximal DVT (%)
PE (%)
13 (5.3) 3
17 (6.7)
11 (4.5)
14 (5.5)
10 (4.0)
12 (4.7)
2 (0.8)
3 (1.2)
1 All patients were also treated with warfarin sodium commencing on the evening of the second
day of Lovenox or standard heparin therapy.
2 VTE = venous thromboembolic event (deep vein thrombosis [DVT] and/or pulmonary
embolism [PE]).
3 The 95% Confidence Intervals for the treatment difference for total VTE was: Lovenox versus
heparin (- 5.6 to 2.7).
14.5 Prophylaxis of Ischemic Complications in Unstable Angina and Non-Q-Wave
Myocardial Infarction
In a multicenter, double-blind, parallel group study, patients who recently experienced unstable
angina or non-Q-wave myocardial infarction were randomized to either Lovenox 1 mg/kg every
12 hours SC or heparin IV bolus (5000 U) followed by a continuous infusion (adjusted to
achieve an aPTT of 55 to 85 seconds). A total of 3171 patients were enrolled in the study, and
3107 patients were treated. Patients ranged in age from 25-94 years (median age 64 years), with
33.4% of patients female and 66.6% male. Race was distributed as follows: 89.8% Caucasian,
4.8% Black, 2.0% Asian, and 3.5% other. All patients were also treated with aspirin 100 to 325
mg per day. Treatment was initiated within 24 hours of the event and continued until clinical
stabilization, revascularization procedures, or hospital discharge, with a maximal duration of 8
days of therapy. The combined incidence of the triple endpoint of death, myocardial infarction,
or recurrent angina was lower for Lovenox compared with heparin therapy at 14 days after
initiation of treatment. The lower incidence of the triple endpoint was sustained up to 30 days
after initiation of treatment. These results were observed in an analysis of both all-randomized
and all-treated patients. The efficacy data are provided below [see Table 23].
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Table 23
Efficacy of Lovenox in the Prophylaxis of Ischemic Complications in Unstable Angina and
Non-Q-Wave Myocardial Infarction
(Combined Endpoint of Death, Myocardial Infarction, or Recurrent Angina)
Indication
Dosing Regimen1
Reduction
(%)
p Value
Lovenox
1mg/kg q12h SC
n (%)
Heparin
aPTT Adjusted
IV Therapy
n (%)
All Treated Unstable
Angina and Non-Q-Wave
MI Patients
1578 (100)
1529 (100)
Timepoint2
48 Hours
96 (6.1)
112 (7.3)
1.2
0.120
14 Days
261 (16.5)
303 (19.8)
3.3
0.017
30 Days
313 (19.8)
358 (23.4)
3.6
0.014
1 All patients were also treated with aspirin 100 to 325 mg per day.
2 Evaluation timepoints are after initiation of treatment. Therapy continued for up to 8 days
(median duration of 2.6 days).
The combined incidence of death or myocardial infarction at all time points was lower for
Lovenox compared to standard heparin therapy, but did not achieve statistical significance. The
efficacy data are provided below [see Table 24].
Table 24
Efficacy of Lovenox in the Prophylaxis of Ischemic Complications in Unstable Angina and
Non-Q-Wave Myocardial Infarction
(Combined Endpoint of Death or Myocardial Infarction)
Indication
Dosing Regimen1
Reduction
(%)
p Value
Lovenox
1 mg/kg q12h SC
n (%)
Heparin
aPTT Adjusted
IV Therapy
n (%)
All Treated Unstable
Angina and Non-Q-Wave
MI Patients
1578 (100)
1529 (100)
Timepoint2
48 Hours
16 (1.0)
20 (1.3)
0.3
0.126
14 Days
76 (4.8)
93 (6.1)
1.3
0.115
30 Days
96 (6.1)
118 (7.7)
1.6
0.069
1 All patients were also treated with aspirin 100 to 325 mg per day.
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2 Evaluation timepoints are after initiation of treatment. Therapy continued for up to 8 days
(median duration of 2.6 days).
In a survey one year following treatment, with information available for 92% of enrolled
patients, the combined incidence of death, myocardial infarction, or recurrent angina remained
lower for Lovenox versus heparin (32.0% vs 35.7%).
Urgent revascularization procedures were performed less frequently in the Lovenox group as
compared to the heparin group, 6.3% compared to 8.2% at 30 days (p = 0.047).
14.6 Treatment of Acute ST-Segment Elevation Myocardial Infarction
In a multicenter, double-blind, double-dummy, parallel group study, patients with acute ST-
segment elevation myocardial infarction (STEMI) who were to be hospitalized within 6 hours of
onset and were eligible to receive fibrinolytic therapy were randomized in a 1:1 ratio to receive
either Lovenox or unfractionated heparin.
Study medication was initiated between 15 minutes before and 30 minutes after the initiation of
fibrinolytic therapy. Unfractionated heparin was administered beginning with an IV bolus of 60
U/kg (maximum 4000 U) and followed with an infusion of 12 U/kg per hour (initial maximum
1000 U per hour) that was adjusted to maintain an aPTT of 1.5 to 2 times the control value. The
IV infusion was to be given for at least 48 hours. The enoxaparin dosing strategy was adjusted
according to the patient’s age and renal function. For patients younger than 75 years of age,
enoxaparin was given as a single 30 mg intravenous bolus plus a 1 mg/kg SC dose followed by
an SC injection of 1 mg/kg every 12 hours. For patients at least 75 years of age, the IV bolus
was not given and the SC dose was reduced to 0.75 mg/kg every 12 hours. For patients with
severe renal insufficiency (estimated creatinine clearance of less than 30 mL per minute), the
dose was to be modified to 1 mg/kg every 24 hours. The SC injections of enoxaparin were given
until hospital discharge or for a maximum of eight days (whichever came first). The mean
treatment duration for enoxaparin was 6.6 days. The mean treatment duration of unfractionated
heparin was 54 hours.
When percutaneous coronary intervention was performed during study medication period,
patients received antithrombotic support with blinded study drug. For patients on enoxaparin,
the PCI was to be performed on enoxaparin (no switch) using the regimen established in
previous studies, i.e. no additional dosing, if the last SC administration was less than 8 hours
before balloon inflation, IV bolus of 0.3 mg/kg enoxaparin if the last SC administration was
more than 8 hours before balloon inflation.
All patients were treated with aspirin for a minimum of 30 days. Eighty percent of patients
received a fibrin-specific agent (19% tenecteplase, 5% reteplase and 55% alteplase) and 20%
received streptokinase.
Among 20,479 patients in the ITT population, the mean age was 60 years, and 76% were male.
Racial distribution was: 87% Caucasian, 9.8% Asian, 0.2% Black, and 2.8% other. Medical
history included previous MI (13%), hypertension (44%), diabetes (15%) and angiographic
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evidence of CAD (5%). Concomitant medication included aspirin (95%), beta-blockers (86%),
ACE inhibitors (78%), statins (70%) and clopidogrel (27%). The MI at entry was anterior in
43%, non-anterior in 56%, and both in 1%.
The primary efficacy end point was the composite of death from any cause or myocardial re-
infarction in the first 30 days after randomization. Total follow-up was one year.
The rate of the primary efficacy end point (death or myocardial re-infarction) was 9.9% in the
enoxaparin group, and 12.0% in the unfractionated heparin group, a 17% reduction in the relative
risk, (P=0.000003) [see Table 25].
Table 25
Efficacy of Lovenox in the Treatment of Acute ST-Segment Elevation Myocardial
Infarction
Enoxaparin
(N=10,256)
UFH
(N=10,223)
Relative Risk
(95% CI)
P Value
Outcome at 48 hours
n (%)
n (%)
Death or Myocardial Re-infarction
478 (4.7)
531 (5.2)
0.90 (0.80 to 1.01)
0.08
Death
383 (3.7)
390 (3.8)
0.98 (0.85 to 1.12)
0.76
Myocardial Re-infarction
102 (1.0)
156 (1.5)
0.65 (0.51 to 0.84)
<0.001
Urgent Revascularization
74 (0.7)
96 (0.9)
0.77 (0.57 to 1.04)
0.09
Death or Myocardial Re-infarction or Urgent
548 (5.3)
622 (6.1)
0.88 (0.79 to 0.98)
0.02
Revascularization
Outcome at 8 Days
Death or Myocardial Re-infarction
Death
Myocardial Re-infarction
Urgent Revascularization
Death or Myocardial Re-infarction or Urgent
Revascularization
740 (7.2)
559 (5.5)
204 (2.0)
145 (1.4)
874 (8.5)
954 (9.3)
605 (5.9)
379 (3.7)
247 (2.4)
1181 (11.6)
0.77 (0.71 to 0.85)
0.92 (0.82 to 1.03)
0.54 (0.45 to 0.63)
0.59 (0.48 to 0.72)
0.74 (0.68 to 0.80)
<0.001
0.15
<0.001
<0.001
<0.001
Outcome at 30 Days
Primary efficacy endpoint
(Death or Myocardial Re-infarction)
1017 (9.9)
1223 (12.0)
0.83 (0.77 to 0.90)
0.000003
Death
708 (6.9)
765 (7.5)
0.92 (0.84 to 1.02)
0.11
Myocardial Re-infarction
352 (3.4)
508 (5.0)
0.69 (0.60 to 0.79)
<0.001
Urgent Revascularization
213 (2.1)
286 (2.8)
0.74 (0.62 to 0.88)
<0.001
Death or Myocardial Re-infarction or Urgent
1199 (11.7)
1479 (14.5)
0.81 (0.75 to 0.87)
<0.001
Revascularization
Note: Urgent revascularization denotes episodes of recurrent myocardial ischemia (without infarction) leading to the
clinical decision to perform coronary revascularization during the same hospitalization. CI denotes confidence intervals.
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The beneficial effect of enoxaparin on the primary end point was consistent across key
subgroups including age, gender, infarct location, history of diabetes, history of prior myocardial
infarction, fibrinolytic agent administered, and time to treatment with study drug (see Figure 1);
however, it is necessary to interpret such subgroup analyses with caution.
Figure 1. Relative Risks of and Absolute Event Rates for the Primary End Point at 30 Days in Various
Subgroups * graph
* The primary efficacy end point was the composite of death from any cause or myocardial re-infarction in the first
30 days. The overall treatment effect of enoxaparin as compared to the unfractionated heparin is shown at the
bottom of the figure. For each subgroup, the circle is proportional to the number and represents the point estimate of
the treatment effect and the horizontal lines represent the 95 percent confidence intervals. Fibrin-specific
fibrinolytic agents included alteplase, tenecteplase and reteplase. Time to treatment indicates the time from the
onset of symptoms to the administration of study drug (median, 3.2 hours).
The beneficial effect of enoxaparin on the primary end point observed during the first 30 days
was maintained over a 12 month follow-up period (see Figure 2).
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Figure 2 - Kaplan-Meier plot - death or myocardial re-infarction at 30 days - ITT population graph
There is a trend in favor of enoxaparin during the first 48 hours, but most of the treatment
difference is attributed to a step increase in the event rate in the UFH group at 48 hours (seen in
Figure 2), an effect that is more striking when comparing the event rates just prior to and just
subsequent to actual times of discontinuation. These results provide evidence that UFH was
effective and that it would be better if used longer than 48 hours. There is a similar increase in
endpoint event rate when enoxaparin was discontinued, suggesting that it too was discontinued
too soon in this study.
The rates of major hemorrhages (defined as requiring 5 or more units of blood for transfusion, or
15% drop in hematocrit or clinically overt bleeding, including intracranial hemorrhage) at 30
days were 2.1% in the enoxaparin group and 1.4% in the unfractionated heparin group. The rates
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of intracranial hemorrhage at 30 days were 0.8% in the enoxaparin group 0.7% in the
unfractionated heparin group. The 30-day rate of the composite endpoint of death, myocardial
re-infarction or ICH (a measure of net clinical benefit) was significantly lower in the enoxaparin
group (10.1%) as compared to the heparin group (12.2%).
16 HOW SUPPLIED/STORAGE AND HANDLING
Lovenox is available in two concentrations [see Tables 26 and 27]:
Table 26
100 mg/mL Concentration
Dosage Unit / Strength1
Anti-Xa
Activity2
Package Size
(per carton)
Label Color
NDC #
0075-
Prefilled Syringes3
30 mg/0.3 mL
40 mg/0.4 mL
3000 IU
4000 IU
10 syringes
10 syringes
Medium Blue
Yellow
0624-30
0620-40
Graduated Prefilled
Syringes3
60 mg/0.6 mL
80 mg/0.8 mL
100 mg/1 mL
6000 IU
8000 IU
10,000 IU
10 syringes
10 syringes
10 syringes
Orange
Brown
Black
0621-60
0622-80
0623-00
Multiple-Dose Vial4
300 mg/3 mL
30,000 IU
1 vial
Red
0626-03
1 Strength represents the number of milligrams of enoxaparin sodium in Water for Injection.
Lovenox 30 and 40 mg prefilled syringes, and 60, 80, and 100 mg graduated prefilled syringes
each contain 10 mg enoxaparin sodium per 0.1 mL Water for Injection.
2 Approximate anti-Factor Xa activity based on reference to the W.H.O. First International Low
Molecular Weight Heparin Reference Standard.
3 Each Lovenox prefilled syringe is for single, one-time use only and is affixed with a 27 gauge x
1/2 inch needle.
4 Each Lovenox multiple-dose vial contains 15 mg benzyl alcohol per 1 mL as a preservative.
Page 40 of 42
Reference ID: 2935974
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 27
150 mg/mL Concentration
Dosage Unit / Strength1
Anti-Xa
Activity2
Package Size
(per carton)
Syringe
Label Color
NDC #
0075-
Graduated Prefilled
Syringes3
120 mg / 0.8 mL
150 mg / 1 mL
12,000 IU
15,000 IU
10 syringes
10 syringes
Purple
Navy Blue
2912-01
2915-01
1 Strength represents the number of milligrams of enoxaparin sodium in Water for Injection.
Lovenox 120 and 150 mg graduated prefilled syringes contain 15 mg enoxaparin sodium per
0.1 mL Water for Injection.
2 Approximate anti-Factor Xa activity based on reference to the W.H.O. First International Low
Molecular Weight Heparin Reference Standard.
3 Each Lovenox graduated prefilled syringe is for single, one-time use only and is affixed with a
27 gauge x 1/2 inch needle.
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room
Temperature].
Do not store the multiple-dose vials for more than 28 days after the first use.
Keep out of the reach of children.
17 PATIENT COUNSELING INFORMATION
If patients have had neuraxial anesthesia or spinal puncture, and particularly, if they are taking
concomitant NSAIDs, platelet inhibitors, or other anticoagulants, they should be informed to
watch for signs and symptoms of spinal or epidural hematoma, such as tingling, numbness
(especially in the lower limbs) and muscular weakness. If any of these symptoms occur the
patient should contact his or her physician immediately.
Additionally, the use of aspirin and other NSAIDs may enhance the risk of hemorrhage. Their
use should be discontinued prior to enoxaparin therapy whenever possible; if co-administration is
essential, the patient’s clinical and laboratory status should be closely monitored [see Drug
Interactions (7)].
Patients should also be informed:
• of the instructions for injecting Lovenox if their therapy is to continue after discharge
from the hospitals.
• it may take them longer than usual to stop bleeding.
• they may bruise and/or bleed more easily when they are treated with Lovenox.
Page 41 of 42
Reference ID: 2935974
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For current labeling information, please visit https://www.fda.gov/drugsatfda
• they should report any unusual bleeding, bruising, or signs of thrombocytopenia (such as
a rash of dark red spots under the skin) to their physician [see Warnings and Precautions
(5.1, 5.5)].
• to tell their physicians and dentists they are taking Lovenox and/or any other product
known to affect bleeding before any surgery is scheduled and before any new drug is
taken [see Warnings and Precautions (5.3)].
• to tell their physicians and dentists of all medications they are taking, including those
obtained without a prescription, such as aspirin or other NSAIDs [see Drug Interactions
(7)].
sanofi-aventis U.S. LLC
Bridgewater, NJ 08807
Multiple-dose vials are also manufactured by DSM Pharmaceuticals, Inc.
Greenville, NC 27835
© 2011 sanofi-aventis U.S. LLC
Page 42 of 42
Reference ID: 2935974
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:46:57.854723
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020164s093lbl.pdf', 'application_number': 20164, 'submission_type': 'SUPPL ', 'submission_number': 93}
|
12,291
|
NDA 20-165/S-024
Page 3
Drug Facts panel:
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-165/S-024
Page 4
User’s Guide: (MRI warning appears on pages 5 and 10)
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-165/S-024
Page 5
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:46:57.864563
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/020165s024lbl.pdf', 'application_number': 20165, 'submission_type': 'SUPPL ', 'submission_number': 24}
|
12,292
|
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
rrent labeling information, please visit https://www.fda.gov/drug
So You’ve Decided to Quit ..................3
Where to Get Help.............................4
Let’s Get Organized............................4
What You’re Up Against......................5
Some Important Warnings ..................5
Let’s Get Started..................................6
Directions...........................................7
The NicoDerm CQ Program
Q
...............8
Copyright © 2013 GlaxoSmithKline Consumer Healthcare, L.P.
2
Plan Ahead .........................................9
How the NicoDerm CQ patch Works
Q
Q
..10
How To Use NicoDerm CQ Patches
Q
Q
...11
Tips To Make Quitting Easier.............18
What To Expect .................................20
When the Struggle is Over................22
Questions and Answers ....................22
KEYS TO SUCCESS
1) You must really want to quit smoking for the NicoDerm® CQ ® patch to help you.
2) Complete the full treatment program, applying a new patch every day.
3) The NicoDerm CQ patch works best when used together with a support program.
Q Q
See page 4 for details. To request a free audio CD containing tips to make
quitting easier, call the toll free number listed below.
4) If you have trouble using the NicoDerm CQ patch, ask your doctor or pharmacist
or call GlaxoSmithKline (English/Spanish) at 1-800-834-5895 weekdays
(9:00 a.m. - 4:30 p.m. ET).
Table of Contents
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Quitting Smoking is Hard!
If you fi nd you cannot stop or if you start
smoking again after using the NicoDerm
CQ patch, please talk to a health care
Q
Q
professional who can help you fi nd a
program that may work better for you.
Breaking this addiction doesn’t happen
overnight.
Because the NicoDerm CQ patch provides
some nicotine, the NicoDerm CQ patch
Q
will help you stop smoking by reducing
nicotine withdrawal symptoms such
as nicotine craving, nervousness and
irritability.
This User’s Guide will give you support as
you become a non-smoker. It will answer
common questions about the NicoDerm
CQ patch and give tips to help you stop
Q
Q
smoking, and should be referred to often.
Copyright © 2013 GlaxoSmithKline Consumer Healthcare, L.P.
3
SO, YOU’ve DECIDED TO QUIT.
Congratulations. Your decision to stop
smoking is one of the most important things
you can do to improve your health. Quitting
smoking is a two-part process that involves:
1) overcoming your physical need for
nicotine, and
2) breaking your smoking habit.
The NicoDerm CQ patch helps smokers quit
Q
Q
by
reducing nicotine withdrawal symptoms. Many
NicoDerm CQ patch users will be able to
Q
stop
smoking for a few days but often will start
smoking again. Most smokers have to try to
quit several times before they completely stop.
Your own chances of quitting smoking
depend on how strongly you are addicted
to nicotine, how much you want to quit,
and how closely you follow a quitting plan like
the one that comes with the NicoDerm CQ patch.
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Copyright © 2013 GlaxoSmithKline Consumer Healthcare, L.P.
4
Where to Get Help.
You are more likely to stop smoking by using
the NicoDerm CQ patch with a support program
Q
that helps you break your smoking habit.
There may be support groups in your area for
people trying to quit. Call your local chapter
of the American Lung Association, American
Cancer Society or American Heart
Association for further information. Toll free
phone numbers are printed on the wallet
card on the back cover of this User’s Guide.
If you fi nd you cannot stop smoking or if
you start smoking again after using the
NicoDerm CQ patch, remember breaking
this addiction doesn’t happen overnight.
You may want to talk to a health care
professional who can help you improve your
chances of quitting the next time you try the
NicoDerm CQ patch or another method.
Let’s Get Organized.
Your reason for quitting may be a
combination of concerns about health, the
effect of smoking on your appearance, and
pressure from your family and friends to
stop smoking. Or maybe you’re concerned
about the dangerous effect of second-hand
smoke on the people you care about.
All of these are good reasons. You probably
have others. Decide your most important
reasons, and write them down on the
wallet card inside the back cover of this
User’s Guide. Carry this card with you. In
diffi cult moments, when you want to
smoke, the card will remind you why you
are quitting.
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Copyright © 2013 GlaxoSmithKline Consumer Healthcare, L.P.
5
What You’re Up Against.
Smoking is addictive in two ways. Your need
for nicotine has become both physical and
mental. You must overcome both addictions
to stop smoking. So while the NicoDerm
CQ patch will
Q
lessen your body’s craving for
nicotine, you’ve got to want to quit smoking
to overcome the mental dependence on
cigarettes. Once you’ve decided that you’re
going to quit, it’s time to get started. But
fi rst, there are some important warnings
you should consider.
Some Important WARNINGS.
This product is only for those who want to
stop smoking.
If you are pregnant or breast-feeding, only
use this medicine on the advice of your
health care provider. Smoking can seriously
harm your child. Try to stop smoking without
using any nicotine replacement medicine.
This medicine is believed to be safer than
smoking. However, the risks to your child
from this medicine are not fully known.
Ask a doctor before use if you have
• heart disease, recent heart attack, or
irregular heartbeat. Nicotine can increase
your heart rate.
• high blood pressure not controlled with
medication. Nicotine can increase your
blood pressure.
• an allergy to adhesive tape or have skin
problems because you are more likely to
get rashes.
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6
Ask a doctor or pharmacist before use if you are
• using a non-nicotine stop smoking drug.
• taking a prescription medicine for
depression or asthma. Your prescription
dose may need to be adjusted.
When using this product
• if you have vivid dreams or other sleep
disturbances, remove this patch at bedtime.
• to avoid possible burns, remove the patch
before undergoing any MRI (magnetic
resonance imaging) procedures (for the
opaque NicoDerm CQ patch only).
Q
Stop use and ask a doctor if
• skin redness caused by the patch does not
go away after four days, or if your skin
swells, or you get a rash.
• irregular heartbeat or palpitations occur.
• you get symptoms of nicotine overdose
such as nausea, vomiting, dizziness,
weakness and rapid heartbeat.
Keep out of reach of children and pets.
Used patches have enough nicotine to
poison children and pets. If swallowed, get
medical help or contact a Poison Control
Center right away. Dispose of the used patch
by folding sticky ends together. Replace in
its pouch and discard.
Let’s Get Started.
If you are under 18 years of age, ask a
doctor before use.
Becoming a non-smoker starts today. Your
fi rst step is to read through this entire User’s
Guide carefully.
First, check that you bought the right
starting dose.
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Reference ID: 3498267
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This label may not be the latest approved by FDA.
rrent labeling information, please visit https://www.fda.gov/drug
Copyright © 2013 GlaxoSmithKline Consumer Healthcare, L.P.
9
Directions: For People who smoke 10 or less
p
cigarettes per day.
g
p
y Do not use STEP 1 (21mg).
Begin with STEP 2 – Initial Treatment Period
(Weeks 1-6): 14mg patches.
Choose your quit date (it should be soon).
This is the day you will begin using the
NicoDerm CQ patch to reduce your cravings
Q
Q
for nicotine. Place the Step 2 reminder on
this date. For the fi rst six weeks, you’ll use
the Step 2 (14mg) NicoDerm CQ patches.
Be sure to follow the directions on page 11.
Continue with STEP 3 – Step Down Treat-
ment Period (Weeks 7-8): 7mg patches.
Completing the full program will increase
your chances of quitting successfully. This is
done by changing over to the Step 3
(7mg) patches for 2 weeks. The two week
step down treatment period allows you to
gradually reduce the amount of nicotine
you get, rather than stopping suddenly, and
will increase your chances of quitting.
Place the Step 3 reminder on the fi rst day
of week seven. Use the 7mg patches for
two weeks.
At the end of 8 weeks you will have com-
pleted treatment. If you feel you need to use
NicoDerm CQ patches for longer than
Q
Q
8 weeks to keep from smoking, talk to your
health care provider.
Plan Ahead.
Because smoking is an addiction, it is not
easy to stop. After you’ve given up nicotine,
you may still have a strong urge to smoke.
Plan ahead NOW for these times, so you’re
not tempted to start smoking again in a
moment of weakness. The following tips
may help:
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Reference ID: 3498267
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Copyright © 2013 GlaxoSmithKline Consumer Healthcare, L.P.
11
Because the NicoDerm CQ patch does not
Q
contain the tar or carbon monoxide of ciga-
p
d
f
p
rette smoke, it does not have the same health
g
k
d
h
h
h
l
g
dangers as tobacco. However, it still delivers
nicotine, the addictive part of cigarette smoke.
g
h
dd
f
k
g
Nicotine can cause side effects such as head-
p
g
d
ff
h
h
d
p
g
ache, nausea, upset stomach, and dizziness.
How To Use
Nicoderm CQ Patches.
Q
Read all the following instructions, and the
instructions on the outer carton, before
using the NicoDerm CQ patch. Refer to them of-
ten to make sure you’re using the NicoDerm CQ
patch correctly. Please refer to the compact disc
for additional help.
1) Begin using the NicoDerm CQ patch on
your quit date.
2) To reduce nicotine craving and other with-
drawal symptoms, use the NicoDerm CQ
patch according to the directions
on pages 7-9.
3) Fold sticky ends of a used NicoDerm CQ
patch together. Replace in its pouch and
discard
When to apply and remove NicoDerm CQ
patches.
Each day apply a new patch to a different
place on skin that is dry, clean and hairless.
You can wear a NicoDerm CQ patch for
Q
either 16 or 24 hours. If you crave
cigarettes when you wake up, wear the
patch for 24 hours. If you begin to have
vivid dreams or other disruptions of your
sleep while wearing the patch for 24 hours, try
taking the patch off at bedtime (after about
16 hours) and putting on a new one when
you get up the next day. To avoid possible
burns, remove the patch before undergoing
any MRI (magnetic resonance imaging)
procedures (for the opaque NicoDerm
CQ patch only).
Q
Q
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Reference ID: 3498267
This label may not be the latest approved by FDA.
rrent labeling information, please visit https://www.fda.gov/drug
This label may not be the latest approved by FDA.
rrent labeling information, please visit https://www.fda.gov/drug
This label may not be the latest approved by FDA.
rrent labeling information, please visit https://www.fda.gov/drug
This label may not be the latest approved by FDA.
rrent labeling information, please visit https://www.fda.gov/drug
This label may not be the latest approved by FDA.
rrent labeling information, please visit https://www.fda.gov/drug
This label may not be the latest approved by FDA.
rrent labeling information, please visit https://www.fda.gov/drug
Copyright © 2013 GlaxoSmithKline Consumer Healthcare, L.P.
17
If your NicoDerm CQ patch comes off
Q
Q
while wearing.
NicoDerm CQ patches generally stick well
Q
Q
to most people’s skin. However, a patch
may occasionally come off. If your
NicoDerm CQ patch falls off during the
Q
Q
day, put on a new patch, making sure you
select a non-hairy, non-irritated area of skin
that is clean and dry.
If the soap you use has lanolin or
moisturizers, the patch may not stick well.
Using a different soap may help. Body
creams, lotions and sunscreens can also
cause problems with keeping your patch
on. Do not apply creams or lotions to the
place on your skin where you will put the
patch.
If you have followed the directions and the
patch still does not stick to you, try using
medical adhesive tape over the patch.
Disposing of NicoDerm CQ patches.
Q
Fold the used patch in half by folding the
sticky ends together. Replace in its pouch.
Discard where it will be out of the reach of
children and pets. Small amounts of nico-
tine, even from a used patch, can poison
children and pets. Keep all nicotine
patches away from children and pets.
Wash your hands after disposing of the
patch.
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• Drink large quantities of water and fruit
juices.
• Try to avoid alcohol, coffee and other
beverages you associate with smoking.
• Remember that temporary urges to
smoke will pass, even if you don’t smoke
a cigarette.
• Keep your hands busy with something
like a pencil or a paper clip.
• Find other activities that help you relax
without cigarettes. Swim, jog, take a
walk, play basketball.
• Don’t worry too much about gaining
weight. Watch what you eat, take time
for daily exercise, and change your eat-
ing habits if you need to.
• Laughter helps. Watch or read
something funny.
Copyright © 2013 GlaxoSmithKline Consumer Healthcare, L.P.
19
• Throw away all your cigarettes, matches,
lighters, ashtrays, etc.
• Keep busy on your quit day. Exercise.
Go to a movie. Take a walk. Get together
with friends.
• Figure out how much money you’ll save
by not smoking. Most ex-smokers can
save more than $1,000 a year on the
price of cigarettes alone.
• Write down what you will do with the
money you save.
• Know your high risk situations and plan
ahead how you will deal with them.
• Visit your dentist and have your teeth
cleaned to get rid of the tobacco stains
Right after Quitting:
• During the fi rst few days after you’ve
stopped smoking, spend as much time as
g
y
y
d
ki
d
h i
g
y
y
possible at places where smoking is
pp
g, p
ibl
l
h
ki
i
pp
g, p
not allowed.
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Reference ID: 3498267
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To request a free audio CD containing
additional tips to help make quitting easier
call 1-800-834-5895. (ONE CD PER
CUSTOMER)
What to Expect.
The First Few Days.
Your body is now coming back into
balance. During the fi rst few days after you
stop smoking, you might feel edgy and
nervous and have trouble concentrating.
You might get headaches, feel dizzy and a
little out of sorts, feel sweaty or have stom-
ach upsets. You might even have trouble
sleeping at fi rst. These are typical nicotine
withdrawal symptoms that will go away
with time. Your smoker’s cough will get
worse before it gets better. But don’t worry,
that’s a good sign. Coughing helps clear the
tar deposits out of your lungs.
After A Week Or Two.
By now you should be feeling more
confi dent that you can handle those
smoking urges. Many of your nicotine
withdrawal symptoms have left by now,
and you should be noticing some positive
signs: less coughing, better breathing and
an improved sense of taste and smell, to
name a few.
After A Month.
You probably have the urge to smoke much
less often now. But urges may still occur,
and when they do, they are likely to be
powerful ones that come out of nowhere.
Don’t let them catch you off guard. Plan
ahead for these diffi cult times.
Copyright © 2013 GlaxoSmithKline Consumer Healthcare, L.P.
20
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Copyright © 2013 GlaxoSmithKline Consumer Healthcare, L.P.
21
Concentrate on the ways non-smokers are
more attractive than smokers. Their skin is
less likely to wrinkle. Their teeth are whiter,
cleaner. Their breath is fresher. Their hair
and clothes smell better. That cough that
seems to make even a laugh sound more
like a rattle is a thing of the past. Their
children and others around them are
healthier, too.
What To Do About Relapse.
What should you do if you slip and start
smoking again? The answer is simple. A
lapse of one or two or even a few cigarettes
should not spoil your efforts! Throw away
your cigarettes, forgive yourself and
continue with the program. Listen to the
Compact Disc again and re-read the User’s
Guide to ensure that you’re using the
NicoDerm CQ patch correctly and follow-
Q
Q
ing the other important tips for dealing
with the mental and social dependence on
nicotine. Your doctor, pharmacist or other
health professional can also provide
useful counseling on the importance of
stopping smoking. You should consider
them partners in your quit attempt.
What To Do About Relapse After a
Successful Quit Attempt.
If you have taken up regular smoking
again, don’t be discouraged. Research
shows that the best thing you can do is try
again, since several quitting attempts may
be needed before you’re successful. And
your chances of quitting successfully
increase with each quit attempt.
The important thing is to learn from your
last attempt.
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Reference ID: 3498267
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• Admit that you’ve slipped, but don’t treat
yourself as a failure.
• Try to identify the “trigger” that caused
you to slip, and prepare a better plan for
dealing with this problem next time.
• Talk positively to yourself – tell yourself
that you have learned something from
this experience.
• Make sure you used NicoDerm CQ
patches correctly.
• Remember that it takes practice to do
anything, and quitting smoking is no
exception.
When the Struggle Is Over.
Once you’ve stopped smoking, take a
second and pat yourself on your back.
Now do it again. You deserve it.
Remember now why you decided to stop
smoking in the fi rst place. Look at your list of
reasons. Read them again. And smile.
Now think about all the money you are
saving and what you’ll do with it. All the non-
smoking places you can go, and what you
might do there. All those years you may have
added to your life, and what you’ll do with
them. Remember that temptation may not be
gone forever. However, the hard part is behind
you so look forward with a positive attitude,
and enjoy your new life as a non-smoker.
Questions & Answers.
1. How will I feel when I stop smoking
and start using the NicoDerm CQ patch?
You’ll need to prepare yourself for some
nicotine withdrawal symptoms. These begin
almost immediately after you stop
Copyright © 2013 GlaxoSmithKline Consumer Healthcare, L.P.
22
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Copyright © 2013 GlaxoSmithKline Consumer Healthcare, L.P.
23
smoking, and are usually at their worst
during the fi rst three or four days.
Understand that any of the following is
possible:
• craving for nicotine
• anxiety, irritability, restlessness, mood
changes, nervousness
• disruptions of your sleep
• drowsiness
• trouble concentrating
• increased appetite and weight gain
• headaches, muscular pain, constipation,
fatigue.
The NicoDerm CQ patch reduces nicotine
Q
withdrawal symptoms such as irritability
and nervousness, as well as the craving
for nicotine you used to satisfy by having
a cigarette.
2. Is the NicoDerm CQ patch just substi-
Q
Q
tuting one form of nicotine for another?
The NicoDerm CQ patch does contain nicotine.
Q
The purpose of the NicoDerm CQ patch is
Q
Q
to provide you with enough nicotine to
reduce the physical withdrawal symptoms
so you can deal with the mental aspects
of quitting.
3. Can I be hurt by using the NicoDerm
CQ patch?
For most adults, the amount of nicotine
delivered from the patch is less than from
smoking. If you believe you may be
sensitive to even this amount of nicotine,
you should not use this product without
advice from your doctor. There are also
some important warnings in this User’s
Guide (See page 5).
99711 NRD CQ UGuide_R4 indd 23
4/19/13 10 01 A
Reference ID: 3498267
This label may not be the latest approved by FDA.
rrent labeling information, please visit https://www.fda.gov/drug
4. Will I gain weight?
Many people do tend to gain a few pounds
the fi rst 8-10 weeks after they stop
smoking. This is a very small price to pay
for the enormous gains that you will make
in your overall health and attractiveness. If
you continue to gain weight after the fi rst
two months, try to analyze what you’re
doing differently. Reduce your fat intake,
choose healthy snacks, and increase your
physical activity to burn off the extra
calories. Drink lots of water. This is good
for your body and skin, and also helps to
reduce the amount you eat.
5. Is the NicoDerm CQ patch more
Q
Q
expensive than smoking?
The total cost of the NicoDerm CQ program
is similar to what a person who smokes
one pack of cigarettes a day would spend
on cigarettes for the same period of time.
Also, use of the NicoDerm CQ patch is
Q
only a short-term cost, while the cost of
smoking is a long-term cost, including
the health problems smoking causes.
6. What if I slip up?
Discard your cigarettes, forgive yourself
and then get back on track. Don’t consider
yourself a failure or punish yourself. In fact,
people who have already tried to quit are
more likely to be successful the next time.
Good Luck!
Copyright © 2013 GlaxoSmithKline Consumer Healthcare, L.P.
24
00000000
99711 NRD CQ UGuide_R4 indd 24
4/19/13 10 01 A
Reference ID: 3498267
This label may not be the latest approved by FDA.
rrent labeling information, please visit https://www.fda.gov/drug
99711 NRD CQ UGuide_R4 indd 25
4/19/13 10 01 A
Reference ID: 3498267
This label may not be the latest approved by FDA.
rrent labeling information, please visit https://www.fda.gov/drug
This label may not be the latest approved by FDA.
rrent labeling information, please visit https://www.fda.gov/drug
This label may not be the latest approved by FDA.
rrent labeling information, please visit https://www.fda.gov/drug
This label may not be the latest approved by FDA.
rrent labeling information, please visit https://www.fda.gov/drug
---------------------------------------------------------------------------------------------------------
This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic
signature.
---------------------------------------------------------------------------------------------------------
/s/
----------------------------------------------------
THERESA M MICHELE
04/30/2014
Reference ID: 3498267
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:46:58.122084
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/020165Orig1s029lbl.pdf', 'application_number': 20165, 'submission_type': 'SUPPL ', 'submission_number': 29}
|
12,293
|
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
So You’ve Decided to Quit ..................3
Where to Get Help .............................4
Let’s Get Organized ............................4
What You’re Up Against ......................5
Some Important Warnings ..................5
Let’s Get Started ..................................6
Directions ...........................................7
The NicoDerm CQ Program
Q
...............8
2
Plan Ahead .........................................9
How the NicoDerm CQ patch Works
Q
..10
How To Use NicoDerm CQ Patches
Q
..11
Tips To Make Quitting Easier .............18
What To Expect .................................20
When the Struggle is Over ................22
Questions and Answers ....................22
KEYS TO SUCCESS
1) You must really want to quit smoking for the NicoDerm® CQ ® patch to help you.
2) Complete the full treatment program, applying a new patch every day.
3) The NicoDerm CQ patch works best when used together with a support program.
Q
See page 4 for details.
4) If you have trouble using the NicoDerm CQ patch, ask your doctor or pharmacist
or call GlaxoSmithKline (English/Spanish) at 1-800-834-5895 weekdays
(9:00 a.m. - 4:30 p.m. ET).
Table of Contents
Reference ID: 3696712
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Quitting Smoking is Hard!
If you fi nd you cannot stop or if you start
smoking again after using the NicoDerm
CQ patch, please talk to a health care
Q
professional who can help you fi nd a
program that may work better for you.
Breaking this addiction doesn’t happen
overnight.
Because the NicoDerm CQ patch provides
some nicotine, the NicoDerm CQ patch
Q
will help you stop smoking by reducing
nicotine withdrawal symptoms such
as nicotine craving, nervousness and
irritability.
This User’s Guide will give you support as
you become a non-smoker. It will answer
common questions about the NicoDerm
CQ patch and give tips to help you stop
Q
smoking, and should be referred to often.
3
SO, YOU’ve DECIDED TO QUIT.
Congratulations. Your decision to stop
smoking is one of the most important things
you can do to improve your health. Quitting
smoking is a two-part process that involves:
1) overcoming your physical need for
nicotine, and
2) breaking your smoking habit.
The NicoDerm CQ patch helps smokers quit
Q
by
reducing nicotine withdrawal symptoms. Many
NicoDerm CQ patch users will be able to
Q
stop smoking for a few days but often will start
smoking again. Most smokers have to try to
quit several times before they completely stop.
Your own chances of quitting smoking
depend on how strongly you are addicted
to nicotine, how much you want to quit,
and how closely you follow a quitting plan like
the one that comes with the NicoDerm CQ patch.
Reference ID: 3696712
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
4
Where to Get Help.
You are more likely to stop smoking by using
the NicoDerm CQ patch with a support program
Q
that helps you break your smoking habit.
There may be support groups in your area for
people trying to quit. Call your local chapter
of the American Lung Association, American
Cancer Society or American Heart
Association for further information. Toll free
phone numbers are printed on the wallet
card on the back cover of this User’s Guide.
If you fi nd you cannot stop smoking or if
you start smoking again after using the
NicoDerm CQ patch, remember breaking
this addiction doesn’t happen overnight.
You may want to talk to a health care
professional who can help you improve your
chances of quitting the next time you try the
NicoDerm CQ patch or another method.
Let’s Get Organized.
Your reason for quitting may be a
combination of concerns about health, the
effect of smoking on your appearance, and
pressure from your family and friends to
stop smoking. Or maybe you’re concerned
about the dangerous effect of second-hand
smoke on the people you care about.
All of these are good reasons. You probably
have others. Decide your most important
reasons, and write them down on the
wallet card inside the back cover of this
User’s Guide. Carry this card with you. In
diffi cult moments, when you want to
smoke, the card will remind you why you
are quitting.
Reference ID: 3696712
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5
What You’re Up Against.
Smoking is addictive in two ways. Your need
for nicotine has become both physical and
mental. You must overcome both addictions
to stop smoking. So while the NicoDerm
CQ patch will
Q
lessen your body’s craving for
nicotine, you’ve got to want to quit smoking
to overcome the mental dependence on
cigarettes. Once you’ve decided that you’re
going to quit, it’s time to get started. But
fi rst, there are some important warnings
you should consider.
Some Important WARNINGS.
This product is only for those who want to
stop smoking.
If you are pregnant or breast-feeding, only
use this medicine on the advice of your
health care provider. Smoking can seriously
harm your child. Try to stop smoking without
using any nicotine replacement medicine.
This medicine is believed to be safer than
smoking. However, the risks to your child
from this medicine are not fully known.
Ask a doctor before use if you have
• heart disease, recent heart attack, or
irregular heartbeat. Nicotine can increase
your heart rate.
• high blood pressure not controlled with
medication. Nicotine can increase your
blood pressure.
• an allergy to adhesive tape or have skin
problems because you are more likely to
get rashes.
Reference ID: 3696712
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
6
Ask a doctor or pharmacist before use if you are
• using a non-nicotine stop smoking drug.
• taking a prescription medicine for
depression or asthma. Your prescription
dose may need to be adjusted.
When using this product
• if you have vivid dreams or other sleep
disturbances, remove this patch at bedtime.
• to avoid possible burns, remove the patch
before undergoing any MRI (magnetic
resonance imaging) procedures (for the
opaque NicoDerm CQ patch only).
Q
Stop use and ask a doctor if
• skin redness caused by the patch does not
go away after four days, or if your skin
swells, or you get a rash.
• irregular heartbeat or palpitations occur.
• you get symptoms of nicotine overdose
such as nausea, vomiting, dizziness,
weakness and rapid heartbeat.
Keep out of reach of children and pets.
Used patches have enough nicotine to
poison children and pets. If swallowed, get
medical help or contact a Poison Control
Center right away. Dispose of the used patch
by folding sticky ends together. Replace in
its pouch and discard.
Let’s Get Started.
If you are under 18 years of age, ask a
doctor before use.
Becoming a non-smoker starts today. Your
fi rst step is to read through this entire User’s
Guide carefully.
First, check that you bought the right
starting dose.
Reference ID: 3696712
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
9
Directions: For People who smoke 10 or less
p
ci arettes er da .
g
p
y Do not use STEP 1 (21 mg).
Begin with STEP 2 – Initial Treatment Period
(Weeks 1-6): 14 mg patches.
Choose your quit date (it should be soon).
This is the day you will begin using the
NicoDerm CQ patch to reduce your cravings
Q
for nicotine. Place the Step 2 reminder on
this date. For the fi rst six weeks, you’ll use
the Step 2 (14 mg) NicoDerm CQ patches.
Be sure to follow the directions on page 11.
Continue with STEP 3 – Step Down
Treatment Period (Weeks 7-8):
7 mg patches.
Completing the full program will increase
your chances of quitting successfully. This is
done by changing over to the Step 3
(7 mg) patches for 2 weeks. The two week
step down treatment period allows you to
gradually reduce the amount of nicotine
you get, rather than stopping suddenly, and
will increase your chances of quitting.
Place the Step 3 reminder on the fi rst day
of week seven. Use the 7 mg patches for
two weeks.
At the end of 8 weeks you will have
completed treatment. If you feel you need to
use NicoDerm CQ patches for longer than
Q
8 weeks to keep from smoking, talk to your
health care provider.
Plan Ahead.
Because smoking is an addiction, it is not
easy to stop. After you’ve given up nicotine,
you may still have a strong urge to smoke.
Plan ahead NOW for these times, so you’re
not tempted to start smoking again in a
moment of weakness. The following tips
may help:
Reference ID: 3696712
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
11
Because the NicoDerm CQ patch does not
Q
contain the tar or carbon monoxide of
p
cigarette smoke, it does not have the same
health dangers as tobacco. However, it still
g
delivers nicotine, the addictive part of
g
cigarette smoke. Nicotine can cause side
p
effects such as headache, nausea, upset
g
stomach, and dizziness.
How To Use
Nicoder
®
m CQ® Patches.
®
Read all the following instructions, and the
instructions on the outer carton, before
using the NicoDerm CQ patch. Refer to them
often to make sure you’re using the NicoDerm
CQ patch correctly.
1) Begin using the NicoDerm CQ patch on
your quit date.
2) To reduce nicotine craving and other
withdrawal symptoms, use the NicoDerm
CQ patch according to the directions
on pages 7-9.
3) Fold sticky ends of a used NicoDerm CQ
patch together. Replace in its pouch and
discard
When to apply and remove NicoDerm CQ
patches.
Each day apply a new patch to a different
place on skin that is dry, clean and hairless.
You can wear a NicoDerm CQ patch for
Q
either 16 or 24 hours. If you crave
cigarettes when you wake up, wear the
patch for 24 hours. If you begin to have
vivid dreams or other disruptions of your
sleep while wearing the patch for 24 hours, try
taking the patch off at bedtime (after about
16 hours) and putting on a new one when
you get up the next day. To avoid possible
burns, remove the patch before undergoing
any MRI (magnetic resonance imaging)
procedures (for the opaque NicoDerm
CQ patch only).
Q
Reference ID: 3696712
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
17
If your NicoDerm® CQ ® patch com
®
es
off while wearing.
NicoDerm CQ patches generally stick well
Q
to most people’s skin. However, a patch
may occasionally come off. If your
NicoDerm CQ patch falls off during the
Q
day, put on a new patch, making sure you
select a non-hairy, non-irritated area of skin
that is clean and dry.
If the soap you use has lanolin or
moisturizers, the patch may not stick well.
Using a different soap may help. Body
creams, lotions and sunscreens can also
cause problems with keeping your patch
on. Do not apply creams or lotions to the
place on your skin where you will put
the patch.
If you have followed the directions and the
patch still does not stick to you, try using
medical adhesive tape over the patch.
Disposing of NicoDerm® CQ ® patches.
®
Fold the used patch in half by folding the
sticky ends together. Replace in its pouch.
Discard where it will be out of the reach of
children and pets. Small amounts of
nicotine, even from a used patch, can
poison children and pets. Keep all
nicotine patches away from children
and pets. Wash your hands after
disposing of the patch.
Reference ID: 3696712
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• Drink large quantities of water and fruit
juices.
• Try to avoid alcohol, coffee and other
beverages you associate with smoking.
• Remember that temporary urges to
smoke will pass, even if you don’t smoke
a cigarette.
• Keep your hands busy with something
like a pencil or a paper clip.
• Find other activities that help you relax
without cigarettes. Swim, jog, take a
walk, play basketball.
• Don’t worry too much about gaining
weight. Watch what you eat, take time
for daily exercise, and change your
eating habits if you need to.
• Laughter helps. Watch or read
something funny.
19
• Throw away all your cigarettes, matches,
lighters, ashtrays, etc.
• Keep busy on your quit day. Exercise.
Go to a movie. Take a walk. Get together
with friends.
• Figure out how much money you’ll save
by not smoking. Most ex-smokers can
save more than $1,000 a year on the
price of cigarettes alone.
• Write down what you will do with the
money you save.
• Know your high risk situations and plan
ahead how you will deal with them.
• Visit your dentist and have your teeth
cleaned to get rid of the tobacco stains
Right after Quitting:
• Durin the fi rst few da s after ou’ve
stop ed smokin s end as much time as
g
y
y
possible at places where smoking is
pp
g, p
not allowed.
Reference ID: 3696712
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
What to Expect.
The First Few Days.
Your body is now coming back into
balance. During the fi rst few days after you
stop smoking, you might feel edgy and
nervous and have trouble concentrating.
You might get headaches, feel dizzy and a
little out of sorts, feel sweaty or have
stomach upsets. You might even have
trouble sleeping at fi rst. These are typical
nicotine withdrawal symptoms that will
go away with time. Your smoker’s cough
will get worse before it gets better. But
don’t worry, that’s a good sign. Coughing
helps clear the tar deposits out of
your lungs.
After A Week Or Two.
By now you should be feeling more
confi dent that you can handle those
smoking urges. Many of your nicotine
withdrawal symptoms have left by now,
and you should be noticing some positive
signs: less coughing, better breathing and
an improved sense of taste and smell, to
name a few.
After A Month.
You probably have the urge to smoke much
less often now. But urges may still occur,
and when they do, they are likely to be
powerful ones that come out of nowhere.
Don’t let them catch you off guard. Plan
ahead for these diffi cult times.
20
Reference ID: 3696712
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
21
Concentrate on the ways non-smokers are
more attractive than smokers. Their skin is
less likely to wrinkle. Their teeth are whiter,
cleaner. Their breath is fresher. Their hair
and clothes smell better. That cough that
seems to make even a laugh sound more
ike a rattle is a thing of the past. Their
children and others around them are
healthier, too.
What To Do About Relapse.
What should you do if you slip and start
smoking again? The answer is simple. A
lapse of one or two or even a few cigarettes
should not spoil your efforts! Throw away
your cigarettes, forgive yourself and
continue with the program. Re-read
the User’s Guide to ensure that you’re
using the NicoDerm CQ patch correctly
Q
and following the other important tips
for dealing with the mental and social
dependence on nicotine. Your doctor,
pharmacist or other health professional
can also provide useful counseling on
the importance of stopping smoking. You
should consider them partners in your
quit attempt.
What To Do About Relapse After a
Successful Quit Attempt.
If you have taken up regular smoking
again, don’t be discouraged. Research
shows that the best thing you can do is try
again, since several quitting attempts may
be needed before you’re successful. And
your chances of quitting successfully
increase with each quit attempt.
The important thing is to learn from your
last attempt.
Reference ID: 3696712
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• Admit that you’ve slipped, but don’t treat
yourself as a failure.
• Try to identify the “trigger” that caused
you to slip, and prepare a better plan for
dealing with this problem next time.
• Talk positively to yourself – tell yourself
that you have learned something from
this experience.
• Make sure you used NicoDerm CQ
patches correctly.
• Remember that it takes practice to do
anything, and quitting smoking is no
exception.
When the Struggle Is Over.
Once you’ve stopped smoking, take a
second and pat yourself on your back.
Now do it again. You deserve it.
Remember now why you decided to stop
smoking in the fi rst place. Look at your list of
reasons. Read them again. And smile.
Now think about all the money you are
saving and what you’ll do with it. All the
non-smoking places you can go, and what
you might do there. All those years you may
have added to your life, and what you’ll
do with them. Remember that temptation
may not be gone forever. However, the hard
part is behind you so look forward with a
positive attitude, and enjoy your new life as
a non-smoker.
Questions & Answers.
1. How will I feel when I stop smoking
and start using the NicoDerm CQ patch?
You’ll need to prepare yourself for some
nicotine withdrawal symptoms. These begin
almost immediately after you stop
22
Reference ID: 3696712
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
23
smoking, and are usually at their worst
during the fi rst three or four days.
Understand that any of the following is
possible:
• craving for nicotine
• anxiety, irritability, restlessness, mood
changes, nervousness
• disruptions of your sleep
• drowsiness
• trouble concentrating
• increased appetite and weight gain
• headaches, muscular pain, constipation,
fatigue.
The NicoDerm CQ patch reduces nicotine
withdrawal symptoms such as irritability
and nervousness, as well as the craving
for nicotine you used to satisfy by having
a cigarette.
2. Is the NicoDerm® CQ ® patch just
®
substituting one form of nicotine
for another?
The NicoDerm CQ patch does contain nicotine.
Q
The purpose of the NicoDerm CQ patch
Q
is to provide you with enough nicotine to
reduce the physical withdrawal symptoms
so you can deal with the mental aspects
of quitting.
3. Can I be hurt by using the
NicoDerm® CQ ® patch?
For most adults, the amount of nicotine
delivered from the patch is less than from
smoking. If you believe you may be
sensitive to even this amount of nicotine,
you should not use this product without
advice from your doctor. There are also
some important warnings in this User’s
Guide (See page 5).
Reference ID: 3696712
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
4. Will I gain weight?
Many people do tend to gain a few pounds
the fi rst 8-10 weeks after they stop
smoking. This is a very small price to pay
for the enormous gains that you will make
in your overall health and attractiveness. If
you continue to gain weight after the fi rst
two months, try to analyze what you’re
doing differently. Reduce your fat intake,
choose healthy snacks, and increase your
physical activity to burn off the extra
calories. Drink lots of water. This is good
for your body and skin, and also helps to
reduce the amount you eat.
5. Is the NicoDerm® CQ ® patch more
®
expensive than smoking?
The total cost of the NicoDerm CQ
program is similar to what a person
who smokes one pack of cigarettes a
day would spend on cigarettes for the
same period of time. Also, use of the
NicoDerm CQ patch is only a short-term
Q
cost, while the cost of smoking is a long-
term cost, including the health problems
smoking causes.
6. What if I slip up?
Discard your cigarettes, forgive yourself
and then get back on track. Don’t consider
yourself a failure or punish yourself. In fact,
people who have already tried to quit are
more likely to be successful the next time.
Good Luck!
24
60466XD
Reference ID: 3696712
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
---------------------------------------------------------------------------------------------------------
This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic
signature.
---------------------------------------------------------------------------------------------------------
/s/
----------------------------------------------------
THERESA M MICHELE
02/03/2015
Reference ID: 3696712
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:46:58.349071
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020165Orig1s034lbl.pdf', 'application_number': 20165, 'submission_type': 'SUPPL ', 'submission_number': 34}
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12,295
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This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
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This label may not be the latest approved by FDA.
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This label may not be the latest approved by FDA.
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This label may not be the latest approved by FDA.
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This label may not be the latest approved by FDA.
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This label may not be the latest approved by FDA.
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This label may not be the latest approved by FDA.
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This label may not be the latest approved by FDA.
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---------------------------------------------------------------------------------------------------------
This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic
signature.
---------------------------------------------------------------------------------------------------------
/s/
----------------------------------------------------
VALERIE S PRATT
05/04/2016
Reference ID: 3926669
(
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custom-source
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2025-02-12T13:46:58.494833
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/20165Orig1s038lbl.pdf', 'application_number': 20165, 'submission_type': 'SUPPL ', 'submission_number': 38}
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12,294
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Reference ID: 3829782
Reference ID: 3830548
(b) (4)
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Reference ID: 3829782
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Reference ID: 3829782
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(b) (4)
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©2015 GSK group of companies.
All Rights Reserved.
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So You’ve Decided to Quit ..................3
Where to Get Help .............................4
Let’s Get Organized ............................4
What You’re Up Against ......................5
Some Important Warnings ..................5
Let’s Get Started ..................................6
Directions ...........................................7
The NicoDerm CQ Program ...............8
2
Plan Ahead .........................................9
How the NicoDerm CQ patch Works ..10
How To Use NicoDerm CQ Patches ..11
Tips To Make Quitting Easier .............18
What To Expect .................................20
When the Struggle is Over ................22
Questions and Answers ....................22
KEYS TO SUCCESS
1) You must really want to quit smoking for the NicoDerm® CQ ® patch to help you.
2) Complete the full treatment program, applying a new patch every day.
3) The NicoDerm CQ patch works best when used together with a support program.
See page 4 for details.
4) If you have trouble using the NicoDerm CQ patch, ask your doctor or pharmacist
or call GlaxoSmithKline (English/Spanish) at 1-800-834-5895 weekdays
(9:00 a.m. - 4:30 p.m. ET).
Table of Contents
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Quitting Smoking is Hard!
If you fi nd you cannot stop or if you start
smoking again after using the NicoDerm
CQ patch, please talk to a health care
professional who can help you fi nd a
program that may work better for you.
Breaking this addiction doesn’t happen
overnight.
Because the NicoDerm CQ patch provides
some nicotine, the NicoDerm CQ patch
will help you stop smoking by reducing
nicotine withdrawal symptoms such
as nicotine craving, nervousness and
irritability.
This User’s Guide will give you support as
you become a non-smoker. It will answer
common questions about the NicoDerm
CQ patch and give tips to help you stop
smoking, and should be referred to often.
3
SO, YOU’ve DECIDED TO QUIT.
Congratulations. Your decision to stop
smoking is one of the most important things
you can do to improve your health. Quitting
smoking is a two-part process that involves:
1) overcoming your physical need for
nicotine, and
2) breaking your smoking habit.
The NicoDerm CQ patch helps smokers quit by
reducing nicotine withdrawal symptoms. Many
NicoDerm CQ patch users will be able to
stop smoking for a few days but often will start
smoking again. Most smokers have to try to
quit several times before they completely stop.
Your own chances of quitting smoking
depend on how strongly you are addicted
to nicotine, how much you want to quit,
and how closely you follow a quitting plan like
the one that comes with the NicoDerm CQ patch.
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4
Where to Get Help.
You are more likely to stop smoking by using
the NicoDerm CQ patch with a support program
that helps you break your smoking habit.
There may be support groups in your area for
people trying to quit. Call your local chapter
of the American Lung Association, American
Cancer Society or American Heart
Association for further information. Toll free
phone numbers are printed on the wallet
card on the back cover of this User’s Guide.
If you fi nd you cannot stop smoking or if
you start smoking again after using the
NicoDerm CQ patch, remember breaking
this addiction doesn’t happen overnight.
You may want to talk to a health care
professional who can help you improve your
chances of quitting the next time you try the
NicoDerm CQ patch or another method.
Let’s Get Organized.
Your reason for quitting may be a
combination of concerns about health, the
effect of smoking on your appearance, and
pressure from your family and friends to
stop smoking. Or maybe you’re concerned
about the dangerous effect of second-hand
smoke on the people you care about.
All of these are good reasons. You probably
have others. Decide your most important
reasons, and write them down on the
wallet card inside the back cover of this
User’s Guide. Carry this card with you. In
diffi cult moments, when you want to
smoke, the card will remind you why you
are quitting.
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5
What You’re Up Against.
Smoking is addictive in two ways. Your need
for nicotine has become both physical and
mental. You must overcome both addictions
to stop smoking. So while the NicoDerm
CQ patch will lessen your body’s craving for
nicotine, you’ve got to want to quit smoking
to overcome the mental dependence on
cigarettes. Once you’ve decided that you’re
going to quit, it’s time to get started. But
fi rst, there are some important warnings
you should consider.
Some Important WARNINGS.
This product is only for those who want to
stop smoking.
If you are pregnant or breast-feeding, only
use this medicine on the advice of your
health care provider. Smoking can seriously
harm your child. Try to stop smoking without
using any nicotine replacement medicine.
This medicine is believed to be safer than
smoking. However, the risks to your child
from this medicine are not fully known.
Ask a doctor before use if you have
• heart disease, recent heart attack, or
irregular heartbeat. Nicotine can increase
your heart rate.
• high blood pressure not controlled with
medication. Nicotine can increase your
blood pressure.
• an allergy to adhesive tape or have skin
problems because you are more likely to
get rashes.
• diabetes
• history of seizures
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6
Ask a doctor or pharmacist before use if you are
• using a non-nicotine stop smoking drug.
• taking a prescription medicine for
depression or asthma. Your prescription
dose may need to be adjusted.
When using this product
• if you have vivid dreams or other sleep
disturbances, remove this patch at bedtime.
• to avoid possible burns, remove the patch
before undergoing any MRI (magnetic
resonance imaging) procedures (for the
opaque NicoDerm CQ patch only).
Stop use and ask a doctor if
• skin redness caused by the patch does not
go away after four days, or if your skin
swells, or you get a rash.
• irregular heartbeat or palpitations occur.
• you get symptoms of nicotine overdose
such as nausea, vomiting, dizziness,
weakness and rapid heartbeat.
• you have symptoms of an allergic
reaction (such as diffi culty breathing
or rash)
Keep out of reach of children and pets.
Used patches have enough nicotine to
poison children and pets. If swallowed, get
medical help or contact a Poison Control
Center right away. Dispose of the used patch
by folding sticky ends together. Replace in
its pouch and discard.
Let’s Get Started.
If you are under 18 years of age, ask a
doctor before use.
Becoming a non-smoker starts today. Your
fi rst step is to read through this entire User’s
Guide carefully.
First, check that you bought the right
starting dose.
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7
If you smoke more than 10 cigarettes per
day, begin with Step 1 (21 mg). As the
carton indicates, people who smoke 10 or
less cigarettes per day should not use Step
1 (21 mg). They should start with Step 2 (14
mg). Throughout this User’s Guide we will
give specifi c instructions for people who
smoke 10 or less cigarettes per day.
Next, set your personalized quitting
schedule.
Take out a calendar that you can use to
track your progress. Pick a quit date, and
mark this on your calendar using the
reminders on the last page of this User’s
Guide, as described
below.
Directions: For People
who smoke more than
10 cigarettes per day:
STEP 1 (Weeks 1-6). Your quit date (and the
day you’ll start using the NicoDerm CQ Patch).
Choose your quit date (it should be soon).
This is the day you will begin using the
NicoDerm CQ patch to reduce your
cravings for nicotine. Place the Step 1
reminder on this date. For the fi rst six
weeks, you’ll use the highest-strength
(21 mg) NicoDerm CQ patches. Be sure to
follow the directions on page 11.
Completing the full program will increase
your chances of quitting successfully. This
is done by changing over to the Step 2 (14
mg) patch for 2 weeks followed by a fi nal 2
weeks with the Step 3 (7 mg) patch. The Step
2 and Step 3 treatment period allows you to
gradually reduce the amount of nicotine
you get, rather than stopping suddenly, and
will increase your chances of quitting.
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STEP 2 (Weeks 7-8). The day you’ll start reducing your use of the NicoDerm CQ patch.
Switching to Step 2 (14 mg) patches after 6 weeks begins to gradually reduce your
nicotine usage. Place the Step 2 reminder on this date (the fi rst day of week seven). Use
the 14 mg patches for two weeks.
STEP 3 (Weeks 9-10). The day you’ll further start reducing your use of the NicoDerm CQ patch.
After eight weeks, nicotine intake is further reduced by moving down to Step 3 (7 mg)
patches. Place the Step 3 reminder on this date (the fi rst day of week nine). Use the
7 mg patches for two weeks.
IT IS IMPORTANT TO COMPLETE TREATMENT
If you still feel the need to use the NicoDerm CQ patch after Week 10,
talk with your health care provider.
8
THE nicoderm® cq ® PROGRAM
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9
Directions: For People who smoke 10 or less
cigarettes per day. Do not use STEP 1 (21 mg).
Begin with STEP 2 – Initial Treatment Period
(Weeks 1-6): 14 mg patches.
Choose your quit date (it should be soon).
This is the day you will begin using the
NicoDerm CQ patch to reduce your cravings
for nicotine. Place the Step 2 reminder on
this date. For the fi rst six weeks, you’ll use
the Step 2 (14 mg) NicoDerm CQ patches.
Be sure to follow the directions on page 11.
Continue with STEP 3 – Step Down
Treatment Period (Weeks 7-8):
7 mg patches.
Completing the full program will increase
your chances of quitting successfully. This is
done by changing over to the Step 3
(7 mg) patches for 2 weeks. The two week
step down treatment period allows you to
gradually reduce the amount of nicotine
you get, rather than stopping suddenly, and
will increase your chances of quitting.
Place the Step 3 reminder on the fi rst day
of week seven. Use the 7 mg patches for
two weeks.
At the end of 8 weeks you will have
completed treatment. If you feel you need to
use NicoDerm CQ patches for longer than
8 weeks to keep from smoking, talk to your
health care provider.
Plan Ahead.
Because smoking is an addiction, it is not
easy to stop. After you’ve given up nicotine,
you may still have a strong urge to smoke.
Plan ahead NOW for these times, so you’re
not tempted to start smoking again in a
moment of weakness. The following tips
may help:
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10
• Keep the phone numbers of supportive
friends and family members handy.
• Keep a record of your quitting process.
In the event that you slip, immediately
stop smoking and resume your quit
attempt by using the NicoDerm CQ
patch. If you smoke at all, write down
what you think caused the slip.
• Put together an Emergency Kit that
includes items that will help take your
mind off occasional urges to smoke. You
might include cinnamon gum or lemon
drops to suck on, relaxing music, and
something for your hands to play with,
like a smooth rock, rubber band, or
small metal balls.
• Set aside some small rewards, like a
new magazine or a gift certifi cate from
your favorite store, which you’ll “give”
yourself after passing diffi cult hurdles.
• Think now about the times when you
most often want a cigarette, and then
plan what else you might do instead of
smoking. For instance, you might plan to
take your coffee break in a new location,
or take a walk right after dinner, so you
won’t be tempted to smoke.
How the Nicoderm®
cq® patch Works.
NicoDerm CQ patches
provide nicotine to your
system. They work as a
temporary aid to help you
quit smoking by reducing nicotine
withdrawal symptoms, including nicotine
craving. The NicoDerm CQ patch
provides a lower level of nicotine to your
blood than cigarettes, and allows you to
gradually do away with your body’s need
for nicotine.
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11
Because the NicoDerm CQ patch does not
contain the tar or carbon monoxide of
cigarette smoke, it does not have the same
health dangers as tobacco. However, it still
delivers nicotine, the addictive part of
cigarette smoke. Nicotine can cause side
effects such as headache, nausea, upset
stomach, and dizziness.
How To Use
Nicoderm® CQ® Patches.
Read all the following instructions, and the
instructions on the outer carton, before
using the NicoDerm CQ patch. Refer to them
often to make sure you’re using the NicoDerm
CQ patch correctly.
1) Begin using the NicoDerm CQ patch on
your quit date.
2) To reduce nicotine craving and other
withdrawal symptoms, use the NicoDerm
CQ patch according to the directions
on pages 7-9.
3) Fold sticky ends of a used NicoDerm CQ
patch together. Replace in its pouch and
discard
When to apply and remove NicoDerm CQ
patches.
Each day apply a new patch to a different
place on skin that is dry, clean and hairless.
You can wear a NicoDerm CQ patch for
either 16 or 24 hours. If you crave
cigarettes when you wake up, wear the
patch for 24 hours. If you begin to have
vivid dreams or other disruptions of your
sleep while wearing the patch for 24 hours, try
taking the patch off at bedtime (after about
16 hours) and putting on a new one when
you get up the next day. To avoid possible
burns, remove the patch before undergoing
any MRI (magnetic resonance imaging)
procedures (for the opaque NicoDerm
CQ patch only).
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INDIVIDUALIZED STOP
FREE
SMOKING PROGRAM
FREE
®
®
• FREE, online individualized stop smoking program.
• Customized for your needs based on your
responses to the enrollment survey.
What is
???
R
d
d a zed S op S
o
g P og a
FREE Individualized Stop Smoking Program
FREE Individualized Stop Smoking Program
12
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• Receive knowledge, support and encouragement
over several weeks to help you break the
psychological and behavioral links to cigarettes.
• Enroll at www.CommittedQuitters.com.
• To receive the available print materials of the
Committed Quitters program in the mail call
1-800-770-0708.
Individualized Stop Smoking Program
Individualized Sto
INDIVIDUALIZED STOP
FREE
SMOKING PROGRAM
FREE
®
®
13
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14
NICODERM and CQ are registered trademarks of the GSK group of companies.
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15
You should not smoke when you are not
wearing the patch.
Remove the used patch and put on a new
patch at the same time every day. Applying
the patch at about the same time each day
(fi rst thing in the morning, for instance) will
help you remember when to put on a new
patch. Do not leave the same NicoDerm
CQ patch on for more than 24 hours
because it may irritate your skin and
because it loses strength after 24 hours.
It is important to use the NicoDerm CQ patch
for the full 10 week treatment period (8 weeks
for people who smoke 10 or fewer cigarettes
per day). If you feel you need to use the
NicoDerm CQ patch for a longer period to keep
from smoking, talk to your health care provider.
How to apply a NicoDerm® CQ ® patch.
1. Do not remove the NicoDerm CQ patch
from its sealed protective pouch until
you are ready to use it. NicoDerm CQ
patches will lose nicotine to the air if
you store them out of the pouch.
2. Choose a non-hairy, clean, dry area of skin.
Do not put a NicoDerm CQ patch on skin
that is burned, broken out, cut, or irritated
in any way. Make sure your skin is free of
lotion and soap before applying a patch.
3. Take patch out of the pouch. Save pouch
for use at time of disposal. A clear,
protective liner covers the
sticky back side of the
NicoDerm CQ patch — the side that
will be put on your skin. The liner has a
slit down the middle to help you remove
it from the patch. With the sticky back
side facing you, pull half the liner away
from the NicoDerm CQ patch starting at
the middle slit, as shown in the illustration
above. Hold the NicoDerm CQ patch at
one of the outside edges (touch the sticky
side as little as possible), and pull off the
other half of the protective liner.
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16
Place the liner back in the pouch. Save
pouch for disposing of the patch after use.
4. Immediately apply the sticky side of the
NicoDerm CQ patch to your skin. Press
the patch fi rmly on your skin with the
heel of your hand for at least 10
seconds. Make sure it sticks
well to your skin, especially
around the edges.
5. Wash your hands when you
have fi nished applying the
NicoDerm CQ patch. Nicotine
on your hands could get into
your eyes and nose, and cause
stinging, redness,
or more serious
problems.
6. After 16 or 24 hours,
remove the patch you
have been wearing. Fold sticky ends of
used NicoDerm CQ patch together.
Replace in its pouch. Discard where it
will be out of the reach of children and
pets. Even used patches have enough
nicotine to poison children and pets.
Wash your hands.
7. Choose a different place on your skin to
apply the next NicoDerm CQ patch and
repeat Steps 1 to 6. Do not apply a new
patch to a previously used skin site for
at least one week.
If your NicoDerm® CQ ® patch gets wet
during wearing.
Water will not harm the NicoDerm CQ
patch you are wearing if applied properly.
You can bathe, swim, or shower for short
periods while you are wearing the
NicoDerm CQ patch.
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urrent labeling information, please visit https://www.fda.gov/drugs
17
If your NicoDerm® CQ ® patch comes
off while wearing.
NicoDerm CQ patches generally stick well
to most people’s skin. However, a patch
may occasionally come off. If your
NicoDerm CQ patch falls off during the
day, put on a new patch, making sure you
select a non-hairy, non-irritated area of skin
that is clean and dry.
If the soap you use has lanolin or
moisturizers, the patch may not stick well.
Using a different soap may help. Body
creams, lotions and sunscreens can also
cause problems with keeping your patch
on. Do not apply creams or lotions to the
place on your skin where you will put
the patch.
If you have followed the directions and the
patch still does not stick to you, try using
medical adhesive tape over the patch.
Disposing of NicoDerm® CQ ® patches.
Fold the used patch in half by folding the
sticky ends together. Replace in its pouch.
Discard where it will be out of the reach of
children and pets. Small amounts of
nicotine, even from a used patch, can
poison children and pets. Keep all
nicotine patches away from children
and pets. Wash your hands after
disposing of the patch.
Reference ID: 3829782
Reference ID: 3830548
This label may not be the latest approved by FDA.
urrent labeling information, please visit https://www.fda.gov/drugs
If your skin reacts to the
NicoDerm® CQ® patch.
When you fi rst put on a NicoDerm CQ
patch, mild itching, burning, or tingling is
normal and should go away within an hour.
After you remove a NicoDerm CQ patch,
the skin under the patch might be somewhat
red. Your skin should not stay red for more
than a day after removing the patch. Stop
use and ask a doctor if skin redness caused
by the patch does not go away after four
days, or if your skin swells, or you get a
rash. Do not put on a new patch.
Storage Instructions.
Keep each NicoDerm CQ patch in
its protective pouch, unopened, until
you are ready to use it, because the
patch will lose nicotine to the air if
it’s outside the pouch.
Store NicoDerm CQ patches at 20-25°C
(68-77°F) because they are sensitive to heat.
Remember, the inside of your car can reach
temperatures much higher than this. A slight
yellowing of the sticky side of the patch is
normal.
Do not use NicoDerm CQ patches stored
in pouches that are open or torn.
Tips to Make Quitting
Easier.
Within the fi rst few weeks of giving up
smoking, you may be tempted to smoke
for pleasure, particularly after completing
a diffi cult task, or at a party or bar. Here
are some tips to help get you through the
important fi rst stages of becoming a
non-smoker:
On Your Quit Date:
• Ask your family, friends and co-workers to
support you in your efforts to stop smoking.
18
Reference ID: 3829782
Reference ID: 3830548
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urrent labeling information, please visit https://www.fda.gov/drugs
• Drink large quantities of water and fruit
juices.
• Try to avoid alcohol, coffee and other
beverages you associate with smoking.
• Remember that temporary urges to
smoke will pass, even if you don’t smoke
a cigarette.
• Keep your hands busy with something
like a pencil or a paper clip.
• Find other activities that help you relax
without cigarettes. Swim, jog, take a
walk, play basketball.
• Don’t worry too much about gaining
weight. Watch what you eat, take time
for daily exercise, and change your
eating habits if you need to.
• Laughter helps. Watch or read
something funny.
19
• Throw away all your cigarettes, matches,
lighters, ashtrays, etc.
• Keep busy on your quit day. Exercise.
Go to a movie. Take a walk. Get together
with friends.
• Figure out how much money you’ll save
by not smoking. Most ex-smokers can
save more than $1,000 a year on the
price of cigarettes alone.
• Write down what you will do with the
money you save.
• Know your high risk situations and plan
ahead how you will deal with them.
• Visit your dentist and have your teeth
cleaned to get rid of the tobacco stains
Right after Quitting:
• During the fi rst few days after you’ve
stopped smoking, spend as much time as
possible at places where smoking is
not allowed.
Reference ID: 3829782
Reference ID: 3830548
This label may not be the latest approved by FDA.
urrent labeling information, please visit https://www.fda.gov/drugs
What to Expect.
The First Few Days.
Your body is now coming back into
balance. During the fi rst few days after you
stop smoking, you might feel edgy and
nervous and have trouble concentrating.
You might get headaches, feel dizzy and a
little out of sorts, feel sweaty or have
stomach upsets. You might even have
trouble sleeping at fi rst. These are typical
nicotine withdrawal symptoms that will
go away with time. Your smoker’s cough
will get worse before it gets better. But
don’t worry, that’s a good sign. Coughing
helps clear the tar deposits out of
your lungs.
After A Week Or Two.
By now you should be feeling more
confi dent that you can handle those
smoking urges. Many of your nicotine
withdrawal symptoms have left by now,
and you should be noticing some positive
signs: less coughing, better breathing and
an improved sense of taste and smell, to
name a few.
After A Month.
You probably have the urge to smoke much
less often now. But urges may still occur,
and when they do, they are likely to be
powerful ones that come out of nowhere.
Don’t let them catch you off guard. Plan
ahead for these diffi cult times.
20
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Reference ID: 3830548
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urrent labeling information, please visit https://www.fda.gov/drugs
21
Concentrate on the ways non-smokers are
more attractive than smokers. Their skin is
less likely to wrinkle. Their teeth are whiter,
cleaner. Their breath is fresher. Their hair
and clothes smell better. That cough that
seems to make even a laugh sound more
like a rattle is a thing of the past. Their
children and others around them are
healthier, too.
What To Do About Relapse.
What should you do if you slip and start
smoking again? The answer is simple. A
lapse of one or two or even a few cigarettes
should not spoil your efforts! Throw away
your cigarettes, forgive yourself and
continue with the program. Re-read
the User’s Guide to ensure that you’re
using the NicoDerm CQ patch correctly
and following the other important tips
for dealing with the mental and social
dependence on nicotine. Your doctor,
pharmacist or other health professional
can also provide useful counseling on
the importance of stopping smoking. You
should consider them partners in your
quit attempt.
What To Do About Relapse After a
Successful Quit Attempt.
If you have taken up regular smoking
again, don’t be discouraged. Research
shows that the best thing you can do is try
again, since several quitting attempts may
be needed before you’re successful. And
your chances of quitting successfully
increase with each quit attempt.
The important thing is to learn from your
last attempt.
Reference ID: 3829782
Reference ID: 3830548
This label may not be the latest approved by FDA.
urrent labeling information, please visit https://www.fda.gov/drugs
• Admit that you’ve slipped, but don’t treat
yourself as a failure.
• Try to identify the “trigger” that caused
you to slip, and prepare a better plan for
dealing with this problem next time.
• Talk positively to yourself – tell yourself
that you have learned something from
this experience.
• Make sure you used NicoDerm CQ
patches correctly.
• Remember that it takes practice to do
anything, and quitting smoking is no
exception.
When the Struggle Is Over.
Once you’ve stopped smoking, take a
second and pat yourself on your back.
Now do it again. You deserve it.
Remember now why you decided to stop
smoking in the fi rst place. Look at your list of
reasons. Read them again. And smile.
Now think about all the money you are
saving and what you’ll do with it. All the
non-smoking places you can go, and what
you might do there. All those years you may
have added to your life, and what you’ll
do with them. Remember that temptation
may not be gone forever. However, the hard
part is behind you so look forward with a
positive attitude, and enjoy your new life as
a non-smoker.
Questions & Answers.
1. How will I feel when I stop smoking
and start using the NicoDerm CQ patch?
You’ll need to prepare yourself for some
nicotine withdrawal symptoms. These begin
almost immediately after you stop
22
Reference ID: 3829782
Reference ID: 3830548
This label may not be the latest approved by FDA.
urrent labeling information, please visit https://www.fda.gov/drugs
23
smoking, and are usually at their worst
during the fi rst three or four days.
Understand that any of the following is
possible:
• craving for nicotine
• anxiety, irritability, restlessness, mood
changes, nervousness
• disruptions of your sleep
• drowsiness
• trouble concentrating
• increased appetite and weight gain
• headaches, muscular pain, constipation,
fatigue.
The NicoDerm CQ patch reduces nicotine
withdrawal symptoms such as irritability
and nervousness, as well as the craving
for nicotine you used to satisfy by having
a cigarette.
2. Is the NicoDerm® CQ ® patch just
substituting one form of nicotine
for another?
The NicoDerm CQ patch does contain nicotine.
The purpose of the NicoDerm CQ patch
is to provide you with enough nicotine to
reduce the physical withdrawal symptoms
so you can deal with the mental aspects
of quitting.
3. Can I be hurt by using the
NicoDerm® CQ ® patch?
For most adults, the amount of nicotine
delivered from the patch is less than from
smoking. If you believe you may be
sensitive to even this amount of nicotine,
you should not use this product without
advice from your doctor. There are also
some important warnings in this User’s
Guide (See page 5).
Reference ID: 3829782
Reference ID: 3830548
This label may not be the latest approved by FDA.
urrent labeling information, please visit https://www.fda.gov/drugs
4. Will I gain weight?
Many people do tend to gain a few pounds
the fi rst 8-10 weeks after they stop
smoking. This is a very small price to pay
for the enormous gains that you will make
in your overall health and attractiveness. If
you continue to gain weight after the fi rst
two months, try to analyze what you’re
doing differently. Reduce your fat intake,
choose healthy snacks, and increase your
physical activity to burn off the extra
calories. Drink lots of water. This is good
for your body and skin, and also helps to
reduce the amount you eat.
5. Is the NicoDerm® CQ ® patch more
expensive than smoking?
The total cost of the NicoDerm CQ
program is similar to what a person
who smokes one pack of cigarettes a
day would spend on cigarettes for the
same period of time. Also, use of the
NicoDerm CQ patch is only a short-term
cost, while the cost of smoking is a long-
term cost, including the health problems
smoking causes.
6. What if I slip up?
Discard your cigarettes, forgive yourself
and then get back on track. Don’t consider
yourself a failure or punish yourself. In fact,
people who have already tried to quit are
more likely to be successful the next time.
Good Luck!
24
60466XE
Reference ID: 3829782
Reference ID: 3830548
This label may not be the latest approved by FDA.
urrent labeling information, please visit https://www.fda.gov/drugs
Reference ID: 3829782
Reference ID: 3830548
This label may not be the latest approved by FDA.
urrent labeling information, please visit https://www.fda.gov/drugs
Reference ID: 3829782
Reference ID: 3830548
This label may not be the latest approved by FDA.
urrent labeling information, please visit https://www.fda.gov/drugs
Reference ID: 3829782
Reference ID: 3830548
This label may not be the latest approved by FDA.
urrent labeling information, please visit https://www.fda.gov/drugs
60466XE
Reference ID: 3829782
Reference ID: 3830548
This label may not be the latest approved by FDA.
urrent labeling information, please visit https://www.fda.gov/drugs
---------------------------------------------------------------------------------------------------------
This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic
signature.
---------------------------------------------------------------------------------------------------------
/s/
----------------------------------------------------
VALERIE S PRATT
10/07/2015
Reference ID: 3830548
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:46:59.118164
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020165Orig1s036lbl.pdf', 'application_number': 20165, 'submission_type': 'SUPPL ', 'submission_number': 36}
|
12,296
|
Standard Magnesium,
Low Magnesium,
Low Magnesium,
Standard Calcium
Standard Calcium
Low Calcium
Main Bag Contents
Dextrose Hydrous,
1.52
2.56
4.36
1.54
2.56
4.36
1.54
2.56
4.36
USP (C6H12O6· H2
O)
g
g
g
g
g
g
g
g
g
Sodium Chloride,USP
581
581
581
552
552
552
552
552
552
(NaCl)
mg
mg
mg
mg
mg
mg
mg
mg
mg
Calcium Chloride,
26.3
26.3
26.3
26.3
26.3
26.3
18.9
18.9
18.9
USP (CaCl2· 2H2
O)
mg
mg
mg
mg
mg
mg
mg
mg
mg
Magnesium Chloride,
15.6
15.6
15.6
5.21
5.21
5.21
5.21
5.21
5.21
USP (MgCl2 · 6H2
O)
mg
mg
mg
mg
mg
mg
mg
mg
mg
Mini-bag Contents
Sodium Lactate
14.4
14.4
14.4
16.7
16.7
16.7
16.7
16.7
16.7
(C3H5NaO3 )
g
g
g
g
g
g
g
g
g
Sodium Bicarbonate
1.20
1.20
1.20
1.20
1.20
1.20
1.20
1.20
1.20
(NaHCO3 )
g
g
g
g
g
g
g
g
g
Total ingredient content AFTER mixing Main Bag and Mini-bag solutions
Dextrose Hydrous,
1.5
2.5
4.25
1.5
2.5
4.25
1.5
2.5
4.25
USP (C6H12O6· H2
O)
g
g
g
g
g
g
g
g
g
Sodium Chloride,USP
567
567
567
538
538
538
538
538
538
(NaCl)
mg
mg
mg
mg
mg
mg
mg
mg
mg
Sodium Lactate
353
353
353
409
409
409
409
409
409
(C3H5NaO3 )
mg
mg
mg
mg
mg
mg
mg
mg
mg
Sodium Bicarbonate
29.4
29.4
29.4
29.4
29.4
29.4
29.4
29.4
29.4
(NaHCO3 )
mg
mg
mg
mg
mg
mg
mg
mg
mg
Calcium Chloride,
25.7
25.7
25.7
25.7
25.7
25.7
18.4
18.4
18.4
USP (CaCl2· 2H2
O)
mg
mg
mg
mg
mg
mg
mg
mg
mg
Magnesium Chloride,
15.2
15.2
15.2
5.08
5.08
5.08
5.08
5.08
5.08
USP (MgCl2 · 6H2
O)
mg
mg
mg
mg
mg
mg
mg
mg
mg
Osmolarity
347
398
486
346
396
485
344
394
483
(mOsmoL/L)(calc)
pH 7.0 ± 0.4
7.0
7.0
7.0
7.0
7.0
7.0
7.0
7.0
7.0
Main Bag Contents
Sodium 99.4 99.4 99.4 94.3 94.3 94.3 94.3 94.3 94.3
Calcium 3.59 3.59 3.59 3.59 3.59 3.59 2.56 2.56 2.56
Magnesium 1.54 1.54 1.54 0.51 0.51 0.51 0.51 0.51 0.51
Chloride
105
105
105 98.4 98.4 98.4 97.4 97.4 97.4
Mini-bag Contents
Sodium 1428 1428 1428 1632 1632 1632 1632 1632 1632
Lactate 1285 1285 1285 1489 1489 1489 1489 1489 1489
Bicarbonate
143
143
143
143
143
143
143
143
143
Total ingredient content AFTER mixing Main Bag and Mini-bag solutions
Sodium
132
132
132
132
132
132
132
132
132
Calcium
3.5
3.5
3.5
3.5
3.5
3.5
2.5
2.5
2.5
Magnesium
1.5
1.5
1.5
0.5
0.5
0.5
0.5
0.5
0.5
Chloride
102
102
102
96
96
96
95
95
95
Lactate 31.5 31.5 31.5 36.5 36.5 36.5 36.5 36.5 36.5
Bicarbonate
3.5
3.5
3.5
3.5
3.5
3.5
3.5
3.5
3.5
1.5%
Dextrose
2.5%
Dextrose
4.25%
Dextrose
1.5%
Dextrose
2.5%
Dextrose
4.25%
Dextrose
1.5%
Dextrose
2.5%
Dextrose
4.25%
Dextrose
Composition / 100ml
Ionic Concentration(mEq/L)
company logo
DELFLEX® Neutral pH
Peritoneal Dialysis Solutions
with Attached stay•safe® Exchange Set
For Intraperitoneal Administration Only
MPS 89-905-65
No Latex
Description
DELFLEX® Neutral pH peritoneal dialysis solutions
(supplied in standard, low magnesium and low
magnesium/low calcium as 2 or 3 Liter product) are
sterile, non-pyrogenic formulations of dextrose and
electrolytes in water for injection, USP, for use in
peritoneal dialysis. In comparison to conventional
peritoneal dialysis solutions, DELFLEX® Neutral pH
solutions are formulated to lower levels of glucose
degradation products and provide a neutral pH of
7.0 ± 0.4, which is closer to physiologic pH. The
osmotic and buffer solutions are stored separately
and mixed by the patient prior to use. The stay•safe®
exchange set utilizes an easy to use dial designed to
eliminate the use of clamps and to prevent touch
contamination of internal connection components.
Composition, calculated osmolarity, pH and ionic
concentrations of the mixed solutions are shown in
Table 2.
Hydrochloric acid, and sodium hydroxide may be
added for pH adjustment. The patient mixed solution
pH is 7.0 ± 0.4.
str
u
ct ural
f
o
rmu
la
Dextrose
USP
is
chemically
designated D-glucose monohydrate
(C6
O6 • H2O) a hexose sugar freely
H12
soluble in water. The structural
formula is shown here:
These solutions do not contain
antimicrobial agents or additional buffers. Exposure
to temperatures above 25°C/77°F during transport
and storage will lead to minor losses in moisture
content. Higher temperatures lead to greater losses.
It is unlikely that these minor losses will lead to
clinically significant changes within the expiration
period. Since the flexible inner bag is compounded
from a specific polyvinyl chloride, water may
permeate from the inner bag into the outerwrap
in quantities insufficient to affect the solution
significantly. Solutions in contact with the plastic
inner bag can cause certain chemical components of
the bag to leach out in very small amounts; however,
the safety of the plastic formulation is supported by
biological tests for plastic containers.
Nominal glucose degradation product (GDP) levels
(immediately following sterilization) in DELFLEX®
Neutral pH solution and DELFLEX® solution are
reported in Table 1. The clinical relevance of these
differences in GDP levels is unknown.
Table 1. Glucose Degra
DELFLEX® Neutral pH
23
51
106
dation Product Levels*
DELFLEX®
267
362
437
Dextrose
Concentration
1.5%
2.5%
4.25%
* This is the sum [μmol/L] of the various component GDPs including: formaldehyde,
acetaldehyde, furaldehyde, glyoxal, methylglyoxal, 5-hydroxymethylfurfural (5-HMF), and
3-deoxyglucosone (3DG).
Clinical Pharmacology
Peritoneal dialysis is the process of fi ltering excess
water and toxins from the bloodstream through
a semi-permeable membrane. This process does
not cure the disease, but prevents progression of
symptoms. Dialysis for chronic kidney failure is
essential to maintain life, unless the patient receives
a kidney transplant. A peritoneal dialysis procedure
utilizes the peritoneum (lining of the abdomen) as
the semi-permeable membrane. The procedure is
conducted by instilling peritoneal dialysis solution
Reference ID: 3252902
Table 2. Composition, Calculated Osmolarity, pH, and Ionic Concentration
2 Liter DELFLEX® Neutral pH
through a catheter in the abdomen into the
peritoneal cavity. Since the peritoneum is heavily
supplied with blood vessels, the contact of the
solution with the peritoneum causes excess water
and toxins in the bloodstream to be drawn across
the membrane into the solution. This osmosis and
diffusion occurs between the plasma of the patient
and the peritoneal dialysis solution. After a period of
time called “dwell time,” the solution is then drained
from the patient.
This solution does not contain potassium. In situations
in which there is a normal serum potassium level or
hypokalemia, the addition of potassium chloride (up
to a concentration of 4 mEq/L) may be indicated to
prevent severe hypokalemia.
Addition of potassium chloride should be made
after careful evaluation of serum and total body
potassium and only under the direction of a
physician.
Clinical studies have demonstrated that the use of low
magnesium solutions resulted in signifi cant increases
in serum CO2 and decreases in serum magnesium
levels. The decrease in magnesium levels did not
cause clinically signifi cant hypomagnesemia.
Indications And Usage
DELFLEX® peritoneal dialysis solutions are indicated
in the treatment of chronic renal failure patients being
3 Liter DELFLEX® Neutral pH
Low Magnesium,
Low Calcium
4.25%
Dextrose
Dextrose Hydrous,
USP (C6H12O6· H2O)
1.52
g
2.54
g
4.32
g
1.52
g
2.54
g
4.32
g
4.32
g
Sodium Chloride,USP
(NaCl)
576
mg
576
mg
576
mg
547
mg
547
mg
547
mg
547
mg
Calcium Chloride,
USP (CaCl2· 2H2O)
26.1
mg
26.1
mg
26.1
mg
26.1
mg
26.1
mg
26.1
mg
18.7
mg
Magnesium Chloride,
USP (MgCl2 · 6H2O)
15.4
mg
15.4
mg
15.4
mg
5.16
mg
5.16
mg
5.16
mg
5.16
mg
25.0
g
1.80
g
4.25
g
538
mg
409
mg
29.4
mg
18.4
mg
5.08
mg
Sodium 98.6
98.6 93.5
93.5
Calcium 3.56
3.56 3.56
2.54
Magnesium 1.52
1.52 0.51
0.51
Chloride 104
104 97.6
96.6
2448
2233
214
132
2.5
0.5
95
36.5
3.5
Standard Magnesium,
Standard Calcium
Low Magnesium,
Standard Calcium
1.5%
Dextrose
2.5%
Dextrose
4.25%
Dextrose
1.5%
Dextrose
2.5%
Dextrose
4.25%
Dextrose
1.5%
Dextrose
2.5%
Dextrose
Composition / 100ml
Main Bag Contents
1.52
g
2.54
g
547
mg
547
mg
18.7
mg
18.7
mg
5.16
mg
5.16
mg
Mini-bag Contents
Sodium Lactate
(C3H5NaO3)
21.6
g
21.6
g
21.6
g
25.0
g
25.0
g
25.0
g
25.0
g
25.0
g
Sodium Bicarbonate
(NaHCO3)
1.80
g
1.80
g
1.80
g
1.80
g
1.80
g
1.80
g
1.80
g
1.80
g
Total ingredient content AFTER mixing Main Bag and Mini-bag solutions
Dextrose Hydrous,
USP (C6H12O6· H2O)
1.5
g
2.5
g
4.25
g
1.5
g
2.5
g
4.25
g
1.5
g
2.5
g
Sodium Chloride,USP
(NaCl)
567
mg
567
mg
567
mg
538
mg
538
mg
538
mg
538
mg
538
mg
Sodium Lactate
(C3H5NaO3)
353
mg
353
mg
353
mg
409
mg
409
mg
409
mg
409
mg
409
mg
Sodium Bicarbonate
(NaHCO3)
29.4
mg
29.4
mg
29.4
mg
29.4
mg
29.4
mg
29.4
mg
29.4
mg
29.4
mg
Calcium Chloride,
USP (CaCl2· 2H2O)
25.7
mg
25.7
mg
25.7
mg
25.7
mg
25.7
mg
25.7
mg
18.4
mg
18.4
mg
Magnesium Chloride,
USP (MgCl2 · 6H2O)
15.2
mg
15.2
mg
15.2
mg
5.08
mg
5.08
mg
5.08
mg
5.08
mg
5.08
mg
Osmolarity
(mOsmoL/L)(calc) 347
398
486
346
396
485
344
394
483
pH 7.0 ± 0.4 7.0
7.0
7.0
7.0
7.0
7.0
7.0
7.0
7.0
Ionic Concentration(mEq/L)
Main Bag Contents
98.6
93.5 93.5 93.5 93.5
3.56
3.56 3.56 2.54 2.54
1.52
0.51 0.51 0.51 0.51
104
97.6 97.6 96.6 96.6
Mini-bag Contents
Sodium 2142 2142 2142 2448 2448 2448 2448 2448
Lactate 1927 1927 1927 2233 2233 2233 2233 2233
Bicarbonate 214
214
214
214
214
214
214
214
Total ingredient content AFTER mixing Main Bag and Mini-bag solutions
Sodium 132
132
132
132
132
132
132
132
Calcium 3.5
3.5
3.5
3.5
3.5
3.5
2.5
2.5
Magnesium 1.5
1.5
1.5
0.5
0.5
0.5
0.5
0.5
Chloride 102
102
102
96
96
96
95
95
Lactate 31.5 31.5 31.5 36.5 36.5 36.5 36.5 36.5
Bicarbonate 3.5
3.5
3.5
3.5
3.5
3.5
3.5
3.5
maintained on peritoneal dialysis when nondialytic
medical therapy is judged to be inadequate.
Contraindications
None known.
Warnings
Not for Intravenous Injection.
Use Aseptic Technique.
It is important to mix the buffer (mini-bag) and
main solutions thoroughly.
Administer within 24
hours after mixing. Once buffer (mini-bag) and main
solutions are mixed, medication may be added prior
to administration.
Peritoneal dialysis should be done with great care
in patients with a number of conditions, including
disruption of the peritoneal membrane or diaphragm
by surgery or trauma, extensive adhesions, bowel
distention,
undiagnosed
abdominal
disease,
abdominal wall infection, hernias or burns, fecal
fistula or colostomy, tense ascites, obesity, large
polycystic kidneys, recent aortic graft replacement,
lactic
acidosis
and
severe
pulmonary
disease.
When assessing peritoneal dialysis as the mode of
therapy in such extreme situations, the benefi ts to
the patient must be weighed against the possible
complications.
Solutions containing lactate ion should be used with
great care in patients with metabolic or respiratory
alkalosis. Lactate should be administered with
great care in those conditions in which there is an
increased level or an impaired utilization of this ion,
such as severe hepatic insufficiency.
An accurate fluid balance record must be kept and
the weight of the patient carefully monitored to avoid
over or under hydration with severe consequences,
including congestive heart failure, volume depletion
and shock.
Excessive use of DELFLEX® peritoneal dialysis
solution with 4.25% dextrose during a peritoneal
dialysis treatment can result in signifi cant removal
of water from the patient.
Stable patients undergoing maintenance peritoneal
dialysis should have routine periodic evaluation
of electrolyte blood chemistries and hematologic
factors, as well as other indicators that determine
the patient’s ongoing status.
After removing the outer wrap, check for minute
leaks by squeezing the container firmly. If leaks
are found, discard the solution because the sterility
may be impaired. (A small amount of moisture may
be present inside the overwrap, which is normal
condensation from the sterilization process).
Serum calcium levels in patients using low calcium
concentrations should be monitored and if found
to be low, the peritoneal solution in use should be
altered to one with a higher calcium concentration.
Precautions
General:
Administer only if the solution is clear, all seals are
intact, and there is no evidence of leaking.
It is important to mix the buffer (mini-bag) and
main solutions thoroughly.
Administer within 24
hours after mixing. Once buffer and main solutions
are mixed, medication may be added prior to
administration.
Do Not Heat In A Microwave Oven
Care should be taken to see that the catheter is
inserted completely, since leakage around the
catheter, if not controlled, can create edema from
subcutaneous infiltration of the dialysis solution.
This will also create an inaccurate fluid balance
measurement.
DELFLEX® Peritoneal Dialysis solutions do not include
potassium. Potassium chloride should only be added
under the direction of a physician after careful
evaluation of both serum and total body potassium.
The overwrap must be removed immediately before
use and is provided with a “Tear Open” feature
to make removal easy. See instructions in the
Directions for Use section.
Disconnect from disk only when knob is in position
4 (••••).
Aseptic technique must be used throughout the
procedure and at its termination in order to reduce
the possibility of infection.
Significant loss of protein, amino acids and water
soluble
vitamins
may
occur
during
peritoneal
dialysis.
Replacement therapy should be provided
as necessary.
Laboratory Tests:
Serum electrolytes, magnesium, bicarbonate levels
and fluid balance should be periodically monitored.
Carcinogenesis, Mutagenesis, Impairment of
Fertility:
Long term animal studies with DELFLEX® peritoneal
dialysis solutions have not been performed to
evaluate
the
carcinogenic
potential,
mutagenic
potential or effect on fertility.
Pregnancy: Teratology Effects:
Pregnancy Category C. Animal reproduction studies
have not been conducted with DELFLEX peritoneal
dialysis solutions.
It is also not known whether
DELFLEX peritoneal dialysis solutions can cause fetal
harm when administered to a pregnant woman or
can affect reproduction capacity. DELFLEX peritoneal
dialysis solutions should be given to a pregnant
woman only if clearly needed.
Nursing Mothers:
Caution
should
be
exercised
when
DELFLEX
peritoneal dialysis solutions are administered to a
nursing woman.
Pediatric Use:
Safety and effectiveness in pediatric patients have
not been established.
Adverse Reactions
Adverse reactions to peritoneal dialysis include
mechanical and solution related problems as well
as the results of contamination of equipment or
improper technique in catheter placement. Abdominal
pain, bleeding, peritonitis, subcutaneous infection
around a peritoneal catheter, catheter blockage,
diffi culty in fluid removal, and ileus are among the
complications of the procedure. Solution related
adverse reactions might include peritonitis, catheter
site infection, electrolyte and fluid
imbalances,
hypovolemia,
hypervolemia,
hypertension,
hypotension, disequilibrium syndrome and muscle
cramping.
If
an
adverse
reaction
does
occur,
institute
appropriate therapeutic procedures according to
the patient’s needs and conditions, and save the
remainder of the fluid in the bag for evaluation if
deemed necessary.
Dosage And Administration
DELFLEX peritoneal dialysis solutions are provided
for intraperitoneal administration only.
The mode
of therapy, frequency of treatment, formulation,
exchange volume, duration of dwell, and length
of dialysis should be selected by the physician
responsible for the treatment of the individual
patient.
To
avoid
the
risk
of
severe
dehydration
or
hypovolemia and to minimize the loss of protein, it
is advisable to select the peritoneal dialysis solution
with lowest level of osmolarity consistent with the
fluid removal requirements for that exchange.
Parenteral drug products should be inspected
visually for particulate matter and discoloration prior
to administration whenever solution and container
permit.
Additives may be incompatible. Do not store solutions
containing additives.
For administration see Directions for Use section.
How Supplied
DELFLEX peritoneal dialysis solutions are delivered
in single-dose flexible bags. All DELFLEX peritoneal
dialysis solutions have overfills declared on the
container label. The flexible containers have the
capacity for drainage in excess of their stated fill
volume for ultrafiltration from the patient.
DELFLEX
peritoneal
dialysis
solutions
with
an
attached stay•safe® exchange set are available in
containers as shown in Table 2 in the Description
section.
Storage Conditions
Store at 25°C (77°F); excursions permitted to
15°-30°C (59°-86°F). See USP Controlled Room
Temperature. Brief exposure to temperatures up
to 40°C/104°F may be tolerated provided the mean
kinetic temperature does not exceed 25°C (77°F).
Keep DELFLEX and all medicines out of the
reach of children.
North America
920 Winter Street
Waltham, MA 02451
1-800-323-5188
Rev 07/11
Patent Pending
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
usage illustratiion
usage
illustrat
iion
Perform Steps 2 Times
Figure F
usag
e illu
stratiion
u
sage illustratii
o
n
turn counter-clockwise.
usag
e
illustrat
iion
usage ill
ustratiio
n
usage
illustra
tiion
Cap
Figure J usage illustratiionusage illustratiionusage illustratiion
usage illustratiion
us
age illustrati
ionusage illustratiionusage illustratiion
Not for Intravenous Injection. Do not microwave.
• Position solution bags and drain bag as shown in
1. With the solution bags stretched out on the
6. Fold mini-bag in half and squeeze it until there is no
5. Remove the cap from the stay•safe disc and throw
Figure C.
work surface, break the red cone by bending.
solution left. Slide folded mini-bag into the slit of the
cap away. Remove the existing cap from the
Warm solution as directed by your healthcare provider.
See
Figure E.
white cover to show the blue cone. See Figure H.
Extension Set connected to the patient’s catheter
by twisting the connection counter-clockwise.
Directions for Use
(If using the Organizer, leave the capped end
Red Cone
of the Extension Set in the Organizer and twist
Get Ready
1. Clean work surface. Use aseptic technique.
the extension set connector counter-clockwise to
remove the set from its cap.)
6. Aseptically connect the Extension set to the
connector on the stay•safe disc. Twist clockwise
2. Gather supplies:
• Warmed DELFLEX Neutral pH Peritoneal Dialysis
to secure the connection.
bag with the attached stay•safe® Exchange Set
7. Remove your mask. Do not open the system
• Povidone iodine prefilled stay•safe cap, a stand
during exchange.
8. Open the Extension set clamp to start drain.
alone item provided separately
Figure C
• stay•safe organizer, a stand alone item provided
Figure H
9. When patient drain is complete, turn the stay•safe
separately (Optional; FMCNA recommends its
• Squeeze the main bag and the mini bag to check for
disc position indicator to Position 2 (••). See
use)
leaks. When squeezing the mini-bag, the bag should
Figure K. This will start flush from the solution
• Prescribed
medicine(s)
if
ordered
by
your
Figure E
remain firm. No solution should leak into the main
bag to the drain bag.
The solution is now ready for use.
healthcare provider
• Mask
bag or into the drain line.
Administer Peritoneal Dialysis Solution
2. Fold the mini-bag in half. Squeeze the solution from
Do not use DELFLEX Neutral pH Solution Set if:
See Figure A for identification of each item described
1. If adding medicine(s):
the mini-bag into the main solution bag by pressing
above.
• leaks are found
• Clean the medication port as instructed by your
the two halves together until the mini-bag is empty.
stay•safe® D isc
• the solution bags are damaged
• solution is cloudy or discolored
healthcare provider.
See Figure F (Step 1).
• Add the medicine(s).
• Red or blue cone is broken
• Turn the bag upside down several times to mix the
Throw away DELFLEX Neutral pH Solution Set and
medicine.
notify your healthcare provider.
2. Hang the solution bag from the I.V. pole. Place the
Figure K
drain bag at floor level.
7. Turn the blue position indicator on the stay•safe
10. After approximately 5 seconds turn the stay•safe
3. Break the blue cone on the bottom of the mini-
disc counter-clockwise until it fits into the cut-out
disc position indicator to Position 3 (•••). See
bag. See Figure I. (if using the Organizer, place
portion of the colored plastic cover on the disc as
Figure L. This will start the patient fill.
the stay•safe disc in the organizer as shown in
illustrated in Figure D. This will allow the effluent
Figure J).
in your peritoneal cavity to drain. Remove the
Delflex Neutral pH PD bag
plastic cover while the indicator is in this position
(Position 1: •). Once the cover is removed, do not
Figure L
11. When fill is complete, turn the stay•safe disc
position indicator to Position 4 (••••). See Figure
Figure I
M. This will insert the closure pin of the disc into the
stay·safe® cap
stay·safe® organizer
extension set connector and seal the system.
3. Push down on main solution bag to flush solution
Figure A
back into the mini-bag. Completely refill mini-bag
with solution. See Figure F (Step 2).
3. Put on the mask. Wash your hands.
4. Repeat steps 2 and 3 above to make sure that all of
4. Clamp the Extension Tube Set coming from your
catheter.
the contents of the mini-bag have been completely
flushed into the main solution bag.
5. Tear the overwrap across from the slit edge to open.
5. Grab the tubing at the bottom of the main solution
Wipe away any moisture from the solution bags.
bag. While keeping the top portion of the bag on the
Some opacity may be observed in the plastic of the
table, flip the bag lengthwise using a back and forth
bag and/or tubing and is due to moisture absorption
motion to mix solutions. See Figure G. Repeat this
during the sterilization process. This is normal and
does not affect the solution quality or safety. The
Figure M
step to mix solutions.
opacity will diminish gradually.
12.Remove the white protective cover from the new
6. Inspect DELFLEX Solution Bags:
stay•safe cap. Save for later use.
13.Remove the Extension set from the stay•safe disc
• Place the DELFLEX Solution set on the work surface.
See Figure B.
4. Remove the new stay•safe cap from its package.
and attach the new stay•safe cap. Twist clockwise
The new stay•safe cap is the stand alone item
to secure the connection.
Do Not Microwave
provided to the patient separately. Refer to “Get
14.Seal the disc by attaching the white protective
Ready” section for stay•safe cap identification.
cover from the stay•safe cap to the disc connector.
(If using the Organizer, place in the right or left
Twist clockwise to secure the connection and
notch of the Organizer as illustrated in Figure J.
prevent leakage from the used system.
Place the existing cap of stay•safe Extension Set,
15.Look at the drained fluid for cloudiness. Measure
Figure D
connected to the patient’s catheter, in the other
the amount of fluid drained. Throw away the fluid
Mix Delfle x® Neutral pH Solution
Figure G
notch of the Organizer)
and used set as instructed by your healthcare
provider. In case of cloudiness, save the fluid and
Important: Mix the mini-bag and main solutions
the exchange set and immediately contact your
thoroughly. Use the solution within 24 hours after
healthcare provider.
mixing.
Figure B
Reference ID: 3252902
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Composition / 100
Standard Magnesium,
Low Magnesium,
Low Magnesium,
Standard Calcium
Standard Calcium
Low Calcium
Main Bag Contents
Dextrose Hydrous, 1.52
2.54
4.32
1.52
2.54
4.32
1.52
2.54
4.32
USP (C6H12O6· H2O)
g
g
g
g
g
g
g
g
g
Sodium Chloride,USP
576
576
576
547
547
547
547
547
547
(NaCl)
mg
mg
mg
mg
mg
mg
mg
mg
mg
Calcium Chloride, 26.1
26.1
26.1
26.1
26.1
26.1
18.7
18.7
18.7
USP (CaCl2· 2H2O)
mg
mg
mg
mg
mg
mg
mg
mg
mg
Magnesium Chloride, 15.4
15.4
15.4
5.16
5.16
5.16
5.16
5.16
5.16
USP (MgCl2 · 6H2O)
mg
mg
mg
mg
mg
mg
mg
mg
mg
Mini-bag Contents
Sodium Lactate
21.6
21.6
21.6
25.0
25.0
25.0
25.0
25.0
25.0
(C3H5NaO3)
g
g
g
g
g
g
g
g
g
Sodium Bicarbonate 1.80
1.80
1.80
1.80
1.80
1.80
1.80
1.80
1.80
(NaHCO3)
g
g
g
g
g
g
g
g
g
1.5%
Total ingredient content AFTER mixing Main Bag and Mini-bag solutions
Dextrose
Dextrose Hydrous,
1.5
2.5
2.5%
4.25
1.5
2.5
4.25
1.5
2.5
4.25
USP (C H O · H O)
6
12
6
2
g
g
g
g
g
g
g
g
g
Dextrose
Sodium Chloride,USP
567
567
567
538
538
538
538
538
538
4.25%
(NaCl)
mg
mg
mg
mg
mg
mg
mg
mg
mg
Dextrose
Sodium Lactate
353
353
353
409
409
409
409
409
409
1.5%
(C3H5NaO3)
mg
mg
mg
mg
mg
mg
mg
mg
mg
Dextrose
Sodium Bicarbonate 29.4
29.4
29.4
29.4
29.4
29.4
29.4
29.4
29.4
2.5%
(NaHCO3)
mg
mg
mg
mg
mg
mg
mg
mg
mg
Dextrose
Calcium Chloride, 25.7
25.7
25.7
25.7
25.7
25.7
18.4
18.4
18.4
4.25%
USP (CaCl · 2H O)
2
2
mg
mg
mg
mg
mg
mg
mg
mg
mg
Dextrose
Magnesium Chloride, 15.2
15.2
15.2
5.08
5.08
5.08
5.08
5.08
5.08
1.5%
USP (MgCl2 · 6H2O)
mg
mg
mg
mg
mg
mg
mg
mg
mg
Dextrose
Osmolarity
347
398
486
346
396
485
344
394
483
2.5%
(mOsmoL/L)(calc)
Dextrose
pH 7.0 ± 0.4 7.0
7.0
7.0
7.0
7.0
7.0
7.0
7.0
7.0
4.25%
Main Bag Contents
Dextrose
Sodium 98.6 98.6 98.6 93.5 93.5 93.5 93.5 93.5 93.5
Calcium 3.56 3.56 3.56 3.56 3.56 3.56 2.54 2.54 2.54
Magnesium 1.52 1.52 1.52 0.51 0.51 0.51 0.51 0.51 0.51
Chloride 104
104
104 97.6 97.6 97.6 96.6 96.6 96.6
Mini-bag Contents
Sodium 2142 2142 2142 2448 2448 2448 2448 2448 2448
Lactate 1927 1927 1927 2233 2233 2233 2233 2233 2233
Bicarbonate 214
214
214
214
214
214
214
214
214
Main Bag and Mini-bag Contents Combined
Sodium 132
132
132
132
132
132
132
132
132
Calcium 3.5
3.5
3.5
3.5
3.5
3.5
2.5
2.5
2.5
Magnesium 1.5
1.5
1.5
0.5
0.5
0.5
0.5
0.5
0.5
Chloride 102
102
102
96
96
96
95
95
95
Lactate 31.5 31.5 31.5 36.5 36.5 36.5 36.5 36.5 36.5
Bicarbonate
ml
Ionic Concentration(mEq/L)
3.5
3.5
3.5
3.5
3.5
3.5
3.5
3.5
3.5
Clinical Pharmacology
st ructu
ra
l
fo
rmu
la
C
N
of chronic r
when nondi
ontrai
one Know
Warning
DELFLEX® Neutral pH
Peritoneal Dialysis Solution
For Intraperitoneal Administration only
MPS 89-905-66
No Latex
Description
DELFLEX® Neutral pH peritoneal dialysis solutions, (standard, low
magnesium and low magnesium/low calcium) are sterile, non-pyrogenic
formulations of dextrose and electrolytes in water for injection, USP, for
use in peritoneal dialysis. In comparison to conventional peritoneal
dialysis solutions, DELFLEX® Neutral pH solutions are formulated to
lower levels of glucose degradation products and provide a neutral pH
of 7.0 ± 0.4, which is closer to physiologic pH. The osmotic and buffer
solutions are stored separately and mixed by the patient prior to use.
Composition, calculated osmolarity, pH and ionic concentrations of the
mixed solutions are shown in Table 2.
D-glucose monohydrate (C6H12O6•H2O) is a
hexose sugar freely soluble in water. It has the
following structural formula:
Calcium Chloride, USP, is chemically designated
calcium chloride dihydrate (CaCl •2H O) white
2
2
fragments or granules freely soluble in water.
Magnesium Chloride, USP, is chemically designated magnesium
chloride hexahydrate (MgCl2•6H2O) colorless flakes or crystals very
soluble in water.
Sodium lactate solution, USP, is chemically designated CH CH(OH)
3
COONa, a 60% aqueous solution miscible in water.
Sodium chloride, USP, is chemically designated NaCl, a white,
crystalline compound freely soluble in water.
Water for injection, USP, is chemically designated H2O.
Hydrochloric acid, and sodium hydroxide may be added for pH
adjustment. pH is 7.0 ± 0.4.
Since the flexible inner bag is compounded from a specific polyvinyl
chloride, water may permeate from the inner bag into the outerwrap
in quantities insufficient to affect the solution significantly. Solutions
in contact with the plastic inner bag can cause certain chemical
components of the bag to leach out in very small amounts; however,
the safety of the plastic formulation is supported by biological tests for
plastic containers.
Nominal glucose degradation product (GDP) levels (immediately
following sterilization) in DELFLEX Neutral pH solution and DELFLEX
solution are reported in Table 1. The clinical relevance of these
differences in GDP levels is unknown.
Table 1. Glucose Degradation Product Levels*
Neutral pH
Dextrose Concentration
DELFLEX®
DELFLEX®
1.5%
23
267
2.5%
51
362
4.25%
106
437
* This is the sum [μmol/L] of the various component GDPs including:
formaldehyde, acetaldehyde, furaldehyde, glyoxal, methylglyoxal, 5-hy-
droxymethylfurfural (5-HMF), and 3-deoxyglucosone (3DG).
89-905-66 Rev 07-11.indd
89-905-66 Rev 07-11.indd 1
Composition, Calculated Osmolarity, pH,
patient receives a kidney transplant. A peritoneal dialysis procedure
Serum calcium levels in patients using low calcium concentrations
infection around a peritoneal catheter, catheter blockage, difficulty in
utilizes the peritoneum (lining of the abdomen) as the semi-permeable
should be monitored and if found to be low, the peritoneal solution in
fluid removal, and ileus are among the complications of the procedure.
and Ionic Concentration
membrane. The procedure is conducted by instilling peritoneal dialysis
use should be altered to one with a higher calcium concentration.
Solution related adverse reactions might include peritonitis, catheter site
solution through a catheter in the abdomen into the peritoneal cavity .
infection, electrolyte and fluid imbalances, hypovolemia, hypervolemia,
Since the peritoneum is heavily supplied with blood vessels, the contact
Precautions
hypertension, hypotension, disequilibrium syndrome and muscle
Table 2. 3 Liter DELFLEX® Neutral pH
of the solution with the peritoneum causes excess water and toxins in
General
cramping.
the bloodstream to be drawn across the membrane into the solution.
Administer only if the solution is clear, all seals are intact, and there is no
If an adverse reaction does occur, institute appropriate therapeutic
This osmosis and diffusion occurs between the plasma of the patient
evidence of leaking. It is important to mix the buffer(mini-bag) and main
procedures according to the patient’s needs and conditions, and
and the peritoneal dialysis solution. After a period of time called ”dwell
solutions thoroughly. Administer within 24 hours after mixing. Once
save the remainder of the fluid in the bag for evaluation if deemed
time,” the solution is then drained from the patient.
solutions are mixed, medication may be added prior to administration.
necessary.
This solution does not contain potassium. In situations in which there
Do Not Heat In A Microwave Oven
Ho
w Supplied
is a normal serum potassium level or hypokalemia, the addition of
potassium chloride (up to a concentration of 4 mEq/L) may be indicated
Care should be taken to see that the catheter is inserted completely,
DELFLEX® peritoneal dialysis solutions are delivered in single-dose
to prevent severe hypokalemia. Addition of potassium chloride should
since leakage around the catheter, if not controlled, can create edema
flexible bags. All DELFLEX® peritoneal dialysis solutions have overfills
be made after careful evaluation of serum and total body potassium
from subcutaneous infiltration of the dialysis solution. This will also
declared on the container label.
The flexible containers have the
and only under the direction of a physician.
create an inaccurate fluid balance measurement.
capacity for drainage in excess of their stated fill volume for ultrafiltration
from the patient.
Clinical studies have demonstrated that the use of low magnesium
Chronic patients that have been stabilized on peritoneal dialysis
solutions resulted in significant increases in serum CO and decreases
therapy should have routine evalutaion of electrolyte blood chemistries
DELFLEX®
2
peritoneal dialysis solutions are available in 3 liter size with
in serum magnesium levels. The decrease in magnesium levels did not
and hematologic factors measured in order to determine the patient’s
the following formulations:
cause clinically significant hypomagnesemia.
ongoing condition.
1.5% Dextrose
®
Indications And Usage
Delflex peritoneal dialysis solutions do not include
potassium.
Potassium chloride should only be added
Ca, mEq/L
3.5 (Standard)
3.5 (Standard)
2.5 (Low)
DELFLEX® peritoneal dialysis solutions are indicated in the treatment
under the direction of a physician after careful evaluation
Mg, mEq/L
1.5 (Standard)
0.5 (Low)
0.5 (Low)
enal failure patients being maintained on peritoneal dialysis
of both ser
alytic medical therapy is judged to be inadequate.
um and total body potassium.
2.5% Dextrose
ndications
Check the inner bag for leaks by gently squeezing the bag before
Ca, mEq/L
3.5 (Standard)
3.5 (Standard)
2.5 (Low)
removing the outer wrap. If after applying pressure on the bag, leaks
Mg, mEq/L
1.5 (Standard)
0.5 (Low)
0.5 (Low)
n
are found, do not use this solution since the sterility of the bag may be
compromised.
4.25% Dextrose
s
Ca, mEq/L
3.5 (Standard)
3.5 (Standard)
2.5 (Low)
Not for Intravenous injection.
The outer wrap must be removed immediately before use and
is provided with a “Tear Open” feature to make removal easy. See
Mg, mEq/L
1.5 (Standard)
0.5 (Low)
0.5 (Low)
Use Aseptic Technique.
detailed instructions in the Directions for Use section.
It is important to mix the buffer (mini-bag) and main solutions thoroughly.
Storage Conditions
Aseptic technique must be used throughout the procedure and at its
Administer within 24 hours after mixing. Once solutions are mixed,
Store at 25° C (77° F); excursions permitted to 15º-30ºC (59º-86ºF). See
termination in order to reduce the possibility of infection.
medication may be added prior to administration.
USP Controlled Room Temperature. Brief exposure to temperatures up
Significant loss of protein, amino acids and water soluble vitamins
to 40ºC/104ºF may be tolerated provided the mean kinetic temperature
Peritoneal dialysis should be done with great care, in patients with a
may occur during peritoneal dialysis. Replacement therapy should be
does not exceed 25ºC (77ºF).
number of conditions, including disruption of the peritoneal membrane
provided as necessary.
or diaphragm by surgery or trauma, extensive adhesions, bowel
Keep DELFLEX and all medicines out of the reach of
distention, undiagnosed abdominal disease, abdominal wall infection,
Laboratory Tests
children.
hernias or burns, fecal fistula or colostomy, tense ascites, obesity, large
Serum electrolytes, magnesium, bicarbonate levels and fluid balance
polycystic kidneys, recent aortic graft replacement, lactic acidosis and
should be periodically monitored.
severe pulmonary disease. When assessing peritoneal dialysis as the
mode of therapy in such extreme situations, the benefits to the patient
Carcinogenesis, Mutagenesis, Impairment of Fertility
must be weighed against the possible complications.
Long term animal studies with DELFLEX® peritoneal dialysis solutions
Solutions containing lactate ion should be used with great care in
have not been performed to evaluate the carcinogenic potential,
patients with metabolic or respiratory alkalosis. Lactate should be
mutagenic potential or effect on fertility.
administered with great care in those conditions in which there is an
Pregnancy: Teratology Effects
increased level or an impaired utilization of this ion, such as severe
hepatic insufficiency.
Pregnancy Category C. Animal reproduction studies have not been
conducted with DELFLEX® peritoneal dialysis solutions. It is also not
An accurate fluid balance record must be kept and the weight of the
known whether DELFLEX® peritoneal dialysis solutions can cause
patient carefully monitored to avoid over or under hydration with severe
fetal harm when administered to a pregnant woman or can affect
consequences, including congestive heart failure, volume depletion
reproduction capacity. DELFLEX® peritoneal dialysis solutions should
and shock.
be given to a pregnant woman only if clearly needed.
Excessive use of DELFLEX® peritoneal dialysis solution with 4.25%
dextrose during a peritoneal dialysis treatment can result in significant
Nursing Mothers
removal of water from the patient.
Caution should be exercised when DELFLEX peritoneal dialysis
®
solutions are administered to a nursing woman.
Stable patients undergoing maintenance peritoneal dialysis should
have routine periodic evaluation of blood chemistries and hematologic
Pediatric Use
factors, as well as other indicators of patient status.
Safety and effectiveness in pediatric patients have not been
After removing the outer wrap, check for minute leaks by squeezing the
Fresenius Medical Care North
established.
container firmly. If leaks are found, discard the solution because the
America
sterility may be impaired. (A small amount of moisture may be present
Adverse Reactions
920 Winter Street
inside the overwrap, which is normal condensation from the sterilization
Adverse reactions occurring with administration of peritoneal dialysis
Peritoneal dialysis is the process of filtering excess water and toxins from
Waltham, MA 02451
process.)
include mechanical and solution related problems as well as the results
the bloodstream through a semi-permeable membrane. This process
1-800-323-5188
of contamination of equipment or improper technique in catheter
does not cure the disease, but prevents progression of symptoms.
placement.
Abdominal pain, bleeding, peritonitis, subcutaneous
Dialysis for chronic kidney failure is essential to maintain life, unless the
Patent Pending
Rev 07/11
10/18/2011
10/18/2011 2:53:40 PM
2:53:40 PM
Reference ID: 3252902
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Main Solution Bag
Mini-bag
Dosage And Administration
DELFLEX® peritoneal dialysis solutions are provided for intraperitoneal
administration only. The mode of therapy, frequency of treatment,
formulation, exchange volume, duration of dwell, and length of dialysis
should be selected by the physician responsible for the treatment of the
individual patient.
To avoid the risk of severe dehydration or hypovolemia and to minimize the
loss of protein, it is advisable to select the peritoneal dialysis solution with
lowest level of osmolarity consistent with the fluid removal requirements
for that exchange.
Not for Intravenous Injection. Do not microwave.
Warm solution as directed by your healthcare provider
Directions for Use
Get Ready
1. Clean work surface. Use aseptic technique.
2. Gather supplies:
• Warmed DELFLEX Neutral pH Peritoneal Dialysis bag
• Prescribed medicine(s), if ordered by your healthcare provider
• Mask
3. Put on mask. Wash your hands.
4. Tear the overwrap across from the slit edge to open. Wipe away any
moisture from the bag. Some opacity may be observed in the plastic
of the bag and/or tubing and is due to moisture absorption during the
sterilization process. This is normal and does not affect the solution
quality or safety. The opacity will diminish gradually.
5. Inspect DELFLEX Solution Bags:
6. Place the DELFLEX solution set on the work surface. See Figure A.
Do not use DELFLEX Neutral pH Solution if:
• leaks are found
• the solution bags are damaged
• solution is cloudy or discolored
• Red cone or blue Safe-Lock connector is broken
Throw away DELFLEX Neutral pH Solution and
notify your healthcare provider.
Mix DELFLEX® Neutral pH Solution
Important: Mix the mini-bag and main bag solutions thoroughly. Use the
solution within 24 hours after mixing.
1. Break the red cone by bending it. See Figure B.
Red Cone
Figure B
2. Fold the mini-bag in half. Squeeze the solution from the mini-bag into
3. Push down on the main solution bag to flush solution back into the
mini-bag. Completely refill the mini-bag with solution. See Figure C
(Step 2).
4. Repeat steps 2 and 3 above to make sure that all of the contents of the
mini-bag have been completely flushed into the main solution bag.
5. Grab the top of the main solution bag. While keeping the bottom portion
of the bag on the table, flip the bag lengthwise using a back and forth
motion to mix the solution. See Figure D. Repeat to mix solution.
Flip over and back
Perform 2 times
Figure D
6. Fold mini-bag in half and squeeze it empty of solution. Slide the folded
mini-bag into the slit of the white cover to show more of the blue Safe-
Lock connector. See Figures E and F.
Mini-bag
Blue Safe-Lock
Connector
White Cover
Figure F
Administer Peritoneal Dialysis Solution
1. If you will be adding medicine(s):
• Clean the medication port as instructed by your healthcare provider.
• Add the medicine(s).
• Turn the bag upside down several times to mix the medicine.
2. Take off the protective cap from the blue Safe-Lock® connector at the
bottom of the mini-bag. Connect the blue Safe-Lock® connector to the
mating Safe-Lock® connector on the fluid delivery set connected to the
PD cycler machine.
3. Remove your mask. Do not open the system during fluid exchange.
4. Break the blue Safe-Lock connector tip as shown in Figure G to start
solution flow.
White Cover
Blue Safe-Lock
Connector Tip
• Squeeze the main solution bag and the mini-bag to check for leaks.
the main solution bag by pressing the two halves together until the mini-
The solution is now ready for use.
bag is empty. See Figure C (Step 1).
• When squeezing the mini-bag, the bag should remain firm and no
solution should leak into the main solution bag or from the blue Safe-
Lock® connector.
Mini-bag
Do Not Microwave
Red Cone
STEP 1
Figure G
Mini-bag
5. Look at the drained fluid for cloudiness. Measure the amount of fluid
STEP 2
drained. Throw away the fluid and used set as instructed by your
White Cover
healthcare provider. In case of cloudiness, save the fluid and the used
Blue Safe-Lock
PUSH
set and immediately contact your healthcare provider.
Connector
DOWN
INSPECT
Figure E
Figure A
Figure C
89-905-66 Rev 07-11.indd Sec1:2
10/18/2011 2:53:48 PM
Reference ID: 3252902
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
9/13/2011 4:26:47 PM
9/13/2011 4:26:47 PM
st
r
uctura
l
formu
la
89-908-85 rev 07-11.indd 1
DELFLEX®
Dextrose Peritoneal Dialysis Solutions
With Attached stay•safe® Exchange Set
For Intraperitoneal Administration Only
89-908-85 rev 07/11
DESCRIPTION
The DELFLEX peritoneal dialysis solutions, standard, low magnesium and low magnesium/low calcium, are sterile, non-pyrogenic formulations of Dextrose and Electrolytes in Water
for Injection, USP, for use in peritoneal dialysis. The stay•safe exchange set utilizes an easy to use dial designed to eliminate the use of clamps and to prevent touch contamination of
internal connection components. Composition, calculated osmolarity, pH and ionic concentrations are shown in the following table.
chart
Calcium with 4.25% Dextrose
Hydrochloric Acid or Sodium Hydroxide may be added for pH adjustment; pH is 5.5 (5.0
Clinical studies have demonstrated that the use of low magnesium solutions resulted
- 6.0) Dextrose USP, is chemically designated D-glucose monohydrate (C6H12O6 • H2O)
in significant increases in serum CO2 and decreases in serum magnesium levels. The
a hexose sugar freely soluble in water. It has the following structural formula:
decrease in magnesium levels did not cause clinically significant hypomagnesemia.
These solutions do not contain antimicrobial agents or additional buffers. Exposure to
None Known.
temperatures above 25°C/77°F during transport and storage will lead to minor losses
in moisture content. Higher temperatures lead to greater losses. It is unlikely that
WARNINGS
these minor losses will lead to clinically significant changes within the expiration period.
Since the flexible inner bag is compounded from a specific polyvinyl chloride, water
Not for Intravenous Injection.
may permeate from the inner bag into the outerwrap in quantities insufficient to affect
Use Aseptic Technique.
the solution significantly. Solutions in contact with the plastic inner bag can leach out
certain of its chemical components in very small amounts; however, the safety of the
Peritoneal dialysis should be done with great care, in patients with a number of
plastic formulation is supported by biological tests for plastic containers.
conditions, including disruption of the peritoneal membrane or diaphragm by surgery
or trauma, extensive adhesions, bowel distention, undiagnosed abdominal disease,
abdominal wall infection, hernias or burns, fecal fistula or colostomy, tense ascites,
CLINICAL PHARMACOLOGY
obesity, large polycystic kidneys, recent aortic graft replacement, lactic acidosis and
Peritoneal dialysis is the process of filtering excess water and toxins from the bloodstream
severe pulmonary disease. When assessing peritoneal dialysis as the mode of therapy
through a semi-permeable membrane. This process does not cure the disease, but
in such extreme situations, the benefits to the patient must be weighed against the
prevents progression of symptoms. Dialysis for chronic kidney failure is essential to
possible complications.
maintain life, unless the patient receives a kidney transplant. A peritoneal dialysis
procedure utilizes the peritoneum (lining of the abdomen) as the semi-permeable
Solutions containing lactate ion should be used with great care in patients with
membrane. The procedure is conducted by instilling peritoneal dialysis solution through
metabolic or respiratory alkalosis. Lactate should be administered with great care in
a catheter in the abdomen into the peritoneal cavity. Since the peritoneum is heavily
those conditions in which there is an increased level or an impaired utilization of this ion,
supplied with blood vessels, the contact of the solution with the peritoneum causes
such as severe hepatic insufficiency.
excess water and toxins in the bloodstream to be drawn across the membrane into the
An accurate fluid balance record must be kept and the weight of the patient carefully
solution. This osmosis and diffusion occurs between the plasma of the patient and the
monitored to avoid over or under hydration with severe consequences, including
peritoneal dialysis solution. After a period of time called “dwell time,” the solution is
congestive heart failure, volume depletion and shock.
then drained from the patient.
Excessive use of DELFLEX peritoneal dialysis solution with 4.25% dextrose during a
This solution does not contain potassium. In situations in which there is a normal
peritoneal dialysis treatment can result in significant removal of water from the patient.
serum potassium level or hypokalemia, the addition of potassium chloride (up to a
concentration of 4 mEq/L) may be indicated to prevent severe hypokalemia. ADDITION
Stable patients undergoing maintenance peritoneal dialysis should have routine
OF POTASSIUM CHLORIDE SHOULD BE MADE AFTER CAREFUL EVALUATION OF
periodic evaluation of electrolyte blood chemistries and hematologic factors, as well as
SERUM AND TOTAL BODY POTASSIUM AND ONLY UNDER THE DIRECTION OF A
other indicators that determine the patient’s ongoing status.
PHYSICIAN.
After removing the outer wrap, check for minute leaks by squeezing the container firmly.
If leaks are found, discard the solution because the sterility may be impaired.
89-908-85 rev 07-11.indd 1
INDICATIONS AND USAGE
DELFLEX peritoneal dialysis solutions are indicated in the treatment of chronic renal
failure patients being maintained on continuous ambulatory peritoneal dialysis when
nondialytic medical therapy is judged to be inadequate.
CONTRAINDICATIONS
Reference ID: 3252902
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
89-908-85 rev 07-11.indd 2
9/13/2011 4:26:57 PM
Serum calcium levels in patients using low calcium concentrations should be monitored
and if found to be low, the peritoneal solution in use should be altered to one with a higher
calcium concentration.
PRECAUTIONS
General:
Do not administer unless the solution is clear, all seals are intact, and there is no evidence
of leaking.
Care should be taken to see that the catheter is inserted completely, since leakage
around the catheter, if not controlled, can create edema from subcutaneous infiltration of
the dialysis solution. This will also create an inaccurate fluid balance measurement.
DELFLEX® Peritoneal Dialysis solutions do not include potassium. Potassium chloride
should only be added under the direction of a physician after careful evaluation of both
serum and total body potassium.
The overwrap must be removed immediately before use and is provided with a “Tear
Open” feature to make removal easy. See instructions in Exchange Procedure section.
Disconnect from disk only when knob is in position 4 (••••).
Aseptic technique must be used throughout the procedure and at its termination in order
to reduce the possibility of infection.
Significant loss of protein, amino acids and water soluble vitamins may occur during
peritoneal dialysis. Replacement therapy should be provided as necessary.
Laboratory Tests:
Serum electrolytes, magnesium, bicarbonate levels and fluid balance should be
periodically monitored.
Carcinogenesis, Mutagenesis, Impairment of Fertility:
Long term animal studies with DELFLEX peritoneal dialysis solutions have not been
performed to evaluate the carcinogenic potential, mutagenic potential or effect on
fertility.
Pregnancy: Teratology Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with
DELFLEX peritoneal dialysis solutions. It is also not known whether DELFLEX peritoneal
dialysis solutions can cause fetal harm when administered to a pregnant woman or can
affect reproduction capacity. DELFLEX peritoneal dialysis solutions should be given to a
pregnant woman only if clearly needed.
Nursing Mothers:
Caution should be exercised when DELFLEX peritoneal dialysis solutions are administered
to a nursing woman.
Pediatric Use:
Safety and effectiveness in pediatric patients have not been established.
ADVERSE REACTIONS
Adverse reactions to peritoneal dialysis include mechanical and solution related problems
as well as the results of contamination of equipment or improper technique in catheter
placement. Abdominal pain, bleeding, peritonitis, subcutaneous infection around a
peritoneal catheter, catheter blockage, difficulty in fluid removal, and ileus are among the
complications of the procedure. Solution related adverse reactions may include peritonitis,
catheter site infection, electrolyte and fluid imbalances, hypovolemia, hypervolemia,
hypertension, hypotension, disequilibrium syndrome and muscle cramping.
If an adverse reaction does occur, institute appropriate therapeutic procedures according
to the patient’s needs and conditions, and save the remainder of the fluid in the bag for
evaluation if deemed necessary.
DOSAGE AND ADMINISTRATION
DELFLEX peritoneal dialysis solutions are provided for intraperitoneal administration only.
The mode of therapy, frequency of treatment, formulation, exchange volume, duration
of dwell, and length of dialysis should be selected by the physician responsible for the
treatment of the individual patient.
To avoid the risk of severe dehydration or hypovolemia and to minimize the loss of protein,
it is advisable to select the peritoneal dialysis solution with lowest level of osmolarity
consistent with the fluid removal requirements for that exchange.
Parenteral drug products should be inspected visually for particulate matter and
discoloration prior to administration whenever solution and container permit.
Additives may be incompatible. Do not store solutions containing additives.
For administration see Exchange Procedure section.
HOW SUPPLIED
DELFLEX peritoneal dialysis solutions are delivered in single-dose flexible bags. All
DELFLEX peritoneal dialysis solutions have overfills declared on the container label. The
flexible containers have the capacity for drainage in excess of their stated fill volume for
ultrafiltration from the patient.
DELFLEX peritoneal dialysis solutions with an attached stay•safe® exchange set are
available in containers as shown in the table in the Description section.
Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F). See USP Controlled
Room Temperature. Brief exposure to temperatures up to 40°C/104°F may be tolerated
provided the mean kinetic temperature does not exceed 25°C (77°F). However, such
exposure should be minimized.
89-908-85 rev 07-11.indd 2
EXCHANGE PROCEDURE (Aseptic technique is required)
1. Clean work surface.
2. Gather supplies:
- Warmed stay•safe® Container
- povidone iodine prefilled stay•safe cap
- stay•safe Organizer (Optional)
- Supplies if adding medication.
3. Close stay•safe extension set clamp.
4. Mask, then wash hands.
5. Open the stay•safe container by tearing from a notched edge of the package
overwrap. Wipe any moisture from the container. Some opacity may be observed
in the plastic of the bag and/or tubing and is due to moisture absorption during the
sterilization process. This is normal and does not affect the solution quality or safety.
The opacity will diminish gradually.
6. Place the stay•safe set on the work surface. Separate the fill and drain bag.
7. Verify the integrity of the solution bag by squeezing the bag to check that there are no
leaks and the solution looks clear. Color variation from clear to slightly yellow will not
affect the product efficacy and may still be used. Check the expiration date. Check
for correct dextrose concentration. Do not use if there is any doubt about the integrity
of the solution or packaging.
8. Turn the position indicator on the stay•safe disc
counter-clockwise until it fits into the cut-out
portion of the colored plastic cover on the disc as
illustrated in Figure 1. Remove the plastic cover
while the indicator is in this position (position 1; •).
Once the cover is removed, do not turn counter
clockwise.
9. If adding medication, prep the medication
port as instructed and add the prescribed
medication. Invert the bag several times to mix
the medication.
10. Hang the solution bag on an I.V. pole and place the drain bag at floor level. Break the
frangible in the solution bag outlet port. (If using the organizer, place the stay•safe
disc in the organizer as illustrated in Figure 2.) usage illustratiion
Figure 1
11. Remove the stay•safe cap from it’s
packaging. (If using the organizer, place
in the right or left notch of the organizer as
illustrated in Figure 2. Place the stay•safe
Extension Set in the other notch of the
organizer.)
12. Remove the protective cap from the
stay•safe disc and discard. Remove the
cap from the extension set by twisting the
connection counter-clockwise. (If using
the organizer, leave the capped end of
the extension set in the organizer and
twist the extension set connector counter
clockwise to remove the set from its cap.)
Aseptically connect the extension set
to the connector on the stay•safe disc.
Twist clockwise to secure the connection. usage illustratiion
13. Remove your mask. The system will not be opened again during the exchange.
14. Open the extension set clamp. Patient outflow (drain) will start immediately.
15. When patient drain is complete, turn the disc position indicator to Position 2 (••). This
will start the flush from the solution bag to the drain bag.
16. After approximately 5 seconds, turn the disc position indicator to Position 3 (•••).
This will start the patient fill.
17. When fill is complete, turn the disc position indicator to Position 4 (••••). This
will insert the closure pin of the disc into the extension set connector and seal the
system.
18. Remove the white protective cover from the new stay•safe cap and reserve for later
use. Do not discard.
19. Remove the extension set from stay•safe disc and attach the new stay•safe cap.
Twist clockwise to secure the connection.
20. Seal the disc by attaching the white protective cover from the stay•safe cap to the
disc connector. Twist clockwise to secure the connection and prevent leakage from
the used system.
21. Observe the drained dialysate for cloudiness and measure the amount drained.
Discard fluid and used set as instructed by the training facility. In case of cloudiness,
save the fluid and the exchange set and immediately call the dialysis center. company logo
Fresenius Medical Care
Fresenius Medical Care North America
920 Winter Street
Waltham, MA 02451
1-800-323-5188
89-908-85 REV 07/11
9/13/2011 4:26:57 PM
Reference ID: 3252902
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2011 2:12:32 P
2011 2:12:32 P
10/18/
DELFLEX®
Dextrose Peritoneal Dialysis Solutions
For Intraperitoneal Administration Only
DESCRIPTION
The DELFLEX peritoneal dialysis solutions, standard, low magnesium, and low magnesium/low calcium, are sterile, non-pyrogenic
formulations of Dextrose and Electrolytes in Water for Injection, USP, for use in peritoneal dialysis. These solutions do not contain
antimicrobial agents or additional buffers. Exposure to temperatures above 25°C/77°F during transport and storage will lead to minor
losses in moisture content. Higher temperatures lead to greater losses. It is unlikely that these minor losses will lead to clinically
significant changes within the expiration period.
Each 100 mL of standard dialysis solution contains 1.5,
Each 100 mL of low magnesium, low calcium dialysis
2.5 or 4.25 g Dextrose, Hydrous, USP, 567 mg Sodium
solution contains 1.5, 2.5 or 4.25 g Dextrose, Hydrous,
Chloride, USP, 392 mg Sodium Lactate, 25.7 mg Calcium
USP, 538 mg Sodium Chloride, USP, 448 mg Sodium
Chloride, USP, 15.2 mg Magnesium Chloride, USP, q.s.
Lactate, 18.4 mg Calcium Chloride, USP, 5.08 mg
Water for Injection, USP, Hydrochloric Acid or Sodium
Magnesium Chloride, USP, q.s. Water for Injection, USP,
Hydroxide may be added for pH adjustment; pH is 5.5
Hydrochloric Acid or Sodium Hydroxide may be added
(5.0-6.0).
for pH adjustment; pH is 5.5 (5.0-6.0).
DELFLEX
DELFLEX
WITH DEXTROSE
LOW MAGNESIUM, LOW CALCIUM
Peritoneal Dialysis Solutions
WITH DEXTROSE
Peritoneal Dialysis Solutions
With 1.5%
With 2.5%
With 4.25%
Dextrose
Dextrose
Dextrose
With 1.5%
With 2.5%
With 4.25%
Dextrose
Dextrose
Dextrose
Dextrose, H2O
15 g/L
25 g/L
42.5 g/L
Sodium
132 mEq/L
132 mEq/L
132 mEq/L
Dextrose, H2O
15 g/L
25 g/L
42.5 g/L
Calcium
3.5 mEq/L
3.5 mEq/L
3.5 mEq/L
Sodium
132 mEq/L
132 mEq/L
132 mEq/L
Magnesium
1.5 mEq/L
1.5 mEq/L
1.5 mEq/L
Calcium
2.5 mEq/L
2.5 mEq/L
2.5 mEq/L
Chloride
102 mEq/L
102 mEq/L
102 mEq/L
Magnesium
0.5 mEq/L
0.5 mEq/L
0.5 mEq/L
Lactate
35 mEq/L
35 mEq/L
35 mEq/L
Chloride
95 mEq/L
95 mEq/L
95 mEq/L
Total Osmolarity
347 mOsmol/L
398 mOsmol/L
486 mOsmol/L
Lactate
40 mEq/L
40 mEq/L
40 mEq/L
PH (5.0 - 6.0)
5.5
5.5
5.5
Total Osmolarity
344 mOsmol/L
394 mOsmol/L
483 mOsmol/L
The total osmolarities shown in the
PH (5.0 - 6.0)
5.5
5.5
5.5
above table are calculated theoretically.
The total osmolarities shown in the
above table are calculated theoretically.
Each 100 mL of low magnesium dialysis solution
Dextrose USP, is chemically designated
contains 1.5, 2.5 or 4.25 g Dextrose, Hydrous, USP, 538
mg Sodium Chloride, USP, 448 mg Sodium Lactate,
D-glucose monohydrate (C6H12O6•H2O) a hexose sugar
25.7 mg Calcium Chloride, USP, 5.08 mg Magnesium
freely soluble in water. It has the following structural
Chloride, USP, q.s. Water for Injection, USP, Hydrochloric
formula:
Acid or Sodium Hydroxide may be added for pH
struct
ur
al
form
ula
adjustment; pH is 5.5 (5.0-6.0).
DELFLEX
LOW MAGNESIUM WITH DEXTROSE
Peritoneal Dialysis Solutions
With 1.5%
With 2.5%
With 4.25%
Dextrose
Dextrose
Dextrose
Calcium Chloride, USP, a chemically designated calcium
Dextrose, H2O
15 g/L
25 g/L
42.5 g/L
chloride dihydrate (CaCl2•2H2O) white fragments or
Sodium
132 mEq/L
132 mEq/L
132 mEq/L
granules freely soluble in water.
Calcium
3.5 mEq/L
3.5 mEq/L
3.5 mEq/L
Magnesium
0.5 mEq/L
0.5 mEq/L
0.5 mEq/L
Chloride
96 mEq/L
96 mEq/L
96 mEq/L
Magnesium Chloride, USP, is chemically designated
Lactate
40 mEq/L
40 mEq/L
40 mEq/L
magnesium
chloride
hexahydrate
(MgCl2•6H2O)
Total Osmolarity
346 mOsmol/L
396 mOsmol/L
485 mOsmol/L
colorless flakes or crystals very soluble in water.
PH (5.0 - 6.0)
5.5
5.5
5.5
The total osmolarities shown in the
Sodium Lactate Solution, USP, is chemically designated
above table are calculated theoretically.
CH3CH(OH)COONa, a 60% aqueous solution miscible
in water.
Sodium Chloride, USP, is chemically designated NaCI, a
white, crystalline compound freely soluble in water.
89-905-61 REV 07/11
10/18/
M
89-905-61 rev 07-11.indd 1-2
DOSAGE AND ADMINISTRATION
Parenteral drug products should be inspected visually for
particulate matter and discoloration prior to administration
DELFLEX® peritoneal dialysis solutions are provided
whenever solution and container permit.
for intraperitoneal administration only. The mode of
therapy, frequency of treatment, formulation, exchange
volume, duration of dwell, and length of dialysis should
be selected by the physician responsible for the treatment
of the individual patient.
To avoid the risk of severe dehydration or hypovolemia
and to minimize the loss of protein, it is advisable to
select the peritoneal dialysis solution with lowest level of
osmolarity consistent with the fluid removal requirements
for that exchange.
To Open
DELFLEX peritoneal dialysis solution flexible bags are
supplied in an overwrap pouch. This outer wrap must
be opened and removed immediately before use of the
product and is provided with a “Tear Open” feature to
make opening easy.
Check the solution to assure that it is clear. Hold the bag
up to a light source and visually inspect for particulate
matter and discoloration prior to administration. Color
may vary from clear to slightly yellow but does not affect
efficacy and may be used. Some opacity may be observed
in the plastic of the bag and/or tubing and is due to
moisture absorption during the sterilization process. This
is normal and does not affect the solution quality or safety.
The opacity will diminish gradually.
To Connect (Aseptic Technique is Required)
DELFLEX peritoneal dialysis solutions utilize a Safe-Lock®
Connection System. This unique system consists of two
Safe-Lock connectors, one located on the administration
port of the bag, and the mating connector is located on
the fluid delivery set. The Safe-Lock connectors were
designed to prevent touch contamination of the internal
connection components.
To connect the bag to the fluid delivery set, unscrew the
protective caps of the bag connector and fluid delivery set
connector. Secure these two connectors with a twisting
motion to lock in place, so that the fluid delivery set
connector is seated over the bag connector O-Ring to
assure a firm and tight fit.
Once the fluid delivery set is secured, to initiate solution
flow, break the cone of the bag connector by placing the
thumb firmly on the tube over the cone and pressing
towards the outer wall of the tube and away from the bag.
Once the cone is broken, a white retaining guide maintains
the cone at a specific distance from the connector so it
will not impede the flow of solution through the Safe-Lock
connector.
Additives may be incompatible. Do not store solutions
containing additives.
HOW SUPPLIED
DELFLEX peritoneal dialysis solutions are delivered in
single-dose flexible bags. All Delflex peritoneal dialysis
solutions have overfills declared on the container label.
The flexible containers have the capacity for drainage in
excess of their stated fill volume for ultrafiltration from the
patient.
DELFLEX peritoneal dialysis solutions are available in the
following sizes and formulations:
1.5% Dextrose
Ca, mEq/L
3.5 (Standard)
3.5 (Standard)
2.5 (Low)
Mg, mEq/L
1.5 (Standard)
0.5 (Low)
0.5 (Low)
1 liter
X
X
X
1.5 liter/2 L bag
X
X
X
2 liter
X
X
X
2 liter/3 L bag
X
X
X
2.5 liter/3 L bag
X
X
X
3 liter
X
X
X
5 liter
X
X
X
2.5% Dextrose
Ca, mEq/L
3.5 (Standard)
3.5 (Standard)
2.5 (Low)
Mg, mEq/L
1.5 (Standard)
0.5 (Low)
0.5 (Low)
1 liter
X
X
X
1.5 liter/2 L bag
X
X
X
2 liter
X
X
2 liter/3 L bag
X
X
X
2.5 liter/3 L bag
X
X
X
3 liter
X
X
X
5 liter
X
X
X
4.25% Dextrose
Ca, mEq/L
3.5 (Standard)
3.5 (Standard)
2.5 (Low)
Mg, mEq/L
1.5 (Standard)
0.5 (Low)
0.5 (Low)
1 liter
X
X
X
1.5 liter/2 L bag
X
X
X
2 liter
X
X
2 liter/3 L bag
X
X
X
2.5 liter/3 L bag
X
X
X
3 liter
X
X
X
5 liter
X
X
X
STORAGE CONDITIONS
STORE AT ROOM TEMPERATURE (25° C).
Protect from freezing and extreme heat.
company logo
Fresenius Medical Care North America
920 Winter Street
Waltham, MA 02451
1-800-323-5188
4
89-905-61 REV 07/11
89-905-61 rev 07-11.indd 1-2
Reference ID: 3252902
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PRECAUTIONS
Pregnancy: Teratology Effects
General:
Pregnancy Category C. Animal reproduction studies have
DELFLEX® peritoneal dialysis solution should not be
not been conducted with DELFLEX peritoneal dialysis
administered unless it is clear, all seals are intact and
solutions. It is also not known whether DELFLEX peritoneal
there is no evidence of leaking.
dialysis solutions can cause fetal harm when administered
to a pregnant woman or can affect reproduction capacity.
Care should be taken to see that the catheter is inserted
DELFLEX peritoneal dialysis solutions should be given to
completely, since leakage around the catheter, if not
a pregnant woman only if clearly needed.
controlled, can create edema from subcutaneous
infiltration of the dialysis solution. This will also create an
Nursing Mothers:
inaccurate fluid balance measurement.
Caution should be exercised when DELFLEX peritoneal
Chronic patients that have been stabilized on peritoneal
dialysis solutions are administered to a nursing woman.
dialysis therapy should have routine evaluation of
electrolyte blood chemistries and hematologic factors
Pediatric Use:
measured in order to determine the patient’s ongoing
Safety and effectiveness in pediatric patients have not
condition.
been established.
DELFLEX PERITONEAL DIALYSIS SOLUTIONS
ADVERSE REACTIONS
DO NOT INCLUDE POTASSIUM. POTASSIUM
CHLORIDE SHOULD ONLY BE ADDED UNDER THE
Adverse reactions occurring with administration of
peritoneal dialysis include mechanical and solution
DIRECTION OF A PHYSICIAN AFTER CAREFUL
related problems as well as the results of contamination of
EVALUATION OF BOTH SERUM AND TOTAL BODY
equipment or improper techni
que in catheter placement.
POTASSIUM.
Abdominal pain, bleeding, peritonitis, subcutaneous
Check the inner bag for leaks by gently squeezing the bag
infection around a peritoneal catheter, catheter blockage,
before removing the outer wrap. If after applying pressure
difficulty in fluid removal, and ileus are among the
on the bag, leaks are found, do not use this solution since
complications of the procedure. Solution related
the sterility of the bag may be compromised.
adverse reactions may include peritonitis, catheter site
infection, electrolyte and fluid imbalances, hypovolemia,
The outer wrap must be removed immediately before
hypervolemia, hypertension, hypotension, disequilibrium
use and is provided with a “Tear Open” feature to make
syndrome and muscle cramping.
removal easy. See detailed instructions in this insert’s last
page.
If an adverse reaction does occur, institute appropriate
Aseptic technique must be used throughout the procedure
therapeutic procedures according to the patient’s
and at its termination in order to reduce the possibility of
needs and conditions, and save the remainder of the
infection.
fluid in the bag for evaluation if deemed necessary.
Significant loss of protein, amino acids and water
soluble vitamins may occur during peritoneal dialysis.
Replacement therapy should be provided as necessary.
Laboratory Tests:
Serum electrolytes, magnesium, bicarbonate levels and
fluid balance should be periodically monitored.
Carcinogenesis,
Mutagenesis,
Impairment
of
Fertility:
Long term animal studies with DELFLEX peritoneal
dialysis solutions have not been performed to evaluate
the carcinogenic potential, mutagenic potential or effect
on fertility.
3
10/18/2011 2:12:38 PM
89-905-61 REV 07/11
10/18/2011 2:12:38 PM
89-905-61 rev 07-11.indd Sec1:2-Sec1:3
Water for injection, USP, is chemically designated H2O.
CONTRAINDICATIONS:
Since the flexible inner bag is compounded from a
None Known
specific polyvinyl chloride, water may permeate from the
WARNINGS:
inner bag into the outerwrap in quantities insufficient to
affect the solution significantly. Solutions in contact with
Not for Intravenous injection.
the plastic inner bag can leach out certain of its chemical
Use Aseptic Technique.
components in very small amounts; however, the safety of
the plastic formulation is supported by biological tests for
Peritoneal dialysis should be done with great care, in
plastic containers.
patients with a number of conditions, including disruption
of the peritoneal membrane or diaphragm by surgery
CLINICAL PHARMACOLOGY
or trauma, extensive adhesions, bowel distention,
Peritoneal dialysis is the process of filtering excess water
undiagnosed
abdominal
disease,
abdominal
wall
and toxins from the bloodstream through a semi-permeable
infection, hernias or burns, fecal fistula or colostomy,
membrane. This process does not cure the disease, but
tense ascites, obesity, large polycystic kidneys, recent
prevents progression of symptoms. Dialysis for chronic
aortic graft replacement, lactic acidosis and severe
kidney failure is essential to maintain life, unless the
pulmonary disease. When assessing peritoneal dialysis
patient receives a kidney transplant. A peritoneal dialysis
as the mode of therapy in such extreme situations, the
procedure utilizes the peritoneum (lining of the abdomen)
benefits to the patient must be weighed against the
as the semi-permeable membrane. The procedure is
possible complications.
conducted by instilling peritoneal dialysis solution through
Solutions containing lactate ion should be used with great
a catheter in the abdomen into the peritoneal cavity. Since
care in patients with metabolic or respiratory alkalosis.
the peritoneum is heavily supplied with blood vessels,
Lactate should be administered with great care in those
the contact of the solution with the peritoneum causes
conditions in which there is an increased level or an
excess water and toxins in the bloodstream to be drawn
impaired utilization of this ion, such as severe hepatic
across the membrane into the solution. This osmosis
insufficiency.
and diffusion occurs between the plasma of the patient
and the peritoneal dialysis solution. After a period of time
An accurate fluid balance record must be kept and the
called ”dwell time,” the solution is then drained from the
weight of the patient carefully monitored to avoid over
patient.
or under hydration with severe consequences, including
congestive heart failure, volume depletion and shock.
This solution does not contain potassium. In situations
in which there is a normal serum potassium level or
Excessive use of DELFLEX peritoneal dialysis solution
hypokalemia, the addition of potassium chloride (up to a
with 4.25% dextrose during a peritoneal dialysis treatment
concentration of 4 mEq/L) may be indicated to prevent
can result in significant removal of water from the patient.
severe hypokalemia.
Addition of potassium chloride
Stable patients undergoing maintenance peritoneal
should be made after careful evaluation of serum and
dialysis should have routine periodic evaluation of blood
total body potassium and only under the direction of a
chemistries and hematologic factors, as well as other
physician.
indicators of patient status.
Clinical studies have demonstrated that the use of low
After removing the outer wrap, check for minute leaks by
magnesium solutions resulted in significant increases in
squeezing the container firmly. If leaks are found, discard
serum CO2
and decreases in serum magnesium levels.
the solution because the sterility may be impaired.
The decrease in magnesium levels did not cause clinically
Serum calcium levels in patients using low calcium
significant hypomagnesemia.
concentrations should be monitored and if found to be
INDICATIONS AND USAGE
low, the peritoneal solution in use should be altered to
one with a higher calcium concentration.
DELFLEX® peritoneal dialysis solutions are indicated
in the treatment of chronic renal failure patients being
maintained on continuous ambulatory peritoneal dialysis
when nondialytic medical therapy is judged to be
inadequate.
2
89-905-61 REV 07/11
89-905-61 rev 07-11.indd Sec1:2-Sec1:3
Reference ID: 3252902
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
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2025-02-12T13:46:59.418334
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/018883s044,020171s026lbl.pdf', 'application_number': 20171, 'submission_type': 'SUPPL ', 'submission_number': 26}
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Figure 1: DELFLEX® Conventional with stay•safe® Exchange Set– 2.5% Dextrose,
Low Mg/Low Ca
Figure 2: DELFLEX® Conventional with stay•safe® Exchange Set – 4.25% Dextrose,
Low Mg/Standard Ca
Reference ID: 3683488
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Figure 3: DELFLEX® Neutral pH with stay•safe® Exchange Set – 1.5% Dextrose,
Low Mg/Low Ca
Figure 4: DELFLEX® Neutral pH with stay•safe® Exchange Set – 2.5% Dextrose,
Low Mg/Standard Ca
Reference ID: 3683488
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Figure 5: DELFLEX® Neutral pH with stay•safe® Exchange Set – 1.5% Dextrose,
Standard Mg/Standard Ca
Figure 6: DELFLEX® Conventional – 4.25% Dextrose, Low Mg/Low Ca
Reference ID: 3683488
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Figure 7: DELFLEX® Conventional – 2.5% Dextrose, Low Mg/Standard Ca
Figure 8: DELFLEX® Conventional – 1.5% Dextrose, Standard Mg/Standard Ca
Reference ID: 3683488
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Figure 9: DELFLEX® Neutral pH – 1.5% Dextrose, Low Mg/Low Ca
Figure 10: DELFLEX® Neutral pH – 1.5% Dextrose, Low Mg/Standard Ca
Reference ID: 3683488
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Figure 11: DELFLEX® Neutral pH – 4.25% Dextrose, Standard Mg/Standard Ca
Reference ID: 3683488
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/018883Orig1s057,020171Orig1s039lbl.pdf', 'application_number': 20171, 'submission_type': 'SUPPL ', 'submission_number': 39}
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NDA 20-180/S-026
Page 3
PROSCAR®
(FINASTERIDE)
TABLETS
DESCRIPTION
PROSCAR* (finasteride), a synthetic 4-azasteroid compound, is a specific inhibitor of steroid Type II
5 -reductase, an intracellular enzyme that converts the androgen testosterone into 5 -dihydrotestosterone
(DHT).
Finasteride is 4-azaandrost-1-ene-17-carboxamide, N-(1,1-dimethylethyl)-3-oxo-,(5 ,17 )-. The empirical
formula of finasteride is C23H36N2O2 and its molecular weight is 372.55. Its structural formula is:
Finasteride is a white crystalline powder with a melting point near 250°C. It is freely soluble in chloroform
and in lower alcohol solvents, but is practically insoluble in water.
PROSCAR (finasteride) tablets for oral administration are film-coated tablets that contain 5 mg of finasteride
and the following inactive ingredients: hydrous lactose, microcrystalline cellulose, pregelatinized starch, sodium
starch glycolate, hydroxypropyl cellulose LF, hydroxypropylmethyl cellulose, titanium dioxide, magnesium
stearate, talc, docusate sodium, FD&C Blue 2 aluminum lake and yellow iron oxide.
CLINICAL PHARMACOLOGY
The development and enlargement of the prostate gland is dependent on the potent androgen,
5 -dihydrotestosterone (DHT). Type II 5 -reductase metabolizes testosterone to DHT in the prostate gland,
liver and skin. DHT induces androgenic effects by binding to androgen receptors in the cell nuclei of these
organs.
Finasteride is a competitive and specific inhibitor of Type II 5 -reductase with which it slowly forms a stable
enzyme complex. Turnover from this complex is extremely slow (t½ ∼ 30 days). This has been demonstrated
both in vivo and in vitro. Finasteride has no affinity for the androgen receptor. In man, the 5 -reduced steroid
metabolites in blood and urine are decreased after administration of finasteride.
In man, a single 5-mg oral dose of PROSCAR produces a rapid reduction in serum DHT concentration, with
the maximum effect observed 8 hours after the first dose. The suppression of DHT is maintained throughout the
24-hour dosing interval and with continued treatment. Daily dosing of PROSCAR at 5 mg/day for up to 4 years
has been shown to reduce the serum DHT concentration by approximately 70%. The median circulating level of
testosterone increased by approximately 10-20% but remained within the physiologic range.
Adult males with genetically inherited Type II 5 -reductase deficiency also have decreased levels of DHT.
Except for the associated urogenital defects present at birth, no other clinical abnormalities related to Type II
5 -reductase deficiency have been observed in these individuals. These individuals have a small prostate gland
throughout life and do not develop BPH.
In patients with BPH treated with finasteride (1-100 mg/day) for 7-10 days prior to prostatectomy, an
approximate 80% lower DHT content was measured in prostatic tissue removed at surgery, compared to
* Registered trademark of MERCK & CO., Inc.
COPYRIGHT © MERCK & CO., Inc., 1992, 1995, 1998
All rights reserved.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-180/S-026
Page 4
placebo; testosterone tissue concentration was increased up to 10 times over pretreatment levels, relative to
placebo. Intraprostatic content of prostate-specific antigen (PSA) was also decreased.
In healthy male volunteers treated with PROSCAR for 14 days, discontinuation of therapy resulted in a
return of DHT levels to pretreatment levels in approximately 2 weeks. In patients treated for three months,
prostate volume, which declined by approximately 20%, returned to close to baseline value after approximately
three months of discontinuation of therapy.
Pharmacokinetics
Absorption
In a study of 15 healthy young subjects, the mean bioavailability of finasteride 5-mg tablets was 63% (range
34-108%), based on the ratio of area under the curve (AUC) relative to an intravenous (IV) reference dose.
Maximum finasteride plasma concentration averaged 37 ng/mL (range, 27-49 ng/mL) and was reached 1-2
hours postdose. Bioavailability of finasteride was not affected by food.
Distribution
Mean steady-state volume of distribution was 76 liters (range, 44-96 liters). Approximately 90% of circulating
finasteride is bound to plasma proteins. There is a slow accumulation phase for finasteride after multiple dosing.
After dosing with 5 mg/day of finasteride for 17 days, plasma concentrations of finasteride were 47 and 54%
higher than after the first dose in men 45-60 years old (n=12) and 70 years old (n=12), respectively. Mean
trough concentrations after 17 days of dosing were 6.2 ng/mL (range, 2.4-9.8 ng/mL) and 8.1 ng/mL (range,
1.8-19.7 ng/mL), respectively, in the two age groups. Although steady state was not reached in this study, mean
trough plasma concentration in another study in patients with BPH (mean age, 65 years) receiving 5 mg/day
was 9.4 ng/mL (range, 7.1-13.3 ng/mL; n=22) after over a year of dosing.
Finasteride has been shown to cross the blood brain barrier but does not appear to distribute preferentially to
the CSF.
In 2 studies of healthy subjects (n=69) receiving PROSCAR 5 mg/day for 6-24 weeks, finasteride
concentrations in semen ranged from undetectable (<0.1 ng/mL) to 10.54 ng/mL. In an earlier study using a less
sensitive assay, finasteride concentrations in the semen of 16 subjects receiving PROSCAR 5 mg/day ranged
from undetectable (<1.0 ng/mL) to 21 ng/mL. Thus, based on a 5-mL ejaculate volume, the amount of
finasteride in semen was estimated to be 50- to 100-fold less than the dose of finasteride (5 g) that had no
effect on circulating DHT levels in men (see also PRECAUTIONS, Pregnancy).
Metabolism
Finasteride is extensively metabolized in the liver, primarily via the cytochrome P450 3A4 enzyme subfamily.
Two metabolites, the t-butyl side chain monohydroxylated and monocarboxylic acid metabolites, have been
identified that possess no more than 20% of the 5α-reductase inhibitory activity of finasteride.
Excretion
In healthy young subjects (n=15), mean plasma clearance of finasteride was 165 mL/min (range, 70-279
mL/min) and mean elimination half-life in plasma was 6 hours (range, 3-16 hours). Following an oral dose of
14C-finasteride in man (n=6), a mean of 39% (range, 32-46%) of the dose was excreted in the urine in the form
of metabolites; 57% (range, 51-64%) was excreted in the feces.
The mean terminal half-life of finasteride in subjects ≥70 years of age was approximately 8 hours (range, 6-
15 hours; n=12), compared with 6 hours (range, 4-12 hours; n=12) in subjects 45-60 years of age. As a result,
mean AUC (0-24 hr) after 17 days of dosing was 15% higher in subjects ≥70 years of age than in subjects 45-
60 years of age (p=0.02).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-180/S-026
Page 5
Special Populations
Pediatric: Finasteride pharmacokinetics have not been investigated in patients <18 years of age.
Gender: Finasteride pharmacokinetics in women are not available.
Geriatric: No dosage adjustment is necessary in the elderly. Although the elimination rate of finasteride is
decreased in the elderly, these findings are of no clinical significance. See also Pharmacokinetics, Excretion,
PRECAUTIONS, Geriatric Use and DOSAGE AND ADMINISTRATION.
Race: The effect of race on finasteride pharmacokinetics has not been studied.
Renal Insufficiency: No dosage adjustment is necessary in patients with renal insufficiency. In patients with
chronic renal impairment, with creatinine clearances ranging from 9.0 to 55 mL/min, AUC, maximum plasma
concentration, half-life, and protein binding after a single dose of 14C-finasteride were similar to values obtained
in healthy volunteers. Urinary excretion of metabolites was decreased in patients with renal impairment. This
decrease was associated with an increase in fecal excretion of metabolites. Plasma concentrations of
metabolites were significantly higher in patients with renal impairment (based on a 60% increase in total
radioactivity AUC). However, finasteride has been well tolerated in BPH patients with normal renal function
receiving up to 80 mg/day for 12 weeks, where exposure of these patients to metabolites would presumably be
much greater.
Hepatic Insufficiency: The effect of hepatic insufficiency on finasteride pharmacokinetics has not been studied.
Caution should be used in the administration of PROSCAR in those patients with liver function abnormalities, as
finasteride is metabolized extensively in the liver.
Drug Interactions (also see PRECAUTIONS, Drug Interactions)
No drug interactions of clinical importance have been identified. Finasteride does not appear to affect the
cytochrome P450-linked drug metabolism enzyme system. Compounds that have been tested in man have
included antipyrine, digoxin, propranolol, theophylline, and warfarin, and no clinically meaningful interactions
were found.
Mean (SD) Pharmacokinetic Parameters
in Healthy Young Subjects (n=15)
Mean (± SD)
Bioavailability
63% (34-108%)*
Clearance (mL/min)
165 (55)
Volume of Distribution (L)
76 (14)
Half-Life (hours)
6.2 (2.1)
*Range
Mean (SD) Noncompartmental Pharmacokinetic Parameters After Multiple Doses of 5
mg/day in Older Men
Mean (± SD)
45-60 years old (n=12)
≥70 years old (n=12)
AUC (ng•hr/mL)
389 (98)
463 (186)
Peak Concentration (ng/mL)
46.2 (8.7)
48.4 (14.7)
Time to Peak (hours)
1.8 (0.7)
1.8 (0.6)
Half-Life (hours)*
6.0 (1.5)
8.2 (2.5)
*First-dose values; all other parameters are last-dose values
Clinical Studies
PROSCAR 5 mg/day was initially evaluated in patients with symptoms of BPH and enlarged prostates by
digital rectal examination in two 1-year, placebo-controlled, randomized, double-blind studies and their 5-year
open extensions.
PROSCAR was further evaluated in the PROSCAR Long-Term Efficacy and Safety Study (PLESS), a
double-blind, randomized, placebo-controlled, 4-year, multicenter study. 3040 patients between the ages of 45
and 78, with moderate to severe symptoms of BPH and an enlarged prostate upon digital rectal examination,
were randomized into the study (1524 to finasteride, 1516 to placebo) and 3016 patients were evaluable for
efficacy. 1883 patients completed the 4-year study (1000 in the finasteride group, 883 in the placebo group).
Effect on Symptom Score
Symptoms were quantified using a score similar to the American Urological Association Symptom Score,
which evaluated both obstructive symptoms (impairment of size and force of stream, sensation of incomplete
bladder emptying, delayed or interrupted urination) and irritative symptoms (nocturia, daytime frequency, need
to strain or push the flow of urine) by rating on a 0 to 5 scale for six symptoms and a 0 to 4 scale for one
symptom, for a total possible score of 34.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-180/S-026
Page 6
Patients in PLESS, had moderate to severe symptoms at baseline (mean of approximately 15 points on a 0-
34 point scale). Patients randomized to PROSCAR who remained on therapy for 4 years had a mean (± 1 SD)
decrease in symptom score of 3.3 (± 5.8) points compared with 1.3 (± 5.6) points in the placebo group. (See
Figure 1.) A statistically significant improvement in symptom score was evident at 1 year in patients treated with
PROSCAR vs placebo (–2.3 vs –1.6), and this improvement continued through Year 4.
Baseline
Year 1
Year 2
Year 3
Year 4
Mean Change from Baseline ± 1 SE
n =
n =
Placebo
Finasteride
1296
1314
1438
1437
1101
1153
961
1047
855
965
-3
-4
-5
-6
-2
-1
0
Figure 1
Symptom Score in PLESS
Results seen in earlier studies were comparable to those seen in PLESS. Although an early improvement in
urinary symptoms was seen in some patients, a therapeutic trial of at least 6 months was generally necessary to
assess whether a beneficial response in symptom relief had been achieved. The improvement in BPH
symptoms was seen during the first year and maintained throughout an additional 5 years of open extension
studies.
Effect on Acute Urinary Retention and the Need for Surgery
In PLESS, efficacy was also assessed by evaluating treatment failures. Treatment failure was prospectively
defined as BPH-related urological events or clinical deterioration, lack of improvement and/or the need for
alternative therapy. BPH-related urological events were defined as urological surgical intervention and acute
urinary retention requiring catheterization. Complete event information was available for 92% of the patients.
The following table (Table 1) summarizes the results.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-180/S-026
Page 7
Table 1
All Treatment Failures in PLESS
Patients (%) *
Event
Placebo
N=1503
Finasteride
N=1513
Relative
Risk**
95% CI
P
Value**
All Treatment Failures
37.1
26.2
0.68
(0.57 to 0.79)
<0.001
Surgical
Interventions for
BPH
10.1
4.6
0.45
(0.32 to 0.63)
<0.001
Acute Urinary
Retention
Requiring
Catheterization
6.6
2.8
0.43
(0.28 to 0.66)
<0.001
Two consecutive
symptom scores
≥20
9.2
6.7
Bladder Stone
0.4
0.5
Incontinence
2.1
1.7
Renal Failure
0.5
0.6
UTI
5.7
4.9
Discontinuation
due to worsening
of BPH, lack of
improvement, or
to receive other
medical treatment
21.8
13.3
*patients with multiple events may be counted more than once for each type of event
**Hazard ratio based on log rank test
Compared with placebo, PROSCAR was associated with a significantly lower risk for acute urinary retention
or the need for BPH-related surgery [13.2% for placebo vs 6.6% for PROSCAR; 51% reduction in risk, 95% CI:
(34 to 63%)]. Compared with placebo, PROSCAR was associated with a significantly lower risk for surgery
[10.1% for placebo vs 4.6% for PROSCAR; 55% reduction in risk, 95% CI: (37 to 68%)] and with a significantly
lower risk of acute urinary retention [6.6% for placebo vs 2.8% for PROSCAR; 57% reduction in risk, 95% CI:
(34 to 72%)]; See Figures 2 and 3.
0
0%
4
8
12
16
20
24
40
36
44
48
28
32
Observation Time (Month)
Finasteride
Placebo
Percent of Patients
15%
10%
5%
Figure 2
Percent of Patients Having Surgery for BPH,
Including TURP
Placebo Group
No. of events, cumulative
No. at risk, per year
37
1503
89
1454
121
1374
152
1314
Finasteride Group
No. of events, cumulative
No. at risk, per year
18
1513
40
1483
49
1438
69
1410
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NDA 20-180/S-026
Page 8
0
0%
4
8
Placebo Group
No. of events, cumulative
No. at risk, per year
36
1503
61
1454
81
1398
99
1347
Finasteride Group
No. of events, cumulative
No. at risk, per year
14
1513
25
1487
32
1449
42
1421
12
16
20
24
40
36
44
48
28
32
Observation Time (Month)
Finasteride
Placebo
Percent of Patients
15%
10%
5%
Figure 3
Percent of Patients Developing Acute Urinary Retention
(Spontaneous and Precipitated)
Effect on Maximum Urinary Flow Rate
In the patients in PLESS who remained on therapy for the duration of the study and had evaluable urinary
flow data, PROSCAR increased maximum urinary flow rate by 1.9 mL/sec compared with 0.2 mL/sec in the
placebo group.
There was a clear difference between treatment groups in maximum urinary flow rate in favor of PROSCAR
by month 4 (1.0 vs 0.3 mL/sec) which was maintained throughout the study. In the earlier 1-year studies,
increase in maximum urinary flow rate was comparable to PLESS and was maintained through the first year and
throughout an additional 5 years of open extension studies.
Effect on Prostate Volume
In PLESS, prostate volume was assessed yearly by magnetic resonance imaging (MRI) in a subset of
patients. In patients treated with PROSCAR who remained on therapy, prostate volume was reduced compared
with both baseline and placebo throughout the 4-year study. PROSCAR decreased prostate volume by 17.9%
(from 55.9 cc at baseline to 45.8 cc at 4 years) compared with an increase of 14.1% (from 51.3 cc to 58.5 cc) in
the placebo group (p<0.001). (See Figure 4.)
Results seen in earlier studies were comparable to those seen in PLESS. Mean prostate volume at baseline
ranged between 40-50 cc. The reduction in prostate volume was seen during the first year and maintained
throughout an additional five years of open extension studies.
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Placebo ( ) n =
Finasteride ( ) n =
136
144
155
157
119
130
98
116
85
102
Figure 4
Prostate Volume in PLESS
Baseline
Year 1
Year 2
Year 3
Year 4
Mean Percent Change from Baseline ± 1 SE
-20
-10
0
10
20
Prostate Volume as a Predictor of Therapeutic Response
A meta-analysis combining 1-year data from seven double-blind, placebo-controlled studies of similar
design, including 4491 patients with symptomatic BPH, demonstrated that, in patients treated with PROSCAR,
the magnitude of symptom response and degree of improvement in maximum urinary flow rate were greater in
patients with an enlarged prostate at baseline.
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Medical Therapy of Prostatic Symptoms
The Medical Therapy of Prostatic Symptoms (MTOPS) Trial was a double-blind, randomized,
placebo-controlled, multicenter, 4- to 6-year study (average 5 years) in 3047 men with symptomatic BPH, who
were randomized to receive PROSCAR 5 mg/day (n=768), doxazosin 4 or 8 mg/day (n=756), the combination of
PROSCAR 5 mg/day and doxazosin 4 or 8 mg/day (n=786), or placebo (n=737). All participants underwent
weekly titration of doxazosin (or its placebo) from 1 to 2 to 4 to 8 mg/day. Only those who tolerated the 4 or
8 mg dose level were kept on doxazosin (or its placebo) in the study. The participant’s final tolerated dose
(either 4 mg or 8 mg) was administered beginning at end-Week 4. The final doxazosin dose was administered
once per day, at bedtime.
The mean patient age at randomization was 62.6 years (±7.3 years). Patients were Caucasian (82%),
African American (9%), Hispanic (7%), Asian (1%) or Native American (<1%). The mean duration of BPH
symptoms was 4.7 years (±4.6 years). Patients had moderate to severe BPH symptoms at baseline with a mean
AUA symptom score of approximately 17 out of 35 points. Mean maximum urinary flow rate was
10.5 mL/sec (±2.6 mL/sec). The mean prostate volume as measured by transrectal ultrasound was 36.3 mL
(±20.1 mL). Prostate volume was ≤20 mL in 16% of patients, ≥50 mL in 18% of patients and between 21 and
49 mL in 66% of patients.
The primary endpoint was a composite measure of the first occurrence of any of the following five
outcomes: a ≥4 point confirmed increase from baseline in symptom score, acute urinary retention, BPH-related
renal insufficiency (creatinine rise), recurrent urinary tract infections or urosepsis, or incontinence. Compared to
placebo, treatment with PROSCAR, doxazosin, or combination therapy resulted in a reduction in the risk of
experiencing one of these five outcome events by 34% (p=0.002), 39% (p<0.001), and 67% (p<0.001),
respectively. Combination therapy resulted in a significant reduction in the risk of the primary endpoint
compared to treatment with PROSCAR alone (49%; p≤0.001) or doxazosin alone (46%; p≤0.001).(See Table 2.)
Table 2
Count and Percent Incidence of Primary Outcome Events
by Treatment Group in MTOPS
Treatment Group
Placebo
Doxazosin
Finasteride
Combination
Total
N=737
N=756
N=768
N=786
N=3047
Event
N (%)
N (%)
N (%)
N (%)
N (%)
AUA 4-point rise
100 (13.6)
59 (7.8)
74 (9.6)
41 (5.2)
274 (9.0)
Acute urinary retention
18 (2.4)
13 (1.7)
6 (0.8)
4 (0.5)
41 (1.3)
Incontinence
8 (1.1)
11 (1.5)
9 (1.2)
3 (0.4)
31 (1.0)
Recurrent UTI/urosepsis
2 (0.3)
2 (0.3)
0 (0.0)
1 (0.1)
5 (0.2)
Creatinine rise
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
Total Events
128 (17.4)
85 (11.2)
89 (11.6)
49 (6.2)
351 (11.5)
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The majority of the events (274 out of 351; 78%) was a confirmed ≥4 point increase in symptom score,
referred to as symptom score progression. The risk of symptom score progression was reduced by 30%
(p=0.016), 46% (p<0.001), and 64% (p<0.001) in patients treated with PROSCAR, doxazosin, or the
combination, respectively, compared to patients treated with placebo (see Figure 5). Combination therapy
significantly reduced the risk of symptom score progression compared to the effect of PROSCAR alone
(p<0.001) and compared to doxazosin alone (p=0.037).
Figure 5
Cumulative Incidence of a 4-Point Rise in AUA Symptom Score by Treatment Group
5
10
15
20
25
0
Percent with Event
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
4.5
5.0
5.5
Years from Randomization
Combination
Finasteride
Doxazosin
Placebo
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Treatment with PROSCAR, doxazosin or the combination of PROSCAR with doxazosin, reduced the mean
symptom score from baseline at year 4. Table 3 provides the mean change from baseline for AUA symptom
score by treatment group for patients who remained on therapy for four years.
Table 3
Change From Baseline in AUA Symptom Score
by Treatment Group at Year 4 in MTOPS
Placebo
N=534
Doxazosin
N=582
Finasteride
N=565
Combination
N=598
Baseline Mean (SD)
16.8 (6.0)
17.0 (5.9)
17.1 (6.0)
16.8 (5.8)
Mean Change
AUA Symptom Score (SD)
-4.9 (5.8)
-6.6 (6.1)
-5.6 (5.9)
-7.4 (6.3)
Comparison to
Placebo (95% CI)
-1.8
(-2.5, -1.1)
-0.7
(-1.4, 0.0)
-2.5
(-3.2, -1.8)
Comparison to
Doxazosin alone (95% CI)
-0.7
(-1.4, 0.0)
Comparison to
Finasteride alone (95%
CI)
-1.8
(-2.5, -1.1)
The results of MTOPS are consistent with the findings of the 4-year, placebo-controlled study PLESS (see CLINICAL
PHARMACOLOGY, Clinical Studies) in that treatment with PROSCAR reduces the risk of acute urinary retention and the
need for BPH-related surgery. In MTOPS, the risk of developing acute urinary retention was reduced by 67% in patients
treated with PROSCAR compared to patients treated with placebo (0.8% for PROSCAR and 2.4% for placebo). Also, the
risk of requiring BPH-related invasive therapy was reduced by 64% in patients treated with PROSCAR compared to
patients treated with placebo (2.0% for PROSCAR and 5.4% for placebo).
Summary of Clinical Studies
The data from these studies, showing improvement in BPH-related symptoms, reduction in treatment failure
(BPH-related urological events), increased maximum urinary flow rates, and decreasing prostate volume,
suggest that PROSCAR arrests the disease process of BPH in men with an enlarged prostate.
INDICATIONS AND USAGE
PROSCAR, is indicated for the treatment of symptomatic benign prostatic hyperplasia (BPH) in men with an
enlarged prostate to:
-Improve symptoms
-Reduce the risk of acute urinary retention
-Reduce the risk of the need for surgery including transurethral resection of the prostate (TURP) and
prostatectomy.
PROSCAR administered in combination with the alpha-blocker doxazosin is indicated to reduce the risk of
symptomatic progression of BPH (a confirmed ≥4 point increase in AUA symptom score).
CONTRAINDICATIONS
PROSCAR is contraindicated in the following:
Hypersensitivity to any component of this medication.
Pregnancy. Finasteride use is contraindicated in women when they are or may potentially be pregnant.
Because of the ability of Type II 5 -reductase inhibitors to inhibit the conversion of testosterone to DHT,
finasteride may cause abnormalities of the external genitalia of a male fetus of a pregnant woman who receives
finasteride. If this drug is used during pregnancy, or if pregnancy occurs while taking this drug, the pregnant
woman should be apprised of the potential hazard to the male fetus. (See also WARNINGS, EXPOSURE OF
WOMEN — RISK TO MALE FETUS and PRECAUTIONS, Information for Patients and Pregnancy.) In female
rats, low doses of finasteride administered during pregnancy have produced abnormalities of the external
genitalia in male offspring.
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WARNINGS
PROSCAR is not indicated for use in pediatric patients (see PRECAUTIONS, Pediatric Use) or women (see
also WARNINGS, EXPOSURE OF WOMEN — RISK TO MALE FETUS; PRECAUTIONS, Information for
Patients and Pregnancy; and HOW SUPPLIED).
EXPOSURE OF WOMEN — RISK TO MALE FETUS
Women should not handle crushed or broken PROSCAR tablets when they are pregnant or may potentially
be pregnant because of the possibility of absorption of finasteride and the subsequent potential risk to a male
fetus. PROSCAR tablets are coated and will prevent contact with the active ingredient during normal handling,
provided that the tablets have not been broken or crushed. (See CONTRAINDICATIONS; PRECAUTIONS,
Information for Patients and Pregnancy; and HOW SUPPLIED).
PRECAUTIONS
General
Prior to initiating therapy with PROSCAR, appropriate evaluation should be performed to identify other
conditions such as infection, prostate cancer, stricture disease, hypotonic bladder or other neurogenic disorders
that might mimic BPH.
Patients with large residual urinary volume and/or severely diminished urinary flow should be carefully
monitored for obstructive uropathy. These patients may not be candidates for finasteride therapy.
Caution should be used in the administration of PROSCAR in those patients with liver function abnormalities,
as finasteride is metabolized extensively in the liver.
Effects on PSA and Prostate Cancer Detection
No clinical benefit has been demonstrated in patients with prostate cancer treated with PROSCAR. Patients
with BPH and elevated PSA were monitored in controlled clinical studies with serial PSAs and prostate biopsies.
In these BPH studies, PROSCAR did not appear to alter the rate of prostate cancer detection, and the overall
incidence of prostate cancer was not significantly different in patients treated with PROSCAR or placebo.
PROSCAR causes a decrease in serum PSA levels by approximately 50% in patients with BPH, even in the
presence of prostate cancer. This decrease is predictable over the entire range of PSA values, although it may
vary in individual patients. Analysis of PSA data from over 3000 patients in PLESS confirmed that in typical
patients treated with PROSCAR for six months or more, PSA values should be doubled for comparison with
normal ranges in untreated men. This adjustment preserves the sensitivity and specificity of the PSA assay and
maintains its ability to detect prostate cancer.
Any sustained increases in PSA levels while on PROSCAR should be carefully evaluated, including
consideration of non-compliance to therapy with PROSCAR.
Percent free PSA (free to total PSA ratio) is not significantly decreased by PROSCAR. The ratio of free to
total PSA remains constant even under the influence of PROSCAR. If clinicians elect to use percent free PSA
as an aid in the detection of prostate cancer in men undergoing finasteride therapy, no adjustment to its value
appears necessary.
Information for Patients
Women should not handle crushed or broken PROSCAR tablets when they are pregnant or may potentially
be pregnant because of the possibility of absorption of finasteride and the subsequent potential risk to the male
fetus (see CONTRAINDICATIONS; WARNINGS, EXPOSURE OF WOMEN — RISK TO MALE FETUS;
PRECAUTIONS, Pregnancy and HOW SUPPLIED).
Physicians should inform patients that the volume of ejaculate may be decreased in some patients during
treatment with PROSCAR. This decrease does not appear to interfere with normal sexual function. However,
impotence and decreased libido may occur in patients treated with PROSCAR (see ADVERSE REACTIONS).
Physicians should instruct their patients to promptly report any changes in their breasts such as lumps, pain
or nipple discharge. Breast changes including breast enlargement, tenderness and neoplasm have been
reported (see ADVERSE REACTIONS).
Physicians should instruct their patients to read the patient package insert before starting therapy with
PROSCAR and to reread it each time the prescription is renewed so that they are aware of current information
for patients regarding PROSCAR.
Drug/Laboratory Test Interactions
In patients with BPH, PROSCAR has no effect on circulating levels of cortisol, estradiol, prolactin, thyroid-
stimulating hormone, or thyroxine. No clinically meaningful effect was observed on the plasma lipid profile (i.e.,
total cholesterol, low density lipoproteins, high density lipoproteins and triglycerides) or bone mineral density.
Increases of about 10% were observed in luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in
patients receiving PROSCAR, but levels remained within the normal range. In healthy volunteers, treatment with
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PROSCAR did not alter the response of LH and FSH to gonadotropin-releasing hormone indicating that the
hypothalamic-pituitary-testicular axis was not affected.
Treatment with PROSCAR for 24 weeks to evaluate semen parameters in healthy male volunteers revealed
no clinically meaningful effects on sperm concentration, mobility, morphology, or pH. A 0.6 mL (22.1%) median
decrease in ejaculate volume with a concomitant reduction in total sperm per ejaculate, was observed. These
parameters remained within the normal range and were reversible upon discontinuation of therapy with an
average time to return to baseline of 84 weeks.
Drug Interactions
No drug interactions of clinical importance have been identified. Finasteride does not appear to affect the
cytochrome P450-linked drug metabolizing enzyme system. Compounds that have been tested in man have
included antipyrine, digoxin, propranolol, theophylline, and warfarin and no clinically meaningful interactions
were found.
Other Concomitant Therapy: Although specific interaction studies were not performed, PROSCAR was
concomitantly used in clinical studies with acetaminophen, acetylsalicylic acid, -blockers, angiotensin-
converting enzyme (ACE) inhibitors, analgesics, anti-convulsants, beta-adrenergic blocking agents, diuretics,
calcium channel blockers, cardiac nitrates, HMG-CoA reductase inhibitors, nonsteroidal anti-inflammatory drugs
(NSAIDs), benzodiazepines, H2 antagonists and quinolone anti-infectives without evidence of clinically
significant adverse interactions.
Carcinogenesis, Mutagenesis, Impairment of Fertility
No evidence of a tumorigenic effect was observed in a 24-month study in Sprague-Dawley rats receiving
doses of finasteride up to 160 mg/kg/day in males and 320 mg/kg/day in females. These doses produced
respective systemic exposure in rats of 111 and 274 times those observed in man receiving the recommended
human dose of 5 mg/day. All exposure calculations were based on calculated AUC (0-24 hr) for animals and
mean AUC (0-24 hr) for man (0.4 g•hr/mL).
In a 19-month carcinogenicity study in CD-1 mice, a statistically significant (p 0.05) increase in the
incidence of testicular Leydig cell adenomas was observed at a dose of 250 mg/kg/day (228 times the human
exposure). In mice at a dose of 25 mg/kg/day (23 times the human exposure, estimated) and in rats at a dose of
40 mg/kg/day (39 times the human exposure) an increase in the incidence of Leydig cell hyperplasia was
observed. A positive correlation between the proliferative changes in the Leydig cells and an increase in serum
LH levels (2-3 fold above control) has been demonstrated in both rodent species treated with high doses of
finasteride. No drug-related Leydig cell changes were seen in either rats or dogs treated with finasteride for
1 year at doses of 20 mg/kg/day and 45 mg/kg/day (30 and 350 times, respectively, the human exposure) or in
mice treated for 19 months at a dose of 2.5 mg/kg/day (2.3 times the human exposure, estimated).
No evidence of mutagenicity was observed in an in vitro bacterial mutagenesis assay, a mammalian cell
mutagenesis assay, or in an in vitro alkaline elution assay. In an in vitro chromosome aberration assay, using
Chinese hamster ovary cells, there was a slight increase in chromosome aberrations. These concentrations
correspond to 4000-5000 times the peak plasma levels in man given a total dose of 5 mg. In an in vivo
chromosome aberration assay in mice, no treatment-related increase in chromosome aberration was observed
with finasteride at the maximum tolerated dose of 250 mg/kg/day (228 times the human exposure) as
determined in the carcinogenicity studies.
In sexually mature male rabbits treated with finasteride at 80 mg/kg/day (543 times the human exposure) for
up to 12 weeks, no effect on fertility, sperm count, or ejaculate volume was seen. In sexually mature male rats
treated with 80 mg/kg/day of finasteride (61 times the human exposure), there were no significant effects on
fertility after 6 or 12 weeks of treatment; however, when treatment was continued for up to 24 or 30 weeks, there
was an apparent decrease in fertility, fecundity and an associated significant decrease in the weights of the
seminal vesicles and prostate. All these effects were reversible within 6 weeks of discontinuation of treatment.
No drug-related effect on testes or on mating performance has been seen in rats or rabbits. This decrease in
fertility in finasteride-treated rats is secondary to its effect on accessory sex organs (prostate and seminal
vesicles) resulting in failure to form a seminal plug. The seminal plug is essential for normal fertility in rats and is
not relevant in man.
Pregnancy
Pregnancy Category X
See CONTRAINDICATIONS.
PROSCAR is not indicated for use in women.
Administration of finasteride to pregnant rats at doses ranging from 100 g/kg/day to 100 mg/kg/day (1-
1000 times the recommended human dose of 5 mg/day) resulted in dose-dependent development of
hypospadias in 3.6 to 100% of male offspring. Pregnant rats produced male offspring with decreased prostatic
and seminal vesicular weights, delayed preputial separation and transient nipple development when given
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finasteride at 30 g/kg/day ( 3/10 of the recommended human dose of 5 mg/day) and decreased anogenital
distance when given finasteride at 3 g/kg/day ( 3/100 of the recommended human dose of 5 mg/day). The
critical period during which these effects can be induced in male rats has been defined to be days 16-17 of
gestation. The changes described above are expected pharmacological effects of drugs belonging to the class
of Type II 5 -reductase inhibitors and are similar to those reported in male infants with a genetic deficiency of
Type II 5 -reductase. No abnormalities were observed in female offspring exposed to any dose of finasteride in
utero.
No developmental abnormalities have been observed in first filial generation (F1) male or female offspring
resulting from mating finasteride-treated male rats (80 mg/kg/day; 61 times the human exposure) with untreated
females. Administration of finasteride at 3 mg/kg/day (30 times the recommended human dose of 5 mg/day)
during the late gestation and lactation period resulted in slightly decreased fertility in F1 male offspring. No
effects were seen in female offspring. No evidence of malformations has been observed in rabbit fetuses
exposed to finasteride in utero from days 6-18 of gestation at doses up to 100 mg/kg/day (1000 times the
recommended human dose of 5 mg/day). However, effects on male genitalia would not be expected since the
rabbits were not exposed during the critical period of genital system development.
The in utero effects of finasteride exposure during the period of embryonic and fetal development were
evaluated in the rhesus monkey (gestation days 20-100), a species more predictive of human development than
rats or rabbits. Intravenous administration of finasteride to pregnant monkeys at doses as high as 800 ng/day (at
least 60 to 120 times the highest estimated exposure of pregnant women to finasteride from semen of men
taking 5 mg/day) resulted in no abnormalities in male fetuses. In confirmation of the relevance of the rhesus
model for human fetal development, oral administration of a dose of finasteride (2 mg/kg/day; 20 times the
recommended human dose of 5 mg/day or approximately 1-2 million times the highest estimated exposure to
finasteride from semen of men taking 5 mg/day) to pregnant monkeys resulted in external genital abnormalities
in male fetuses. No other abnormalities were observed in male fetuses and no finasteride-related abnormalities
were observed in female fetuses at any dose.
Nursing Mothers
PROSCAR is not indicated for use in women.
It is not known whether finasteride is excreted in human milk.
Pediatric Use
PROSCAR is not indicated for use in pediatric patients.
Safety and effectiveness in pediatric patients have not been established.
Geriatric Use
Of the total number of subjects included in PLESS, 1480 and 105 subjects were 65 and over and 75 and
over, respectively. No overall differences in safety or effectiveness were observed between these subjects and
younger subjects, and other reported clinical experience has not identified differences in responses between the
elderly and younger patients. No dosage adjustment is necessary in the elderly (see CLINICAL
PHARMACOLOGY, Pharmacokinetics and Clinical Studies).
ADVERSE REACTIONS
PROSCAR is generally well tolerated; adverse reactions usually have been mild and transient.
4-Year Placebo-Controlled Study
In PLESS, 1524 patients treated with PROSCAR and 1516 patients treated with placebo were evaluated for
safety over a period of 4 years. The most frequently reported adverse reactions were related to sexual function.
3.7% (57 patients) treated with PROSCAR and 2.1% (32 patients) treated with placebo discontinued therapy as
a result of adverse reactions related to sexual function, which are the most frequently reported adverse
reactions.
Table 4 presents the only clinical adverse reactions considered possibly, probably or definitely drug related
by the investigator, for which the incidence on PROSCAR was 1% and greater than placebo over the 4 years
of the study. In years 2-4 of the study, there was no significant difference between treatment groups in the
incidences of impotence, decreased libido and ejaculation disorder.
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TABLE 4
Drug-Related Adverse Experiences
Year 1
(%)
Years 2, 3 and 4*
(%)
Finasteride
Placebo
Finasteride
Placebo
Impotence
8.1
3.7
5.1
5.1
Decreased
Libido
6.4
3.4
2.6
2.6
Decreased
Volume of
Ejaculate
3.7
0.8
1.5
0.5
Ejaculation
Disorder
0.8
0.1
0.2
0.1
Breast
Enlargement
0.5
0.1
1.8
1.1
Breast
Tenderness
0.4
0.1
0.7
0.3
Rash
0.5
0.2
0.5
0.1
*Combined Years 2-4
N = 1524 and 1516, finasteride vs placebo, respectively
Phase III Studies and 5-Year Open Extensions
The adverse experience profile in the 1-year, placebo-controlled, Phase III studies, the 5-year open
extensions, and PLESS were similar.
Medical Therapy of Prostatic Symptoms (MTOPS) Study
The incidence rates of drug-related adverse experiences reported by ≥2% of patients in any treatment group
in the MTOPS Study are listed in Table 5.
The individual adverse effects which occurred more frequently in the combination group compared to either
drug alone were: asthenia, postural hypotension, peripheral edema, dizziness, decreased libido, rhinitis,
abnormal ejaculation, impotence and abnormal sexual function (see Table 5). Of these, the incidence of
abnormal ejaculation in patients receiving combination therapy was comparable to the sum of the incidences of
this adverse experience reported for the two monotherapies.
Combination therapy with finasteride and doxazosin was associated with no new clinical adverse experience.
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Four patients in MTOPS reported the adverse experience breast cancer. Three of these patients were on
finasteride only and one was on combination therapy. (See ADVERSE REACTIONS, Long-Term Data.)
The MTOPS Study was not specifically designed to make statistical comparisons between groups for
reported adverse experiences. In addition, direct comparisons of safety data between the MTOPS study and
previous studies of the single agents may not be appropriate based upon differences in patient population,
dosage or dose regimen, and other procedural and study design elements.
Table 5
Incidence ≥ 2% in One or More Treatment Groups
Drug-Related Clinical Adverse Experiences in MTOPS
Adverse Experience
Placebo
Doxazosin
4mg or 8mg*
Finasteride
Combination
(N=737)
(N=756)
(N=768)
(N=786)
(%)
(%)
(%)
(%)
Body as a whole
Asthenia
7.1
15.7
5.3
16.8
2.3
4.1
2.0
2.3
Cardiovascular
Hypotension
0.7
3.4
1.2
1.5
Postural Hypotension
8.0
16.7
9.1
17.8
Metabolic and Nutritional
Peripheral Edema
0.9
2.6
1.3
3.3
Nervous
Dizziness
8.1
17.7
7.4
23.2
Libido Decreased
5.7
7.0
10.0
11.6
Somnolence
1.5
3.7
1.7
3.1
Respiratory
Dyspnea
0.7
2.1
0.7
1.9
Rhinitis
0.5
1.3
1.0
2.4
Urogenital
Abnormal Ejaculation
2.3
4.5
7.2
14.1
Gynecomastia
0.7
1.1
2.2
1.5
Impotence
12.2
14.4
18.5
22.6
Sexual Function Abnormal
0.9
2.0
2.5
3.1
*Doxazosin dose was achieved by weekly titration (1 to 2 to 4 to 8 mg). The final tolerated dose (4 mg or 8 mg) was
administered at end-Week 4. Only those patients tolerating at least 4 mg were kept on doxazosin. The majority of
patients received the 8-mg dose over the duration of the study.
Long-Term Data
There is no evidence of increased adverse experiences with increased duration of treatment with
PROSCAR. New reports of drug-related sexual adverse experiences decreased with duration of therapy.
During the 4- to 6-year placebo- and comparator-controlled MTOPS study that enrolled 3047 men, there
were 4 cases of breast cancer in men treated with finasteride but no cases in men not treated with
finasteride. During the 4-year, placebo-controlled PLESS study that enrolled 3040 men, there were 2 cases
of breast cancer in placebo-treated men, but no cases were reported in men treated with finasteride. The
relationship between long-term use of finasteride and male breast neoplasia is currently unknown.
In a 7-year placebo-controlled trial that enrolled 18,882 healthy men, 9060 had prostate needle biopsy
data available for analysis. In the PROSCAR group, 280 (6.4%) men had prostate cancer with Gleason
scores of 7-10 detected on needle biopsy vs. 237 (5.1%) men in the placebo group. Of the total cases of
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prostate cancer diagnosed in this study, approximately 98% were classified as intracapsular (stage T1 or
T2). The clinical significance of these findings is unknown.
Post-Marketing Experience
The following additional adverse effects have been reported in post-marketing experience:
- hypersensitivity reactions, including pruritus, urticaria, and swelling of the lips and face
- testicular pain.
OVERDOSAGE
Patients have received single doses of PROSCAR up to 400 mg and multiple doses of PROSCAR up to
80 mg/day for three months without adverse effects. Until further experience is obtained, no specific treatment
for an overdose with PROSCAR can be recommended.
Significant lethality was observed in male and female mice at single oral doses of 1500 mg/m2 (500 mg/kg)
and in female and male rats at single oral doses of 2360 mg/m2 (400 mg/kg) and 5900 mg/m2 (1000 mg/kg),
respectively.
DOSAGE AND ADMINISTRATION
The recommended dose is 5 mg orally once a day.
PROSCAR can be administered alone or in combination with the alpha-blocker doxazosin (see CLINICAL
PHARMACOLOGY, Clinical Studies).
PROSCAR may be administered with or without meals.
No dosage adjustment is necessary for patients with renal impairment or for the elderly (see CLINICAL
PHARMACOLOGY, Pharmacokinetics).
HOW SUPPLIED
No. 3094 — PROSCAR tablets 5 mg are blue, modified apple-shaped, film-coated tablets, with the code
MSD 72 on one side and PROSCAR on the other. They are supplied as follows:
NDC 0006-0072-31 unit of use bottles of 30
NDC 0006-0072-58 unit of use bottles of 100
NDC 0006-0072-28 unit dose packages of 100
NDC 0006-0072-82 bottles of 1000.
Storage and Handling
Store at room temperatures below 30°C (86°F). Protect from light and keep container tightly closed.
Women should not handle crushed or broken PROSCAR tablets when they are pregnant or may potentially
be pregnant because of the possibility of absorption of finasteride and the subsequent potential risk to a male
fetus (see WARNINGS, EXPOSURE OF WOMEN — RISK TO MALE FETUS, and PRECAUTIONS, Information
for Patients and Pregnancy).
Issued
Printed in USA
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-180/S-026
Page 19
PROSCAR® (Finasteride) Tablets
Patient Information about
PROSCAR® (Prahs-car)
Generic name: finasteride
(fin-AS-tur-eyed)
PROSCAR* is for use by men only.
Please read this leaflet before you start taking PROSCAR. Also, read it each time you renew your prescription,
just in case anything has changed. Remember, this leaflet does not take the place of careful discussions with
your doctor. You and your doctor should discuss PROSCAR when you start taking your medication and at
regular checkups.
Why your doctor has prescribed PROSCAR
Your doctor has prescribed PROSCAR because you have a medical condition called benign prostatic
hyperplasia or BPH. This occurs only in men.
What is BPH?
BPH is an enlargement of the prostate gland. After age 50, most men develop enlarged prostates. The prostate
is located below the bladder. As the prostate enlarges, it may slowly restrict the flow of urine. This can lead to
symptoms such as:
•
a weak or interrupted urinary stream
•
a feeling that you cannot empty your bladder completely
•
a feeling of delay or hesitation when you start to urinate
•
a need to urinate often, especially at night
•
a feeling that you must urinate right away.
In some men, BPH can lead to serious problems, including urinary tract infections, a sudden inability to pass
urine (acute urinary retention), as well as the need for surgery.
Treatment options for BPH
There are three main treatment options for symptoms of BPH:
•
Program of monitoring or “Watchful Waiting”. If a man has an enlarged prostate gland and no symptoms
or if his symptoms do not bother him, he and his doctor may decide on a program of monitoring which would
include regular checkups, instead of medication or surgery.
•
Medication. Your doctor may prescribe PROSCAR for BPH. See “What PROSCAR does” below.
•
Surgery. Some patients may need surgery. Your doctor can suggest several different surgical procedures
for BPH. Which procedure is best depends on your symptoms and medical condition.
There are two main treatment options to reduce the risk of serious problems due to BPH:
•
Medication. Your doctor may prescribe PROSCAR for BPH. See “What PROSCAR does” below.
•
Surgery. Some patients may need surgery. Your doctor can suggest several different surgical procedures
for BPH. Which procedure is best depends on your symptoms and medical condition.
What PROSCAR does
*Registered trademark of MERCK & CO., INC.
COPYRIGHT © MERCK & CO., INC., 1992, 1995, 1998
All rights reserved.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-180/S-026
Page 20
PROSCAR lowers levels of a key hormone called DHT (dihydrotestosterone), which is a major cause of prostate
growth. Lowering DHT leads to shrinkage of the enlarged prostate gland in most men. This can lead to gradual
improvement in urine flow and symptoms over the next several months. PROSCAR will help reduce the risk of
developing a sudden inability to pass urine and the need for surgery. However, since each case of BPH is
different, you should know that:
•
Even though the prostate shrinks, you may NOT notice an improvement in urine flow or symptoms.
•
You may need to take PROSCAR for six (6) months or more to see whether it improves your symptoms.
•
Therapy with PROSCAR may reduce your risk for a sudden inability to pass urine and the need for surgery.
What you need to know while taking PROSCAR
•
You must see your doctor regularly. While taking PROSCAR, you must have regular checkups. Follow
your doctor's advice about when to have these checkups.
•
About side effects. Like all prescription drugs, PROSCAR may cause side effects. Side effects due to
PROSCAR may include impotence (an inability to have an erection) or less desire for sex.
Some men taking PROSCAR may have changes or problems with ejaculation, such as a decrease in the
amount of semen released during sex. This decrease in the amount of semen does not appear to interfere
with normal sexual function. In some cases these side effects went away while the patient continued to take
PROSCAR.
In addition, some men may have breast enlargement and/or tenderness. You should promptly report to your
doctor any changes in your breasts such as lumps, pain or nipple discharge. Some men have reported
allergic reactions such as rash, itching, hives, and swelling of the lips and face. Rarely, testicular pain has
been reported.
You should discuss side effects with your doctor before taking PROSCAR and anytime you think you are having
a side effect.
•
Checking for prostate cancer. Your doctor has prescribed PROSCAR for symptomatic BPH and not for
cancer — but a man can have BPH and prostate cancer at the same time. Doctors usually recommend that
men be checked for prostate cancer once a year when they turn 50 (or 40 if a family member has had
prostate cancer). These checks should continue while you take PROSCAR. PROSCAR is not a treatment for
prostate cancer.
•
About Prostate-Specific Antigen (PSA).
Your doctor may have done a blood test called PSA. PROSCAR can alter PSA values. For more information,
talk to your doctor.
•
A warning about PROSCAR and pregnancy.
PROSCAR is for use by MEN only.
Women who are or may potentially be pregnant must not use PROSCAR. They should also not handle
crushed or broken tablets of PROSCAR.
If a woman who is pregnant with a male baby absorbs the active ingredient in PROSCAR after oral use or
through the skin, it may cause the male baby to be born with abnormalities of the sex organs.
PROSCAR tablets are coated and will prevent contact with the active ingredient during normal handling,
provided that the tablets are not broken or crushed.
If a woman who is pregnant comes into contact with the active ingredient in PROSCAR, a doctor should be
consulted.
Remember, these warnings apply only when the woman is pregnant or could potentially be pregnant.
How to take PROSCAR
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-180/S-026
Page 21
Follow your doctor's advice about how to take PROSCAR. You must take it every day. You may take it with or
between meals. To avoid forgetting to take PROSCAR, it may be helpful to take it at the same time every day.
Your doctor may prescribe PROSCAR along with another medicine, an alpha-blocker called doxazosin, to help
you better manage your BPH symptoms.
Do not share PROSCAR with anyone else; it was prescribed only for you.
Keep PROSCAR and all medicines out of the reach of children.
FOR MORE INFORMATION ABOUT ‘PROSCAR’ AND BPH, TALK WITH YOUR DOCTOR.
IN ADDITION, TALK TO YOUR PHARMACIST OR OTHER HEALTH CARE PROVIDER.
MERCK & CO., INC.
Issued
Whitehouse Station, NJ 08889, USA
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:46:59.643478
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/020180s026lbl.pdf', 'application_number': 20180, 'submission_type': 'SUPPL ', 'submission_number': 26}
|
12,299
|
Merck & Co., Inc.
PROSCAR®
(FINASTERIDE)
TABLETS
DESCRIPTION
PROSCAR* (finasteride), a synthetic 4-azasteroid compound, is a specific inhibitor of steroid Type II
5α-reductase,
an
intracellular
enzyme
that
converts
the
androgen
testosterone
into
5α-dihydrotestosterone (DHT).
Finasteride is 4-azaandrost-1-ene-17-carboxamide, N-(1,1-dimethylethyl)-3-oxo-,(5α,17β)-. The
empirical formula of finasteride is C23H36N2O2 and its molecular weight is 372.55. Its structural formula is: structural formula
Finasteride is a white crystalline powder with a melting point near 250°C. It is freely soluble in
chloroform and in lower alcohol solvents, but is practically insoluble in water.
PROSCAR (finasteride) tablets for oral administration are film-coated tablets that contain 5 mg of
finasteride and the following inactive ingredients: hydrous lactose, microcrystalline cellulose,
pregelatinized
starch,
sodium
starch
glycolate,
hydroxypropyl
cellulose
LF,
hydroxypropyl
methylcellulose, titanium dioxide, magnesium stearate, talc, docusate sodium, FD&C Blue 2 aluminum
lake and yellow iron oxide.
CLINICAL PHARMACOLOGY
The development and enlargement of the prostate gland is dependent on the potent androgen,
5α-dihydrotestosterone (DHT). Type II 5α−reductase metabolizes testosterone to DHT in the prostate
gland, liver and skin. DHT induces androgenic effects by binding to androgen receptors in the cell nuclei
of these organs.
Finasteride is a competitive and specific inhibitor of Type II 5α-reductase with which it slowly forms a
stable enzyme complex. Turnover from this complex is extremely slow (t½ ∼ 30 days). This has been
demonstrated both in vivo and in vitro. Finasteride has no affinity for the androgen receptor. In man, the
5α-reduced steroid metabolites in blood and urine are decreased after administration of finasteride.
In man, a single 5-mg oral dose of PROSCAR produces a rapid reduction in serum DHT
concentration, with the maximum effect observed 8 hours after the first dose. The suppression of DHT is
maintained throughout the 24-hour dosing interval and with continued treatment. Daily dosing of
PROSCAR at 5 mg/day for up to 4 years has been shown to reduce the serum DHT concentration by
approximately 70%. The median circulating level of testosterone increased by approximately 10-20% but
remained within the physiologic range.
Adult males with genetically inherited Type II 5α-reductase deficiency also have decreased levels of
DHT. Except for the associated urogenital defects present at birth, no other clinical abnormalities related
*Registered trademark of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
Copyright © 1992, 1995, 1998 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
All rights reserved
PROSCAR® (Finasteride) Tablets
9631305
to Type II 5α-reductase deficiency have been observed in these individuals. These individuals have a
small prostate gland throughout life and do not develop BPH.
In patients with BPH treated with finasteride (1-100 mg/day) for 7-10 days prior to prostatectomy, an
approximate 80% lower DHT content was measured in prostatic tissue removed at surgery, compared to
placebo; testosterone tissue concentration was increased up to 10 times over pretreatment levels,
relative to placebo. Intraprostatic content of prostate-specific antigen (PSA) was also decreased.
In healthy male volunteers treated with PROSCAR for 14 days, discontinuation of therapy resulted in
a return of DHT levels to pretreatment levels in approximately 2 weeks. In patients treated for three
months, prostate volume, which declined by approximately 20%, returned to close to baseline value after
approximately three months of discontinuation of therapy.
Pharmacokinetics
Absorption
In a study of 15 healthy young subjects, the mean bioavailability of finasteride 5-mg tablets was 63%
(range 34-108%), based on the ratio of area under the curve (AUC) relative to an intravenous (IV)
reference dose. Maximum finasteride plasma concentration averaged 37 ng/mL (range, 27-49 ng/mL)
and was reached 1-2 hours postdose. Bioavailability of finasteride was not affected by food.
Distribution
Mean steady-state volume of distribution was 76 liters (range, 44-96 liters). Approximately 90% of
circulating finasteride is bound to plasma proteins. There is a slow accumulation phase for finasteride
after multiple dosing. After dosing with 5 mg/day of finasteride for 17 days, plasma concentrations of
finasteride were 47 and 54% higher than after the first dose in men 45-60 years old (n=12) and ≥70 years
old (n=12), respectively. Mean trough concentrations after 17 days of dosing were 6.2 ng/mL (range, 2.4
9.8 ng/mL) and 8.1 ng/mL (range, 1.8-19.7 ng/mL), respectively, in the two age groups. Although steady
state was not reached in this study, mean trough plasma concentration in another study in patients with
BPH (mean age, 65 years) receiving 5 mg/day was 9.4 ng/mL (range, 7.1-13.3 ng/mL; n=22) after over a
year of dosing.
Finasteride has been shown to cross the blood brain barrier but does not appear to distribute
preferentially to the CSF.
In 2 studies of healthy subjects (n=69) receiving PROSCAR 5 mg/day for 6-24 weeks, finasteride
concentrations in semen ranged from undetectable (<0.1 ng/mL) to 10.54 ng/mL. In an earlier study using
a less sensitive assay, finasteride concentrations in the semen of 16 subjects receiving PROSCAR
5 mg/day ranged from undetectable (<1.0 ng/mL) to 21 ng/mL. Thus, based on a 5-mL ejaculate volume,
the amount of finasteride in semen was estimated to be 50- to 100-fold less than the dose of finasteride
(5 μg) that had no effect on circulating DHT levels in men (see also PRECAUTIONS, Pregnancy).
Metabolism
Finasteride is extensively metabolized in the liver, primarily via the cytochrome P450 3A4 enzyme
subfamily. Two metabolites, the t-butyl side chain monohydroxylated and monocarboxylic acid
metabolites, have been identified that possess no more than 20% of the 5α-reductase inhibitory activity of
finasteride.
Excretion
In healthy young subjects (n=15), mean plasma clearance of finasteride was 165 mL/min (range, 70
279 mL/min) and mean elimination half-life in plasma was 6 hours (range, 3-16 hours). Following an oral
dose of 14C-finasteride in man (n=6), a mean of 39% (range, 32-46%) of the dose was excreted in the
urine in the form of metabolites; 57% (range, 51-64%) was excreted in the feces.
The mean terminal half-life of finasteride in subjects ≥70 years of age was approximately 8 hours
(range, 6-15 hours; n=12), compared with 6 hours (range, 4-12 hours; n=12) in subjects 45-60 years of
age. As a result, mean AUC(0-24 hr) after 17 days of dosing was 15% higher in subjects ≥70 years of age
than in subjects 45-60 years of age (p=0.02).
Special Populations
Pediatric: Finasteride pharmacokinetics have not been investigated in patients <18 years of age.
Gender: Finasteride pharmacokinetics in women are not available.
Geriatric: No dosage adjustment is necessary in the elderly. Although the elimination rate of finasteride is
decreased in the elderly, these findings are of no clinical significance. (See also Pharmacokinetics,
Excretion, PRECAUTIONS, Geriatric Use and DOSAGE AND ADMINISTRATION.)
Race: The effect of race on finasteride pharmacokinetics has not been studied.
Renal Insufficiency: No dosage adjustment is necessary in patients with renal insufficiency. In patients
with chronic renal impairment, with creatinine clearances ranging from 9.0 to 55 mL/min, AUC, maximum
plasma concentration, half-life, and protein binding after a single dose of 14C-finasteride were similar to
values obtained in healthy volunteers. Urinary excretion of metabolites was decreased in patients with
2
PROSCAR® (Finasteride) Tablets
9631305
renal impairment. This decrease was associated with an increase in fecal excretion of metabolites.
Plasma concentrations of metabolites were significantly higher in patients with renal impairment (based
on a 60% increase in total radioactivity AUC). However, finasteride has been well tolerated in BPH
patients with normal renal function receiving up to 80 mg/day for 12 weeks, where exposure of these
patients to metabolites would presumably be much greater.
Hepatic Insufficiency: The effect of hepatic insufficiency on finasteride pharmacokinetics has not been
studied. Caution should be used in the administration of PROSCAR in those patients with liver function
abnormalities, as finasteride is metabolized extensively in the liver.
Drug Interactions (see also PRECAUTIONS, Drug Interactions)
No drug interactions of clinical importance have been identified. Finasteride does not appear to affect
the cytochrome P450-linked drug metabolism enzyme system. Compounds that have been tested in man
have included antipyrine, digoxin, propranolol, theophylline, and warfarin, and no clinically meaningful
interactions were found.
Mean (SD) Pharmacokinetic Parameters
in Healthy Young Subjects (n=15)
Mean (± SD)
Bioavailability
63% (34-108%)*
Clearance (mL/min)
165 (55)
Volume of Distribution (L)
76 (14)
Half-Life (hours)
6.2 (2.1)
*Range
Mean (SD) Noncompartmental Pharmacokinetic Parameters After Multiple Doses of 5
mg/day in Older Men
Mean (± SD)
45-60 years old (n=12)
≥70 years old (n=12)
AUC (ng•hr/mL)
389 (98)
463 (186)
Peak Concentration (ng/mL)
46.2 (8.7)
48.4 (14.7)
Time to Peak (hours)
1.8 (0.7)
1.8 (0.6)
Half-Life (hours)*
6.0 (1.5)
8.2 (2.5)
*First-dose values; all other parameters are last-dose values
Clinical Studies
PROSCAR 5 mg/day was initially evaluated in patients with symptoms of BPH and enlarged prostates
by digital rectal examination in two 1-year, placebo-controlled, randomized, double-blind studies and their
5-year open extensions.
PROSCAR was further evaluated in the PROSCAR Long-Term Efficacy and Safety Study (PLESS), a
double-blind, randomized, placebo-controlled, 4-year, multicenter study. 3040 patients between the ages
of 45 and 78, with moderate to severe symptoms of BPH and an enlarged prostate upon digital rectal
examination, were randomized into the study (1524 to finasteride, 1516 to placebo) and 3016 patients
were evaluable for efficacy. 1883 patients completed the 4-year study (1000 in the finasteride group, 883
in the placebo group).
Effect on Symptom Score
Symptoms were quantified using a score similar to the American Urological Association Symptom
Score, which evaluated both obstructive symptoms (impairment of size and force of stream, sensation of
incomplete bladder emptying, delayed or interrupted urination) and irritative symptoms (nocturia, daytime
frequency, need to strain or push the flow of urine) by rating on a 0 to 5 scale for six symptoms and a 0 to
4 scale for one symptom, for a total possible score of 34.
Patients in PLESS had moderate to severe symptoms at baseline (mean of approximately 15 points
on a 0-34 point scale). Patients randomized to PROSCAR who remained on therapy for 4 years had a
mean (± 1 SD) decrease in symptom score of 3.3 (± 5.8) points compared with 1.3 (± 5.6) points in the
placebo group. (See Figure 1.) A statistically significant improvement in symptom score was evident at
1 year in patients treated with PROSCAR vs placebo (–2.3 vs –1.6), and this improvement continued
through Year 4.
3
PROSCAR® (Finasteride) Tablets
9631305
Figure 1
Symptom Score in PLESS
0
-1
-2
-3
-4
-5
-6
Symptom S
core in
PLESS
Results seen in earlier studies were comparable to those seen in PLESS. Although an early
improvement in urinary symptoms was seen in some patients, a therapeutic trial of at least 6 months was
generally necessary to assess whether a beneficial response in symptom relief had been achieved. The
improvement in BPH symptoms was seen during the first year and maintained throughout an additional
5 years of open extension studies.
Effect on Acute Urinary Retention and the Need for Surgery
In PLESS, efficacy was also assessed by evaluating treatment failures. Treatment failure was
prospectively defined as BPH-related urological events or clinical deterioration, lack of improvement
and/or the need for alternative therapy. BPH-related urological events were defined as urological surgical
intervention and acute urinary retention requiring catheterization. Complete event information was
available for 92% of the patients. The following table (Table 1) summarizes the results.
Mean Change from Baseline ± 1 SE
Table 1
All Treatment Failures in PLESS
Patients (%) *
Event
Placebo
N=1503
Finasteride
N=1513
Relative
Risk**
95% CI
P
Value**
All Treatment Failures
37.1
26.2
0.68
(0.57 to 0.79)
<0.001
Surgical
Interventions for
BPH
10.1
4.6
0.45
(0.32 to 0.63)
<0.001
Acute Urinary
Retention
Requiring
Catheterization
6.6
2.8
0.43
(0.28 to 0.66)
<0.001
Two consecutive
symptom scores
≥20
9.2
6.7
Bladder Stone
0.4
0.5
Incontinence
2.1
1.7
Renal Failure
0.5
0.6
UTI
5.7
4.9
Discontinuation
due to worsening
of BPH, lack of
improvement, or
to receive other
medical
treatment
21.8
13.3
*patients with multiple events may be counted more than once for each type of event
4
PROSCAR® (Finasteride) Tablets
9631305
**Hazard ratio based on log rank test
Compared with placebo, PROSCAR was associated with a significantly lower risk for acute urinary
retention or the need for BPH-related surgery [13.2% for placebo vs 6.6% for PROSCAR; 51% reduction
in risk, 95% CI: (34 to 63%)]. Compared with placebo, PROSCAR was associated with a significantly
lower risk for surgery [10.1% for placebo vs 4.6% for PROSCAR; 55% reduction in risk, 95% CI: (37 to
68%)] and with a significantly lower risk of acute urinary retention [6.6% for placebo vs 2.8% for
PROSCAR; 57% reduction in risk, 95% CI: (34 to 72%)]; see Figures 2 and 3.
Figure 2
Percent of Patients Having Surgery for BPH,
Including TURP
Per
cent of Pati
ents Hav
ing Surgery for BPH,
Inc
ludi
ng TURP
0
4
8
12
16
20
24
28
32
36
40
44
48
Observation Time (Month)
Placebo Group
No. of events, cumulative
No. at risk, per year
37
1503
89
1454
121
1374
152
1314
Finasteride Group
No. of events, cumulative
No. at risk, per year
18
1513
40
1483
49
1438
69
1410
Figure 3
Percent of Patients Developing Acute Urinary Retention
(Spontaneous and Precipitated)
Per
cent of Pati
ents Dev
eloping Acute Urinar
y Re
tent
ion (Spontaneous and Precipitated)
0
4
8
12
16
20
24
28
32
36
40
44
48
Observation Time (Month)
Placebo Group
No. of events, cumulative
No. at risk, per year
Finasteride Group
No. of events, cumulative
No. at risk, per year
36
1503
14
1513
61
1454
25
1487
81
1398
32
1449
99
1347
42
1421
5
PROSCAR® (Finasteride) Tablets
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Effect on Maximum Urinary Flow Rate
In the patients in PLESS who remained on therapy for the duration of the study and had evaluable
urinary flow data, PROSCAR increased maximum urinary flow rate by 1.9 mL/sec compared with 0.2
mL/sec in the placebo group.
There was a clear difference between treatment groups in maximum urinary flow rate in favor of
PROSCAR by month 4 (1.0 vs 0.3 mL/sec) which was maintained throughout the study. In the earlier 1
year studies, increase in maximum urinary flow rate was comparable to PLESS and was maintained
through the first year and throughout an additional 5 years of open extension studies.
Effect on Prostate Volume
In PLESS, prostate volume was assessed yearly by magnetic resonance imaging (MRI) in a subset of
patients. In patients treated with PROSCAR who remained on therapy, prostate volume was reduced
compared with both baseline and placebo throughout the 4-year study. PROSCAR decreased prostate
volume by 17.9% (from 55.9 cc at baseline to 45.8 cc at 4 years) compared with an increase of 14.1%
(from 51.3 cc to 58.5 cc) in the placebo group (p<0.001). (See Figure 4.)
Results seen in earlier studies were comparable to those seen in PLESS. Mean prostate volume at
baseline ranged between 40-50 cc. The reduction in prostate volume was seen during the first year and
maintained throughout an additional five years of open extension studies.
Figure 4
Prostate Volume in PLESS
Mean Percent Change from Baseline ± 1 SE
20
10
0
-10
-20 Prostate Volume in PLESS
Baseline
Year 1
Year 2
Year 3
Year 4
Placebo ( ) n =
155
136
119
98
85
Finasteride ( ) n =
157
144
130
116
102
Prostate Volume as a Predictor of Therapeutic Response
A meta-analysis combining 1-year data from seven double-blind, placebo-controlled studies of similar
design, including 4491 patients with symptomatic BPH, demonstrated that, in patients treated with
PROSCAR, the magnitude of symptom response and degree of improvement in maximum urinary flow
rate were greater in patients with an enlarged prostate at baseline.
Medical Therapy of Prostatic Symptoms
The Medical Therapy of Prostatic Symptoms (MTOPS) Trial was a double-blind, randomized,
placebo-controlled, multicenter, 4- to 6-year study (average 5 years) in 3047 men with symptomatic BPH,
who were randomized to receive PROSCAR 5 mg/day (n=768), doxazosin 4 or 8 mg/day (n=756), the
combination of PROSCAR 5 mg/day and doxazosin 4 or 8 mg/day (n=786), or placebo (n=737). All
participants underwent weekly titration of doxazosin (or its placebo) from 1 to 2 to 4 to 8 mg/day. Only
those who tolerated the 4 or 8 mg dose level were kept on doxazosin (or its placebo) in the study. The
participant’s final tolerated dose (either 4 mg or 8 mg) was administered beginning at end-Week 4. The
final doxazosin dose was administered once per day, at bedtime.
The mean patient age at randomization was 62.6 years (±7.3 years). Patients were Caucasian (82%),
African American (9%), Hispanic (7%), Asian (1%) or Native American (<1%). The mean duration of BPH
symptoms was 4.7 years (±4.6 years). Patients had moderate to severe BPH symptoms at baseline with
a mean AUA symptom score of approximately 17 out of 35 points. Mean maximum urinary flow rate was
10.5 mL/sec (±2.6 mL/sec). The mean prostate volume as measured by transrectal ultrasound was
36.3 mL (±20.1 mL). Prostate volume was ≤20 mL in 16% of patients, ≥50 mL in 18% of patients and
between 21 and 49 mL in 66% of patients.
6
Cum
ula
tive Inc
id
enc
e o
f
a 4-Point Rise in A
UA Symptom S
core by Trea
tment Grou
p
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9631305
The primary endpoint was a composite measure of the first occurrence of any of the following five
outcomes: a ≥4 point confirmed increase from baseline in symptom score, acute urinary retention, BPH-
related renal insufficiency (creatinine rise), recurrent urinary tract infections or urosepsis, or incontinence.
Compared to placebo, treatment with PROSCAR, doxazosin, or combination therapy resulted in a
reduction in the risk of experiencing one of these five outcome events by 34% (p=0.002), 39% (p<0.001),
and 67% (p<0.001), respectively. Combination therapy resulted in a significant reduction in the risk of the
primary endpoint compared to treatment with PROSCAR alone (49%; p≤0.001) or doxazosin alone (46%;
p≤0.001). (See Table 2.)
Table 2
Count and Percent Incidence of Primary Outcome Events
by Treatment Group in MTOPS
Event
Treatment Group
Placebo
N=737
N (%)
Doxazosin
N=756
N (%)
Finasteride
N=768
N (%)
Combination
N=786
N (%)
Total
N=3047
N (%)
AUA 4-point rise
Acute urinary retention
Incontinence
Recurrent UTI/urosepsis
Creatinine rise
Total Events
100 (13.6)
18 (2.4)
8 (1.1)
2 (0.3)
0 (0.0)
128 (17.4)
59 (7.8)
13 (1.7)
11 (1.5)
2 (0.3)
0 (0.0)
85 (11.2)
74 (9.6)
6 (0.8)
9 (1.2)
0 (0.0)
0 (0.0)
89 (11.6)
41 (5.2)
4 (0.5)
3 (0.4)
1 (0.1)
0 (0.0)
49 (6.2)
274 (9.0)
41 (1.3)
31 (1.0)
5 (0.2)
0 (0.0)
351 (11.5)
The majority of the events (274 out of 351; 78%) was a confirmed ≥4 point increase in symptom score,
referred to as symptom score progression. The risk of symptom score progression was reduced by 30%
(p=0.016), 46% (p<0.001), and 64% (p<0.001) in patients treated with PROSCAR, doxazosin, or the
combination, respectively, compared to patients treated with placebo (see Figure 5). Combination therapy
significantly reduced the risk of symptom score progression compared to the effect of PROSCAR alone
(p<0.001) and compared to doxazosin alone (p=0.037).
Figure 5
Cumulative Incidence of a 4-Point Rise in AUA Symptom Score by Treatment Group
Years from Randomization
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Treatment with PROSCAR, doxazosin or the combination of PROSCAR with doxazosin, reduced the
mean symptom score from baseline at year 4. Table 3 provides the mean change from baseline for AUA
symptom score by treatment group for patients who remained on therapy for four years.
Table 3
Change From Baseline in AUA Symptom Score
by Treatment Group at Year 4 in MTOPS
Placebo
N=534
Doxazosin
N=582
Finasteride
N=565
Combination
N=598
Baseline Mean (SD)
16.8 (6.0)
17.0 (5.9)
17.1 (6.0)
16.8 (5.8)
Mean Change
AUA Symptom Score (SD)
-4.9 (5.8)
-6.6 (6.1)
-5.6 (5.9)
-7.4 (6.3)
Comparison to
Placebo (95% CI)
-1.8
(-2.5, -1.1)
-0.7
(-1.4, 0.0)
-2.5
(-3.2, -1.8)
Comparison to
Doxazosin alone (95% CI)
-0.7
(-1.4, 0.0)
Comparison to
Finasteride alone (95%
CI)
-1.8
(-2.5, -1.1)
The results of MTOPS are consistent with the findings of the 4-year, placebo-controlled study PLESS
(see CLINICAL PHARMACOLOGY, Clinical Studies) in that treatment with PROSCAR reduces the risk of
acute urinary retention and the need for BPH-related surgery. In MTOPS, the risk of developing acute
urinary retention was reduced by 67% in patients treated with PROSCAR compared to patients treated
with placebo (0.8% for PROSCAR and 2.4% for placebo). Also, the risk of requiring BPH-related invasive
therapy was reduced by 64% in patients treated with PROSCAR compared to patients treated with
placebo (2.0% for PROSCAR and 5.4% for placebo).
Summary of Clinical Studies
The data from these studies, showing improvement in BPH-related symptoms, reduction in treatment
failure (BPH-related urological events), increased maximum urinary flow rates, and decreasing prostate
volume, suggest that PROSCAR arrests the disease process of BPH in men with an enlarged prostate.
INDICATIONS AND USAGE
PROSCAR is indicated for the treatment of symptomatic benign prostatic hyperplasia (BPH) in men
with an enlarged prostate to:
-Improve symptoms
-Reduce the risk of acute urinary retention
-Reduce the risk of the need for surgery including transurethral resection of the prostate (TURP) and
prostatectomy.
PROSCAR administered in combination with the alpha-blocker doxazosin is indicated to reduce the
risk of symptomatic progression of BPH (a confirmed ≥4 point increase in AUA symptom score).
CONTRAINDICATIONS
PROSCAR is contraindicated in the following:
Hypersensitivity to any component of this medication.
Pregnancy. Finasteride use is contraindicated in women when they are or may potentially be
pregnant. Because of the ability of Type II 5α-reductase inhibitors to inhibit the conversion of testosterone
to DHT, finasteride may cause abnormalities of the external genitalia of a male fetus of a pregnant
woman who receives finasteride. If this drug is used during pregnancy, or if pregnancy occurs while
taking this drug, the pregnant woman should be apprised of the potential hazard to the male fetus. (See
also WARNINGS, EXPOSURE OF WOMEN — RISK TO MALE FETUS and PRECAUTIONS, Information
for Patients and Pregnancy.) In female rats, low doses of finasteride administered during pregnancy have
produced abnormalities of the external genitalia in male offspring.
WARNINGS
PROSCAR is not indicated for use in pediatric patients (see PRECAUTIONS, Pediatric Use) or
women (see also WARNINGS, EXPOSURE OF WOMEN — RISK TO MALE FETUS; PRECAUTIONS,
Information for Patients and Pregnancy; and HOW SUPPLIED).
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EXPOSURE OF WOMEN — RISK TO MALE FETUS
Women should not handle crushed or broken PROSCAR tablets when they are pregnant or may
potentially be pregnant because of the possibility of absorption of finasteride and the subsequent
potential risk to a male fetus. PROSCAR tablets are coated and will prevent contact with the active
ingredient during normal handling, provided that the tablets have not been broken or crushed. (See
CONTRAINDICATIONS; PRECAUTIONS, Information for Patients and Pregnancy; and HOW
SUPPLIED.)
PRECAUTIONS
General
Prior to initiating therapy with PROSCAR, appropriate evaluation should be performed to identify other
conditions such as infection, prostate cancer, stricture disease, hypotonic bladder or other neurogenic
disorders that might mimic BPH.
Patients with large residual urinary volume and/or severely diminished urinary flow should be carefully
monitored for obstructive uropathy. These patients may not be candidates for finasteride therapy.
Caution should be used in the administration of PROSCAR in those patients with liver function
abnormalities, as finasteride is metabolized extensively in the liver.
Effects on PSA and Prostate Cancer Detection
No clinical benefit has been demonstrated in patients with prostate cancer treated with PROSCAR.
Patients with BPH and elevated PSA were monitored in controlled clinical studies with serial PSAs and
prostate biopsies. In these BPH studies, PROSCAR did not appear to alter the rate of prostate cancer
detection, and the overall incidence of prostate cancer was not significantly different in patients treated
with PROSCAR or placebo.
PROSCAR causes a decrease in serum PSA levels by approximately 50% in patients with BPH. This
decrease is predictable over the entire range of PSA values, although it may vary in individual patients.
Analysis of PSA data from over 3000 patients in PLESS confirmed that in typical patients treated with
PROSCAR for six months or more, PSA values should be doubled for comparison with normal ranges in
untreated men. This adjustment preserves the sensitivity and specificity of the PSA assay and maintains
its ability to detect prostate cancer. PROSCAR may also cause decreases in serum PSA in the presence
of prostate cancer.
Any confirmed increases in PSA levels from nadir while on PROSCAR may signal the presence of
prostate cancer and should be carefully evaluated, even if those values are still within the normal range
for men not taking a 5α-reductase inhibitor. Non-compliance with PROSCAR therapy may also affect
PSA test results.
Percent free PSA (free to total PSA ratio) is not significantly decreased by PROSCAR. The ratio of
free to total PSA remains constant even under the influence of PROSCAR. If clinicians elect to use
percent free PSA as an aid in the detection of prostate cancer in men undergoing finasteride therapy, no
adjustment to its value appears necessary.
Information for Patients
Women should not handle crushed or broken PROSCAR tablets when they are pregnant or may
potentially be pregnant because of the possibility of absorption of finasteride and the subsequent
potential risk to the male fetus (see CONTRAINDICATIONS; WARNINGS, EXPOSURE OF WOMEN —
RISK TO MALE FETUS; PRECAUTIONS, Pregnancy and HOW SUPPLIED).
Physicians should inform patients that the volume of ejaculate may be decreased in some patients
during treatment with PROSCAR. This decrease does not appear to interfere with normal sexual function.
However, impotence and decreased libido may occur in patients treated with PROSCAR (see ADVERSE
REACTIONS).
Physicians should instruct their patients to promptly report any changes in their breasts such as
lumps, pain or nipple discharge. Breast changes including breast enlargement, tenderness and neoplasm
have been reported (see ADVERSE REACTIONS).
Physicians should instruct their patients to read the patient package insert before starting therapy
with PROSCAR and to reread it each time the prescription is renewed so that they are aware of current
information for patients regarding PROSCAR.
Drug/Laboratory Test Interactions
In patients with BPH, PROSCAR has no effect on circulating levels of cortisol, estradiol, prolactin,
thyroid-stimulating hormone, or thyroxine. No clinically meaningful effect was observed on the plasma
lipid profile (i.e., total cholesterol, low density lipoproteins, high density lipoproteins and triglycerides) or
bone mineral density. Increases of about 10% were observed in luteinizing hormone (LH) and follicle
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stimulating hormone (FSH) in patients receiving PROSCAR, but levels remained within the normal range.
In healthy volunteers, treatment with PROSCAR did not alter the response of LH and FSH to
gonadotropin-releasing hormone indicating that the hypothalamic-pituitary-testicular axis was not
affected.
Treatment with PROSCAR for 24 weeks to evaluate semen parameters in healthy male volunteers
revealed no clinically meaningful effects on sperm concentration, mobility, morphology, or pH. A 0.6 mL
(22.1%) median decrease in ejaculate volume with a concomitant reduction in total sperm per ejaculate
was observed. These parameters remained within the normal range and were reversible upon
discontinuation of therapy with an average time to return to baseline of 84 weeks.
Drug Interactions
No drug interactions of clinical importance have been identified. Finasteride does not appear to affect
the cytochrome P450-linked drug metabolizing enzyme system. Compounds that have been tested in
man have included antipyrine, digoxin, propranolol, theophylline, and warfarin and no clinically
meaningful interactions were found.
Other Concomitant Therapy: Although specific interaction studies were not performed, PROSCAR
was concomitantly used in clinical studies with acetaminophen, acetylsalicylic acid, α-blockers,
angiotensin-converting enzyme (ACE) inhibitors, analgesics, anti-convulsants, beta-adrenergic blocking
agents, diuretics, calcium channel blockers, cardiac nitrates, HMG-CoA reductase inhibitors, nonsteroidal
anti-inflammatory drugs (NSAIDs), benzodiazepines, H2 antagonists and quinolone anti-infectives without
evidence of clinically significant adverse interactions.
Carcinogenesis, Mutagenesis, Impairment of Fertility
No evidence of a tumorigenic effect was observed in a 24-month study in Sprague-Dawley rats
receiving doses of finasteride up to 160 mg/kg/day in males and 320 mg/kg/day in females. These doses
produced respective systemic exposure in rats of 111 and 274 times those observed in man receiving the
recommended human dose of 5 mg/day. All exposure calculations were based on calculated AUC(0-24 hr)
for animals and mean AUC(0-24 hr) for man (0.4 μg•hr/mL).
In a 19-month carcinogenicity study in CD-1 mice, a statistically significant (p≤0.05) increase in the
incidence of testicular Leydig cell adenomas was observed at a dose of 250 mg/kg/day (228 times the
human exposure). In mice at a dose of 25 mg/kg/day (23 times the human exposure, estimated) and in
rats at a dose of ≥40 mg/kg/day (39 times the human exposure) an increase in the incidence of Leydig
cell hyperplasia was observed. A positive correlation between the proliferative changes in the Leydig cells
and an increase in serum LH levels (2- to 3-fold above control) has been demonstrated in both rodent
species treated with high doses of finasteride. No drug-related Leydig cell changes were seen in either
rats or dogs treated with finasteride for 1 year at doses of 20 mg/kg/day and 45 mg/kg/day (30 and 350
times, respectively, the human exposure) or in mice treated for 19 months at a dose of 2.5 mg/kg/day (2.3
times the human exposure, estimated).
No evidence of mutagenicity was observed in an in vitro bacterial mutagenesis assay, a mammalian
cell mutagenesis assay, or in an in vitro alkaline elution assay. In an in vitro chromosome aberration
assay, using Chinese hamster ovary cells, there was a slight increase in chromosome aberrations. These
concentrations correspond to 4000-5000 times the peak plasma levels in man given a total dose of 5 mg.
In an in vivo chromosome aberration assay in mice, no treatment-related increase in chromosome
aberration was observed with finasteride at the maximum tolerated dose of 250 mg/kg/day (228 times the
human exposure) as determined in the carcinogenicity studies.
In sexually mature male rabbits treated with finasteride at 80 mg/kg/day (543 times the human
exposure) for up to 12 weeks, no effect on fertility, sperm count, or ejaculate volume was seen. In
sexually mature male rats treated with 80 mg/kg/day of finasteride (61 times the human exposure), there
were no significant effects on fertility after 6 or 12 weeks of treatment; however, when treatment was
continued for up to 24 or 30 weeks, there was an apparent decrease in fertility, fecundity and an
associated significant decrease in the weights of the seminal vesicles and prostate. All these effects were
reversible within 6 weeks of discontinuation of treatment. No drug-related effect on testes or on mating
performance has been seen in rats or rabbits. This decrease in fertility in finasteride-treated rats is
secondary to its effect on accessory sex organs (prostate and seminal vesicles) resulting in failure to form
a seminal plug. The seminal plug is essential for normal fertility in rats and is not relevant in man.
Pregnancy
Pregnancy Category X
See CONTRAINDICATIONS.
PROSCAR is not indicated for use in women.
Administration of finasteride to pregnant rats at doses ranging from 100 μg/kg/day to 100 mg/kg/day
(1-1000 times the recommended human dose of 5 mg/day) resulted in dose-dependent development of
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hypospadias in 3.6 to 100% of male offspring. Pregnant rats produced male offspring with decreased
prostatic and seminal vesicular weights, delayed preputial separation and transient nipple development
when given finasteride at ≥30 μg/kg/day (≥3/10 of the recommended human dose of 5 mg/day) and
decreased anogenital distance when given finasteride at ≥3 μg/kg/day (≥3/100 of the recommended
human dose of 5 mg/day). The critical period during which these effects can be induced in male rats has
been defined to be days 16-17 of gestation. The changes described above are expected pharmacological
effects of drugs belonging to the class of Type II 5α-reductase inhibitors and are similar to those reported
in male infants with a genetic deficiency of Type II 5α-reductase. No abnormalities were observed in
female offspring exposed to any dose of finasteride in utero.
No developmental abnormalities have been observed in first filial generation (F1) male or female
offspring resulting from mating finasteride-treated male rats (80 mg/kg/day; 61 times the human
exposure) with untreated females. Administration of finasteride at 3 mg/kg/day (30 times the
recommended human dose of 5 mg/day) during the late gestation and lactation period resulted in slightly
decreased fertility in F1 male offspring. No effects were seen in female offspring. No evidence of
malformations has been observed in rabbit fetuses exposed to finasteride in utero from days 6-18 of
gestation at doses up to 100 mg/kg/day (1000 times the recommended human dose of 5 mg/day).
However, effects on male genitalia would not be expected since the rabbits were not exposed during the
critical period of genital system development.
The in utero effects of finasteride exposure during the period of embryonic and fetal development
were evaluated in the rhesus monkey (gestation days 20-100), a species more predictive of human
development than rats or rabbits. Intravenous administration of finasteride to pregnant monkeys at doses
as high as 800 ng/day (at least 60 to 120 times the highest estimated exposure of pregnant women to
finasteride from semen of men taking 5 mg/day) resulted in no abnormalities in male fetuses. In
confirmation of the relevance of the rhesus model for human fetal development, oral administration of a
dose of finasteride (2 mg/kg/day; 20 times the recommended human dose of 5 mg/day or approximately
1-2 million times the highest estimated exposure to finasteride from semen of men taking 5 mg/day) to
pregnant monkeys resulted in external genital abnormalities in male fetuses. No other abnormalities were
observed in male fetuses and no finasteride-related abnormalities were observed in female fetuses at any
dose.
Nursing Mothers
PROSCAR is not indicated for use in women.
It is not known whether finasteride is excreted in human milk.
Pediatric Use
PROSCAR is not indicated for use in pediatric patients.
Safety and effectiveness in pediatric patients have not been established.
Geriatric Use
Of the total number of subjects included in PLESS, 1480 and 105 subjects were 65 and over and 75
and over, respectively. No overall differences in safety or effectiveness were observed between these
subjects and younger subjects, and other reported clinical experience has not identified differences in
responses between the elderly and younger patients. No dosage adjustment is necessary in the elderly
(see CLINICAL PHARMACOLOGY, Pharmacokinetics and Clinical Studies).
ADVERSE REACTIONS
PROSCAR is generally well tolerated; adverse reactions usually have been mild and transient.
4-Year Placebo-Controlled Study
In PLESS, 1524 patients treated with PROSCAR and 1516 patients treated with placebo were
evaluated for safety over a period of 4 years. The most frequently reported adverse reactions were
related to sexual function. 3.7% (57 patients) treated with PROSCAR and 2.1% (32 patients) treated with
placebo discontinued therapy as a result of adverse reactions related to sexual function, which are the
most frequently reported adverse reactions.
Table 4 presents the only clinical adverse reactions considered possibly, probably or definitely drug
related by the investigator, for which the incidence on PROSCAR was ≥1% and greater than placebo
over the 4 years of the study. In years 2-4 of the study, there was no significant difference between
treatment groups in the incidences of impotence, decreased libido and ejaculation disorder.
TABLE 4
Drug-Related Adverse Experiences
Year 1
(%)
Years 2, 3 and 4*
(%)
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Finasteride
Placebo
Finasteride
Placebo
Impotence
8.1
3.7
5.1
5.1
Decreased
Libido
6.4
3.4
2.6
2.6
Decreased
Volume of
Ejaculate
3.7
0.8
1.5
0.5
Ejaculation
Disorder
0.8
0.1
0.2
0.1
Breast
Enlargement
0.5
0.1
1.8
1.1
Breast
Tenderness
0.4
0.1
0.7
0.3
Rash
0.5
0.2
0.5
0.1
*Combined Years 2-4
N = 1524 and 1516, finasteride vs placebo, respectively
Phase III Studies and 5-Year Open Extensions
The adverse experience profile in the 1-year, placebo-controlled, Phase III studies, the 5-year open
extensions, and PLESS were similar.
Medical Therapy of Prostatic Symptoms (MTOPS) Study
The incidence rates of drug-related adverse experiences reported by ≥2% of patients in any treatment
group in the MTOPS Study are listed in Table 5.
The individual adverse effects which occurred more frequently in the combination group compared to
either drug alone were: asthenia, postural hypotension, peripheral edema, dizziness, decreased libido,
rhinitis, abnormal ejaculation, impotence and abnormal sexual function (see Table 5). Of these, the
incidence of abnormal ejaculation in patients receiving combination therapy was comparable to the sum
of the incidences of this adverse experience reported for the two monotherapies.
Combination therapy with finasteride and doxazosin was associated with no new clinical adverse
experience.
Four patients in MTOPS reported the adverse experience breast cancer. Three of these patients were
on finasteride only and one was on combination therapy. (See ADVERSE REACTIONS, Long-Term
Data.)
The MTOPS Study was not specifically designed to make statistical comparisons between groups for
reported adverse experiences. In addition, direct comparisons of safety data between the MTOPS study
and previous studies of the single agents may not be appropriate based upon differences in patient
population, dosage or dose regimen, and other procedural and study design elements.
Table 5
Incidence ≥ 2% in One or More Treatment Groups
Drug-Related Clinical Adverse Experiences in MTOPS
Adverse Experience
Placebo
(N=737)
(%)
Doxazosin
4 mg or 8 mg*
(N=756)
(%)
Finasteride
(N=768)
(%)
Combination
(N=786)
(%)
Body as a whole
Asthenia
Headache
7.1
2.3
15.7
4.1
5.3
2.0
16.8
2.3
Cardiovascular
Hypotension
Postural Hypotension
0.7
8.0
3.4
16.7
1.2
9.1
1.5
17.8
Metabolic and Nutritional
Peripheral Edema
0.9
2.6
1.3
3.3
Nervous
Dizziness
Libido Decreased
Somnolence
8.1
5.7
1.5
17.7
7.0
3.7
7.4
10.0
1.7
23.2
11.6
3.1
Respiratory
Dyspnea
Rhinitis
0.7
0.5
2.1
1.3
0.7
1.0
1.9
2.4
Urogenital
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Abnormal Ejaculation
Gynecomastia
Impotence
Sexual Function Abnormal
2.3
0.7
12.2
0.9
4.5
1.1
14.4
2.0
7.2
2.2
18.5
2.5
14.1
1.5
22.6
3.1
*Doxazosin dose was achieved by weekly titration (1 to 2 to 4 to 8 mg). The final tolerated dose (4 mg or 8 mg) was administered at end-Week 4.
Only those patients tolerating at least 4 mg were kept on doxazosin. The majority of patients received the 8-mg dose over the duration of the
study.
Long-Term Data
There is no evidence of increased adverse experiences with increased duration of treatment with
PROSCAR. New reports of drug-related sexual adverse experiences decreased with duration of therapy.
During the 4- to 6-year placebo- and comparator-controlled MTOPS study that enrolled 3047 men,
there were 4 cases of breast cancer in men treated with finasteride but no cases in men not treated with
finasteride. During the 4-year, placebo-controlled PLESS study that enrolled 3040 men, there were 2
cases of breast cancer in placebo-treated men, but no cases were reported in men treated with
finasteride. The relationship between long-term use of finasteride and male breast neoplasia is currently
unknown.
In a 7-year placebo-controlled trial that enrolled 18,882 healthy men, 9060 had prostate needle
biopsy data available for analysis. In the PROSCAR group, 280 (6.4%) men had prostate cancer with
Gleason scores of 7-10 detected on needle biopsy vs. 237 (5.1%) men in the placebo group. Of the total
cases of prostate cancer diagnosed in this study, approximately 98% were classified as intracapsular
(stage T1 or T2). The clinical significance of these findings is unknown. This information from the
literature (Thompson IM, Goodman PJ, Tangen CM, et al. The influence of finasteride on the
development of prostate cancer. N Engl J Med 2003;349:213-22) is provided for consideration by
physicians when PROSCAR is used as indicated (see INDICATIONS AND USAGE). PROSCAR is not
approved to reduce the risk of developing prostate cancer.
Post-Marketing Experience
The following additional adverse effects have been reported in post-marketing experience:
- hypersensitivity reactions, including pruritus, urticaria, and swelling of the lips and face
- testicular pain
- male breast cancer.
OVERDOSAGE
Patients have received single doses of PROSCAR up to 400 mg and multiple doses of PROSCAR up
to 80 mg/day for three months without adverse effects. Until further experience is obtained, no specific
treatment for an overdose with PROSCAR can be recommended.
Significant lethality was observed in male and female mice at single oral doses of 1500 mg/m2 (500
mg/kg) and in female and male rats at single oral doses of 2360 mg/m2 (400 mg/kg) and 5900 mg/m2
(1000 mg/kg), respectively.
DOSAGE AND ADMINISTRATION
The recommended dose is 5 mg orally once a day.
PROSCAR can be administered alone or in combination with the alpha-blocker doxazosin (see
CLINICAL PHARMACOLOGY, Clinical Studies).
PROSCAR may be administered with or without meals.
No dosage adjustment is necessary for patients with renal impairment or for the elderly (see
CLINICAL PHARMACOLOGY, Pharmacokinetics).
HOW SUPPLIED
No. 3094 — PROSCAR tablets 5 mg are blue, modified apple-shaped, film-coated tablets, with the
code MSD 72 on one side and PROSCAR on the other. They are supplied as follows:
NDC 0006-0072-31 unit of use bottles of 30
NDC 0006-0072-58 unit of use bottles of 100
Storage and Handling
Store at room temperatures below 30°C (86°F). Protect from light and keep container tightly closed.
Women should not handle crushed or broken PROSCAR tablets when they are pregnant or may
potentially be pregnant because of the possibility of absorption of finasteride and the subsequent
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potential risk to a male fetus (see WARNINGS, EXPOSURE OF WOMEN — RISK TO MALE FETUS,
and PRECAUTIONS, Information for Patients and Pregnancy). Merck & Co., Inc.
Issued October 2010
Printed in USA
14
PROSCAR® (Finasteride) Tablets
Patient Information about
PROSCAR® (Prahs-car)
Generic name: finasteride
(fin-AS-tur-eyed)
PROSCAR
* is for use by men only.
Please read this leaflet before you start taking PROSCAR. Also, read it each time you renew your
prescription, just in case anything has changed. Remember, this leaflet does not take the place of careful
discussions with your doctor. You and your doctor should discuss PROSCAR when you start taking your
medication and at regular checkups.
What is PROSCAR?
PROSCAR is a medication used to treat symptoms of benign prostatic hyperplasia (BPH) in men with an
enlarged prostate. PROSCAR may also be used to reduce the risk of a sudden inability to pass urine and
the need for surgery related to BPH in men with an enlarged prostate.
PROSCAR may be prescribed along with another medicine, an alpha-blocker called doxazosin, to help
you better manage your BPH symptoms.
Who should NOT take PROSCAR?
PROSCAR is for use by MEN only.
Do Not Take PROSCAR if you are:
•
a woman who is pregnant or may potentially be pregnant. PROSCAR may harm your unborn
baby. Do not touch or handle crushed or broken PROSCAR tablets (see “A warning about
PROSCAR and pregnancy”).
•
allergic to finasteride or any of the ingredients in PROSCAR. See the end of this leaflet for a
complete list of ingredients in PROSCAR.
A warning about PROSCAR and pregnancy:
Women who are or may potentially be pregnant must not use PROSCAR. They should also not handle
crushed or broken tablets of PROSCAR. PROSCAR tablets are coated and will prevent contact with the
active ingredient during normal handling, provided that the tablets are not broken or crushed.
If a woman who is pregnant with a male baby absorbs the active ingredient in PROSCAR after oral use or
through the skin, it may cause the male baby to be born with abnormalities of the sex organs. If a woman
who is pregnant comes into contact with the active ingredient in PROSCAR, a doctor should be
consulted.
How should I take PROSCAR?
Follow your doctor's instruction.
•
Take one tablet by mouth each day. To avoid forgetting to take PROSCAR, you can take it at the
same time every day.
•
If you forget to take PROSCAR, do not take an extra tablet. Just take the next tablet as usual.
* Registered trademark of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
Copyright © 1992, 1995, 1998 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
All rights reserved
PROSCAR® (Finasteride) Tablets
9631305
•
You may take PROSCAR with or without food.
•
Do not share PROSCAR with anyone else; it was prescribed only for you.
What are the possible side effects of PROSCAR?
The most common side effects of PROSCAR include:
•
trouble getting or keeping an erection (impotence)
•
decrease in sex drive
•
decreased volume of ejaculate
•
ejaculation disorders
•
enlarged or painful breast. You should promptly report to your doctor any changes in your breasts
such as lumps, pain or nipple discharge.
In addition, the following have been reported in general use with PROSCAR:
•
allergic reactions, including rash, itching, hives, and swelling of the lips and face
•
rarely, some men may have testicular pain
•
in rare cases, male breast cancer has been reported.
You should discuss side effects with your doctor before taking PROSCAR and anytime you think you are
having a side effect. These are not all the possible side effects with PROSCAR. For more information,
ask your doctor or pharmacist.
Call your doctor for medical advice about side effects. You may report side effects to FDA at: 1-800-FDA
1088.
What you need to know while taking PROSCAR:
•
You should see your doctor regularly while taking PROSCAR. Follow your doctor's advice
about when to have these checkups.
•
Checking for prostate cancer. Your doctor has prescribed PROSCAR for BPH and not for
treatment of prostate cancer — but a man can have BPH and prostate cancer at the same time.
Checking for prostate cancer should continue while you take PROSCAR.
•
About Prostate-Specific Antigen (PSA). Your doctor may have done a blood test called PSA
for the screening of prostate cancer. Because PROSCAR decreases PSA levels, you should tell
your doctor(s) that you are taking PROSCAR. Changes in PSA levels will need to be carefully
evaluated by your doctor(s). Any increase in follow-up PSA levels from their lowest point should
be carefully evaluated, even if the test results are still within the normal range. You should also
tell your doctor if you have not been taking PROSCAR as prescribed because this may affect the
PSA test results. For more information, talk to your doctor.
How should I store PROSCAR?
•
Store PROSCAR tablets in a dry place at room temperature.
•
Keep PROSCAR in the original container and keep the container closed.
PROSCAR tablets are coated and will prevent contact with the active ingredient during
normal handling, provided that the tablets are not broken or crushed.
Keep PROSCAR and all medications out of the reach of children.
Do not give your PROSCAR tablets to anyone else. It has been prescribed only for you.
For more information call 1-800-633-4477.
2
PROSCAR® (Finasteride) Tablets
9631305
What are the ingredients in PROSCAR?
Active ingredients: finasteride
Inactive ingredients: hydrous lactose, microcrystalline cellulose, pregelatinized starch, sodium starch
glycolate, hydroxypropyl cellulose LF, hydroxypropyl methylcellulose, titanium dioxide, magnesium
stearate, talc, docusate sodium, FD&C Blue 2 aluminum lake and yellow iron oxide.
What is BPH?
BPH is an enlargement of the prostate gland. The prostate is located below the bladder. As the prostate
enlarges, it may slowly restrict the flow of urine. This can lead to symptoms such as:
•
a weak or interrupted urinary stream
•
a feeling that you cannot empty your bladder completely
•
a feeling of delay or hesitation when you start to urinate
•
a need to urinate often, especially at night
•
a feeling that you must urinate right away.
In some men, BPH can lead to serious problems, including urinary tract infections, a sudden inability to
pass urine (acute urinary retention), as well as the need for surgery.
What PROSCAR does:
PROSCAR lowers levels of a hormone called DHT (dihydrotestosterone), which is a cause of prostate
growth. Lowering DHT leads to shrinkage of the enlarged prostate gland in most men. This can lead to
gradual improvement in urine flow and symptoms over the next several months. PROSCAR will help
reduce the risk of developing a sudden inability to pass urine and the need for surgery related to an
enlarged prostate. However, since each case of BPH is different, you should know that:
•
Even though the prostate shrinks, you may NOT notice an improvement in urine flow or
symptoms.
•
You may need to take PROSCAR for six (6) months or more to see whether it improves your
symptoms.
•
Therapy with PROSCAR may reduce your risk for a sudden inability to pass urine and the need
for surgery for an enlarged prostate. Merck & Co., Inc.
Issued October 2010
3
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custom-source
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2025-02-12T13:46:59.725499
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020180s037lbl.pdf', 'application_number': 20180, 'submission_type': 'SUPPL ', 'submission_number': 37}
|
12,300
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HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
PROSCAR safely and effectively. See full prescribing information
for PROSCAR.
PROSCAR® (finasteride) Tablets
Initial U.S. Approval: 1992
---------------------------RECENT MAJOR CHANGES --------------------------
Indications and Usage, Limitations of Use (1.3)
06/2011
Warnings and Precautions
Increased Risk of High-Grade Prostate Cancer (5.2)
06/2011
----------------------------INDICATIONS AND USAGE ---------------------------
PROSCAR, is a 5α-reductase inhibitor, indicated for the treatment of
symptomatic benign prostatic hyperplasia (BPH) in men with an
enlarged prostate to (1.1):
Improve symptoms
Reduce the risk of acute urinary retention
Reduce the risk of the need for surgery including transurethral
resection of the prostate (TURP) and prostatectomy.
PROSCAR administered in combination with the alpha-blocker
doxazosin is indicated to reduce the risk of symptomatic progression of
BPH (a confirmed 4 point increase in American Urological Association
(AUA) symptom score) (1.2).
Limitations of Use: PROSCAR is not approved for the prevention of
prostate cancer (1.3).
----------------------- DOSAGE AND ADMINISTRATION-----------------------
PROSCAR may be administered with or without meals (2).
Monotherapy: One tablet (5 mg) taken once a day (2.1).
Combination with Doxazosin: One tablet (5 mg) taken once a day in
combination with the alpha-blocker doxazosin (2.2).
--------------------- DOSAGE FORMS AND STRENGTHS --------------------
5-mg film-coated tablets (3).
------------------------------ CONTRAINDICATIONS ------------------------------
Hypersensitivity to any components of this product (4).
Women who are or may potentially be pregnant (4, 5.4, 8.1, 16).
------------------------WARNINGS AND PRECAUTIONS-----------------------
PROSCAR reduces serum prostate specific antigen (PSA) levels
by approximately 50%. However, any confirmed increase in PSA
while on PROSCAR may signal the presence of prostate cancer
and should be evaluated, even if those values are still within the
normal range for men not taking a 5α-reductase inhibitor (5.1).
PROSCAR may increase the risk of high-grade prostate cancer
(5.2, 6.1).
Women should not handle crushed or broken PROSCAR tablets
when they are pregnant or may potentially be pregnant due to
potential risk to a male fetus (5.3, 8.1, 16).
PROSCAR is not indicated for use in pediatric patients or women
(5.4, 8.1, 8.3, 8.4, 12.3).
Prior
to
initiating
treatment
with
PROSCAR
for
BPH,
consideration should be given to other urological conditions that
may cause similar symptoms (5.6).
------------------------------ ADVERSE REACTIONS------------------------------
The drug-related adverse reactions, reported in ≥1% in patients treated
with PROSCAR and greater than in patients treated with placebo over
a 4-year study are: impotence, decreased libido, decreased volume of
ejaculate, breast enlargement, breast tenderness and rash (6.1).
To report SUSPECTED ADVERSE REACTIONS, contact Merck
Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., at 1-877
888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
See
17
for
PATIENT
COUNSELING
INFORMATION
and
FDA-approved patient labeling.
Revised: April 2012
FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
1.1
Monotherapy
1.2
Combination with Alpha-Blocker
1.3
Limitations of Use
2
DOSAGE AND ADMINISTRATION
2.1
Monotherapy
2.2
Combination with Alpha-Blocker
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1 Effects on Prostate Specific Antigen (PSA) and the Use of
PSA in Prostate Cancer Detection
5.2
Increased Risk of High-Grade Prostate Cancer
5.3
Exposure of Women — Risk to Male Fetus
5.4
Pediatric Patients and Women
5.5
Effect on Semen Characteristics
5.6
Consideration of Other Urological Conditions
6
ADVERSE REACTIONS
6.1
Clinical Trials Experience
6.2
Postmarketing Experience
7
DRUG INTERACTIONS
7.1
Cytochrome
P450-Linked
Drug
Metabolizing
Enzyme
System
7.2
Other Concomitant Therapy
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
8.3
Nursing Mothers
8.4
Pediatric Use
8.5
Geriatric Use
8.6
Hepatic Impairment
8.7
Renal Impairment
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
14.1 Monotherapy
14.2 Combination with Alpha-Blocker Therapy
14.3 Summary of Clinical Studies
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
17.1 Increased Risk of High-Grade Prostate Cancer
17.2 Exposure of Women — Risk to Male Fetus
17.3 Additional Instructions
*Sections or subsections omitted from the full prescribing information
are not listed.
1
Reference ID: 3114705
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
FULL PRESCRIBING INFORMATION
1
INDICATIONS AND USAGE
1.1
Monotherapy
PROSCAR
® is indicated for the treatment of symptomatic benign prostatic hyperplasia (BPH) in men
with an enlarged prostate to:
-Improve symptoms
-Reduce the risk of acute urinary retention
-Reduce the risk of the need for surgery including transurethral resection of the prostate (TURP) and
prostatectomy.
1.2
Combination with Alpha-Blocker
PROSCAR administered in combination with the alpha-blocker doxazosin is indicated to reduce the
risk of symptomatic progression of BPH (a confirmed 4 point increase in American Urological
Association (AUA) symptom score).
1.3
Limitations of Use
PROSCAR is not approved for the prevention of prostate cancer.
2
DOSAGE AND ADMINISTRATION
PROSCAR may be administered with or without meals.
2.1
Monotherapy
The recommended dose of PROSCAR is one tablet (5 mg) taken once a day [see Clinical Studies
(14.1)].
2.2
Combination with Alpha-Blocker
The recommended dose of PROSCAR is one tablet (5 mg) taken once a day in combination with the
alpha-blocker doxazosin [see Clinical Studies (14.2)].
3
DOSAGE FORMS AND STRENGTHS
5-mg blue, modified apple-shaped, film-coated tablets, with the code MSD 72 on one side and
PROSCAR on the other.
4
CONTRAINDICATIONS
PROSCAR is contraindicated in the following:
Hypersensitivity to any component of this medication.
Pregnancy. Finasteride use is contraindicated in women when they are or may potentially be
pregnant. Because of the ability of Type II 5α-reductase inhibitors to inhibit the conversion of
testosterone to 5α-dihydrotestosterone (DHT), finasteride may cause abnormalities of the
external genitalia of a male fetus of a pregnant woman who receives finasteride. If this drug is
used during pregnancy, or if pregnancy occurs while taking this drug, the pregnant woman
should be apprised of the potential hazard to the male fetus. [See also Warnings and
Precautions (5.3), Use in Specific Populations (8.1), How Supplied/Storage and Handling
(16) and Patient Counseling Information (17.2).] In female rats, low doses of finasteride
administered during pregnancy have produced abnormalities of the external genitalia in male
offspring.
5
WARNINGS AND PRECAUTIONS
5.1
Effects on Prostate Specific Antigen (PSA) and the Use of PSA in Prostate Cancer
Detection
In clinical studies, PROSCAR reduced serum PSA concentration by approximately 50% within six
months of treatment. This decrease is predictable over the entire range of PSA values in patients with
symptomatic BPH, although it may vary in individuals.
For interpretation of serial PSAs in men taking PROSCAR, a new PSA baseline should be established
at least six months after starting treatment and PSA monitored periodically thereafter. Any confirmed
2
Reference ID: 3114705
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
increase from the lowest PSA value while on PROSCAR may signal the presence of prostate cancer and
should be evaluated, even if PSA levels are still within the normal range for men not taking a 5α
reductase inhibitor. Non-compliance with PROSCAR therapy may also affect PSA test results. To
interpret an isolated PSA value in patients treated with PROSCAR for six months or more, PSA values
should be doubled for comparison with normal ranges in untreated men. These adjustments preserve the
utility of PSA to detect prostate cancer in men treated with PROSCAR.
PROSCAR may also cause decreases in serum PSA in the presence of prostate cancer.
The ratio of free to total PSA (percent free PSA) remains constant even under the influence of
PROSCAR. If clinicians elect to use percent free PSA as an aid in the detection of prostate cancer in men
undergoing finasteride therapy, no adjustment to its value appears necessary.
5.2
Increased Risk of High-Grade Prostate Cancer
Men aged 55 and over with a normal digital rectal examination and PSA ≤3.0 ng/mL at baseline taking
finasteride 5 mg/day in the 7-year Prostate Cancer Prevention Trial (PCPT) had an increased risk of
Gleason score 8-10 prostate cancer (finasteride 1.8% vs placebo 1.1%). [See Indications and Usage
(1.3) and Adverse Reactions (6.1).] Similar results were observed in a 4-year placebo-controlled clinical
trial with another 5α-reductase inhibitor (dutasteride, AVODART) (1% dutasteride vs 0.5% placebo). 5α
reductase inhibitors may increase the risk of development of high-grade prostate cancer. Whether the
effect of 5α-reductase inhibitors to reduce prostate volume, or study-related factors, impacted the results
of these studies has not been established.
5.3
Exposure of Women — Risk to Male Fetus
Women should not handle crushed or broken PROSCAR tablets when they are pregnant or may
potentially be pregnant because of the possibility of absorption of finasteride and the subsequent
potential risk to a male fetus. PROSCAR tablets are coated and will prevent contact with the active
ingredient during normal handling, provided that the tablets have not been broken or crushed. [See
Contraindications (4), Use in Specific Populations (8.1), Clinical Pharmacology (12.3), How
Supplied/Storage and Handling (16) and Patient Counseling Information (17.2).]
5.4
Pediatric Patients and Women
PROSCAR is not indicated for use in pediatric patients [see Use in Specific Populations (8.4) and
Clinical Pharmacology (12.3)] or women [see also Warnings and Precautions (5.3), Use in Specific
Populations (8.1), Clinical Pharmacology (12.3), How Supplied/Storage and Handling (16) and Patient
Counseling Information (17.2)].
5.5
Effect on Semen Characteristics
Treatment with PROSCAR for 24 weeks to evaluate semen parameters in healthy male volunteers
revealed no clinically meaningful effects on sperm concentration, mobility, morphology, or pH. A 0.6 mL
(22.1%) median decrease in ejaculate volume with a concomitant reduction in total sperm per ejaculate
was observed. These parameters remained within the normal range and were reversible upon
discontinuation of therapy with an average time to return to baseline of 84 weeks.
5.6
Consideration of Other Urological Conditions
Prior to initiating treatment with PROSCAR, consideration should be given to other urological
conditions that may cause similar symptoms. In addition, prostate cancer and BPH may coexist.
Patients with large residual urinary volume and/or severely diminished urinary flow should be carefully
monitored for obstructive uropathy. These patients may not be candidates for finasteride therapy.
6
ADVERSE REACTIONS
6.1
Clinical Trials Experience
PROSCAR is generally well tolerated; adverse reactions usually have been mild and transient.
4-Year Placebo-Controlled Study (PLESS)
In PLESS, 1524 patients treated with PROSCAR and 1516 patients treated with placebo were
evaluated for safety over a period of 4 years. The most frequently reported adverse reactions were
related to sexual function. 3.7% (57 patients) treated with PROSCAR and 2.1% (32 patients) treated with
placebo discontinued therapy as a result of adverse reactions related to sexual function, which are the
most frequently reported adverse reactions.
Table 1 presents the only clinical adverse reactions considered possibly, probably or definitely drug
related by the investigator, for which the incidence on PROSCAR was ≥1% and greater than placebo
3
Reference ID: 3114705
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
over the 4 years of the study. In years 2-4 of the study, there was no significant difference between
treatment groups in the incidences of impotence, decreased libido and ejaculation disorder.
Table 1
Drug-Related Adverse Experiences
Year 1
(%)
Years 2, 3 and 4*
(%)
Finasteride
Placebo
Finasteride
Placebo
Impotence
8.1
3.7
5.1
5.1
Decreased
Libido
6.4
3.4
2.6
2.6
Decreased
Volume of
Ejaculate
3.7
0.8
1.5
0.5
Ejaculation
Disorder
0.8
0.1
0.2
0.1
Breast
Enlargement
0.5
0.1
1.8
1.1
Breast
Tenderness
0.4
0.1
0.7
0.3
Rash
0.5
0.2
0.5
0.1
*Combined Years 2-4
N = 1524 and 1516, finasteride vs placebo, respectively
Phase III Studies and 5-Year Open Extensions
The adverse experience profile in the 1-year, placebo-controlled, Phase III studies, the 5-year open
extensions, and PLESS were similar.
Medical Therapy of Prostatic Symptoms (MTOPS) Study
In the MTOPS study, 3047 men with symptomatic BPH were randomized to receive PROSCAR
5 mg/day (n=768), doxazosin 4 or 8 mg/day (n=756), the combination of PROSCAR 5 mg/day and
doxazosin 4 or 8 mg/day (n=786), or placebo (n=737) for 4 to 6 years. [See Clinical Studies (14.2).]
The incidence rates of drug-related adverse experiences reported by 2% of patients in any treatment
group in the MTOPS Study are listed in Table 2.
The individual adverse effects which occurred more frequently in the combination group compared to
either drug alone were: asthenia, postural hypotension, peripheral edema, dizziness, decreased libido,
rhinitis, abnormal ejaculation, impotence and abnormal sexual function (see Table 2). Of these, the
incidence of abnormal ejaculation in patients receiving combination therapy was comparable to the sum
of the incidences of this adverse experience reported for the two monotherapies.
Combination therapy with finasteride and doxazosin was associated with no new clinical adverse
experience.
Four patients in MTOPS reported the adverse experience breast cancer. Three of these patients were
on finasteride only and one was on combination therapy. [See Long Term Data.]
The MTOPS Study was not specifically designed to make statistical comparisons between groups for
reported adverse experiences. In addition, direct comparisons of safety data between the MTOPS study
and previous studies of the single agents may not be appropriate based upon differences in patient
population, dosage or dose regimen, and other procedural and study design elements.
4
Reference ID: 3114705
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 2
Incidence ≥2% in One or More Treatment Groups
Drug-Related Clinical Adverse Experiences in MTOPS
Adverse Experience
Placebo
(N=737)
(%)
Doxazosin
4 mg or 8 mg*
(N=756)
(%)
Finasteride
(N=768)
(%)
Combination
(N=786)
(%)
Body as a whole
Asthenia
Headache
7.1
2.3
15.7
4.1
5.3
2.0
16.8
2.3
Cardiovascular
Hypotension
Postural Hypotension
0.7
8.0
3.4
16.7
1.2
9.1
1.5
17.8
Metabolic and Nutritional
Peripheral Edema
0.9
2.6
1.3
3.3
Nervous
Dizziness
Libido Decreased
Somnolence
8.1
5.7
1.5
17.7
7.0
3.7
7.4
10.0
1.7
23.2
11.6
3.1
Respiratory
Dyspnea
Rhinitis
0.7
0.5
2.1
1.3
0.7
1.0
1.9
2.4
Urogenital
Abnormal Ejaculation
Gynecomastia
Impotence
Sexual Function Abnormal
2.3
0.7
12.2
0.9
4.5
1.1
14.4
2.0
7.2
2.2
18.5
2.5
14.1
1.5
22.6
3.1
*Doxazosin dose was achieved by weekly titration (1 to 2 to 4 to 8 mg). The final tolerated dose (4 mg or 8 mg) was administered at end-Week 4.
Only those patients tolerating at least 4 mg were kept on doxazosin. The majority of patients received the 8-mg dose over the duration of the
study.
Long-Term Data
High-Grade Prostate Cancer
The PCPT trial was a 7-year randomized, double-blind, placebo-controlled trial that enrolled 18,882
men ≥55 years of age with a normal digital rectal examination and a PSA ≤3.0 ng/mL. Men received
either PROSCAR (finasteride 5 mg) or placebo daily. Patients were evaluated annually with PSA and
digital rectal exams. Biopsies were performed for elevated PSA, an abnormal digital rectal exam, or the
end of study. The incidence of Gleason score 8-10 prostate cancer was higher in men treated with
finasteride (1.8%) than in those treated with placebo (1.1%) [see Indications and Usage (1.3) and
Warnings and Precautions (5.2)]. In a 4-year placebo-controlled clinical trial with another 5α-reductase
inhibitor (dutasteride, AVODART), similar results for Gleason score 8-10 prostate cancer were observed
(1% dutasteride vs 0.5% placebo).
No clinical benefit has been demonstrated in patients with prostate cancer treated with PROSCAR.
Breast Cancer
During the 4- to 6-year placebo- and comparator-controlled MTOPS study that enrolled 3047 men,
there were 4 cases of breast cancer in men treated with finasteride but no cases in men not treated with
finasteride. During the 4-year, placebo-controlled PLESS study that enrolled 3040 men, there were 2
cases of breast cancer in placebo-treated men but no cases in men treated with finasteride. During the 7
year placebo-controlled Prostate Cancer Prevention Trial (PCPT) that enrolled 18,882 men, there was 1
case of breast cancer in men treated with finasteride, and 1 case of breast cancer in men treated with
placebo. The relationship between long-term use of finasteride and male breast neoplasia is currently
unknown.
Sexual Function
5
Reference ID: 3114705
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
There is no evidence of increased sexual adverse experiences with increased duration of treatment
with PROSCAR. New reports of drug-related sexual adverse experiences decreased with duration of
therapy.
6.2
Postmarketing Experience
The following additional adverse effects have been reported in post-marketing experience with
PROSCAR and/or finasteride at lower doses. Because these reactions are reported voluntarily from a
population of uncertain size, it is not always possible to reliably estimate their frequency or establish a
causal relationship to drug exposure:
- hypersensitivity reactions, including pruritus, urticaria, and swelling of the lips and face
- testicular pain
- erectile dysfunction (ED) that continued after discontinuation of treatment, reported rarely in men taking
PROSCAR for the treatment of BPH. Most men were older and were taking concomitant medications
and/or had co-morbid conditions with a known association to ED. The independent role of PROSCAR in
these events is unknown.
- male infertility and/or poor seminal quality have been reported rarely in men taking PROSCAR for the
treatment of BPH. The independent role of PROSCAR in these events is unknown. Normalization or
improvement of seminal quality has been reported after discontinuation of finasteride.
- depression
- decreased libido that continued after discontinuation of treatment
- male breast cancer.
7
DRUG INTERACTIONS
7.1
Cytochrome P450-Linked Drug Metabolizing Enzyme System
No drug interactions of clinical importance have been identified. Finasteride does not appear to affect
the cytochrome P450-linked drug metabolizing enzyme system. Compounds that have been tested in
man have included antipyrine, digoxin, propranolol, theophylline, and warfarin and no clinically
meaningful interactions were found.
7.2
Other Concomitant Therapy
Although specific interaction studies were not performed, PROSCAR was concomitantly used in
clinical studies with acetaminophen, acetylsalicylic acid, α-blockers, angiotensin-converting enzyme
(ACE) inhibitors, analgesics, anti-convulsants, beta-adrenergic blocking agents, diuretics, calcium
channel blockers, cardiac nitrates, HMG-CoA reductase inhibitors, nonsteroidal anti-inflammatory drugs
(NSAIDs), benzodiazepines, H2 antagonists and quinolone anti-infectives without evidence of clinically
significant adverse interactions.
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Pregnancy Category X. [See Contraindications (4).]
PROSCAR is contraindicated for use in women who are or may become pregnant. PROSCAR is a
Type II 5α-reductase inhibitor that prevents conversion of testosterone to 5α-dihydrotestosterone (DHT),
a hormone necessary for normal development of male genitalia. In animal studies, finasteride caused
abnormal development of external genitalia in male fetuses. If this drug is used during pregnancy, or if the
patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to
the male fetus.
Abnormal male genital development is an expected consequence when conversion of testosterone to
5α-dihydrotestosterone (DHT) is inhibited by 5α-reductase inhibitors. These outcomes are similar to those
reported in male infants with genetic 5α-reductase deficiency. Women could be exposed to finasteride
through contact with crushed or broken PROSCAR tablets or semen from a male partner taking
PROSCAR. With regard to finasteride exposure through the skin, PROSCAR tablets are coated and will
prevent skin contact with finasteride during normal handling if the tablets have not been crushed or
broken. Women who are pregnant or may become pregnant should not handle crushed or broken
PROSCAR tablets because of possible exposure of a male fetus. If a pregnant woman comes in contact
with crushed or broken PROSCAR tablets, the contact area should be washed immediately with soap and
water. With regard to potential finasteride exposure through semen, two studies have been conducted in
6
Reference ID: 3114705
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
men receiving PROSCAR 5 mg/day that measured finasteride concentrations in semen [see Clinical
Pharmacology (12.3)].
In an embryo-fetal development study, pregnant rats received finasteride during the period of major
organogenesis (gestation days 6 to 17). At maternal doses of oral finasteride approximately 0.1 to 86
times the maximum recommended human dose (MRHD) of 5 mg/day (based on AUC at animal doses of
0.1 to 100 mg/kg/day) there was a dose-dependent increase in hypospadias that occurred in 3.6 to 100%
of male offspring. Exposure multiples were estimated using data from nonpregnant rats. Days 16 to 17
days of gestation is a critical period in male fetal rats for differentiation of the external genitalia. At oral
maternal doses approximately 0.03 times the MRHD (based on AUC at animal dose of 0.03 mg/kg/day),
male offspring had decreased prostatic and seminal vesicular weights, delayed preputial separation and
transient nipple development. Decreased anogenital distance occurred in male offspring of pregnant rats
that received approximately 0.003 times the MRHD (based on AUC at animal dose of 0.003 mg/kg/day).
No abnormalities were observed in female offspring at any maternal dose of finasteride.
No developmental abnormalities were observed in the offspring of untreated females mated with
finasteride treated male rats that received approximately 61 times the MRHD (based on AUC at animal
dose of 80 mg/kg/day). Slightly decreased fertility was observed in male offspring after administration of
about 3 times the MRHD (based on AUC at animal dose of 3 mg/kg/day) to female rats during late
gestation and lactation. No effects on fertility were seen in female offspring under these conditions.
No evidence of male external genital malformations or other abnormalities were observed in rabbit
fetuses exposed to finasteride during the period of major organogenesis (gestation days 6-18) at
maternal oral doses up to 100 mg/kg /day, (finasteride exposure levels were not measured in rabbits).
However, this study may not have included the critical period for finasteride effects on development of
male external genitalia in the rabbit.
The fetal effects of maternal finasteride exposure during the period of embryonic and fetal
development were evaluated in the rhesus monkey (gestation days 20-100), in a species and
development period more predictive of specific effects in humans than the studies in rats and rabbits.
Intravenous administration of finasteride to pregnant monkeys at doses as high as 800 ng/day (estimated
maximal blood concentration of 1.86 ng/mL or about 143 times the highest estimated exposure of
pregnant women to finasteride from semen of men taking 5 mg/day) resulted in no abnormalities in male
fetuses. In confirmation of the relevance of the rhesus model for human fetal development, oral
administration of a dose of finasteride (2 mg/kg/day or approximately 18,000 times the highest estimated
blood levels of finasteride from semen of men taking 5 mg/day) to pregnant monkeys resulted in external
genital abnormalities in male fetuses. No other abnormalities were observed in male fetuses and no
finasteride-related abnormalities were observed in female fetuses at any dose.
8.3
Nursing Mothers
PROSCAR is not indicated for use in women.
It is not known whether finasteride is excreted in human milk.
8.4
Pediatric Use
PROSCAR is not indicated for use in pediatric patients.
Safety and effectiveness in pediatric patients have not been established.
8.5
Geriatric Use
Of the total number of subjects included in PLESS, 1480 and 105 subjects were 65 and over and 75
and over, respectively. No overall differences in safety or effectiveness were observed between these
subjects and younger subjects, and other reported clinical experience has not identified differences in
responses between the elderly and younger patients. No dosage adjustment is necessary in the elderly
[see Clinical Pharmacology (12.3) and Clinical Studies (14)].
8.6
Hepatic Impairment
Caution should be exercised in the administration of PROSCAR in those patients with liver function
abnormalities, as finasteride is metabolized extensively in the liver [see Clinical Pharmacology (12.3)].
8.7
Renal Impairment
No dosage adjustment is necessary in patients with renal impairment [see Clinical Pharmacology
(12.3)].
7
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10
OVERDOSAGE
Patients have received single doses of PROSCAR up to 400 mg and multiple doses of PROSCAR up
to 80 mg/day for three months without adverse effects. Until further experience is obtained, no specific
treatment for an overdose with PROSCAR can be recommended.
Significant lethality was observed in male and female mice at single oral doses of 1500 mg/m2 (500
mg/kg) and in female and male rats at single oral doses of 2360 mg/m2 (400 mg/kg) and 5900 mg/m2
(1000 mg/kg), respectively.
11
DESCRIPTION
PROSCAR (finasteride), a synthetic 4-azasteroid compound, is a specific inhibitor of steroid Type II
5α-reductase,
an
intracellular
enzyme
that
converts
the
androgen
testosterone
into
5α-dihydrotestosterone (DHT).
Finasteride is 4-azaandrost-1-ene-17-carboxamide, N-(1,1-dimethylethyl)-3-oxo-,(5α,17β)-. The
empirical formula of finasteride is C23H36N2O2 and its molecular weight is 372.55. Its structural formula is: structural formula
Finasteride is a white crystalline powder with a melting point near 250°C. It is freely soluble in
chloroform and in lower alcohol solvents, but is practically insoluble in water.
PROSCAR (finasteride) tablets for oral administration are film-coated tablets that contain 5 mg of
finasteride and the following inactive ingredients: hydrous lactose, microcrystalline cellulose,
pregelatinized
starch,
sodium
starch
glycolate,
hydroxypropyl
cellulose
LF,
hydroxypropyl
methylcellulose, titanium dioxide, magnesium stearate, talc, docusate sodium, FD&C Blue 2 aluminum
lake and yellow iron oxide.
12
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
The development and enlargement of the prostate gland is dependent on the potent androgen,
5α-dihydrotestosterone (DHT). Type II 5α-reductase metabolizes testosterone to DHT in the prostate
gland, liver and skin. DHT induces androgenic effects by binding to androgen receptors in the cell nuclei
of these organs.
Finasteride is a competitive and specific inhibitor of Type II 5α-reductase with which it slowly forms a
stable enzyme complex. Turnover from this complex is extremely slow (t½ 30 days). This has been
demonstrated both in vivo and in vitro. Finasteride has no affinity for the androgen receptor. In man, the
5α-reduced steroid metabolites in blood and urine are decreased after administration of finasteride.
12.2 Pharmacodynamics
In man, a single 5-mg oral dose of PROSCAR produces a rapid reduction in serum DHT
concentration, with the maximum effect observed 8 hours after the first dose. The suppression of DHT is
maintained throughout the 24-hour dosing interval and with continued treatment. Daily dosing of
PROSCAR at 5 mg/day for up to 4 years has been shown to reduce the serum DHT concentration by
approximately 70%. The median circulating level of testosterone increased by approximately 10-20% but
remained within the physiologic range. In a separate study in healthy men treated with finasteride 1 mg
8
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per day (n=82) or placebo (n=69), mean circulating levels of testosterone and estradiol were increased by
approximately 15% as compared to baseline, but these remained within the physiologic range.
In patients receiving PROSCAR 5 mg/day, increases of about 10% were observed in luteinizing
hormone (LH) and follicle-stimulating hormone (FSH), but levels remained within the normal range. In
healthy volunteers, treatment with PROSCAR did not alter the response of LH and FSH to gonadotropin-
releasing hormone indicating that the hypothalamic-pituitary-testicular axis was not affected.
In patients with BPH, PROSCAR has no effect on circulating levels of cortisol, prolactin, thyroid-
stimulating hormone, or thyroxine. No clinically meaningful effect was observed on the plasma lipid profile
(i.e., total cholesterol, low density lipoproteins, high density lipoproteins and triglycerides) or bone mineral
density.
Adult males with genetically inherited Type II 5α-reductase deficiency also have decreased levels of
DHT. Except for the associated urogenital defects present at birth, no other clinical abnormalities related
to Type II 5α-reductase deficiency have been observed in these individuals. These individuals have a
small prostate gland throughout life and do not develop BPH.
In patients with BPH treated with finasteride (1-100 mg/day) for 7-10 days prior to prostatectomy, an
approximate 80% lower DHT content was measured in prostatic tissue removed at surgery, compared to
placebo; testosterone tissue concentration was increased up to 10 times over pretreatment levels,
relative to placebo. Intraprostatic content of PSA was also decreased.
In healthy male volunteers treated with PROSCAR for 14 days, discontinuation of therapy resulted in a
return of DHT levels to pretreatment levels in approximately 2 weeks. In patients treated for three months,
prostate volume, which declined by approximately 20%, returned to close to baseline value after
approximately three months of discontinuation of therapy.
12.3
Pharmacokinetics
Absorption
In a study of 15 healthy young subjects, the mean bioavailability of finasteride 5-mg tablets was 63%
(range 34-108%), based on the ratio of area under the curve (AUC) relative to an intravenous (IV)
reference dose. Maximum finasteride plasma concentration averaged 37 ng/mL (range, 27-49 ng/mL)
and was reached 1-2 hours postdose. Bioavailability of finasteride was not affected by food.
Distribution
Mean steady-state volume of distribution was 76 liters (range, 44-96 liters). Approximately 90% of
circulating finasteride is bound to plasma proteins. There is a slow accumulation phase for finasteride
after multiple dosing. After dosing with 5 mg/day of finasteride for 17 days, plasma concentrations of
finasteride were 47 and 54% higher than after the first dose in men 45-60 years old (n=12) and 70 years
old (n=12), respectively. Mean trough concentrations after 17 days of dosing were 6.2 ng/mL (range, 2.4
9.8 ng/mL) and 8.1 ng/mL (range, 1.8-19.7 ng/mL), respectively, in the two age groups. Although steady
state was not reached in this study, mean trough plasma concentration in another study in patients with
BPH (mean age, 65 years) receiving 5 mg/day was 9.4 ng/mL (range, 7.1-13.3 ng/mL; n=22) after over a
year of dosing.
Finasteride has been shown to cross the blood brain barrier but does not appear to distribute
preferentially to the CSF.
In 2 studies of healthy subjects (n=69) receiving PROSCAR 5 mg/day for 6-24 weeks, finasteride
concentrations in semen ranged from undetectable (<0.1 ng/mL) to 10.54 ng/mL. In an earlier study using
a less sensitive assay, finasteride concentrations in the semen of 16 subjects receiving PROSCAR
5 mg/day ranged from undetectable (<1.0 ng/mL) to 21 ng/mL. Thus, based on a 5-mL ejaculate volume,
the amount of finasteride in semen was estimated to be 50- to 100-fold less than the dose of finasteride
(5 g) that had no effect on circulating DHT levels in men [see also Use in Specific Populations (8.1)].
Metabolism
Finasteride is extensively metabolized in the liver, primarily via the cytochrome P450 3A4 enzyme
subfamily. Two metabolites, the t-butyl side chain monohydroxylated and monocarboxylic acid
metabolites, have been identified that possess no more than 20% of the 5-reductase inhibitory activity of
finasteride.
Excretion
In healthy young subjects (n=15), mean plasma clearance of finasteride was 165 mL/min (range, 70
279 mL/min) and mean elimination half-life in plasma was 6 hours (range, 3-16 hours). Following an oral
dose of 14C-finasteride in man (n=6), a mean of 39% (range, 32-46%) of the dose was excreted in the
urine in the form of metabolites; 57% (range, 51-64%) was excreted in the feces.
9
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The mean terminal half-life of finasteride in subjects 70 years of age was approximately 8 hours
(range, 6-15 hours; n=12), compared with 6 hours (range, 4-12 hours; n=12) in subjects 45-60 years of
age. As a result, mean AUC(0-24 hr) after 17 days of dosing was 15% higher in subjects 70 years of age
than in subjects 45-60 years of age (p=0.02).
Table 3
Mean (SD) Pharmacokinetic Parameters
in Healthy Young Subjects (n=15)
Mean ( SD)
Bioavailability
63% (34-108%)*
Clearance (mL/min)
165 (55)
Volume of Distribution (L)
76 (14)
Half-Life (hours)
6.2 (2.1)
*Range
Pediatric
Finasteride pharmacokinetics have not been investigated in patients <18 years of age.
Finasteride is not indicated for use in pediatric patients [see Warnings and Precautions (5.4), Use in
Specific Populations (8.4)].
Gender
Finasteride is not indicated for use in women [see Contraindications (4), Warnings and Precautions
(5.3 and 5.4), Use in Specific Populations (8.1), How Supplied/Storage and Handling (16) and Patient
Counseling Information (17.2)].
Geriatric
No dosage adjustment is necessary in the elderly. Although the elimination rate of finasteride is
decreased in the elderly, these findings are of no clinical significance. [See Clinical Pharmacology (12.3)
and Use in Specific Populations (8.5).]
Table 4
Mean (SD) Noncompartmental Pharmacokinetic Parameters After Multiple Doses of 5
mg/day in Older Men
Mean ( SD)
45-60 years old (n=12)
70 years old (n=12)
AUC (nghr/mL)
389 (98)
463 (186)
Peak Concentration (ng/mL)
46.2 (8.7)
48.4 (14.7)
Time to Peak (hours)
1.8 (0.7)
1.8 (0.6)
Half-Life (hours)*
6.0 (1.5)
8.2 (2.5)
*First-dose values; all other parameters are last-dose values
Race
The effect of race on finasteride pharmacokinetics has not been studied.
Hepatic Impairment
The effect of hepatic impairment on finasteride pharmacokinetics has not been studied. Caution
should be exercised in the administration of PROSCAR in those patients with liver function abnormalities,
as finasteride is metabolized extensively in the liver.
Renal Impairment
No dosage adjustment is necessary in patients with renal impairment. In patients with chronic renal
impairment, with creatinine clearances ranging from 9.0 to 55 mL/min, AUC, maximum plasma
concentration, half-life, and protein binding after a single dose of 14C-finasteride were similar to values
obtained in healthy volunteers. Urinary excretion of metabolites was decreased in patients with renal
impairment. This decrease was associated with an increase in fecal excretion of metabolites. Plasma
concentrations of metabolites were significantly higher in patients with renal impairment (based on a 60%
increase in total radioactivity AUC). However, finasteride has been well tolerated in BPH patients with
normal renal function receiving up to 80 mg/day for 12 weeks, where exposure of these patients to
metabolites would presumably be much greater.
10
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13
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
No evidence of a tumorigenic effect was observed in a 24-month study in Sprague-Dawley rats
receiving doses of finasteride up to 160 mg/kg/day in males and 320 mg/kg/day in females. These doses
produced respective systemic exposure in rats of 111 and 274 times those observed in man receiving the
recommended human dose of 5 mg/day. All exposure calculations were based on calculated AUC(0-24 hr)
for animals and mean AUC(0-24 hr) for man (0.4 µg•hr/mL).
In a 19-month carcinogenicity study in CD-1 mice, a statistically significant (p≤0.05) increase in the
incidence of testicular Leydig cell adenomas was observed at 228 times the human exposure (250
mg/kg/day). In mice at 23 times the human exposure, estimated (25 mg/kg/day) and in rats at 39 times
the human exposure (40 mg/kg/day) an increase in the incidence of Leydig cell hyperplasia was
observed. A positive correlation between the proliferative changes in the Leydig cells and an increase in
serum LH levels (2- to 3-fold above control) has been demonstrated in both rodent species treated with
high doses of finasteride. No drug-related Leydig cell changes were seen in either rats or dogs treated
with finasteride for 1 year at 30 and 350 times (20 mg/kg/day and 45 mg/kg/day, respectively) or in mice
treated for 19 months at 2.3 times the human exposure, estimated (2.5 mg/kg/day).
No evidence of mutagenicity was observed in an in vitro bacterial mutagenesis assay, a mammalian
cell mutagenesis assay, or in an in vitro alkaline elution assay. In an in vitro chromosome aberration
assay, using Chinese hamster ovary cells, there was a slight increase in chromosome aberrations. These
concentrations correspond to 4000-5000 times the peak plasma levels in man given a total dose of 5 mg.
In an in vivo chromosome aberration assay in mice, no treatment-related increase in chromosome
aberration was observed with finasteride at the maximum tolerated dose of 250 mg/kg/day (228 times the
human exposure) as determined in the carcinogenicity studies.
In sexually mature male rabbits treated with finasteride at 543 times the human exposure (80
mg/kg/day) for up to 12 weeks, no effect on fertility, sperm count, or ejaculate volume was seen. In
sexually mature male rats treated with 61 times the human exposure (80 mg/kg/day), there were no
significant effects on fertility after 6 or 12 weeks of treatment; however, when treatment was continued for
up to 24 or 30 weeks, there was an apparent decrease in fertility, fecundity and an associated significant
decrease in the weights of the seminal vesicles and prostate. All these effects were reversible within
6 weeks of discontinuation of treatment. No drug-related effect on testes or on mating performance has
been seen in rats or rabbits. This decrease in fertility in finasteride-treated rats is secondary to its effect
on accessory sex organs (prostate and seminal vesicles) resulting in failure to form a seminal plug. The
seminal plug is essential for normal fertility in rats and is not relevant in man.
14
CLINICAL STUDIES
14.1 Monotherapy
PROSCAR 5 mg/day was initially evaluated in patients with symptoms of BPH and enlarged prostates
by digital rectal examination in two 1-year, placebo-controlled, randomized, double-blind studies and their
5-year open extensions.
PROSCAR was further evaluated in the PROSCAR Long-Term Efficacy and Safety Study (PLESS), a
double-blind, randomized, placebo-controlled, 4-year, multicenter study. 3040 patients between the ages
of 45 and 78, with moderate to severe symptoms of BPH and an enlarged prostate upon digital rectal
examination, were randomized into the study (1524 to finasteride, 1516 to placebo) and 3016 patients
were evaluable for efficacy. 1883 patients completed the 4-year study (1000 in the finasteride group, 883
in the placebo group).
Effect on Symptom Score
Symptoms were quantified using a score similar to the American Urological Association Symptom
Score, which evaluated both obstructive symptoms (impairment of size and force of stream, sensation of
incomplete bladder emptying, delayed or interrupted urination) and irritative symptoms (nocturia, daytime
frequency, need to strain or push the flow of urine) by rating on a 0 to 5 scale for six symptoms and a 0 to
4 scale for one symptom, for a total possible score of 34.
Patients in PLESS had moderate to severe symptoms at baseline (mean of approximately 15 points
on a 0-34 point scale). Patients randomized to PROSCAR who remained on therapy for 4 years had a
mean ( 1 SD) decrease in symptom score of 3.3 ( 5.8) points compared with 1.3 ( 5.6) points in the
placebo group. (See Figure 1.) A statistically significant improvement in symptom score was evident at
11
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1 year in patients treated with PROSCAR vs placebo (–2.3 vs –1.6), and this improvement continued
through Year 4.
Figure 1
Symptom Score in PLESS
Mean Change from Baseline ± 1 SE
0
-1
-2
-3
-4
-5
-6
graph
Results seen in earlier studies were comparable to those seen in PLESS. Although an early
improvement in urinary symptoms was seen in some patients, a therapeutic trial of at least 6 months was
generally necessary to assess whether a beneficial response in symptom relief had been achieved. The
improvement in BPH symptoms was seen during the first year and maintained throughout an additional
5 years of open extension studies.
Effect on Acute Urinary Retention and the Need for Surgery
In PLESS, efficacy was also assessed by evaluating treatment failures. Treatment failure was
prospectively defined as BPH-related urological events or clinical deterioration, lack of improvement
and/or the need for alternative therapy. BPH-related urological events were defined as urological surgical
intervention and acute urinary retention requiring catheterization. Complete event information was
available for 92% of the patients. The following table (Table 5) summarizes the results.
Table 5
All Treatment Failures in PLESS
Patients (%)*
Event
Placebo
N=1503
Finasteride
N=1513
Relative
Risk
†
95% CI
P
Value
†
All Treatment
Failures
37.1
26.2
0.68
(0.57 to 0.79)
<0.001
12
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Surgical
Interventions
for BPH
10.1
4.6
0.45
(0.32 to 0.63)
<0.001
Acute Urinary
Retention
Requiring
Catheterization
6.6
2.8
0.43
(0.28 to 0.66)
<0.001
Two
consecutive
symptom
scores 20
9.2
6.7
Bladder Stone
0.4
0.5
Incontinence
2.1
1.7
Renal Failure
0.5
0.6
UTI
5.7
4.9
Discontinuation
due to
worsening of
BPH, lack of
improvement,
or to receive
other medical
treatment
21.8
13.3
*patients with multiple events may be counted more than once for each type of event
†Hazard ratio based on log rank test
Compared with placebo, PROSCAR was associated with a significantly lower risk for acute urinary
retention or the need for BPH-related surgery [13.2% for placebo vs 6.6% for PROSCAR; 51% reduction
in risk, 95% CI: (34 to 63%)]. Compared with placebo, PROSCAR was associated with a significantly
lower risk for surgery [10.1% for placebo vs 4.6% for PROSCAR; 55% reduction in risk, 95% CI: (37 to
68%)] and with a significantly lower risk of acute urinary retention [6.6% for placebo vs 2.8% for
PROSCAR; 57% reduction in risk, 95% CI: (34 to 72%)]; see Figures 2 and 3.
Figure 2
Percent of Patients Having Surgery for BPH,
Including TURP
gr
aph
Observation Time (Month)
Placebo Group
No. of events, cumulative
37
89
121
152
No. at risk, per year
1503
1454
1374
1314
Finasteride Group
No. of events, cumulative
18
40
49
69
No. at risk, per year
1513
1483
1438
1410
13
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Figure 3
Percent of Patients Developing Acute Urinary Retention
(Spontaneous and Precipitated)
gra
ph
0
4
8
12
16
20
24
28
Observation Time (Month)
32
36
40
44
48
Placebo Group
No. of events, cumulative
No. at risk, per year
36
1503
61
1454
81
1398
99
1347
Finasteride Group
No. of events, cumulative
No. at risk, per year
14
1513
25
1487
32
1449
42
1421
Effect on Maximum Urinary Flow Rate
In the patients in PLESS who remained on therapy for the duration of the study and had evaluable
urinary flow data, PROSCAR increased maximum urinary flow rate by 1.9 mL/sec compared with 0.2
mL/sec in the placebo group.
There was a clear difference between treatment groups in maximum urinary flow rate in favor of
PROSCAR by month 4 (1.0 vs 0.3 mL/sec) which was maintained throughout the study. In the earlier 1
year studies, increase in maximum urinary flow rate was comparable to PLESS and was maintained
through the first year and throughout an additional 5 years of open extension studies.
Effect on Prostate Volume
In PLESS, prostate volume was assessed yearly by magnetic resonance imaging (MRI) in a subset of
patients. In patients treated with PROSCAR who remained on therapy, prostate volume was reduced
compared with both baseline and placebo throughout the 4-year study. PROSCAR decreased prostate
volume by 17.9% (from 55.9 cc at baseline to 45.8 cc at 4 years) compared with an increase of 14.1%
(from 51.3 cc to 58.5 cc) in the placebo group (p<0.001). (See Figure 4.)
Results seen in earlier studies were comparable to those seen in PLESS. Mean prostate volume at
baseline ranged between 40-50 cc. The reduction in prostate volume was seen during the first year and
maintained throughout an additional five years of open extension studies.
14
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Figure 4
Prostate Volume in PLESS
Mean Percent Change from Baseline ± 1 SE
20
10
0
-10
-20 graph
Baseline
Year 1
Year 2
Year 3
Year 4
Placebo ( ) n =
155
136
119
98
85
Finasteride ( ) n =
157
144
130
116
102
Prostate Volume as a Predictor of Therapeutic Response
A meta-analysis combining 1-year data from seven double-blind, placebo-controlled studies of similar
design, including 4491 patients with symptomatic BPH, demonstrated that, in patients treated with
PROSCAR, the magnitude of symptom response and degree of improvement in maximum urinary flow
rate were greater in patients with an enlarged prostate at baseline.
14.2 Combination with Alpha-Blocker Therapy
The Medical Therapy of Prostatic Symptoms (MTOPS) Trial was a double-blind, randomized,
placebo-controlled, multicenter, 4- to 6-year study (average 5 years) in 3047 men with symptomatic BPH,
who were randomized to receive PROSCAR 5 mg/day (n=768), doxazosin 4 or 8 mg/day (n=756), the
combination of PROSCAR 5 mg/day and doxazosin 4 or 8 mg/day (n=786), or placebo (n=737). All
participants underwent weekly titration of doxazosin (or its placebo) from 1 to 2 to 4 to 8 mg/day. Only
those who tolerated the 4 or 8 mg dose level were kept on doxazosin (or its placebo) in the study. The
participant’s final tolerated dose (either 4 mg or 8 mg) was administered beginning at end-Week 4. The
final doxazosin dose was administered once per day, at bedtime.
The mean patient age at randomization was 62.6 years (7.3 years). Patients were Caucasian (82%),
African American (9%), Hispanic (7%), Asian (1%) or Native American (<1%). The mean duration of BPH
symptoms was 4.7 years (4.6 years). Patients had moderate to severe BPH symptoms at baseline with
a mean AUA symptom score of approximately 17 out of 35 points. Mean maximum urinary flow rate was
10.5 mL/sec (2.6 mL/sec). The mean prostate volume as measured by transrectal ultrasound was
36.3 mL (20.1 mL). Prostate volume was 20 mL in 16% of patients, 50 mL in 18% of patients and
between 21 and 49 mL in 66% of patients.
The primary endpoint was a composite measure of the first occurrence of any of the following five
outcomes: a 4 point confirmed increase from baseline in symptom score, acute urinary retention, BPH-
related renal insufficiency (creatinine rise), recurrent urinary tract infections or urosepsis, or incontinence.
Compared to placebo, treatment with PROSCAR, doxazosin, or combination therapy resulted in a
reduction in the risk of experiencing one of these five outcome events by 34% (p=0.002), 39% (p<0.001),
and 67% (p<0.001), respectively. Combination therapy resulted in a significant reduction in the risk of the
primary endpoint compared to treatment with PROSCAR alone (49%; p≤0.001) or doxazosin alone (46%;
p≤0.001). (See Table 6.)
Table 6
Count and Percent Incidence of Primary Outcome Events
by Treatment Group in MTOPS
Treatment Group
Placebo
N=737
Doxazosin
N=756
Finasteride
N=768
Combination
N=786
Total
N=3047
15
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Event
N (%)
N (%)
N (%)
N (%)
N (%)
AUA 4-point rise
100 (13.6)
59 (7.8)
74 (9.6)
41 (5.2)
274 (9.0)
Acute urinary retention
18 (2.4)
13 (1.7)
6 (0.8)
4 (0.5)
41 (1.3)
Incontinence
8 (1.1)
11 (1.5)
9 (1.2)
3 (0.4)
31 (1.0)
Recurrent UTI/urosepsis
2 (0.3)
2 (0.3)
0 (0.0)
1 (0.1)
5 (0.2)
Creatinine rise
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
Total Events
128 (17.4)
85 (11.2)
89 (11.6)
49 (6.2)
351 (11.5)
gra
ph
The majority of the events (274 out of 351; 78%) was a confirmed 4 point increase in symptom score,
referred to as symptom score progression. The risk of symptom score progression was reduced by 30%
(p=0.016), 46% (p<0.001), and 64% (p<0.001) in patients treated with PROSCAR, doxazosin, or the
combination, respectively, compared to patients treated with placebo (see Figure 5). Combination therapy
significantly reduced the risk of symptom score progression compared to the effect of PROSCAR alone
(p<0.001) and compared to doxazosin alone (p=0.037).
Figure 5
Cumulative Incidence of a 4-Point Rise in AUA Symptom Score by Treatment Group
Years from Randomization
Treatment with PROSCAR, doxazosin or the combination of PROSCAR with doxazosin, reduced the
mean symptom score from baseline at year 4. Table 7 provides the mean change from baseline for AUA
symptom score by treatment group for patients who remained on therapy for four years.
Table 7
Change From Baseline in AUA Symptom Score
by Treatment Group at Year 4 in MTOPS
Placebo
N=534
Doxazosin
N=582
Finasteride
N=565
Combination
N=598
Baseline Mean (SD)
16.8 (6.0)
17.0 (5.9)
17.1 (6.0)
16.8 (5.8)
Mean Change
AUA Symptom Score
(SD)
-4.9 (5.8)
-6.6 (6.1)
-5.6 (5.9)
-7.4 (6.3)
Comparison to
Placebo (95% CI)
-1.8
(-2.5, -1.1)
-0.7
(-1.4, 0.0)
-2.5
(-3.2, -1.8)
16
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Comparison to
Doxazosin alone (95%
CI)
-0.7
(-1.4, 0.0)
Comparison to
Finasteride alone (95%
CI)
-1.8
(-2.5, -1.1)
The results of MTOPS are consistent with the findings of the 4-year, placebo-controlled study PLESS
[see Clinical Studies (14.1)] in that treatment with PROSCAR reduces the risk of acute urinary retention
and the need for BPH-related surgery. In MTOPS, the risk of developing acute urinary retention was
reduced by 67% in patients treated with PROSCAR compared to patients treated with placebo (0.8% for
PROSCAR and 2.4% for placebo). Also, the risk of requiring BPH-related invasive therapy was reduced
by 64% in patients treated with PROSCAR compared to patients treated with placebo (2.0% for
PROSCAR and 5.4% for placebo).
14.3
Summary of Clinical Studies
The data from these studies, showing improvement in BPH-related symptoms, reduction in treatment
failure (BPH-related urological events), increased maximum urinary flow rates, and decreasing prostate
volume, suggest that PROSCAR arrests the disease process of BPH in men with an enlarged prostate.
16
HOW SUPPLIED/STORAGE AND HANDLING
No. 3094 — PROSCAR tablets 5 mg are blue, modified apple-shaped, film-coated tablets, with the
code MSD 72 on one side and PROSCAR on the other. They are supplied as follows:
NDC 0006-0072-31 unit of use bottles of 30
NDC 0006-0072-58 unit of use bottles of 100.
Storage and Handling
Store at room temperatures below 30°C (86°F). Protect from light and keep container tightly closed.
Women should not handle crushed or broken PROSCAR tablets when they are pregnant or may
potentially be pregnant because of the possibility of absorption of finasteride and the subsequent
potential risk to a male fetus [see Warnings and Precautions (5.3), Use in Specific Populations (8.1) and
Patient Counseling Information (17.2)].
17
PATIENT COUNSELING INFORMATION
See FDA-Approved Patient Labeling (Patient Information).
17.1
Increased Risk of High-Grade Prostate Cancer
Patients should be informed that there was an increase in high-grade prostate cancer in men treated
with 5α-reductase inhibitors indicated for BPH treatment, including PROSCAR, compared to those
treated with placebo in studies looking at the use of these drugs to prevent prostate cancer [see
Indications and Usage (1.3), Warnings and Precautions (5.2), and Adverse Reactions (6.1)].
17.2
Exposure of Women – Risk to Male Fetus
Physicians should inform patients that women who are pregnant or may potentially be pregnant
should not handle crushed or broken PROSCAR tablets because of the possibility of absorption of
finasteride and the subsequent potential risk to the male fetus. PROSCAR tablets are coated and will
prevent contact with the active ingredient during normal handling, provided that the tablets have not been
broken or crushed. If a woman who is pregnant or may potentially be pregnant comes in contact with
crushed or broken PROSCAR tablets, the contact area should be washed immediately with soap and
water [see Contraindications (4), Warnings and Precautions (5.3), Use in Specific Populations (8.1) and
How Supplied/Storage and Handling (16)].
17.3
Additional Instructions
Physicians should inform patients that the volume of ejaculate may be decreased in some patients
during treatment with PROSCAR. This decrease does not appear to interfere with normal sexual function.
However, impotence and decreased libido may occur in patients treated with PROSCAR [see Adverse
Reactions (6.1)].
Physicians should instruct their patients to promptly report any changes in their breasts such as
lumps, pain or nipple discharge. Breast changes including breast enlargement, tenderness and neoplasm
have been reported [see Adverse Reactions (6.1)].
17
Reference ID: 3114705
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Physicians should instruct their patients to read the patient package insert before starting therapy with
PROSCAR and to reread it each time the prescription is renewed so that they are aware of current
information for patients regarding PROSCAR. company logo
Copyright © 1992, 1995, 1998, 2011 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
All rights reserved.
Revised: April 2012
18
Reference ID: 3114705
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PROSCAR® (finasteride) Tablets
Patient Information about
PROSCAR® (Prahs-car)
Generic name: finasteride
(fin-AS-tur-eyed)
PROSCAR is for use by men only.
Please read this leaflet before you start taking PROSCAR. Also, read it each time you renew your
prescription, just in case anything has changed. Remember, this leaflet does not take the place of careful
discussions with your doctor. You and your doctor should discuss PROSCAR when you start taking your
medication and at regular checkups.
What is PROSCAR?
PROSCAR is a medication used to treat symptoms of benign prostatic hyperplasia (BPH) in men with an
enlarged prostate. PROSCAR may also be used to reduce the risk of a sudden inability to pass urine and
the need for surgery related to BPH in men with an enlarged prostate.
PROSCAR may be prescribed along with another medicine, an alpha-blocker called doxazosin, to help
you better manage your BPH symptoms.
Who should NOT take PROSCAR?
PROSCAR is for use by MEN only.
Do Not Take PROSCAR if you are:
a woman who is pregnant or may potentially be pregnant. PROSCAR may harm your unborn
baby. Do not touch or handle crushed or broken PROSCAR tablets (see “A warning about
PROSCAR and pregnancy”).
allergic to finasteride or any of the ingredients in PROSCAR. See the end of this leaflet for a
complete list of ingredients in PROSCAR.
A warning about PROSCAR and pregnancy:
Women who are or may potentially be pregnant must not use PROSCAR. They should also not handle
crushed or broken tablets of PROSCAR. PROSCAR tablets are coated and will prevent contact with the
active ingredient during normal handling, provided that the tablets are not broken or crushed.
If a woman who is pregnant with a male baby absorbs the active ingredient in PROSCAR after oral use or
through the skin, it may cause the male baby to be born with abnormalities of the sex organs. If a woman
who is pregnant comes into contact with the active ingredient in PROSCAR, a doctor should be
consulted.
How should I take PROSCAR?
Follow your doctor's instruction.
Take one tablet by mouth each day. To avoid forgetting to take PROSCAR, you can take it at the
same time every day.
If you forget to take PROSCAR, do not take an extra tablet. Just take the next tablet as usual.
You may take PROSCAR with or without food.
Do not share PROSCAR with anyone else; it was prescribed only for you.
Reference ID: 3114705
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
What are the possible side effects of PROSCAR?
PROSCAR may increase the chance of a more serious form of prostate cancer.
The most common side effects of PROSCAR include:
trouble getting or keeping an erection (impotence)
decrease in sex drive
decreased volume of ejaculate
ejaculation disorders
enlarged or painful breast. You should promptly report to your doctor any changes in your breasts
such as lumps, pain or nipple discharge.
The following have been reported in general use with PROSCAR and/or finasteride at lower doses:
allergic reactions, including rash, itching, hives, and swelling of the lips and face
rarely, some men may have testicular pain
trouble getting or keeping an erection that continued after stopping the medication
male infertility and/or poor quality of semen. Improvement in the quality of semen has been
reported after stopping the medication.
depression
decrease in sex drive that continued after stopping the medication
in rare cases, male breast cancer has been reported.
You should discuss side effects with your doctor before taking PROSCAR and anytime you think you are
having a side effect. These are not all the possible side effects with PROSCAR. For more information,
ask your doctor or pharmacist.
Call your doctor for medical advice about side effects. You may report side effects to FDA at: 1-800-FDA
1088.
What you need to know while taking PROSCAR:
You should see your doctor regularly while taking PROSCAR. Follow your doctor's advice
about when to have these checkups.
Checking for prostate cancer. Your doctor has prescribed PROSCAR for BPH and not for
treatment of prostate cancer — but a man can have BPH and prostate cancer at the same time.
Your doctor may continue checking for prostate cancer while you take PROSCAR.
About Prostate-Specific Antigen (PSA). Your doctor may have done a blood test called PSA
for the screening of prostate cancer. Because PROSCAR decreases PSA levels, you should tell
your doctor(s) that you are taking PROSCAR. Changes in PSA levels will need to be evaluated
by your doctor(s). Any increase in follow-up PSA levels from their lowest point may signal the
presence of prostate cancer and should be evaluated, even if the test results are still within the
normal range. You should also tell your doctor if you have not been taking PROSCAR as
prescribed because this may affect the PSA test results. For more information, talk to your doctor.
How should I store PROSCAR?
Store PROSCAR tablets in a dry place at room temperature.
Keep PROSCAR in the original container and keep the container closed.
PROSCAR tablets are coated and will prevent contact with the active ingredient during
normal handling, provided that the tablets are not broken or crushed.
Keep PROSCAR and all medications out of the reach of children.
Do not give your PROSCAR tablets to anyone else. It has been prescribed only for you.
2
Reference ID: 3114705
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
For more information call 1-800-622-4477.
What are the ingredients in PROSCAR?
Active ingredients: finasteride
Inactive ingredients: hydrous lactose, microcrystalline cellulose, pregelatinized starch, sodium starch
glycolate, hydroxypropyl cellulose LF, hydroxypropyl methylcellulose, titanium dioxide, magnesium
stearate, talc, docusate sodium, FD&C Blue 2 aluminum lake and yellow iron oxide.
What is BPH?
BPH is an enlargement of the prostate gland. The prostate is located below the bladder. As the prostate
enlarges, it may slowly restrict the flow of urine. This can lead to symptoms such as:
a weak or interrupted urinary stream
a feeling that you cannot empty your bladder completely
a feeling of delay or hesitation when you start to urinate
a need to urinate often, especially at night
a feeling that you must urinate right away.
In some men, BPH can lead to serious problems, including urinary tract infections, a sudden inability to
pass urine (acute urinary retention), as well as the need for surgery.
What PROSCAR does:
PROSCAR lowers levels of a hormone called DHT (dihydrotestosterone), which is a cause of prostate
growth. Lowering DHT leads to shrinkage of the enlarged prostate gland in most men. This can lead to
gradual improvement in urine flow and symptoms over the next several months. PROSCAR will help
reduce the risk of developing a sudden inability to pass urine and the need for surgery related to an
enlarged prostate. However, since each case of BPH is different, you should know that:
Even though the prostate shrinks, you may NOT notice an improvement in urine flow or
symptoms.
You may need to take PROSCAR for six (6) months or more to see whether it improves your
symptoms.
Therapy with PROSCAR may reduce your risk for a sudden inability to pass urine and the need
for surgery for an enlarged prostate. company logo
Copyright © 1992, 1995, 1998, 2011 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
All rights reserved.
Revised: April 2012
3
Reference ID: 3114705
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:46:59.889245
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/020180s040s041s042lbl.pdf', 'application_number': 20180, 'submission_type': 'SUPPL ', 'submission_number': 41}
|
12,301
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HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
PROSCAR safely and effectively. See full prescribing information
for PROSCAR.
PROSCAR® (finasteride) Tablets
Initial U.S. Approval: 1992
----------------------------INDICATIONS AND USAGE ---------------------------
PROSCAR, is a 5α-reductase inhibitor, indicated for the treatment of
symptomatic benign prostatic hyperplasia (BPH) in men with an
enlarged prostate to (1.1):
Improve symptoms
Reduce the risk of acute urinary retention
Reduce the risk of the need for surgery including transurethral
resection of the prostate (TURP) and prostatectomy.
PROSCAR administered in combination with the alpha-blocker
doxazosin is indicated to reduce the risk of symptomatic progression of
BPH (a confirmed 4 point increase in American Urological Association
(AUA) symptom score) (1.2).
Limitations of Use: PROSCAR is not approved for the prevention of
prostate cancer (1.3).
----------------------- DOSAGE AND ADMINISTRATION-----------------------
PROSCAR may be administered with or without meals (2).
Monotherapy: One tablet (5 mg) taken once a day (2.1).
Combination with Doxazosin: One tablet (5 mg) taken once a day in
combination with the alpha-blocker doxazosin (2.2).
--------------------- DOSAGE FORMS AND STRENGTHS --------------------
5-mg film-coated tablets (3).
------------------------------ CONTRAINDICATIONS ------------------------------
Hypersensitivity to any components of this product (4).
Women who are or may potentially be pregnant (4, 5.4, 8.1, 16).
------------------------WARNINGS AND PRECAUTIONS-----------------------
PROSCAR reduces serum prostate specific antigen (PSA) levels
by approximately 50%. However, any confirmed increase in PSA
while on PROSCAR may signal the presence of prostate cancer
and should be evaluated, even if those values are still within the
normal range for men not taking a 5α-reductase inhibitor (5.1).
PROSCAR may increase the risk of high-grade prostate cancer
(5.2, 6.1).
Women should not handle crushed or broken PROSCAR tablets
when they are pregnant or may potentially be pregnant due to
potential risk to a male fetus (5.3, 8.1, 16).
PROSCAR is not indicated for use in pediatric patients or women
(5.4, 8.1, 8.3, 8.4, 12.3).
Prior
to
initiating
treatment
with
PROSCAR
for
BPH,
consideration should be given to other urological conditions that
may cause similar symptoms (5.6).
------------------------------ ADVERSE REACTIONS------------------------------
The drug-related adverse reactions, reported in ≥1% in patients treated
with PROSCAR and greater than in patients treated with placebo over
a 4-year study are: impotence, decreased libido, decreased volume of
ejaculate, breast enlargement, breast tenderness and rash (6.1).
To report SUSPECTED ADVERSE REACTIONS, contact Merck
Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., at 1-877
888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
See
17
for
PATIENT
COUNSELING
INFORMATION
and
FDA-approved patient labeling.
Revised: 09/2013
FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
1.1
Monotherapy
1.2
Combination with Alpha-Blocker
1.3
Limitations of Use
2
DOSAGE AND ADMINISTRATION
2.1
Monotherapy
2.2
Combination with Alpha-Blocker
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1 Effects on Prostate Specific Antigen (PSA) and the Use of
PSA in Prostate Cancer Detection
5.2
Increased Risk of High-Grade Prostate Cancer
5.3
Exposure of Women — Risk to Male Fetus
5.4
Pediatric Patients and Women
5.5
Effect on Semen Characteristics
5.6
Consideration of Other Urological Conditions
6
ADVERSE REACTIONS
6.1
Clinical Trials Experience
6.2
Postmarketing Experience
7
DRUG INTERACTIONS
7.1
Cytochrome
P450-Linked
Drug
Metabolizing
Enzyme
System
7.2
Other Concomitant Therapy
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
8.3
Nursing Mothers
8.4
Pediatric Use
8.5
Geriatric Use
8.6
Hepatic Impairment
8.7
Renal Impairment
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
14.1 Monotherapy
14.2 Combination with Alpha-Blocker Therapy
14.3 Summary of Clinical Studies
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
17.1 Increased Risk of High-Grade Prostate Cancer
17.2 Exposure of Women — Risk to Male Fetus
17.3 Additional Instructions
*Sections or subsections omitted from the full prescribing information
are not listed.
1
Reference ID: 3468742
FULL PRESCRIBING INFORMATION
1
INDICATIONS AND USAGE
1.1
Monotherapy
PROSCAR
® is indicated for the treatment of symptomatic benign prostatic hyperplasia (BPH) in men
with an enlarged prostate to:
-Improve symptoms
-Reduce the risk of acute urinary retention
-Reduce the risk of the need for surgery including transurethral resection of the prostate (TURP) and
prostatectomy.
1.2
Combination with Alpha-Blocker
PROSCAR administered in combination with the alpha-blocker doxazosin is indicated to reduce the
risk of symptomatic progression of BPH (a confirmed 4 point increase in American Urological
Association (AUA) symptom score).
1.3
Limitations of Use
PROSCAR is not approved for the prevention of prostate cancer.
2
DOSAGE AND ADMINISTRATION
PROSCAR may be administered with or without meals.
2.1
Monotherapy
The recommended dose of PROSCAR is one tablet (5 mg) taken once a day [see Clinical Studies
(14.1)].
2.2
Combination with Alpha-Blocker
The recommended dose of PROSCAR is one tablet (5 mg) taken once a day in combination with the
alpha-blocker doxazosin [see Clinical Studies (14.2)].
3
DOSAGE FORMS AND STRENGTHS
5-mg blue, modified apple-shaped, film-coated tablets, with the code MSD 72 on one side and
PROSCAR on the other.
4
CONTRAINDICATIONS
PROSCAR is contraindicated in the following:
Hypersensitivity to any component of this medication.
Pregnancy. Finasteride use is contraindicated in women when they are or may potentially be
pregnant. Because of the ability of Type II 5α-reductase inhibitors to inhibit the conversion of
testosterone to 5α-dihydrotestosterone (DHT), finasteride may cause abnormalities of the
external genitalia of a male fetus of a pregnant woman who receives finasteride. If this drug is
used during pregnancy, or if pregnancy occurs while taking this drug, the pregnant woman
should be apprised of the potential hazard to the male fetus. [See also Warnings and
Precautions (5.3), Use in Specific Populations (8.1), How Supplied/Storage and Handling
(16) and Patient Counseling Information (17.2).] In female rats, low doses of finasteride
administered during pregnancy have produced abnormalities of the external genitalia in male
offspring.
5
WARNINGS AND PRECAUTIONS
5.1
Effects on Prostate Specific Antigen (PSA) and the Use of PSA in Prostate Cancer
Detection
In clinical studies, PROSCAR reduced serum PSA concentration by approximately 50% within six
months of treatment. This decrease is predictable over the entire range of PSA values in patients with
symptomatic BPH, although it may vary in individuals.
2
Reference ID: 3468742
For interpretation of serial PSAs in men taking PROSCAR, a new PSA baseline should be established
at least six months after starting treatment and PSA monitored periodically thereafter. Any confirmed
increase from the lowest PSA value while on PROSCAR may signal the presence of prostate cancer and
should be evaluated, even if PSA levels are still within the normal range for men not taking a 5α
reductase inhibitor. Non-compliance with PROSCAR therapy may also affect PSA test results. To
interpret an isolated PSA value in patients treated with PROSCAR for six months or more, PSA values
should be doubled for comparison with normal ranges in untreated men. These adjustments preserve the
utility of PSA to detect prostate cancer in men treated with PROSCAR.
PROSCAR may also cause decreases in serum PSA in the presence of prostate cancer.
The ratio of free to total PSA (percent free PSA) remains constant even under the influence of
PROSCAR. If clinicians elect to use percent free PSA as an aid in the detection of prostate cancer in men
undergoing finasteride therapy, no adjustment to its value appears necessary.
5.2
Increased Risk of High-Grade Prostate Cancer
Men aged 55 and over with a normal digital rectal examination and PSA ≤3.0 ng/mL at baseline taking
finasteride 5 mg/day in the 7-year Prostate Cancer Prevention Trial (PCPT) had an increased risk of
Gleason score 8-10 prostate cancer (finasteride 1.8% vs placebo 1.1%). [See Indications and Usage
(1.3) and Adverse Reactions (6.1).] Similar results were observed in a 4-year placebo-controlled clinical
trial with another 5α-reductase inhibitor (dutasteride, AVODART) (1% dutasteride vs 0.5% placebo). 5α
reductase inhibitors may increase the risk of development of high-grade prostate cancer. Whether the
effect of 5α-reductase inhibitors to reduce prostate volume, or study-related factors, impacted the results
of these studies has not been established.
5.3
Exposure of Women — Risk to Male Fetus
Women should not handle crushed or broken PROSCAR tablets when they are pregnant or may
potentially be pregnant because of the possibility of absorption of finasteride and the subsequent
potential risk to a male fetus. PROSCAR tablets are coated and will prevent contact with the active
ingredient during normal handling, provided that the tablets have not been broken or crushed. [See
Contraindications (4), Use in Specific Populations (8.1), Clinical Pharmacology (12.3), How
Supplied/Storage and Handling (16) and Patient Counseling Information (17.2).]
5.4
Pediatric Patients and Women
PROSCAR is not indicated for use in pediatric patients [see Use in Specific Populations (8.4) and
Clinical Pharmacology (12.3)] or women [see also Warnings and Precautions (5.3), Use in Specific
Populations (8.1), Clinical Pharmacology (12.3), How Supplied/Storage and Handling (16) and Patient
Counseling Information (17.2)].
5.5
Effect on Semen Characteristics
Treatment with PROSCAR for 24 weeks to evaluate semen parameters in healthy male volunteers
revealed no clinically meaningful effects on sperm concentration, mobility, morphology, or pH. A 0.6 mL
(22.1%) median decrease in ejaculate volume with a concomitant reduction in total sperm per ejaculate
was observed. These parameters remained within the normal range and were reversible upon
discontinuation of therapy with an average time to return to baseline of 84 weeks.
5.6
Consideration of Other Urological Conditions
Prior to initiating treatment with PROSCAR, consideration should be given to other urological
conditions that may cause similar symptoms. In addition, prostate cancer and BPH may coexist.
Patients with large residual urinary volume and/or severely diminished urinary flow should be carefully
monitored for obstructive uropathy. These patients may not be candidates for finasteride therapy.
6
ADVERSE REACTIONS
6.1
Clinical Trials Experience
PROSCAR is generally well tolerated; adverse reactions usually have been mild and transient.
4-Year Placebo-Controlled Study (PLESS)
In PLESS, 1524 patients treated with PROSCAR and 1516 patients treated with placebo were
evaluated for safety over a period of 4 years. The most frequently reported adverse reactions were
related to sexual function. 3.7% (57 patients) treated with PROSCAR and 2.1% (32 patients) treated with
placebo discontinued therapy as a result of adverse reactions related to sexual function, which are the
most frequently reported adverse reactions.
3
Reference ID: 3468742
Table 1 presents the only clinical adverse reactions considered possibly, probably or definitely drug
related by the investigator, for which the incidence on PROSCAR was ≥1% and greater than placebo
over the 4 years of the study. In years 2-4 of the study, there was no significant difference between
treatment groups in the incidences of impotence, decreased libido and ejaculation disorder.
Table 1: Drug-Related Adverse Experiences
Year 1
(%)
Years 2, 3 and 4*
(%)
Finasteride
Placebo
Finasteride
Placebo
Impotence
8.1
3.7
5.1
5.1
Decreased
Libido
6.4
3.4
2.6
2.6
Decreased
Volume of
Ejaculate
3.7
0.8
1.5
0.5
Ejaculation
Disorder
0.8
0.1
0.2
0.1
Breast
Enlargement
0.5
0.1
1.8
1.1
Breast
Tenderness
0.4
0.1
0.7
0.3
Rash
0.5
0.2
0.5
0.1
*Combined Years 2-4
N = 1524 and 1516, finasteride vs placebo, respectively
Phase III Studies and 5-Year Open Extensions
The adverse experience profile in the 1-year, placebo-controlled, Phase III studies, the 5-year open
extensions, and PLESS were similar.
Medical Therapy of Prostatic Symptoms (MTOPS) Study
In the MTOPS study, 3047 men with symptomatic BPH were randomized to receive PROSCAR
5 mg/day (n=768), doxazosin 4 or 8 mg/day (n=756), the combination of PROSCAR 5 mg/day and
doxazosin 4 or 8 mg/day (n=786), or placebo (n=737) for 4 to 6 years. [See Clinical Studies (14.2).]
The incidence rates of drug-related adverse experiences reported by 2% of patients in any treatment
group in the MTOPS Study are listed in Table 2.
The individual adverse effects which occurred more frequently in the combination group compared to
either drug alone were: asthenia, postural hypotension, peripheral edema, dizziness, decreased libido,
rhinitis, abnormal ejaculation, impotence and abnormal sexual function (see Table 2). Of these, the
incidence of abnormal ejaculation in patients receiving combination therapy was comparable to the sum
of the incidences of this adverse experience reported for the two monotherapies.
Combination therapy with finasteride and doxazosin was associated with no new clinical adverse
experience.
Four patients in MTOPS reported the adverse experience breast cancer. Three of these patients were
on finasteride only and one was on combination therapy. [See Long-Term Data.]
The MTOPS Study was not specifically designed to make statistical comparisons between groups for
reported adverse experiences. In addition, direct comparisons of safety data between the MTOPS study
and previous studies of the single agents may not be appropriate based upon differences in patient
population, dosage or dose regimen, and other procedural and study design elements.
4
Reference ID: 3468742
Table 2: Incidence ≥2% in One or More Treatment Groups
Drug-Related Clinical Adverse Experiences in MTOPS
Adverse Experience
Placebo
(N=737)
(%)
Doxazosin
4 mg or 8 mg*
(N=756)
(%)
Finasteride
(N=768)
(%)
Combination
(N=786)
(%)
Body as a whole
Asthenia
Headache
7.1
2.3
15.7
4.1
5.3
2.0
16.8
2.3
Cardiovascular
Hypotension
Postural Hypotension
0.7
8.0
3.4
16.7
1.2
9.1
1.5
17.8
Metabolic and Nutritional
Peripheral Edema
0.9
2.6
1.3
3.3
Nervous
Dizziness
Libido Decreased
Somnolence
8.1
5.7
1.5
17.7
7.0
3.7
7.4
10.0
1.7
23.2
11.6
3.1
Respiratory
Dyspnea
Rhinitis
0.7
0.5
2.1
1.3
0.7
1.0
1.9
2.4
Urogenital
Abnormal Ejaculation
Gynecomastia
Impotence
Sexual Function Abnormal
2.3
0.7
12.2
0.9
4.5
1.1
14.4
2.0
7.2
2.2
18.5
2.5
14.1
1.5
22.6
3.1
*Doxazosin dose was achieved by weekly titration (1 to 2 to 4 to 8 mg). The final tolerated dose (4 mg or 8 mg) was administered at end-Week 4.
Only those patients tolerating at least 4 mg were kept on doxazosin. The majority of patients received the 8-mg dose over the duration of the
study.
Long-Term Data
High-Grade Prostate Cancer
The PCPT trial was a 7-year randomized, double-blind, placebo-controlled trial that enrolled 18,882
men ≥55 years of age with a normal digital rectal examination and a PSA ≤3.0 ng/mL. Men received
either PROSCAR (finasteride 5 mg) or placebo daily. Patients were evaluated annually with PSA and
digital rectal exams. Biopsies were performed for elevated PSA, an abnormal digital rectal exam, or the
end of study. The incidence of Gleason score 8-10 prostate cancer was higher in men treated with
finasteride (1.8%) than in those treated with placebo (1.1%) [see Indications and Usage (1.3) and
Warnings and Precautions (5.2)]. In a 4-year placebo-controlled clinical trial with another 5α-reductase
inhibitor (dutasteride, AVODART), similar results for Gleason score 8-10 prostate cancer were observed
(1% dutasteride vs 0.5% placebo).
No clinical benefit has been demonstrated in patients with prostate cancer treated with PROSCAR.
Breast Cancer
During the 4- to 6-year placebo- and comparator-controlled MTOPS study that enrolled 3047 men,
there were 4 cases of breast cancer in men treated with finasteride but no cases in men not treated with
finasteride. During the 4-year, placebo-controlled PLESS study that enrolled 3040 men, there were 2
cases of breast cancer in placebo-treated men but no cases in men treated with finasteride. During the 7
year placebo-controlled Prostate Cancer Prevention Trial (PCPT) that enrolled 18,882 men, there was 1
case of breast cancer in men treated with finasteride, and 1 case of breast cancer in men treated with
placebo. The relationship between long-term use of finasteride and male breast neoplasia is currently
unknown.
Sexual Function
5
Reference ID: 3468742
There is no evidence of increased sexual adverse experiences with increased duration of treatment
with PROSCAR. New reports of drug-related sexual adverse experiences decreased with duration of
therapy.
6.2
Postmarketing Experience
The following additional adverse events have been reported in postmarketing experience with
PROSCAR. Because these events are reported voluntarily from a population of uncertain size, it is not
always possible to reliably estimate their frequency or establish a causal relationship to drug exposure:
- hypersensitivity reactions, such as pruritus, urticaria, and angioedema (including swelling of the lips,
tongue, throat, and face)
- testicular pain
- sexual dysfunction that continued after discontinuation of treatment, including erectile dysfunction,
decreased libido and ejaculation disorders (e.g. reduced ejaculate volume). These events were reported
rarely in men taking PROSCAR for the treatment of BPH. Most men were older and were taking
concomitant medications and/or had co-morbid conditions. The independent role of PROSCAR in these
events is unknown.
- male infertility and/or poor seminal quality were reported rarely in men taking PROSCAR for the
treatment of BPH. Normalization or improvement of poor seminal quality has been reported after
discontinuation of finasteride. The independent role of PROSCAR in these events is unknown.
- depression
- male breast cancer.
The following additional adverse event related to sexual dysfunction that continued after
discontinuation of treatment has been reported in postmarketing experience with finasteride at lower
doses used to treat male pattern baldness. Because the event is reported voluntarily from a population of
uncertain size, it is not always possible to reliably estimate its frequency or establish a causal relationship
to drug exposure:
- orgasm disorders
7
DRUG INTERACTIONS
7.1
Cytochrome P450-Linked Drug Metabolizing Enzyme System
No drug interactions of clinical importance have been identified. Finasteride does not appear to affect
the cytochrome P450-linked drug metabolizing enzyme system. Compounds that have been tested in
man have included antipyrine, digoxin, propranolol, theophylline, and warfarin and no clinically
meaningful interactions were found.
7.2
Other Concomitant Therapy
Although specific interaction studies were not performed, PROSCAR was concomitantly used in
clinical studies with acetaminophen, acetylsalicylic acid, α-blockers, angiotensin-converting enzyme
(ACE) inhibitors, analgesics, anti-convulsants, beta-adrenergic blocking agents, diuretics, calcium
channel blockers, cardiac nitrates, HMG-CoA reductase inhibitors, nonsteroidal anti-inflammatory drugs
(NSAIDs), benzodiazepines, H2 antagonists and quinolone anti-infectives without evidence of clinically
significant adverse interactions.
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Pregnancy Category X. [See Contraindications (4).]
PROSCAR is contraindicated for use in women who are or may become pregnant. PROSCAR is a
Type II 5α-reductase inhibitor that prevents conversion of testosterone to 5α-dihydrotestosterone (DHT),
a hormone necessary for normal development of male genitalia. In animal studies, finasteride caused
abnormal development of external genitalia in male fetuses. If this drug is used during pregnancy, or if the
patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to
the male fetus.
Abnormal male genital development is an expected consequence when conversion of testosterone to
5α-dihydrotestosterone (DHT) is inhibited by 5α-reductase inhibitors. These outcomes are similar to those
reported in male infants with genetic 5α-reductase deficiency. Women could be exposed to finasteride
6
Reference ID: 3468742
through contact with crushed or broken PROSCAR tablets or semen from a male partner taking
PROSCAR. With regard to finasteride exposure through the skin, PROSCAR tablets are coated and will
prevent skin contact with finasteride during normal handling if the tablets have not been crushed or
broken. Women who are pregnant or may become pregnant should not handle crushed or broken
PROSCAR tablets because of possible exposure of a male fetus. If a pregnant woman comes in contact
with crushed or broken PROSCAR tablets, the contact area should be washed immediately with soap and
water. With regard to potential finasteride exposure through semen, two studies have been conducted in
men receiving PROSCAR 5 mg/day that measured finasteride concentrations in semen [see Clinical
Pharmacology (12.3)].
In an embryo-fetal development study, pregnant rats received finasteride during the period of major
organogenesis (gestation days 6 to 17). At maternal doses of oral finasteride approximately 0.1 to 86
times the maximum recommended human dose (MRHD) of 5 mg/day (based on AUC at animal doses of
0.1 to 100 mg/kg/day) there was a dose-dependent increase in hypospadias that occurred in 3.6 to 100%
of male offspring. Exposure multiples were estimated using data from nonpregnant rats. Days 16 to 17 of
gestation is a critical period in male fetal rats for differentiation of the external genitalia. At oral maternal
doses approximately 0.03 times the MRHD (based on AUC at animal dose of 0.03 mg/kg/day), male
offspring had decreased prostatic and seminal vesicular weights, delayed preputial separation and
transient nipple development. Decreased anogenital distance occurred in male offspring of pregnant rats
that received approximately 0.003 times the MRHD (based on AUC at animal dose of 0.003 mg/kg/day).
No abnormalities were observed in female offspring at any maternal dose of finasteride.
No developmental abnormalities were observed in the offspring of untreated females mated with
finasteride treated male rats that received approximately 61 times the MRHD (based on AUC at animal
dose of 80 mg/kg/day). Slightly decreased fertility was observed in male offspring after administration of
about 3 times the MRHD (based on AUC at animal dose of 3 mg/kg/day) to female rats during late
gestation and lactation. No effects on fertility were seen in female offspring under these conditions.
No evidence of male external genital malformations or other abnormalities were observed in rabbit
fetuses exposed to finasteride during the period of major organogenesis (gestation days 6-18) at
maternal oral doses up to 100 mg/kg/day, (finasteride exposure levels were not measured in rabbits).
However, this study may not have included the critical period for finasteride effects on development of
male external genitalia in the rabbit.
The fetal effects of maternal finasteride exposure during the period of embryonic and fetal
development were evaluated in the rhesus monkey (gestation days 20-100), in a species and
development period more predictive of specific effects in humans than the studies in rats and rabbits.
Intravenous administration of finasteride to pregnant monkeys at doses as high as 800 ng/day (estimated
maximal blood concentration of 1.86 ng/mL or about 143 times the highest estimated exposure of
pregnant women to finasteride from semen of men taking 5 mg/day) resulted in no abnormalities in male
fetuses. In confirmation of the relevance of the rhesus model for human fetal development, oral
administration of a dose of finasteride (2 mg/kg/day or approximately 18,000 times the highest estimated
blood levels of finasteride from semen of men taking 5 mg/day) to pregnant monkeys resulted in external
genital abnormalities in male fetuses. No other abnormalities were observed in male fetuses and no
finasteride-related abnormalities were observed in female fetuses at any dose.
8.3
Nursing Mothers
PROSCAR is not indicated for use in women.
It is not known whether finasteride is excreted in human milk.
8.4
Pediatric Use
PROSCAR is not indicated for use in pediatric patients.
Safety and effectiveness in pediatric patients have not been established.
8.5
Geriatric Use
Of the total number of subjects included in PLESS, 1480 and 105 subjects were 65 and over and 75
and over, respectively. No overall differences in safety or effectiveness were observed between these
subjects and younger subjects, and other reported clinical experience has not identified differences in
responses between the elderly and younger patients. No dosage adjustment is necessary in the elderly
[see Clinical Pharmacology (12.3) and Clinical Studies (14)].
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8.6
Hepatic Impairment
Caution should be exercised in the administration of PROSCAR in those patients with liver function
abnormalities, as finasteride is metabolized extensively in the liver [see Clinical Pharmacology (12.3)].
8.7
Renal Impairment
No dosage adjustment is necessary in patients with renal impairment [see Clinical Pharmacology
(12.3)].
10
OVERDOSAGE
Patients have received single doses of PROSCAR up to 400 mg and multiple doses of PROSCAR up
to 80 mg/day for three months without adverse effects. Until further experience is obtained, no specific
treatment for an overdose with PROSCAR can be recommended.
Significant lethality was observed in male and female mice at single oral doses of 1500 mg/m2 (500
mg/kg) and in female and male rats at single oral doses of 2360 mg/m2 (400 mg/kg) and 5900 mg/m2
(1000 mg/kg), respectively.
11
DESCRIPTION
PROSCAR (finasteride), a synthetic 4-azasteroid compound, is a specific inhibitor of steroid Type II
5α-reductase,
an
intracellular
enzyme
that
converts
the
androgen
testosterone
into
5α-dihydrotestosterone (DHT).
Finasteride is 4-azaandrost-1-ene-17-carboxamide, N-(1,1-dimethylethyl)-3-oxo-,(5α,17β)-. The
empirical formula of finasteride is C23H36N2O2 and its molecular weight is 372.55. Its structural formula is: structural formula
Finasteride is a white crystalline powder with a melting point near 250°C. It is freely soluble in
chloroform and in lower alcohol solvents, but is practically insoluble in water.
PROSCAR (finasteride) tablets for oral administration are film-coated tablets that contain 5 mg of
finasteride and the following inactive ingredients: hydrous lactose, microcrystalline cellulose,
pregelatinized
starch,
sodium
starch
glycolate,
hydroxypropyl
cellulose
LF,
hydroxypropyl
methylcellulose, titanium dioxide, magnesium stearate, talc, docusate sodium, FD&C Blue 2 aluminum
lake and yellow iron oxide.
12
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
The development and enlargement of the prostate gland is dependent on the potent androgen,
5α-dihydrotestosterone (DHT). Type II 5α-reductase metabolizes testosterone to DHT in the prostate
gland, liver and skin. DHT induces androgenic effects by binding to androgen receptors in the cell nuclei
of these organs.
Finasteride is a competitive and specific inhibitor of Type II 5α-reductase with which it slowly forms a
stable enzyme complex. Turnover from this complex is extremely slow (t½ 30 days). This has been
demonstrated both in vivo and in vitro. Finasteride has no affinity for the androgen receptor. In man, the
5α-reduced steroid metabolites in blood and urine are decreased after administration of finasteride.
8
Reference ID: 3468742
12.2 Pharmacodynamics
In man, a single 5-mg oral dose of PROSCAR produces a rapid reduction in serum DHT
concentration, with the maximum effect observed 8 hours after the first dose. The suppression of DHT is
maintained throughout the 24-hour dosing interval and with continued treatment. Daily dosing of
PROSCAR at 5 mg/day for up to 4 years has been shown to reduce the serum DHT concentration by
approximately 70%. The median circulating level of testosterone increased by approximately 10-20% but
remained within the physiologic range. In a separate study in healthy men treated with finasteride 1 mg
per day (n=82) or placebo (n=69), mean circulating levels of testosterone and estradiol were increased by
approximately 15% as compared to baseline, but these remained within the physiologic range.
In patients receiving PROSCAR 5 mg/day, increases of about 10% were observed in luteinizing
hormone (LH) and follicle-stimulating hormone (FSH), but levels remained within the normal range. In
healthy volunteers, treatment with PROSCAR did not alter the response of LH and FSH to gonadotropin-
releasing hormone indicating that the hypothalamic-pituitary-testicular axis was not affected.
In patients with BPH, PROSCAR has no effect on circulating levels of cortisol, prolactin, thyroid-
stimulating hormone, or thyroxine. No clinically meaningful effect was observed on the plasma lipid profile
(i.e., total cholesterol, low density lipoproteins, high density lipoproteins and triglycerides) or bone mineral
density.
Adult males with genetically inherited Type II 5α-reductase deficiency also have decreased levels of
DHT. Except for the associated urogenital defects present at birth, no other clinical abnormalities related
to Type II 5α-reductase deficiency have been observed in these individuals. These individuals have a
small prostate gland throughout life and do not develop BPH.
In patients with BPH treated with finasteride (1-100 mg/day) for 7-10 days prior to prostatectomy, an
approximate 80% lower DHT content was measured in prostatic tissue removed at surgery, compared to
placebo; testosterone tissue concentration was increased up to 10 times over pretreatment levels,
relative to placebo. Intraprostatic content of PSA was also decreased.
In healthy male volunteers treated with PROSCAR for 14 days, discontinuation of therapy resulted in a
return of DHT levels to pretreatment levels in approximately 2 weeks. In patients treated for three months,
prostate volume, which declined by approximately 20%, returned to close to baseline value after
approximately three months of discontinuation of therapy.
12.3
Pharmacokinetics
Absorption
In a study of 15 healthy young subjects, the mean bioavailability of finasteride 5-mg tablets was 63%
(range 34-108%), based on the ratio of area under the curve (AUC) relative to an intravenous (IV)
reference dose. Maximum finasteride plasma concentration averaged 37 ng/mL (range, 27-49 ng/mL)
and was reached 1-2 hours postdose. Bioavailability of finasteride was not affected by food.
Distribution
Mean steady-state volume of distribution was 76 liters (range, 44-96 liters). Approximately 90% of
circulating finasteride is bound to plasma proteins. There is a slow accumulation phase for finasteride
after multiple dosing. After dosing with 5 mg/day of finasteride for 17 days, plasma concentrations of
finasteride were 47 and 54% higher than after the first dose in men 45-60 years old (n=12) and 70 years
old (n=12), respectively. Mean trough concentrations after 17 days of dosing were 6.2 ng/mL (range, 2.4
9.8 ng/mL) and 8.1 ng/mL (range, 1.8-19.7 ng/mL), respectively, in the two age groups. Although steady
state was not reached in this study, mean trough plasma concentration in another study in patients with
BPH (mean age, 65 years) receiving 5 mg/day was 9.4 ng/mL (range, 7.1-13.3 ng/mL; n=22) after over a
year of dosing.
Finasteride has been shown to cross the blood brain barrier but does not appear to distribute
preferentially to the CSF.
In 2 studies of healthy subjects (n=69) receiving PROSCAR 5 mg/day for 6-24 weeks, finasteride
concentrations in semen ranged from undetectable (<0.1 ng/mL) to 10.54 ng/mL. In an earlier study using
a less sensitive assay, finasteride concentrations in the semen of 16 subjects receiving PROSCAR
5 mg/day ranged from undetectable (<1.0 ng/mL) to 21 ng/mL. Thus, based on a 5-mL ejaculate volume,
the amount of finasteride in semen was estimated to be 50- to 100-fold less than the dose of finasteride
(5 g) that had no effect on circulating DHT levels in men [see also Use in Specific Populations (8.1)].
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Reference ID: 3468742
Metabolism
Finasteride is extensively metabolized in the liver, primarily via the cytochrome P450 3A4 enzyme
subfamily. Two metabolites, the t-butyl side chain monohydroxylated and monocarboxylic acid
metabolites, have been identified that possess no more than 20% of the 5-reductase inhibitory activity of
finasteride.
Excretion
In healthy young subjects (n=15), mean plasma clearance of finasteride was 165 mL/min (range, 70
279 mL/min) and mean elimination half-life in plasma was 6 hours (range, 3-16 hours). Following an oral
dose of 14C-finasteride in man (n=6), a mean of 39% (range, 32-46%) of the dose was excreted in the
urine in the form of metabolites; 57% (range, 51-64%) was excreted in the feces.
The mean terminal half-life of finasteride in subjects 70 years of age was approximately 8 hours
(range, 6-15 hours; n=12), compared with 6 hours (range, 4-12 hours; n=12) in subjects 45-60 years of
age. As a result, mean AUC(0-24 hr) after 17 days of dosing was 15% higher in subjects 70 years of age
than in subjects 45-60 years of age (p=0.02).
Table 3: Mean (SD) Pharmacokinetic Parameters in Healthy
Young Subjects (n=15)
Mean ( SD)
Bioavailability
63% (34-108%)*
Clearance (mL/min)
165 (55)
Volume of Distribution (L)
76 (14)
Half-Life (hours)
6.2 (2.1)
*Range
Pediatric
Finasteride pharmacokinetics have not been investigated in patients <18 years of age.
Finasteride is not indicated for use in pediatric patients [see Warnings and Precautions (5.4), Use in
Specific Populations (8.4)].
Gender
Finasteride is not indicated for use in women [see Contraindications (4), Warnings and Precautions
(5.3 and 5.4), Use in Specific Populations (8.1), How Supplied/Storage and Handling (16) and Patient
Counseling Information (17.2)].
Geriatric
No dosage adjustment is necessary in the elderly. Although the elimination rate of finasteride is
decreased in the elderly, these findings are of no clinical significance. [See Clinical Pharmacology (12.3)
and Use in Specific Populations (8.5).]
Table 4: Mean (SD) Noncompartmental Pharmacokinetic Parameters After Multiple Doses
of 5 mg/day in Older Men
Mean ( SD)
45-60 years old (n=12)
70 years old (n=12)
AUC (nghr/mL)
389 (98)
463 (186)
Peak Concentration (ng/mL)
46.2 (8.7)
48.4 (14.7)
Time to Peak (hours)
1.8 (0.7)
1.8 (0.6)
Half-Life (hours)*
6.0 (1.5)
8.2 (2.5)
*First-dose values; all other parameters are last-dose values
Race
The effect of race on finasteride pharmacokinetics has not been studied.
Hepatic Impairment
The effect of hepatic impairment on finasteride pharmacokinetics has not been studied. Caution
should be exercised in the administration of PROSCAR in those patients with liver function abnormalities,
as finasteride is metabolized extensively in the liver.
Renal Impairment
No dosage adjustment is necessary in patients with renal impairment. In patients with chronic renal
impairment, with creatinine clearances ranging from 9.0 to 55 mL/min, AUC, maximum plasma
concentration, half-life, and protein binding after a single dose of 14C-finasteride were similar to values
10
Reference ID: 3468742
obtained in healthy volunteers. Urinary excretion of metabolites was decreased in patients with renal
impairment. This decrease was associated with an increase in fecal excretion of metabolites. Plasma
concentrations of metabolites were significantly higher in patients with renal impairment (based on a 60%
increase in total radioactivity AUC). However, finasteride has been well tolerated in BPH patients with
normal renal function receiving up to 80 mg/day for 12 weeks, where exposure of these patients to
metabolites would presumably be much greater.
13
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
No evidence of a tumorigenic effect was observed in a 24-month study in Sprague-Dawley rats
receiving doses of finasteride up to 160 mg/kg/day in males and 320 mg/kg/day in females. These doses
produced respective systemic exposure in rats of 111 and 274 times those observed in man receiving the
recommended human dose of 5 mg/day. All exposure calculations were based on calculated AUC(0-24 hr)
for animals and mean AUC(0-24 hr) for man (0.4 µg•hr/mL).
In a 19-month carcinogenicity study in CD-1 mice, a statistically significant (p≤0.05) increase in the
incidence of testicular Leydig cell adenomas was observed at 228 times the human exposure (250
mg/kg/day). In mice at 23 times the human exposure, estimated (25 mg/kg/day) and in rats at 39 times
the human exposure (40 mg/kg/day) an increase in the incidence of Leydig cell hyperplasia was
observed. A positive correlation between the proliferative changes in the Leydig cells and an increase in
serum LH levels (2- to 3-fold above control) has been demonstrated in both rodent species treated with
high doses of finasteride. No drug-related Leydig cell changes were seen in either rats or dogs treated
with finasteride for 1 year at 30 and 350 times (20 mg/kg/day and 45 mg/kg/day, respectively) or in mice
treated for 19 months at 2.3 times the human exposure, estimated (2.5 mg/kg/day).
No evidence of mutagenicity was observed in an in vitro bacterial mutagenesis assay, a mammalian
cell mutagenesis assay, or in an in vitro alkaline elution assay. In an in vitro chromosome aberration
assay, using Chinese hamster ovary cells, there was a slight increase in chromosome aberrations. These
concentrations correspond to 4000-5000 times the peak plasma levels in man given a total dose of 5 mg.
In an in vivo chromosome aberration assay in mice, no treatment-related increase in chromosome
aberration was observed with finasteride at the maximum tolerated dose of 250 mg/kg/day (228 times the
human exposure) as determined in the carcinogenicity studies.
In sexually mature male rabbits treated with finasteride at 543 times the human exposure (80
mg/kg/day) for up to 12 weeks, no effect on fertility, sperm count, or ejaculate volume was seen. In
sexually mature male rats treated with 61 times the human exposure (80 mg/kg/day), there were no
significant effects on fertility after 6 or 12 weeks of treatment; however, when treatment was continued for
up to 24 or 30 weeks, there was an apparent decrease in fertility, fecundity and an associated significant
decrease in the weights of the seminal vesicles and prostate. All these effects were reversible within
6 weeks of discontinuation of treatment. No drug-related effect on testes or on mating performance has
been seen in rats or rabbits. This decrease in fertility in finasteride-treated rats is secondary to its effect
on accessory sex organs (prostate and seminal vesicles) resulting in failure to form a seminal plug. The
seminal plug is essential for normal fertility in rats and is not relevant in man.
14
CLINICAL STUDIES
14.1 Monotherapy
PROSCAR 5 mg/day was initially evaluated in patients with symptoms of BPH and enlarged prostates
by digital rectal examination in two 1-year, placebo-controlled, randomized, double-blind studies and their
5-year open extensions.
PROSCAR was further evaluated in the PROSCAR Long-Term Efficacy and Safety Study (PLESS), a
double-blind, randomized, placebo-controlled, 4-year, multicenter study. 3040 patients between the ages
of 45 and 78, with moderate to severe symptoms of BPH and an enlarged prostate upon digital rectal
examination, were randomized into the study (1524 to finasteride, 1516 to placebo) and 3016 patients
were evaluable for efficacy. 1883 patients completed the 4-year study (1000 in the finasteride group, 883
in the placebo group).
11
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Effect on Symptom Score
Symptoms were quantified using a score similar to the American Urological Association Symptom
Score, which evaluated both obstructive symptoms (impairment of size and force of stream, sensation of
incomplete bladder emptying, delayed or interrupted urination) and irritative symptoms (nocturia, daytime
frequency, need to strain or push the flow of urine) by rating on a 0 to 5 scale for six symptoms and a 0 to
4 scale for one symptom, for a total possible score of 34.
Patients in PLESS had moderate to severe symptoms at baseline (mean of approximately 15 points
on a 0-34 point scale). Patients randomized to PROSCAR who remained on therapy for 4 years had a
mean ( 1 SD) decrease in symptom score of 3.3 ( 5.8) points compared with 1.3 ( 5.6) points in the
placebo group. (See Figure 1.) A statistically significant improvement in symptom score was evident at
1 year in patients treated with PROSCAR vs placebo (–2.3 vs –1.6), and this improvement continued
through Year 4. graph
Results seen in earlier studies were comparable to those seen in PLESS. Although an early
improvement in urinary symptoms was seen in some patients, a therapeutic trial of at least 6 months was
generally necessary to assess whether a beneficial response in symptom relief had been achieved. The
improvement in BPH symptoms was seen during the first year and maintained throughout an additional
5 years of open extension studies.
Effect on Acute Urinary Retention and the Need for Surgery
In PLESS, efficacy was also assessed by evaluating treatment failures. Treatment failure was
prospectively defined as BPH-related urological events or clinical deterioration, lack of improvement
and/or the need for alternative therapy. BPH-related urological events were defined as urological surgical
intervention and acute urinary retention requiring catheterization. Complete event information was
available for 92% of the patients. The following table (Table 5) summarizes the results.
Table 5: All Treatment Failures in PLESS
Patients (%)*
Event
Placebo
N=1503
Finasteride
N=1513
Relative
Risk
†
95% CI
P
Value
†
All Treatment
Failures
37.1
26.2
0.68
(0.57 to 0.79)
<0.001
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Surgical
Interventions
for BPH
10.1
4.6
0.45
(0.32 to 0.63)
<0.001
Acute Urinary
Retention
Requiring
Catheterization
6.6
2.8
0.43
(0.28 to 0.66)
<0.001
Two
consecutive
symptom
scores 20
9.2
6.7
Bladder Stone
0.4
0.5
Incontinence
2.1
1.7
Renal Failure
0.5
0.6
UTI
5.7
4.9
Discontinuation
due to
worsening of
BPH, lack of
improvement,
or to receive
other medical
treatment
21.8
13.3
*patients with multiple events may be counted more than once for each type of event
†Hazard ratio based on log rank test
Compared with placebo, PROSCAR was associated with a significantly lower risk for acute urinary
retention or the need for BPH-related surgery [13.2% for placebo vs 6.6% for PROSCAR; 51% reduction
in risk, 95% CI: (34 to 63%)]. Compared with placebo, PROSCAR was associated with a significantly
lower risk for surgery [10.1% for placebo vs 4.6% for PROSCAR; 55% reduction in risk, 95% CI: (37 to
68%)] and with a significantly lower risk of acute urinary retention [6.6% for placebo vs 2.8% for
PROSCAR; 57% reduction in risk, 95% CI: (34 to 72%)]; see Figures 2 and 3. graph
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graph
Effect on Maximum Urinary Flow Rate
In the patients in PLESS who remained on therapy for the duration of the study and had evaluable
urinary flow data, PROSCAR increased maximum urinary flow rate by 1.9 mL/sec compared with 0.2
mL/sec in the placebo group.
There was a clear difference between treatment groups in maximum urinary flow rate in favor of
PROSCAR by month 4 (1.0 vs 0.3 mL/sec) which was maintained throughout the study. In the earlier 1
year studies, increase in maximum urinary flow rate was comparable to PLESS and was maintained
through the first year and throughout an additional 5 years of open extension studies.
Effect on Prostate Volume
In PLESS, prostate volume was assessed yearly by magnetic resonance imaging (MRI) in a subset of
patients. In patients treated with PROSCAR who remained on therapy, prostate volume was reduced
compared with both baseline and placebo throughout the 4-year study. PROSCAR decreased prostate
volume by 17.9% (from 55.9 cc at baseline to 45.8 cc at 4 years) compared with an increase of 14.1%
(from 51.3 cc to 58.5 cc) in the placebo group (p<0.001). (See Figure 4.)
Results seen in earlier studies were comparable to those seen in PLESS. Mean prostate volume at
baseline ranged between 40-50 cc. The reduction in prostate volume was seen during the first year and
maintained throughout an additional five years of open extension studies.
14
Reference ID: 3468742
graph
Prostate Volume as a Predictor of Therapeutic Response
A meta-analysis combining 1-year data from seven double-blind, placebo-controlled studies of similar
design, including 4491 patients with symptomatic BPH, demonstrated that, in patients treated with
PROSCAR, the magnitude of symptom response and degree of improvement in maximum urinary flow
rate were greater in patients with an enlarged prostate at baseline.
14.2 Combination with Alpha-Blocker Therapy
The Medical Therapy of Prostatic Symptoms (MTOPS) Trial was a double-blind, randomized,
placebo-controlled, multicenter, 4- to 6-year study (average 5 years) in 3047 men with symptomatic BPH,
who were randomized to receive PROSCAR 5 mg/day (n=768), doxazosin 4 or 8 mg/day (n=756), the
combination of PROSCAR 5 mg/day and doxazosin 4 or 8 mg/day (n=786), or placebo (n=737). All
participants underwent weekly titration of doxazosin (or its placebo) from 1 to 2 to 4 to 8 mg/day. Only
those who tolerated the 4 or 8 mg dose level were kept on doxazosin (or its placebo) in the study. The
participant’s final tolerated dose (either 4 mg or 8 mg) was administered beginning at end-Week 4. The
final doxazosin dose was administered once per day, at bedtime.
The mean patient age at randomization was 62.6 years (7.3 years). Patients were Caucasian (82%),
African American (9%), Hispanic (7%), Asian (1%) or Native American (<1%). The mean duration of BPH
symptoms was 4.7 years (4.6 years). Patients had moderate to severe BPH symptoms at baseline with
a mean AUA symptom score of approximately 17 out of 35 points. Mean maximum urinary flow rate was
10.5 mL/sec (2.6 mL/sec). The mean prostate volume as measured by transrectal ultrasound was
36.3 mL (20.1 mL). Prostate volume was 20 mL in 16% of patients, 50 mL in 18% of patients and
between 21 and 49 mL in 66% of patients.
The primary endpoint was a composite measure of the first occurrence of any of the following five
outcomes: a 4 point confirmed increase from baseline in symptom score, acute urinary retention, BPH-
related renal insufficiency (creatinine rise), recurrent urinary tract infections or urosepsis, or incontinence.
Compared to placebo, treatment with PROSCAR, doxazosin, or combination therapy resulted in a
reduction in the risk of experiencing one of these five outcome events by 34% (p=0.002), 39% (p<0.001),
and 67% (p<0.001), respectively. Combination therapy resulted in a significant reduction in the risk of the
primary endpoint compared to treatment with PROSCAR alone (49%; p≤0.001) or doxazosin alone (46%;
p≤0.001). (See Table 6.)
Table 6: Count and Percent Incidence of Primary Outcome Events by Treatment Group in MTOPS
Treatment Group
Placebo
Doxazosin
Finasteride
Combination
Total
N=737
N=756
N=768
N=786
N=3047
Event
N (%)
N (%)
N (%)
N (%)
N (%)
15
Reference ID: 3468742
AUA 4-point rise
Acute urinary retention
Incontinence
Recurrent UTI/urosepsis
Creatinine rise
Total Events
100 (13.6)
18 (2.4)
8 (1.1)
2 (0.3)
0 (0.0)
128 (17.4)
59 (7.8)
13 (1.7)
11 (1.5)
2 (0.3)
0 (0.0)
85 (11.2)
74 (9.6)
6 (0.8)
9 (1.2)
0 (0.0)
0 (0.0)
89 (11.6)
41 (5.2)
4 (0.5)
3 (0.4)
1 (0.1)
0 (0.0)
49 (6.2)
274 (9.0)
41 (1.3)
31 (1.0)
5 (0.2)
0 (0.0)
351 (11.5)
The majority of the events (274 out of 351; 78%) was a confirmed 4 point increase in symptom score,
referred to as symptom score progression. The risk of symptom score progression was reduced by 30%
(p=0.016), 46% (p<0.001), and 64% (p<0.001) in patients treated with PROSCAR, doxazosin, or the
combination, respectively, compared to patients treated with placebo (see Figure 5). Combination therapy
significantly reduced the risk of symptom score progression compared to the effect of PROSCAR alone
(p<0.001) and compared to doxazosin alone (p=0.037). graph
Treatment with PROSCAR, doxazosin or the combination of PROSCAR with doxazosin, reduced the
mean symptom score from baseline at year 4. Table 7 provides the mean change from baseline for AUA
symptom score by treatment group for patients who remained on therapy for four years.
Table 7: Change From Baseline in AUA Symptom Score by Treatment Group at Year 4 in MTOPS
Placebo
N=534
Doxazosin
N=582
Finasteride
N=565
Combination
N=598
Baseline Mean (SD)
16.8 (6.0)
17.0 (5.9)
17.1 (6.0)
16.8 (5.8)
Mean Change
AUA Symptom Score
(SD)
-4.9 (5.8)
-6.6 (6.1)
-5.6 (5.9)
-7.4 (6.3)
Comparison to
Placebo (95% CI)
-1.8
(-2.5, -1.1)
-0.7
(-1.4, 0.0)
-2.5
(-3.2, -1.8)
Comparison to
Doxazosin alone (95%
CI)
-0.7
(-1.4, 0.0)
16
Reference ID: 3468742
Comparison to
-1.8
Finasteride alone (95%
(-2.5, -1.1)
CI)
The results of MTOPS are consistent with the findings of the 4-year, placebo-controlled study PLESS
[see Clinical Studies (14.1)] in that treatment with PROSCAR reduces the risk of acute urinary retention
and the need for BPH-related surgery. In MTOPS, the risk of developing acute urinary retention was
reduced by 67% in patients treated with PROSCAR compared to patients treated with placebo (0.8% for
PROSCAR and 2.4% for placebo). Also, the risk of requiring BPH-related invasive therapy was reduced
by 64% in patients treated with PROSCAR compared to patients treated with placebo (2.0% for
PROSCAR and 5.4% for placebo).
14.3
Summary of Clinical Studies
The data from these studies, showing improvement in BPH-related symptoms, reduction in treatment
failure (BPH-related urological events), increased maximum urinary flow rates, and decreasing prostate
volume, suggest that PROSCAR arrests the disease process of BPH in men with an enlarged prostate.
16
HOW SUPPLIED/STORAGE AND HANDLING
No. 3094 — PROSCAR tablets 5 mg are blue, modified apple-shaped, film-coated tablets, with the
code MSD 72 on one side and PROSCAR on the other. They are supplied as follows:
NDC 0006-0072-31 unit of use bottles of 30
NDC 0006-0072-58 unit of use bottles of 100.
Storage and Handling
Store at room temperatures below 30°C (86°F). Protect from light and keep container tightly closed.
Women should not handle crushed or broken PROSCAR tablets when they are pregnant or may
potentially be pregnant because of the possibility of absorption of finasteride and the subsequent
potential risk to a male fetus [see Warnings and Precautions (5.3), Use in Specific Populations (8.1) and
Patient Counseling Information (17.2)].
17
PATIENT COUNSELING INFORMATION
See FDA-Approved Patient Labeling (Patient Information).
17.1
Increased Risk of High-Grade Prostate Cancer
Patients should be informed that there was an increase in high-grade prostate cancer in men treated
with 5α-reductase inhibitors indicated for BPH treatment, including PROSCAR, compared to those
treated with placebo in studies looking at the use of these drugs to prevent prostate cancer [see
Indications and Usage (1.3), Warnings and Precautions (5.2), and Adverse Reactions (6.1)].
17.2
Exposure of Women — Risk to Male Fetus
Physicians should inform patients that women who are pregnant or may potentially be pregnant
should not handle crushed or broken PROSCAR tablets because of the possibility of absorption of
finasteride and the subsequent potential risk to the male fetus. PROSCAR tablets are coated and will
prevent contact with the active ingredient during normal handling, provided that the tablets have not been
broken or crushed. If a woman who is pregnant or may potentially be pregnant comes in contact with
crushed or broken PROSCAR tablets, the contact area should be washed immediately with soap and
water [see Contraindications (4), Warnings and Precautions (5.3), Use in Specific Populations (8.1) and
How Supplied/Storage and Handling (16)].
17.3
Additional Instructions
Physicians should inform patients that the volume of ejaculate may be decreased in some patients
during treatment with PROSCAR. This decrease does not appear to interfere with normal sexual function.
However, impotence and decreased libido may occur in patients treated with PROSCAR [see Adverse
Reactions (6.1)].
Physicians should instruct their patients to promptly report any changes in their breasts such as
lumps, pain or nipple discharge. Breast changes including breast enlargement, tenderness and neoplasm
have been reported [see Adverse Reactions (6.1)].
17
Reference ID: 3468742
Physicians should instruct their patients to read the patient package insert before starting therapy with
PROSCAR and to reread it each time the prescription is renewed so that they are aware of current
information for patients regarding PROSCAR. company logo
For patent information: www.merck.com/product/patent/home.html
Copyright © 1992, 1995, 1998, 2011 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
All rights reserved.
uspi-mk0906-5t-1309r011
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Reference ID: 3468742
PROSCAR® (finasteride) Tablets
Patient Information about
PROSCAR® (Prahs-car)
Generic name: finasteride
(fin-AS-tur-eyed)
PROSCAR is for use by men only.
Please read this leaflet before you start taking PROSCAR. Also, read it each time you renew your
prescription, just in case anything has changed. Remember, this leaflet does not take the place of careful
discussions with your doctor. You and your doctor should discuss PROSCAR when you start taking your
medication and at regular checkups.
What is PROSCAR?
PROSCAR is a medication used to treat symptoms of benign prostatic hyperplasia (BPH) in men with an
enlarged prostate. PROSCAR may also be used to reduce the risk of a sudden inability to pass urine and
the need for surgery related to BPH in men with an enlarged prostate.
PROSCAR may be prescribed along with another medicine, an alpha-blocker called doxazosin, to help
you better manage your BPH symptoms.
Who should NOT take PROSCAR?
PROSCAR is for use by MEN only.
Do Not Take PROSCAR if you are:
a woman who is pregnant or may potentially be pregnant. PROSCAR may harm your unborn
baby. Do not touch or handle crushed or broken PROSCAR tablets (see “A warning about
PROSCAR and pregnancy”).
allergic to finasteride or any of the ingredients in PROSCAR. See the end of this leaflet for a
complete list of ingredients in PROSCAR.
A warning about PROSCAR and pregnancy:
Women who are or may potentially be pregnant must not use PROSCAR. They should also not handle
crushed or broken tablets of PROSCAR. PROSCAR tablets are coated and will prevent contact with the
active ingredient during normal handling, provided that the tablets are not broken or crushed.
If a woman who is pregnant with a male baby absorbs the active ingredient in PROSCAR after oral use or
through the skin, it may cause the male baby to be born with abnormalities of the sex organs. If a woman
who is pregnant comes into contact with the active ingredient in PROSCAR, a doctor should be
consulted.
How should I take PROSCAR?
Follow your doctor's instruction.
Take one tablet by mouth each day. To avoid forgetting to take PROSCAR, you can take it at the
same time every day.
If you forget to take PROSCAR, do not take an extra tablet. Just take the next tablet as usual.
You may take PROSCAR with or without food.
Do not share PROSCAR with anyone else; it was prescribed only for you.
Reference ID: 3468742
What are the possible side effects of PROSCAR?
PROSCAR may increase the chance of a more serious form of prostate cancer.
The most common side effects of PROSCAR include:
trouble getting or keeping an erection (impotence)
decrease in sex drive
decreased volume of ejaculate
ejaculation disorders
enlarged or painful breast. You should promptly report to your doctor any changes in your breasts
such as lumps, pain or nipple discharge.
The following have been reported in general use with PROSCAR and/or finasteride at lower doses:
allergic reactions, including rash, itching, hives, and swelling of the lips, tongue, throat, and face
rarely, some men may have testicular pain
trouble getting or keeping an erection that continued after stopping the medication
problems with ejaculation that continued after stopping the medication
male infertility and/or poor quality of semen. Improvement in the quality of semen has been
reported after stopping the medication.
depression
decrease in sex drive that continued after stopping the medication
in rare cases, male breast cancer has been reported.
You should discuss side effects with your doctor before taking PROSCAR and anytime you think you are
having a side effect. These are not all the possible side effects with PROSCAR. For more information,
ask your doctor or pharmacist.
Call your doctor for medical advice about side effects. You may report side effects to FDA at: 1-800-FDA
1088.
What you need to know while taking PROSCAR:
You should see your doctor regularly while taking PROSCAR. Follow your doctor's advice
about when to have these checkups.
Checking for prostate cancer. Your doctor has prescribed PROSCAR for BPH and not for
treatment of prostate cancer — but a man can have BPH and prostate cancer at the same time.
Your doctor may continue checking for prostate cancer while you take PROSCAR.
About Prostate-Specific Antigen (PSA). Your doctor may have done a blood test called PSA
for the screening of prostate cancer. Because PROSCAR decreases PSA levels, you should tell
your doctor(s) that you are taking PROSCAR. Changes in PSA levels will need to be evaluated
by your doctor(s). Any increase in follow-up PSA levels from their lowest point may signal the
presence of prostate cancer and should be evaluated, even if the test results are still within the
normal range. You should also tell your doctor if you have not been taking PROSCAR as
prescribed because this may affect the PSA test results. For more information, talk to your doctor.
How should I store PROSCAR?
Store PROSCAR tablets in a dry place at room temperature.
Keep PROSCAR in the original container and keep the container closed.
PROSCAR tablets are coated and will prevent contact with the active ingredient during
normal handling, provided that the tablets are not broken or crushed.
Keep PROSCAR and all medications out of the reach of children.
2
Reference ID: 3468742
Do not give your PROSCAR tablets to anyone else. It has been prescribed only for you.
For more information call 1-800-622-4477.
What are the ingredients in PROSCAR?
Active ingredients: finasteride
Inactive ingredients: hydrous lactose, microcrystalline cellulose, pregelatinized starch, sodium starch
glycolate, hydroxypropyl cellulose LF, hydroxypropyl methylcellulose, titanium dioxide, magnesium
stearate, talc, docusate sodium, FD&C Blue 2 aluminum lake and yellow iron oxide.
What is BPH?
BPH is an enlargement of the prostate gland. The prostate is located below the bladder. As the prostate
enlarges, it may slowly restrict the flow of urine. This can lead to symptoms such as:
a weak or interrupted urinary stream
a feeling that you cannot empty your bladder completely
a feeling of delay or hesitation when you start to urinate
a need to urinate often, especially at night
a feeling that you must urinate right away.
In some men, BPH can lead to serious problems, including urinary tract infections, a sudden inability to
pass urine (acute urinary retention), as well as the need for surgery.
What PROSCAR does:
PROSCAR lowers levels of a hormone called DHT (dihydrotestosterone), which is a cause of prostate
growth. Lowering DHT leads to shrinkage of the enlarged prostate gland in most men. This can lead to
gradual improvement in urine flow and symptoms over the next several months. PROSCAR will help
reduce the risk of developing a sudden inability to pass urine and the need for surgery related to an
enlarged prostate. However, since each case of BPH is different, you should know that:
Even though the prostate shrinks, you may NOT notice an improvement in urine flow or
symptoms.
You may need to take PROSCAR for six (6) months or more to see whether it improves your
symptoms.
Therapy with PROSCAR may reduce your risk for a sudden inability to pass urine and the need
for surgery for an enlarged prostate.
For patent information: www.merck.com/product/patent/home.html
Copyright © 1992, 1995, 1998, 2011 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
All rights reserved.
Revised: 09/2013
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/020180s044lbl.pdf', 'application_number': 20180, 'submission_type': 'SUPPL ', 'submission_number': 44}
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/nda/99/20182s6_Carnitor_prntlbl.pdf', 'application_number': 20182, 'submission_type': 'SUPPL ', 'submission_number': 6}
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Reference ID: 3296493
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Reference ID: 3296493
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Reference ID: 3296493
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Reference ID: 3296493
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Reference ID: 3296493
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Reference ID: 3296493
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Reference ID: 3296493
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Reference ID: 3296493
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Reference ID: 3296493
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Reference ID: 3296493
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Reference ID: 3296493
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Reference ID: 3296493
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Reference ID: 3296493
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Reference ID: 3296493
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Reference ID: 3296493
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/017512s113,020163s020,020183s019lbl.pdf', 'application_number': 20183, 'submission_type': 'SUPPL ', 'submission_number': 19}
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DIANEAL Peritoneal Dialysis Solution
For intraperitoneal administration only
DIANEAL
PD-2
Peritoneal
Dialysis
Solution
With 1.5%
Dextrose
DIANEAL
PD-2
Peritoneal
Dialysis
Solution
With 2.5%
Dextrose
DIANEAL
PD-2
Peritoneal
Dialysis
Solution
With
4.25%
Dextrose
DIANEAL
Low
Calcium
(2.5
mEq/L)
Peritoneal
Dialysis
Solution
With 1.5%
Dextrose
DIANEAL
Low
Calcium
(2.5
mEq/L)
Peritoneal
Dialysis
Solution
With 2.5%
Dextrose
DIANEAL
Low
Calcium
(2.5
mEq/L)
Peritoneal
Dialysis
Solution
With
4.25%
Dextrose
DESCRIPTION
DIANEAL Peritoneal Dialysis Solutions are sterile, nonpyrogenic solutions in flexible containers for
intraperitoneal administration only. The peritoneal dialysis solutions contain no bacteriostatic or
antimicrobial agents.
Composition, calculated osmolarity, pH, and ionic concentrations are shown in Tables 1-6.
DIANEAL is a hyperosmolar solution.
The plastic container is fabricated from polyvinyl chloride (PL 146 Plastic). Exposure to temperatures
above 25°C/77°F during transport and storage will lead to minor losses in moisture content. Higher
temperatures lead to greater losses. It is unlikely that these minor losses will lead to clinically
significant changes within the expiration period. The amount of water that can permeate from inside
the solution container into the overwrap is insufficient to affect the solution significantly.
Solutions in contact with the plastic container can leach out certain of its chemical components in
very small amounts within the expiration period, e.g. di-2-ethylhexyl phthalate (DEHP), up to 5 parts
per million; however, the safety of the plastic has been confirmed in tests in animals according to
USP biological tests for plastic containers as well as by cell culture toxicity studies.
CLINICAL PHARMACOLOGY
Mechanism of Action
DIANEAL is a hypertonic peritoneal dialysis solution containing dextrose, a monosaccharide, as the
primary osmotic agent. An osmotic gradient must be created between the peritoneal membrane and
the dialysis solution in order for ultrafiltration to occur. The hypertonic concentration of glucose in
DIANEAL exerts an osmotic pressure across the peritoneal membrane resulting in transcapillary
ultrafiltration. Like other peritoneal dialysis solutions, DIANEAL contains electrolytes to facilitate the
correction of electrolyte abnormalities. DIANEAL contains a buffer, lactate, to help normalize acid-
base abnormalities.
Pharmacokinetics of DIANEAL
Glucose content in DIANEAL is expressed as dextrose monohydrate and is available in three
concentrations: 1.5%, 2.5% and 4.25%.
Reference ID: 3814105
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Glucose is rapidly absorbed from the peritoneal cavity by diffusion and appears quickly in the
circulation due to the high glucose concentration gradient between DIANEAL compared to blood
capillary glucose level. Absorption per unit time will be the highest at the start of an exchange and
decreases over time. The rate of glucose absorption will be dependent upon the transport
characteristics of the patient’s peritoneal membrane as determined by a peritoneal equilibration test
(PET). Glucose absorption will also depend upon the concentration of glucose used for the
exchange and the length of the dwell. Glucose is metabolized by normal cellular pathways (e.g.
glycolysis) and provides a source of calories and may elevate blood glucose levels.
Transport of other molecules across the peritoneal membrane, such as lactate, will occur by
diffusion. Metabolism of lactate occurs in the liver and results in the generation of the bicarbonate.
Transport of other molecules will be dependent upon the molecular size of the solute, the
concentration gradient, and the effective peritoneal surface area as determined by the PET.
INDICATIONS AND USAGE
DIANEAL peritoneal dialysis solutions are indicated for patients in acute or chronic renal failure
when nondialytic medical therapy is judged to be inadequate.
CONTRAINDICATIONS
DIANEAL is contraindicated in patients with pre-existing severe lactic acidosis.
WARNINGS
Encapsulating Peritoneal Sclerosis (EPS) is considered to be a known, rare complication of
peritoneal dialysis therapy. EPS has been reported in patients using peritoneal dialysis solutions
including DIANEAL. Infrequently, fatal outcomes of EPS have been reported with DIANEAL.
Because Dianeal is a dextrose-based solution, patients with allergy to corn or corn products are at
increased risk for allergic reaction, which may include anaphylactic/anaphylactoid reactions. Stop the
infusion immediately, drain the solution from the peritoneal cavity and treat appropriately if any signs
or symptoms of a suspected hypersensitivity reaction develop.
Patients with severe lactic acidosis should not be treated with lactate-based peritoneal dialysis
solutions (See Contraindications). Patients with conditions known to increase the risk of lactic
acidosis [e.g., severe hypotension or sepsis that can be associated with acute renal failure, hepatic
failure, inborn errors of metabolism, and treatment with drugs such as nucleoside/nucleotide reverse
transcriptase inhibitors (NRTIs)] must be monitored for the occurrence of lactic acidosis before the
start of treatment and during treatment with lactate-based peritoneal dialysis solutions.
When prescribing the solution to be used for an individual patient, consideration should be given to
the potential interaction between the dialysis treatment and therapy directed at other existing
illnesses. Serum potassium levels should be monitored carefully in patients treated with cardiac
glycosides. For example, rapid potassium removal may create arrhythmias in cardiac patients using
digitalis or similar drugs; digitalis toxicity may be masked by hyperkalemia, hypermagnesemia, or
hypocalcemia. Correction of electrolytes by dialysis may precipitate signs and symptoms of digitalis
excess. Conversely, toxicity may occur at suboptimal dosages of digitalis if potassium is low or
calcium is high.
Diabetics require careful monitoring of insulin requirements and other treatments for hyperglycemia
during and following dialysis with dextrose containing solutions.
Reference ID: 3814105
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For current labeling information, please visit https://www.fda.gov/drugsatfda
PRECAUTIONS
General
Peritoneal-Dialysis Related
DIANEAL is intended for intraperitoneal administration only. Not for intravenous administration.
The following conditions may predispose to adverse reactions to peritoneal dialysis procedures:
abdominal conditions, including uncorrectable mechanical defects that prevent effective peritoneal
dialysis or increase the risk of infection, disruption of the peritoneal membrane and diaphragm by
surgery, congenital anomalies or trauma prior to complete healing, abdominal tumors, abdominal
wall infections, hernias, fecal fistula, colostomies or ileostomies, frequent episodes of diverticulitis,
inflammatory or ischemic bowel disease, large polycystic kidneys, or other conditions that
compromise the integrity of the abdominal wall, abdominal surface, or intra-abdominal cavity, such
as documented loss of peritoneal function or extensive adhesions that compromise peritoneal
function. Conditions that preclude normal nutrition, impaired respiratory function, recent aortic graft
placement, and potassium deficiency may also predispose to complications of peritoneal dialysis.
Aseptic technique must be employed throughout the peritoneal dialysis procedure to reduce the
possibility of infection.
Following use, the drained fluid should be inspected for the presence of fibrin or cloudiness, which
may indicate the presence of peritonitis.
If peritonitis occurs, the choice and dosage of antibiotics should be based upon the results of
identification and sensitivity studies of the isolated organism(s) when possible. Prior to identification
of the involved organism(s), broad-spectrum antibiotics may be indicated.
Overinfusion of peritoneal dialysis solution volume into the peritoneal cavity may be characterized by
abdominal distention, feeling of fullness and/or shortness of breath. Treatment of overinfusion is to
drain the peritoneal dialysis solution from the peritoneal cavity.
Need for Trained Physician
Treatment should be initiated and monitored under the supervision of a physician knowledgeable in
the management of patients with renal failure.
A patient’s volume status should be carefully monitored to avoid hyper- or hypovolemia and
potentially severe consequences including congestive heart failure, volume depletion and
hypovolemic shock. An accurate fluid balance record must be kept and the patient’s body weight
monitored. Excessive use of DIANEAL peritoneal dialysis solution with higher dextrose concentration
during a peritoneal dialysis treatment may result in significant removal of water from the patient (see
Dosage and Administration).
Significant losses of protein, amino acids, water-soluble vitamins and other medicines may occur
during peritoneal dialysis. The patient’s nutritional status should be monitored and replacement
therapy should be provided as necessary.
Information for Patients
Patients should be instructed not to use solutions if they are cloudy, discolored, contain visible
particulate matter, or if they show evidence of leaking containers (see Dosage and Administration).
Aseptic technique must be employed throughout the procedure.
An improper clamping sequence may result in infusion of air into the peritoneum (see Dosage and
Administration, Directions for Use).
Reference ID: 3814105
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For current labeling information, please visit https://www.fda.gov/drugsatfda
To reduce possible discomfort during administration, patients should be instructed that solutions may
be warmed to 37°C (98°F) prior to use. Only dry heat should be used. It is best to warm solutions
within the overwrap using a heating pad. To avoid contamination, solutions should not be immersed
in water for warming. Do not use a microwave oven to warm the solution (see Dosage and
Administration, Directions for Use).
Laboratory Tests
Serum Electrolytes
DIANEAL does not contain potassium. Evaluate serum potassium prior to administering potassium
chloride to the patient. In situations where there is a normal serum potassium level or hypokalemia,
addition of potassium chloride (up to a concentration of 4 mEq/L) to the solution may be necessary
to prevent severe hypokalemia. This should be made under careful evaluation of serum and total
body potassium, and only under the direction of a physician.
Fluid, hematology, blood chemistry, electrolyte concentrations, and bicarbonate should be monitored
periodically. If serum magnesium levels are low, magnesium supplements may be used.
Patients receiving DIANEAL solutions should have their calcium levels monitored for the
development of hypocalcemia or hypercalcemia. In these circumstances, adjustments to the dosage
of the phosphate binders, vitamin D analogs, and/or calcimimetics should be considered by the
physician. DIANEAL Low Calcium (2.5 mEq/L) Peritoneal Dialysis solution should be considered for
use in patients with hypercalcemia.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Studies to evaluate the carcinogenic or mutagenic potential of this product, or its potential to affect
fertility adversely, have not been performed.
Drug Interactions
No clinical drug interaction studies were performed. As with other dialysis solutions, blood
concentrations of dialyzable drugs may be reduced by dialysis. Dosage adjustment of concomitant
medications may be necessary. In patients using cardiac glycosides (digoxin and others), plasma
levels of calcium, potassium and magnesium must be carefully monitored (see Warnings).
Use in Specific Population
Pregnancy
Pregnancy Category C. DIANEAL is a peritoneal dialysis solution of electrolytes, lactate and
dextrose and is pharmacologically inactive. Animal reproduction studies have not been conducted
with DIANEAL dialysis solution. While there are no adequate and well controlled studies in pregnant
women, appropriate administration of DIANEAL with monitoring of fluid, electrolyte, acid-base and
glucose balance, is not expected to cause fetal harm, or affect reproductive capacity. Maintenance
of normal acid-base balance is important for fetal well being. Physicians should carefully consider
the potential risks and benefits for each specific patient before prescribing DIANEAL.
Nursing Mothers
DIANEAL is a dialysis solution of electrolytes, lactate and dextrose and is pharmacologically
inactive. The components of DIANEAL are excreted in human milk. Appropriate administration of
DIANEAL with monitoring of fluid, electrolyte, acid-base and glucose balance, is not expected to
harm a nursing infant. Physicians should carefully consider the potential risks and benefits for each
specific patient before prescribing DIANEAL.
Pediatric Use
Safety and effectiveness have been established based on published clinical data. No adequate and
well-controlled studies have been conducted with DIANEAL solutions in pediatric patients.
Reference ID: 3814105
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Geriatric Use
Safety and effectiveness have been established based on published clinical data.
ADVERSE REACTIONS
The following adverse reactions have been identified during post approval use of DIANEAL.
Because these reactions are reported voluntarily from a population of uncertain size, it is not always
possible to reliably estimate their frequency or establish a causal relationship during drug exposure.
Adverse reactions are listed by MedDRA System Organ Class (SOC), then by Preferred Term in
order of severity.
INFECTIONS AND INFESTATIONS: Fungal peritonitis, Peritonitis bacterial, Catheter related
infection
METABOLISM AND NUTRITION DISORDERS: Hypovolemia, Hypervolemia, Fluid retention,
Hypokalemia, Hyponatremia, Dehydration, Hypochloremia
VASCULAR DISORDERS: Hypotension, Hypertension
RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS: Dyspnea
GASTROINTESTINAL DISORDERS: Sclerosing encapsulating peritonitis, Peritonitis, Peritoneal
cloudy effluent, Vomiting, Diarrhea, Nausea, Constipation, Abdominal pain, Abdominal distension,
Abdominal discomfort
SKIN AND SUBCUTANEOUS DISORDERS: Stevens-Johnson syndrome, Urticaria, Rash, (including
pruritic, erythematous and generalized), Pruritus
MUSCULOSKELETAL, CONNECTIVE TISSUE DISORDERS: Myalgia, Muscle spasms,
Musculoskeletal pain
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS: Generalized edema,
Pyrexia, Malaise, Infusion site pain, Catheter related complication
DRUG ABUSE AND DEPENDENCE
There has been no observed potential of drug abuse or dependence with DIANEAL solution.
OVERDOSAGE
There is a potential for overdose resulting in hypervolemia, hypovolemia, electrolyte disturbances or
hyperglycemia. Excessive use of DIANEAL peritoneal dialysis solution with 4.25% dextrose during a
peritoneal dialysis treatment can result in significant removal of water from the patient.
DOSAGE AND ADMINISTRATION
DIANEAL peritoneal dialysis solutions are intended for intraperitoneal administration only.
The mode of therapy, frequency of treatment, formulation, exchange volume, duration of dwell, and
length of dialysis should be selected by the physician responsible for and supervising the treatment
of the individual patient. DIANEAL should be administered at a rate that is comfortable for the
patient, generally over a period of 10-20 minutes for a single exchange.
Patients on continuous ambulatory peritoneal dialysis (CAPD) typically perform 4 cycles per day (24
hours). Patients on automated peritoneal dialysis (APD) typically perform 4-5 cycles at night and up
Reference ID: 3814105
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
to 2 cycles during the day. The fill volume depends on body size, usually from 2.0 to 2.5 liters per
1.73m2 .
To avoid the risk of severe dehydration and hypovolemia and to minimize the loss of protein, it is
advisable to select the peritoneal dialysis solution with the lowest level of osmolarity consistent with
the fluid removal requirements for that exchange. As the patient’s body weight becomes closer to the
ideal dry weight, lowering the dextrose concentration of DIANEAL is recommended. DIANEAL
4.25% dextrose-containing solution has the highest osmolarity of the DIANEAL solutions and using it
for all exchanges may cause dehydration.
Solutions that are cloudy, discolored, contain visible particulate matter, or show evidence of leakage
should not be used.
Following use, the drained fluid should be inspected for the presence of fibrin or cloudiness which
may indicate the presence of peritonitis.
For single use only. Discard unused portion.
It is recommended that patients being placed on peritoneal dialysis and/or their caretaker(s) should
be appropriately trained.
Addition of Potassium
Potassium is omitted from DIANEAL solutions because dialysis may be performed to correct
hyperkalemia. In situations where there is a normal serum potassium level or hypokalemia, the
addition of potassium chloride (up to a concentration of 4 mEq/L) may be indicated to prevent severe
hypokalemia. The decision to add potassium chloride should be made by the physician after careful
evaluation of serum potassium.
Addition of Insulin
Patients with insulin-dependent diabetes may require modification of insulin dosage following
initiation of treatment with DIANEAL. Appropriate monitoring of blood glucose should be performed
when initiating DIANEAL in diabetic patients and insulin dosage adjusted if needed (see Warnings).
Addition of Heparin
No human drug interaction studies with heparin were conducted. In vitro studies demonstrated no
evidence of incompatibility of heparin with DIANEAL.
Addition of Antibiotics
No formal clinical drug interaction studies have been performed. In vitro studies of the following
medications have demonstrated stability with DIANEAL: amphotericin B, ampicillin, cefazolin,
cefepime, cefotaxime, ceftazidime, ceftriaxone, ciprofloxacin, clindamycin, deferoxamine,
erythromycin, gentamicin, linezolid, mezlocillin, miconazole, moxifloxacin, nafcillin, ofloxacin,
penicillin G, piperacillin, sulfamethoxazole/trimethoprim, ticarcillin, tobramycin, and vancomycin.
However, aminoglycosides should not be mixed with penicillins due to chemical incompatibility.
Directions for Use
For complete CAPD and APD system preparation, see directions accompanying ancillary
equipment.
Aseptic technique must be used throughout the peritoneal dialysis procedure.
Warming
For patient comfort, DIANEAL can be warmed to 37°C (98°F). Only dry heat should be used. It is
best to warm solutions within the overwrap using a heating pad. Do not immerse DIANEAL in water
for warming. Do not use a microwave oven to warm DIANEAL.
Reference ID: 3814105
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
To Open
To open, tear the overwrap down at the slit and remove the solution container. Some opacity of the
plastic, due to moisture absorption during the sterilization process, may be observed. This does not
affect the solution quality or safety and may often leave a slight amount of moisture within the
overwrap. The opacity should diminish gradually.
Inspect for Container Integrity
Inspect the bag connector to ensure the tip protector (pull ring, blue pull tip, or blue twist-off tip) is
attached. Do not use if the tip protector is not attached to the connector. Inspect the DIANEAL
container for signs of leakage and check for minute leaks by squeezing the container firmly. If the
container has frangible(s), inspect that they are positioned correctly and are not broken. Do not use
DIANEAL if the frangible(s) are broken or leaks are suspected as sterility may be impaired.
For DIANEAL in ULTRABAG, inspect the tubing and drain container for presence of solution. Small
droplets are acceptable, but if solution flows past the frangible prior to use, do not use and discard
the units.
Adding Medications
Some drug additives may be incompatible with DIANEAL. See DOSAGE AND ADMINISTRATION
section for additional information. If the resealable rubber plug on the medication port is missing or
partly removed, do not use the product if medication is to be added.
1. Put on mask. Clean and/or disinfect hands.
2. Prepare medication port site using aseptic technique.
3. Using a syringe with a 1-inch long, 25- to 19-gauge needle, puncture the medication port and
inject additive.
4. Reposition container with container ports up and evacuate medication port by squeezing and
tapping it.
5. Mix solution and additive thoroughly.
Administration instructions for CAPD therapy using ULTRABAG containers
(Products listed in Tables 1-2)
Put on mask. Clean and/or disinfect hands. Using aseptic technique;
1) Uncoil tubing and drain bag, ensuring that the transfer set is closed.
2) Immediately attach the solution container to patient connector (transfer set).
3) Break the connector (Y-set) frangible.
4) Remove the tip protector from connector of solution container. Do not reuse the solution or
container once the tip protector is removed.
5) Clamp solution line and then break frangible near solution bag. Hang solution container and
place the drainage container below the level of the abdomen.
6) Open transfer set to drain the solution from abdomen. If drainage cannot be established,
contact your clinician. When drainage complete, close transfer set.
7) Remove clamp from solution line and flush new solution to flow into the drainage container
for 5 seconds to prime the line. Clamp drain line after flush complete.
8) Open transfer set to fill. When fill complete, close transfer set.
9) Disconnect ULTRABAG from transfer set and apply MINICAP.
10) Upon completion of therapy, discard any unused portion.
Administration instructions for APD therapy using containers with pull rings or blue pull tips
(Products listed in Tables 3-5)
Put on mask. Clean and/or disinfect hands. Using aseptic technique;
Reference ID: 3814105
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For current labeling information, please visit https://www.fda.gov/drugsatfda
1) Remove the tip protector from connector of solution container. Do not reuse the solution or
container once the tip protector is removed.
2) Immediately attach the solution container to an appropriate automated peritoneal dialysis set.
3) Continue therapy as instructed in user manual or directions accompanying tubing sets for
automated peritoneal dialysis.
4) Upon completion of therapy, discard any unused portion.
Administration instructions for APD therapy using containers with blue twist-off tips
(Products listed in Table 6)
Put on mask. Clean and/or disinfect hands. Using aseptic technique;
1) Place and fasten blue outlet port clamp on solution bag administration port, between the blue
connector and the solution container.
2) Remove the blue twist-off tip from connector of solution container. Do not reuse the solution
or container once the blue twist-off tip is removed.
3) Immediately insert the spike of the automated peritoneal dialysis set into the solution bag
port.
4) Continue therapy as instructed in user manual or directions accompanying tubing sets for
automated peritoneal dialysis.
5) Upon completion of therapy, discard any unused portion.
HOW SUPPLIED
DIANEAL peritoneal dialysis solutions are available in nominal size flexible containers as shown in
Tables 1-6.
All DIANEAL peritoneal dialysis solutions have overfills which are declared on container labeling.
Freezing of solution may occur at temperatures below 0°C (32°F). Allow to thaw naturally in ambient
conditions and thoroughly mix contents by shaking.
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is
recommended the product be stored at room temperature (25°C/77°F): brief exposure up to 40°C
(104°F) does not adversely affect the product.
Reference ID: 3814105
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 1. DIANEAL PD-2 Peritoneal Dialysis Solution (ULTRABAG CONTAINER for CAPD therapy)
Composition/100 mL
OSMOLARITY
(mOsmol/L) (calc)
pH
Ionic Concentration
(mEq/L)
How Supplied
*Dextrose, Hydrous, USP
Sodium Chloride, USP (NaCl)
Sodium Lactate (C3 H5 NaO3 )
Calcium Chloride, USP (CaCl2 •2H2 O)
Magnesium Chloride, USP (MgCl2 •6H2 O)
Sodium
Calcium
Magnesium
Chloride
Lactate
Fill
Volume
(mL)
Container
Size (mL)
Code
NDC
DIANEAL PD-2
Peritoneal Dialysis
Solution with
1.5% Dextrose
1.5 g
538 mg
448 mg
25.7 mg
5.08 mg
346
5.2
(4.0 to
6.5)
132
3.5
0.5
96
40
2000
2500
3000
2000
3000
5000
5B9866
5B9868
5B9857
0941-0426-52
0941-0426-53
0941-0426-55
DIANEAL PD-2
Peritoneal Dialysis
Solution with
2.5% Dextrose
2.5 g
538 mg
448 mg
25.7 mg
5.08 mg
396
5.2
(4.0 to
6.5)
132
3.5
0.5
96
40
2000
2500
3000
2000
3000
5000
5B9876
5B9878
5B9858
0941-0427-52
0941-0427-53
0941-0427-55
DIANEAL PD-2
Peritoneal Dialysis
Solution with
4.25% Dextrose
4.25 g
538 mg
448 mg
25.7 mg
5.08 mg
485
5.2
(4.0 to
6.5)
132
3.5
0.5
96
40
2000
2500
3000
2000
3000
5000
5B9896
5B9898
5B9859
0941-0429-52
0941-0429-53
0941-0429-55
Reference ID: 3814105
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 2. DIANEAL Low Calcium (2.5 mEq/L) Peritoneal Dialysis Solution (ULTRABAG CONTAINER for CAPD therapy)
Composition/100 mL
OSMOLARITY
(mOsmol/L) (calc)
pH
Ionic Concentration
(mEq/L)
How Supplied
*Dextrose, Hydrous, USP
Sodium Chloride, USP (NaCl)
Sodium Lactate (C3 H5 NaO3 )
Calcium Chloride, USP (CaCl2 •2H2 O)
Magnesium Chloride, USP (MgCl2 •6H2 O)
Sodium
Calcium
Magnesium
Chloride
Lactate
Fill
Volume
(mL)
Container
Size (mL)
Code
NDC
DIANEAL Low
Calcium (2.5 mEq/L)
Peritoneal Dialysis
Solution with 1.5%
Dextrose
1.5 g
538 mg 448 mg
18.3
mg
5.08
mg
344
5.2
(4.0 to 6.5)
132
2.5
0.5
95
40
1500
2000
2500
3000
2000
2000
3000
5000
5B9765
5B9766
5B9768
5B9757
0941-0424-51
0941-0424-52
0941-0424-53
0941-0424-55
DIANEAL Low
Calcium (2.5 mEq/L)
Peritoneal Dialysis
Solution with 2.5%
Dextrose
2.5 g
538 mg 448 mg
18.3
mg
5.08
mg
395
5.2
(4.0 to 6.5)
132
2.5
0.5
95
40
1500
2000
2500
3000
2000
2000
3000
5000
5B9775
5B9776
5B9778
5B9758
0941-0430-51
0941-0430-52
0941-0430-53
0941-0430-55
DIANEAL Low
Calcium (2.5 mEq/L)
Peritoneal Dialysis
Solution with 4.25%
Dextrose
4.25 g 538 mg 448 mg
18.3
mg
5.08
mg
483
5.2
(4.0 to 6.5)
132
2.5
0.5
95
40
1500
2000
2500
3000
2000
2000
3000
5000
5B9795
5B9796
5B9798
5B9759
0941-0433-51
0941-0433-52
0941-0433-53
0941-0433-55
Reference ID: 3814105
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 3. DIANEAL PD-2 Peritoneal Dialysis Solution (AMBU-FLEX CONTAINER with pull ring for APD therapy)
Composition/100 mL
Ionic Concentration
(mEq/L)
How Supplied
(NaCl)
3 )
5 NaO
(CaCl
2 •6H2 O)
Fill
Container
SP
, U
SP
SP
USP (MgCl
e,
Volume
Size
Code
NDC
*Dextrose, Hydrous
Sodium Chloride, U
Sodium Lactate (C3 H
Calcium Chloride, U
2 •2H2 O)
Magnesium Chlorid
OSMOLARITY
(mOsmol/L) (calc)
pH
Sodium
Calcium
Magnesium
Chloride
Lactate
(mL)
(mL)
DIANEAL PD-2
Peritoneal Dialysis
Solution with 1.5%
Dextrose
AMBU-FLEX II
CONTAINER
1.5 g
538 mg
448 mg
25.7 mg
5.08 mg
346
5.2
(4.0 to 6.5)
132
3.5
0.5
96
40
1000
2000
3000
5000
6000
1000
3000
3000
6000
6000
L5B5163
L5B5166
L5B5169
L5B5193
L5B9710
0941-0411-05
0941-0411-06
0941-0411-04
0941-0411-07
0941-0411-11
DIANEAL PD-2
Peritoneal Dialysis
Solution with 2.5%
Dextrose
AMBU-FLEX II
CONTAINER
2.5 g
538 mg
448 mg
25.7 mg
5.08 mg
396
5.2
(4.0 to 6.5)
132
3.5
0.5
96
40
1000
2000
3000
5000
6000
1000
3000
3000
6000
6000
L5B5173
L5B5177
L5B5179
L5B5194
L5B9711
0941-0413-05
0941-0413-06
0941-0413-04
0941-0413-07
0941-0413-01
DIANEAL PD-2
Peritoneal Dialysis
Solution with
4.25% Dextrose
AMBU-FLEX II
CONTAINER
4.25 g
538 mg
448 mg
25.7 mg
5.08 mg
485
5.2
(4.0 to 6.5)
132
3.5
0.5
96
40
1000
2000
3000
5000
6000
1000
3000
3000
6000
6000
L5B5183
L5B5187
L5B5189
L5B5195
L5B9712
0941-0415-05
0941-0415-06
0941-0415-04
0941-0415-07
0941-0415-01
Reference ID: 3814105
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 4. DIANEAL Low Calcium (2.5 mEq/L) Peritoneal Dialysis Solution (AMBU-FLEX CONTAINER with pull ring for APD therapy)
Composition/100 mL
Ionic Concentration
(mEq/L)
How Supplied
(NaCl)
3 )
5 NaO
(CaCl
SP (MgCl
Fill
Container
SP
U
SP
SP
e, U
Volume
Size
Code
NDC
*Dextrose, Hydrous,
Sodium Chloride, U
Sodium Lactate (C3 H
Calcium Chloride, U
2 •2H2 O)
Magnesium Chlorid
2 •6H2 O)
OSMOLARITY
(mOsmol/L) (calc)
pH
Sodium
Calcium
Magnesium
Chloride
Lactate
(mL)
(mL)
DIANEAL Low
Calcium (2.5 mEq/L)
Peritoneal Dialysis
Solution with 1.5%
Dextrose
AMBU-FLEX II
CONTAINER
1.5 g
538 mg
448 mg 18.3 mg 5.08 mg
344
5.2
(4.0 to 6.5)
132
2.5
0.5
95
40
2000
3000
5000
6000
3000
3000
6000
6000
L5B4825
L5B9901
L5B4826
L5B9770
0941-0409-06
0941-0409-05
0941-0409-07
0941-0409-01
DIANEAL Low
Calcium (2.5 mEq/L)
Peritoneal Dialysis
Solution with 2.5%
Dextrose
AMBU-FLEX II
CONTAINER
2.5 g
538 mg
448 mg 18.3 mg 5.08 mg
395
5.2
(4.0 to 6.5)
132
2.5
0.5
95
40
2000
3000
5000
6000
3000
3000
6000
6000
L5B9727
L5B9902
L5B5202
L5B9771
0941-0457-08
0941-0457-02
0941-0457-05
0941-0457-01
DIANEAL Low
Calcium (2.5 mEq/L)
Peritoneal Dialysis
Solution with 4.25%
Dextrose
AMBU-FLEX II
CONTAINER
4.25 g
538 mg
448 mg 18.3 mg 5.08 mg
483
5.2
(4.0 to 6.5)
132
2.5
0.5
95
40
2000
3000
5000
6000
3000
3000
6000
6000
L5B9747
L5B9903
L5B5203
L5B9772
0941-0459-08
0941-0459-02
0941-0459-05
0941-0459-01
Reference ID: 3814105
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 5. DIANEAL Low Calcium (2.5 mEq/L) Peritoneal Dialysis Solution Made in Ireland (Plastic container with blue pull tip for APD therapy)
Composition/100 mL
Ionic Concentration
(mEq/L)
How Supplied
)
3 )
H 5 NaO
2 •2H2 O)
gCl
Fill
Container
aCl
l
aC
(M
Volume
Size
Code
NDC
*Dextrose, Hydrous
Sodium Chloride (N
Sodium Lactate (C3
Calcium Chloride (C
Magnesium Chloride
2 •6H2 O)
OSMOLARITY
(mOsmol/L) (calc)
pH
Sodium
Calcium
Magnesium
Chloride
Lactate
(mL)
(mL)
DIANEAL Low
Calcium (2.5 mEq/L)
Peritoneal Dialysis
Solution with 1.5%
Dextrose
1.5 g
538 mg
448 mg 18.4 mg 5.08 mg
344
5.0 to 6.5
132
2.5
0.5
95
40
5000
5000
EZPB5245R 0941-0484-01
DIANEAL Low
Calcium (2.5 mEq/L)
Peritoneal Dialysis
Solution with 2.5%
Dextrose
2.5 g
538 mg
448 mg 18.4 mg 5.08 mg
395
5.0 to 6.5
132
2.5
0.5
95
40
5000
5000
EZPB5255R 0941-0487-01
DIANEAL Low
Calcium (2.5 mEq/L)
Peritoneal Dialysis
Solution with 4.25%
Dextrose
4.25 g
538 mg
448 mg 18.4 mg 5.08 mg
483
5.0 to 6.5
132
2.5
0.5
95
40
5000
5000
EZPB5265R 0941-0490-01
Reference ID: 3814105
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 6. DIANEAL Low Calcium (2.5 mEq/L) Peritoneal Dialysis Solution Made in Mexico (Plastic container with blue twist-off tip for APD therapy)
Composition/100 mL
Ionic Concentration
(mEq/L)
How Supplied
(NaCl)
3)
5NaO
2 •2H2 O)
SP (MgCl
Fill
Container
SP
U
P
SP (CaCl
, U
Volume
Size
Code
NDC
*Dextrose, Hydrous,
Sodium Chloride, US
Sodium Lactate (C3 H
Calcium Chloride, U
Magnesium Chloride
2 •6H2 O)
OSMOLARITY
(mOsmol/L) (calc)
pH
Sodium
Calcium
Magnesium
Chloride
Lactate
(mL)
(mL)
DIANEAL Low
Calcium (2.5 mEq/L)
Peritoneal Dialysis
Solution with 1.5%
Dextrose
1.5 g
538 mg
448 mg 18.3 mg 5.08 mg
344
5.0 to 5.6
132
2.5
0.5
95
40
6000
6000
VBB4928US 0941-0472-01
DIANEAL Low
Calcium (2.5 mEq/L)
Peritoneal Dialysis
Solution with 2.5%
Dextrose
2.5 g
538 mg
448 mg 18.3 mg 5.08 mg
395
5.0 to 5.6
132
2.5
0.5
95
40
6000
6000
VBB4931US 0941-0475-01
Reference ID: 3814105
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
structural formula
BAXTER, DIANEAL, AMBU-FLEX, ULTRABAG, MINICAP, and PL 146 are trademarks of Baxter
International, Inc.
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
Printed in USA
08/2015
071975233
Reference ID: 3814105
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:47:00.255158
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/017512s122,020163s027,020183s026lbl.pdf', 'application_number': 20183, 'submission_type': 'SUPPL ', 'submission_number': 26}
|
12,303
|
NDA 18-948/S-022
NDA 19-257/S-010
NDA 20-182/S-008
Page 3
CARNITOR
®
(levocarnitine)
CARNITOR® (levocarnitine) Tablets (330 mg)
CARNITOR® (levocarnitine) Oral Solution (1 g per 10 mL multidose)
For oral use only. Not for parenteral use.
DESCRIPTION
CARNITOR® (levocarnitine) is a carrier molecule in the transport of long-chain fatty acids across the inner
mitochondrial membrane.
The chemical name of levocarnitine is 3-carboxy-2(R)-hydroxy-N,N,N-trimethyl-1-propanaminium, inner
salt. Levocarnitine is a white crystalline, hygroscopic powder. It is readily soluble in water, hot alcohol,
and insoluble in acetone. The specific rotation of levocarnitine is between -29° and -32°. Its chemical
structure is:
C
H
O
H
CH2
CH2COO
(CH3)3N
-
+
Empirical Formula:
C7H15NO3
Molecular Weight:
161.20
Each CARNITOR® (levocarnitine) Tablet contains 330 mg of levocarnitine and the inactive ingredients
magnesium stearate, microcrystalline cellulose and povidone.
Each 118 mL container of CARNITOR® (levocarnitine) Oral Solution contains 1 g of levocarnitine/10 mL.
Also contains: Artificial Cherry Flavor, D,L-Malic Acid, Purified Water, Sucrose Syrup. Methylparaben
NF and Propylparaben NF are added as preservatives. The pH is approximately 5.
CLINICAL PHARMACOLOGY
CARNITOR® (levocarnitine) is a naturally occurring substance required in mammalian energy metabolism.
It has been shown to facilitate long-chain fatty acid entry into cellular mitochondria, thereby delivering
substrate for oxidation and subsequent energy production. Fatty acids are utilized as an energy substrate in
all tissues except the brain. In skeletal and cardiac muscle, fatty acids are the main substrate for energy
production.
Primary systemic carnitine deficiency is characterized by low concentrations of levocarnitine in plasma,
RBC, and/or tissues. It has not been possible to determine which symptoms are due to carnitine deficiency
and which are due to an underlying organic acidemia, as symptoms of both abnormalities may be expected
to improve with CARNITOR®. The literature reports that carnitine can promote the excretion of excess
organic or fatty acids in patients with defects in fatty acid metabolism and/or specific organic acidopathies
that bioaccumulate acylCoA esters.1-6
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-948/S-022
NDA 19-257/S-010
NDA 20-182/S-008
Page 4
Secondary carnitine deficiency can be a consequence of inborn errors of metabolism. CARNITOR® may
alleviate the metabolic abnormalities of patients with inborn errors that result in accumulation of toxic
organic acids. Conditions for which this effect has been demonstrated are: glutaric aciduria II, methyl
malonic aciduria, propionic acidemia, and medium chain fatty acylCoA dehydrogenase deficiency.7,8
Autointoxication occurs in these patients due to the accumulation of acylCoA compounds that disrupt
intermediary metabolism. The subsequent hydrolysis of the acylCoA compound to its free acid results in
acidosis which can be life-threatening. Levocarnitine clears the acylCoA compound by formation of
acylcarnitine, which is quickly excreted. Carnitine deficiency is defined biochemically as abnormally low
plasma concentrations of free carnitine, less than 20 µmol/L at one week post term and may be associated
with low tissue and/or urine concentrations. Further, this condition may be associated with a plasma
concentration ratio of acylcarnitine/levocarnitine greater than 0.4 or abnormally elevated concentrations of
acylcarnitine in the urine. In premature infants and newborns, secondary deficiency is defined as plasma
levocarnitine concentrations below age-related normal concentrations.
PHARMACOKINETICS
In a relative bioavailability study in 15 healthy adult male volunteers, CARNITOR® Tablets were found to
be bio-equivalent to CARNITOR® Oral Solution. Following 4 days of dosing with 6 tablets of
CARNITOR® 330 mg b.i.d. or 2 g of CARNITOR® oral solution b.i.d., the maximum plasma concentration
(Cmax) was about 80 µmol/L and the time to maximum plasma concentration (Tmax) occurred at 3.3 hours.
The plasma concentration profiles of levocarnitine after a slow 3 minute intravenous bolus dose of 20
mg/kg of CARNITOR® were described by a two-compartment model. Following a single i.v.
administration, approximately 76% of the levocarnitine dose was excreted in the urine during the 0-24h
interval. Using plasma concentrations uncorrected for endogenous levocarnitine, the mean distribution half
life was 0.585 hours and the mean apparent terminal elimination half life was 17.4 hours.
The absolute bioavailability of levocarnitine from the two oral formulations of CARNITOR®, calculated
after correction for circulating endogenous plasma concentrations of levocarnitine, was 15.1 ± 5.3% for
CARNITOR® Tablets and 15.9 ± 4.9% for CARNITOR® Oral Solution.
Total body clearance of levocarnitine (Dose/AUC including endogenous baseline concentrations) was a
mean of 4.00 L/h.
Levocarnitine was not bound to plasma protein or albumin when tested at any concentration or with any
species including the human.9
METABOLISM AND EXCRETION
In a pharmacokinetic study where five normal adult male volunteers received an oral dose of [3H-methyl]-
L-carnitine following 15 days of a high carnitine diet and additional carnitine supplement, 58 to 65% of the
administered radioactive dose was recovered in the urine and feces in 5 to 11 days. Maximum
concentration of [3H-methyl]-L-carnitine in serum occurred from 2.0 to 4.5 hr after drug administration.
Major metabolites found were trimethylamine N-oxide, primarily in urine (8% to 49% of the administered
dose) and [3H]-γ-butyrobetaine, primarily in feces (0.44% to 45% of the administered dose). Urinary
excretion of levocarnitine was about 4 to 8% of the dose. Fecal excretion of total carnitine was less than
1% of the administered dose.10
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-948/S-022
NDA 19-257/S-010
NDA 20-182/S-008
Page 5
After attainment of steady state following 4 days of oral administration of CARNITOR® Tablets (1980 mg
q12h) or Oral Solution (2000 mg q12h) to 15 healthy male volunteers, the mean urinary excretion of
levocarnitine during a single dosing interval (12h) was about 9% of the orally administered dose
(uncorrected for endogenous urinary excretion).
INDICATIONS AND USAGE
CARNITOR® (levocarnitine) is indicated in the treatment of primary systemic carnitine deficiency. In the
reported cases, the clinical presentation consisted of recurrent episodes of Reye-like encephalopathy,
hypoketotic hypoglycemia, and/or cardiomyopathy. Associated symptoms included hypotonia, muscle
weakness and failure to thrive. A diagnosis of primary carnitine deficiency requires that serum, red cell
and/or tissue carnitine levels be low and that the patient does not have a primary defect in fatty acid or
organic acid oxidation (see Clinical Pharmacology). In some patients, particularly those presenting with
cardiomyopathy, carnitine supplementation rapidly alleviated signs and symptoms. Treatment should
include, in addition to carnitine, supportive and other therapy as indicated by the condition of the patient.
CARNITOR® (levocarnitine) is also indicated for acute and chronic treatment of patients with an inborn
error of metabolism which results in a secondary carnitine deficiency.
CONTRAINDICATIONS
None known.
WARNINGS
None.
PRECAUTIONS
General
CARNITOR® (levocarnitine) Oral Solution is for oral/internal use only.
Not for parenteral use.
Gastrointestinal reactions may result from a too rapid consumption of carnitine. CARNITOR®
(levocarnitine) Oral Solution may be consumed alone, or dissolved in drinks or other liquid foods to reduce
taste fatigue. It should be consumed slowly and doses should be spaced evenly throughout the day to
maximize tolerance.
The safety and efficacy of oral levocarnitine has not been evaluated in patients with renal insufficiency.
Chronic administration of high doses of oral levocarnitine in patients with severely compromised renal
function or in ESRD patients on dialysis may result in accumulation of the potentially toxic metabolites,
trimethylamine (TMA) and trimethylamine-N-oxide (TMAO), since these metabolites are normally
excreted in the urine.
Carcinogenesis, mutagenesis, impairment of fertility
Mutagenicity tests performed in Salmonella typhimurium, Saccharomyces cerevisiae, and
Schizosaccharomyces pombe indicate that levocarnitine is not mutagenic. No long-term animal studies
have been performed to evaluate the carcinogenic potential of levocarnitine.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-948/S-022
NDA 19-257/S-010
NDA 20-182/S-008
Page 6
Pregnancy
Pregnancy Category B.
Reproductive studies have been performed in rats and rabbits at doses up to 3.8 times the human dose on
the basis of surface area and have revealed no evidence of impaired fertility or harm to the fetus due to
CARNITOR®. There are, however, no adequate and well controlled studies in pregnant women.
Because animal reproduction studies are not always predictive of human response, this drug should be used
during pregnancy only if clearly needed.
Nursing Mothers
Levocarnitine supplementation in nursing mothers has not been specifically studied.
Studies in dairy cows indicate that the concentration of levocarnitine in milk is increased following
exogenous administration of levocarnitine. In nursing mothers receiving levocarnitine, any risks to the
child of excess carnitine intake need to be weighed against the benefits of levocarnitine supplementation to
the mother. Consideration may be given to discontinuation of nursing or of levocarnitine treatment.
Pediatric Use
See Dosage and Administration.
ADVERSE REACTIONS
Various mild gastrointestinal complaints have been reported during the long-term administration of oral L-
or D,L-carnitine; these include transient nausea and vomiting, abdominal cramps, and diarrhea. Mild
myasthenia has been described only in uremic patients receiving D,L-carnitine. Gastrointestinal adverse
reactions with CARNITOR® (levocarnitine) Oral Solution dissolved in liquids might be avoided by a slow
consumption of the solution or by a greater dilution. Decreasing the dosage often diminishes or eliminates
drug-related patient body odor or gastrointestinal symptoms when present. Tolerance should be monitored
very closely during the first week of administration, and after any dosage increases.
Seizures have been reported to occur in patients with or without pre-existing seizure activity receiving
either oral or intravenous levocarnitine. In patients with pre-existing seizure activity, an increase in seizure
frequency and/or severity has been reported.
OVERDOSAGE
There have been no reports of toxicity from levocarnitine overdosage. Levocarnitine is easily removed
from plasma by dialysis. The intravenous LD50 of levocarnitine in rats is 5.4 g/kg and the oral LD50 of
levocarnitine in mice is 19.2 g/kg. Large doses of levocarnitine may cause diarrhea.
DOSAGE AND ADMINISTRATION
CARNITOR® (levocarnitine) Tablets.
Adults: The recommended oral dosage for adults is 990 mg two or three times a day using the 330 mg
tablets, depending on clinical response.
Infants and children: The recommended oral dosage for infants and children is between 50 and 100
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-948/S-022
NDA 19-257/S-010
NDA 20-182/S-008
Page 7
mg/kg/day in divided doses, with a maximum of 3 g/day. Dosage should begin at 50 mg/kg/day. The exact
dosage will depend on clinical response.
Monitoring should include periodic blood chemistries, vital signs, plasma carnitine concentrations and
overall clinical condition.
CARNITOR® (levocarnitine) Oral Solution.
For oral use only. Not for parenteral use.
Adults: The recommended dosage of levocarnitine is 1 to 3 g/day for a 50 kg subject, which is
equivalent to 10 to 30 mL/day of CARNITOR® (levocarnitine) Oral Solution. Higher doses should be
administered only with caution and only where clinical and biochemical considerations make it seem
likely that higher doses will be of benefit. Dosage should start at 1 g/day, (10 mL/day), and be
increased slowly while assessing tolerance and therapeutic response. Monitoring should include
periodic blood chemistries, vital signs, plasma carnitine concentrations, and overall clinical condition.
Infants and children: The recommended dosage of levocarnitine is 50 to 100 mg/kg/day which is equivalent
to 0.5 mL/kg/day CARNITOR® (levocarnitine) Oral Solution. Higher doses should be administered only
with caution and only where clinical and biochemical considerations make it seem likely that higher doses
will be of benefit. Dosage should start at 50 mg/kg/day, and be increased slowly to a maximum of 3 g/day
(30 mL/day) while assessing tolerance and therapeutic response. Monitoring should include periodic blood
chemistries, vital signs, plasma carnitine concentrations, and overall clinical condition.
CARNITOR® (levocarnitine) Oral Solution may be consumed alone or dissolved in drink or other liquid
food. Doses should be spaced evenly throughout the day (every three or four hours) preferably during or
following meals and should be consumed slowly in order to maximize tolerance.
HOW SUPPLIED
CARNITOR® (levocarnitine) Tablets are supplied as 330 mg tablets embossed with “CARNITOR ST” in
individual blisters, packaged in boxes of 90 (NDC 54482-144-07). Store at controlled room temperature
(25°C). See USP.
CARNITOR® (levocarnitine) Oral Solution is supplied in 118 mL (4 FL. OZ.) multiple-unit plastic
containers. The multiple-unit containers are packaged 24 per case (NDC 54482-145-08). Store at
controlled room temperature (25°C). See USP. CARNITOR® (levocarnitine) Oral Solution is manufactured
for Sigma-Tau Pharmaceuticals, Inc. by: Alpharma USPD, Inc. Baltimore, MD 21244-2654 and/or Hi-Tech
Pharmacal Co., Inc. Amityville, NY 11701.
CARNITOR® (levocarnitine) is also available in the following dosage forms for intravenous injection:
CARNITOR® (levocarnitine) Injection is available in 1 g per 5 mL single dose vials packaged 5 vials per
carton (NDC 54482-147-01). CARNITOR® (levocarnitine) Injection 5 mL vial is manufactured for Sigma-
Tau Pharmaceuticals, Inc. by Chesapeake Biological Laboratories, Inc. Baltimore, MD 21230-2591.
CARNITOR® (levocarnitine) Injection is also available in 1 g per 5 mL single dose ampoules packaged 5
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-948/S-022
NDA 19-257/S-010
NDA 20-182/S-008
Page 8
ampoules per carton (NDC 54482-146-09). Made in Italy.
Rx only.
REFERENCES
1. Bohmer, T., Rydning, A. and Solberg, H.E. 1974. Carnitine levels in human serum in health and
disease. Clin. Chim. Acta 57:55-61.
2. Brooks, H., Goldberg, L., Holland, R. et al. 1977. Carnitine-induced effects on cardiac and
peripheral hemodynamics. J. Clin. Pharmacol. 17:561-568.
3. Christiansen, R., Bremer, J. 1976. Active transport of butyrobetaine and carnitine into isolated liver
cells. Biochim. Biophys. Acta 448:562-577.
4. Lindstedt, S. and Lindstedt, G. 1961. Distribution and excretion of carnitine in the rat. Acta Chem.
Scand. 15:701-702.
5. Rebouche, C.J. and Engel, A.G. 1983. Carnitine metabolism and deficiency syndromes. Mayo Clin.
Proc. 58:533-540.
6. Rebouche, C.J. and Paulson, D.J. 1986. Carnitine metabolism and function in humans. Ann. Rev.
Nutr. 6:41-66.
7. Scriver, C.R., Beaudet, A.L., Sly, W.S. and Valle, D. 1989. The Metabolic Basis of Inherited
Disease. New York: McGraw-Hill.
8. Schaub, J., Van Hoof, F. and Vis, H.L. 1991. Inborn Errors of Metabolism. New York: Raven
Press.
9. Marzo, A., Arrigoni Martelli, E., Mancinelli, A., Cardace, G., Corbelletta, C., Bassani, E. and
Solbiati, M. 1991. Protein binding of L-carnitine family components. Eur. J. Drug Met.
Pharmacokin., Special Issue III: 364-368.
10. Rebouche, C.J. 1991. Quantitative estimation of absorption and degradation of a carnitine
supplement by human adults. Metabolism 40:1305-1310.
sigma-tau
industrie farmaceutiche riunite
532910
s. p. a.
Pharmaceuticals,
Inc.
Gaithersburg, MD 20877
PREVIOUS EDITION IS OBSOLETE
Date of Issue: 03/02 OPI-5-E
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-948/S-022
NDA 19-257/S-010
NDA 20-182/S-008
Page 9
CARNITOR
®
(levocarnitine)
CARNITOR® (levocarnitine) Tablets (330 mg)
CARNITOR® (levocarnitine) Oral Solution (1 g per 10 mL multidose)
For oral use only. Not for parenteral use.
DESCRIPTION
CARNITOR® (levocarnitine) is a carrier molecule in the transport of long-chain fatty acids across the inner
mitochondrial membrane.
The chemical name of levocarnitine is 3-carboxy-2(R)-hydroxy-N,N,N-trimethyl-1-propanaminium, inner
salt. Levocarnitine is a white crystalline, hygroscopic powder. It is readily soluble in water, hot alcohol,
and insoluble in acetone. The specific rotation of levocarnitine is between -29° and -32°. Its chemical
structure is:
C
H
O
H
CH2
CH2COO
(CH3)3N
-
+
Empirical Formula:
C7H15NO3
Molecular Weight:
161.20
Each CARNITOR® (levocarnitine) Tablet contains 330 mg of levocarnitine and the inactive ingredients
magnesium stearate, microcrystalline cellulose and povidone.
Each 118 mL container of CARNITOR® (levocarnitine) Oral Solution contains 1 g of levocarnitine/10 mL.
Also contains: Artificial Cherry Flavor, D,L-Malic Acid, Purified Water, Sucrose Syrup. Methylparaben
NF and Propylparaben NF are added as preservatives. The pH is approximately 5.
CLINICAL PHARMACOLOGY
CARNITOR® (levocarnitine) is a naturally occurring substance required in mammalian energy metabolism.
It has been shown to facilitate long-chain fatty acid entry into cellular mitochondria, thereby delivering
substrate for oxidation and subsequent energy production. Fatty acids are utilized as an energy substrate in
all tissues except the brain. In skeletal and cardiac muscle, fatty acids are the main substrate for energy
production.
Primary systemic carnitine deficiency is characterized by low concentrations of levocarnitine in plasma,
RBC, and/or tissues. It has not been possible to determine which symptoms are due to carnitine deficiency
and which are due to an underlying organic acidemia, as symptoms of both abnormalities may be expected
to improve with CARNITOR®. The literature reports that carnitine can promote the excretion of excess
organic or fatty acids in patients with defects in fatty acid metabolism and/or specific organic acidopathies
that bioaccumulate acylCoA esters.1-6
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-948/S-022
NDA 19-257/S-010
NDA 20-182/S-008
Page 10
Secondary carnitine deficiency can be a consequence of inborn errors of metabolism. CARNITOR® may
alleviate the metabolic abnormalities of patients with inborn errors that result in accumulation of toxic
organic acids. Conditions for which this effect has been demonstrated are: glutaric aciduria II, methyl
malonic aciduria, propionic acidemia, and medium chain fatty acylCoA dehydrogenase deficiency.7,8
Autointoxication occurs in these patients due to the accumulation of acylCoA compounds that disrupt
intermediary metabolism. The subsequent hydrolysis of the acylCoA compound to its free acid results in
acidosis which can be life-threatening. Levocarnitine clears the acylCoA compound by formation of
acylcarnitine, which is quickly excreted. Carnitine deficiency is defined biochemically as abnormally low
plasma concentrations of free carnitine, less than 20 µmol/L at one week post term and may be associated
with low tissue and/or urine concentrations. Further, this condition may be associated with a plasma
concentration ratio of acylcarnitine/levocarnitine greater than 0.4 or abnormally elevated concentrations of
acylcarnitine in the urine. In premature infants and newborns, secondary deficiency is defined as plasma
levocarnitine concentrations below age-related normal concentrations.
PHARMACOKINETICS
In a relative bioavailability study in 15 healthy adult male volunteers, CARNITOR® Tablets were found to
be bio-equivalent to CARNITOR® Oral Solution. Following 4 days of dosing with 6 tablets of
CARNITOR® 330 mg b.i.d. or 2 g of CARNITOR® oral solution b.i.d., the maximum plasma concentration
(Cmax) was about 80 µmol/L and the time to maximum plasma concentration (Tmax) occurred at 3.3 hours.
The plasma concentration profiles of levocarnitine after a slow 3 minute intravenous bolus dose of 20
mg/kg of CARNITOR® were described by a two-compartment model. Following a single i.v.
administration, approximately 76% of the levocarnitine dose was excreted in the urine during the 0-24h
interval. Using plasma concentrations uncorrected for endogenous levocarnitine, the mean distribution half
life was 0.585 hours and the mean apparent terminal elimination half life was 17.4 hours.
The absolute bioavailability of levocarnitine from the two oral formulations of CARNITOR®, calculated
after correction for circulating endogenous plasma concentrations of levocarnitine, was 15.1 ± 5.3% for
CARNITOR® Tablets and 15.9 ± 4.9% for CARNITOR® Oral Solution.
Total body clearance of levocarnitine (Dose/AUC including endogenous baseline concentrations) was a
mean of 4.00 L/h.
Levocarnitine was not bound to plasma protein or albumin when tested at any concentration or with any
species including the human.9
METABOLISM AND EXCRETION
In a pharmacokinetic study where five normal adult male volunteers received an oral dose of [3H-methyl]-
L-carnitine following 15 days of a high carnitine diet and additional carnitine supplement, 58 to 65% of the
administered radioactive dose was recovered in the urine and feces in 5 to 11 days. Maximum
concentration of [3H-methyl]-L-carnitine in serum occurred from 2.0 to 4.5 hr after drug administration.
Major metabolites found were trimethylamine N-oxide, primarily in urine (8% to 49% of the administered
dose) and [3H]-γ-butyrobetaine, primarily in feces (0.44% to 45% of the administered dose). Urinary
excretion of levocarnitine was about 4 to 8% of the dose. Fecal excretion of total carnitine was less than
1% of the administered dose.10
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-948/S-022
NDA 19-257/S-010
NDA 20-182/S-008
Page 11
After attainment of steady state following 4 days of oral administration of CARNITOR® Tablets (1980 mg
q12h) or Oral Solution (2000 mg q12h) to 15 healthy male volunteers, the mean urinary excretion of
levocarnitine during a single dosing interval (12h) was about 9% of the orally administered dose
(uncorrected for endogenous urinary excretion).
INDICATIONS AND USAGE
CARNITOR® (levocarnitine) is indicated in the treatment of primary systemic carnitine deficiency. In the
reported cases, the clinical presentation consisted of recurrent episodes of Reye-like encephalopathy,
hypoketotic hypoglycemia, and/or cardiomyopathy. Associated symptoms included hypotonia, muscle
weakness and failure to thrive. A diagnosis of primary carnitine deficiency requires that serum, red cell
and/or tissue carnitine levels be low and that the patient does not have a primary defect in fatty acid or
organic acid oxidation (see Clinical Pharmacology). In some patients, particularly those presenting with
cardiomyopathy, carnitine supplementation rapidly alleviated signs and symptoms. Treatment should
include, in addition to carnitine, supportive and other therapy as indicated by the condition of the patient.
CARNITOR® (levocarnitine) is also indicated for acute and chronic treatment of patients with an inborn
error of metabolism which results in a secondary carnitine deficiency.
CONTRAINDICATIONS
None known.
WARNINGS
None.
PRECAUTIONS
General
CARNITOR® (levocarnitine) Oral Solution is for oral/internal use only.
Not for parenteral use.
Gastrointestinal reactions may result from a too rapid consumption of carnitine. CARNITOR®
(levocarnitine) Oral Solution may be consumed alone, or dissolved in drinks or other liquid foods to reduce
taste fatigue. It should be consumed slowly and doses should be spaced evenly throughout the day to
maximize tolerance.
The safety and efficacy of oral levocarnitine has not been evaluated in patients with renal insufficiency.
Chronic administration of high doses of oral levocarnitine in patients with severely compromised renal
function or in ESRD patients on dialysis may result in accumulation of the potentially toxic metabolites,
trimethylamine (TMA) and trimethylamine-N-oxide (TMAO), since these metabolites are normally
excreted in the urine.
Carcinogenesis, mutagenesis, impairment of fertility
Mutagenicity tests performed in Salmonella typhimurium, Saccharomyces cerevisiae, and
Schizosaccharomyces pombe indicate that levocarnitine is not mutagenic. No long-term animal studies
have been performed to evaluate the carcinogenic potential of levocarnitine.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-948/S-022
NDA 19-257/S-010
NDA 20-182/S-008
Page 12
Pregnancy
Pregnancy Category B.
Reproductive studies have been performed in rats and rabbits at doses up to 3.8 times the human dose on
the basis of surface area and have revealed no evidence of impaired fertility or harm to the fetus due to
CARNITOR®. There are, however, no adequate and well controlled studies in pregnant women.
Because animal reproduction studies are not always predictive of human response, this drug should be used
during pregnancy only if clearly needed.
Nursing Mothers
Levocarnitine supplementation in nursing mothers has not been specifically studied.
Studies in dairy cows indicate that the concentration of levocarnitine in milk is increased following
exogenous administration of levocarnitine. In nursing mothers receiving levocarnitine, any risks to the
child of excess carnitine intake need to be weighed against the benefits of levocarnitine supplementation to
the mother. Consideration may be given to discontinuation of nursing or of levocarnitine treatment.
Pediatric Use
See Dosage and Administration.
ADVERSE REACTIONS
Various mild gastrointestinal complaints have been reported during the long-term administration of oral L-
or D,L-carnitine; these include transient nausea and vomiting, abdominal cramps, and diarrhea. Mild
myasthenia has been described only in uremic patients receiving D,L-carnitine. Gastrointestinal adverse
reactions with CARNITOR® (levocarnitine) Oral Solution dissolved in liquids might be avoided by a slow
consumption of the solution or by a greater dilution. Decreasing the dosage often diminishes or eliminates
drug-related patient body odor or gastrointestinal symptoms when present. Tolerance should be monitored
very closely during the first week of administration, and after any dosage increases.
Seizures have been reported to occur in patients with or without pre-existing seizure activity receiving
either oral or intravenous levocarnitine. In patients with pre-existing seizure activity, an increase in seizure
frequency and/or severity has been reported.
OVERDOSAGE
There have been no reports of toxicity from levocarnitine overdosage. Levocarnitine is easily removed
from plasma by dialysis. The intravenous LD50 of levocarnitine in rats is 5.4 g/kg and the oral LD50 of
levocarnitine in mice is 19.2 g/kg. Large doses of levocarnitine may cause diarrhea.
DOSAGE AND ADMINISTRATION
CARNITOR® (levocarnitine) Tablets.
Adults: The recommended oral dosage for adults is 990 mg two or three times a day using the 330 mg
tablets, depending on clinical response.
Infants and children: The recommended oral dosage for infants and children is between 50 and 100
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-948/S-022
NDA 19-257/S-010
NDA 20-182/S-008
Page 13
mg/kg/day in divided doses, with a maximum of 3 g/day. Dosage should begin at 50 mg/kg/day. The exact
dosage will depend on clinical response.
Monitoring should include periodic blood chemistries, vital signs, plasma carnitine concentrations and
overall clinical condition.
CARNITOR® (levocarnitine) Oral Solution.
For oral use only. Not for parenteral use.
Adults: The recommended dosage of levocarnitine is 1 to 3 g/day for a 50 kg subject, which is
equivalent to 10 to 30 mL/day of CARNITOR® (levocarnitine) Oral Solution. Higher doses should be
administered only with caution and only where clinical and biochemical considerations make it seem
likely that higher doses will be of benefit. Dosage should start at 1 g/day, (10 mL/day), and be
increased slowly while assessing tolerance and therapeutic response. Monitoring should include
periodic blood chemistries, vital signs, plasma carnitine concentrations, and overall clinical condition.
Infants and children: The recommended dosage of levocarnitine is 50 to 100 mg/kg/day which is equivalent
to 0.5 mL/kg/day CARNITOR® (levocarnitine) Oral Solution. Higher doses should be administered only
with caution and only where clinical and biochemical considerations make it seem likely that higher doses
will be of benefit. Dosage should start at 50 mg/kg/day, and be increased slowly to a maximum of 3 g/day
(30 mL/day) while assessing tolerance and therapeutic response. Monitoring should include periodic blood
chemistries, vital signs, plasma carnitine concentrations, and overall clinical condition.
CARNITOR® (levocarnitine) Oral Solution may be consumed alone or dissolved in drink or other liquid
food. Doses should be spaced evenly throughout the day (every three or four hours) preferably during or
following meals and should be consumed slowly in order to maximize tolerance.
HOW SUPPLIED
CARNITOR® (levocarnitine) Tablets are supplied as 330 mg tablets embossed with “CARNITOR ST” in
individual blisters, packaged in boxes of 90 (NDC 54482-144-07). Store at controlled room temperature
(25°C). See USP.
CARNITOR® (levocarnitine) Oral Solution is supplied in 118 mL (4 FL. OZ.) multiple-unit plastic
containers. The multiple-unit containers are packaged 24 per case (NDC 54482-145-08). Store at
controlled room temperature (25°C). See USP. CARNITOR® (levocarnitine) Oral Solution is manufactured
for Sigma-Tau Pharmaceuticals, Inc. by: Alpharma USPD, Inc. Baltimore, MD 21244-2654 and/or Hi-Tech
Pharmacal Co., Inc. Amityville, NY 11701.
CARNITOR® (levocarnitine) is also available in the following dosage forms for intravenous injection:
CARNITOR® (levocarnitine) Injection is available in 1 g per 5 mL single dose vials packaged 5 vials per
carton (NDC 54482-147-01). CARNITOR® (levocarnitine) Injection 5 mL vial is manufactured for Sigma-
Tau Pharmaceuticals, Inc. by Chesapeake Biological Laboratories, Inc. Baltimore, MD 21230-2591.
CARNITOR® (levocarnitine) Injection is also available in 1 g per 5 mL single dose ampoules packaged 5
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-948/S-022
NDA 19-257/S-010
NDA 20-182/S-008
Page 14
ampoules per carton (NDC 54482-146-09). Made in Italy.
Rx only.
REFERENCES
11. Bohmer, T., Rydning, A. and Solberg, H.E. 1974. Carnitine levels in human serum in health and
disease. Clin. Chim. Acta 57:55-61.
12. Brooks, H., Goldberg, L., Holland, R. et al. 1977. Carnitine-induced effects on cardiac and
peripheral hemodynamics. J. Clin. Pharmacol. 17:561-568.
13. Christiansen, R., Bremer, J. 1976. Active transport of butyrobetaine and carnitine into isolated liver
cells. Biochim. Biophys. Acta 448:562-577.
14. Lindstedt, S. and Lindstedt, G. 1961. Distribution and excretion of carnitine in the rat. Acta Chem.
Scand. 15:701-702.
15. Rebouche, C.J. and Engel, A.G. 1983. Carnitine metabolism and deficiency syndromes. Mayo Clin.
Proc. 58:533-540.
16. Rebouche, C.J. and Paulson, D.J. 1986. Carnitine metabolism and function in humans. Ann. Rev.
Nutr. 6:41-66.
17. Scriver, C.R., Beaudet, A.L., Sly, W.S. and Valle, D. 1989. The Metabolic Basis of Inherited
Disease. New York: McGraw-Hill.
18. Schaub, J., Van Hoof, F. and Vis, H.L. 1991. Inborn Errors of Metabolism. New York: Raven
Press.
19. Marzo, A., Arrigoni Martelli, E., Mancinelli, A., Cardace, G., Corbelletta, C., Bassani, E. and
Solbiati, M. 1991. Protein binding of L-carnitine family components. Eur. J. Drug Met.
Pharmacokin., Special Issue III: 364-368.
20. Rebouche, C.J. 1991. Quantitative estimation of absorption and degradation of a carnitine
supplement by human adults. Metabolism 40:1305-1310.
Manufactured by: Alpharma USPD,
Inc. Baltimore, MD 21244-2654 for
Sigma-Tau
Pharmaceuticals,
Inc.
sigma-tau
Pharmaceuticals,
Inc.
Gaithersburg, MD 20877
PREVIOUS EDITION IS OBSOLETE
Date of Issue: 03/02 OPI(A)-5-E
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-948/S-022
NDA 19-257/S-010
NDA 20-182/S-008
Page 15
C A R N I T O R
®
(levocarnitine)
CARNITOR® (levocarnitine) Injection 1 g per 5 mL vial
FOR INTRAVENOUS USE ONLY.
DESCRIPTION
CARNITOR® (levocarnitine) is a carrier molecule in the transport of long-chain fatty acids across the inner
mitochondrial membrane.
The chemical name of levocarnitine is 3-carboxy-2(R)-hydroxy-N,N,N-trimethyl-1-propanaminium, inner
salt. Levocarnitine is a white crystalline, hygroscopic powder. It is readily soluble in water, hot alcohol, and
insoluble in acetone. The specific rotation of levocarnitine is between -29° and -32°. Its chemical structure
is:
C
H
O
H
CH2
CH2COO
(CH3)3N
-
+
Empirical Formula:
C7H15NO3
Molecular Weight:
161.20
CARNITOR® (levocarnitine) Injection is a sterile aqueous solution containing 1 g of levocarnitine per 5
mL vial. The pH is adjusted to 6.0 - 6.5 with hydrochloric acid or sodium hydroxide.
CLINICAL PHARMACOLOGY
CARNITOR® (levocarnitine) is a naturally occurring substance required in mammalian energy metabolism.
It has been shown to facilitate long-chain fatty acid entry into cellular mitochondria, thereby delivering
substrate for oxidation and subsequent energy production. Fatty acids are utilized as an energy substrate in
all tissues except the brain. In skeletal and cardiac muscle, fatty acids are the main substrate for energy
production.
Primary systemic carnitine deficiency is characterized by low concentrations of levocarnitine in plasma,
RBC, and/or tissues. It has not been possible to determine which symptoms are due to carnitine deficiency
and which are due to an underlying organic acidemia, as symptoms of both abnormalities may be expected
to improve with CARNITOR®. The literature reports that carnitine can promote the excretion of excess
organic or fatty acids in patients with defects in fatty acid metabolism and/or specific organic acidopathies
that bioaccumulate acylCoA esters.1-6
Secondary carnitine deficiency can be a consequence of inborn errors of metabolism or iatrogenic factors
such as hemodialysis. CARNITOR® may alleviate the metabolic abnormalities of patients with inborn
errors that result in accumulation of toxic organic acids. Conditions for which this effect has been
demonstrated are: glutaric aciduria II, methyl malonic aciduria, propionic acidemia, and medium chain
fatty acylCoA dehydrogenase deficiency.7,8 Autointoxication occurs in these patients due to the
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-948/S-022
NDA 19-257/S-010
NDA 20-182/S-008
Page 16
accumulations of acylCoA compounds that disrupt intermediary metabolism. The subsequent hydrolysis of
the acylCoA compound to its free acid results in acidosis which can be life-threatening. Levocarnitine
clears the acylCoA compound by formation of acylcarnitine, which is quickly excreted. Carnitine
deficiency is defined biochemically as abnormally low plasma concentrations of free carnitine, less than 20
µmol/L at one week post term and may be associated with low tissue and/or urine concentrations. Further,
this condition may be associated with a plasma concentration ratio of acylcarnitine/levocarnitine greater
than 0.4 or abnormally elevated concentrations of acylcarnitine in the urine. In premature infants and
newborns, secondary deficiency is defined as plasma levocarnitine concentrations below age-related
normal concentrations.
End Stage Renal Disease (ESRD) patients on maintenance hemodialysis may have low plasma carnitine
concentrations and an increased ratio of acylcarnitine/carnitine because of reduced intake of meat and dairy
products, reduced renal synthesis and dialytic losses. Certain clinical conditions common in hemodialysis
patients such as malaise, muscle weakness, cardiomyopathy and cardiac arrhythmias may be related to
abnormal carnitine metabolism.
Pharmacokinetic and clinical studies with CARNITOR® have shown that administration of levocarnitine to
ESRD patients on hemodialysis results in increased plasma levocarnitine concentrations.
PHARMACOKINETICS
In a relative bioavailability study in 15 healthy adult male volunteers, CARNITOR® Tablets were found to
be bio-equivalent to CARNITOR® Oral Solution. Following 4 days of dosing with 6 tablets of
CARNITOR® 330 mg b.i.d. or 2 g of CARNITOR® oral solution b.i.d., the maximum plasma concentration
(Cmax) was about 80 µmol/L and the time to maximum plasma concentration (Tmax) occurred at 3.3 hours.
The plasma concentration profiles of levocarnitine after a slow 3 minute intravenous bolus dose of 20
mg/kg of CARNITOR® were described by a two-compartment model. Following a single i.v.
administration, approximately 76% of the levocarnitine dose was excreted in the urine during the 0-24h
interval. Using plasma concentrations uncorrected for endogenous levocarnitine, the mean distribution half
life was 0.585 hours and the mean apparent terminal elimination half life was 17.4 hours.
The absolute bioavailability of levocarnitine from the two oral formulations of CARNITOR®, calculated
after correction for circulating endogenous plasma concentrations of levocarnitine, was 15.1 ± 5.3% for
CARNITOR® Tablets and 15.9 ± 4.9% for CARNITOR® Oral Solution.
Total body clearance of levocarnitine (Dose/AUC including endogenous baseline concentrations) was a
mean of 4.00 L/h.
Levocarnitine was not bound to plasma protein or albumin when tested at any concentration or with any
species including the human.9
In a 9-week study, 12 ESRD patients undergoing hemodialysis for at least 6 months received CARNITOR®
20 mg/kg three times per week after dialysis. Prior to initiation of CARNITOR® therapy, mean plasma
levocarnitine concentrations were approximately 20 µmol/L pre-dialysis and 6 µmol/L post-dialysis. The
table summarizes the pharmacokinetic data (mean ± SD µmol/L) after the first dose of CARNITOR® and
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NDA 19-257/S-010
NDA 20-182/S-008
Page 17
after 8 weeks of CARNITOR® therapy.
N=12
Baseline
Single dose
8 weeks
Cmax
-
1139 ± 240
1190 ± 270
Trough (pre-
dialysis, pre-dose) 21.3 ± 7.7
68.4 ± 26.1
190 ± 55
After one week of CARNITOR® therapy (3 doses), all patients had trough concentrations between 54 and
180 µmol/L (normal 40-50 µmol/L) and concentrations remained relatively stable or increased over the
course of the study.
In a similar study in ESRD patients also receiving 20 mg/kg CARNITOR® 3 times per week after
hemodialysis, 12- and 24-week mean pre-dialysis (trough) levocarnitine concentrations were 189 (N=25)
and 243 (N=23) µmol/L, respectively.
In a dose-ranging study in ESRD patients undergoing hemodialysis, patients received 10, 20, or 40 mg/kg
CARNITOR® 3 times per week following dialysis (N~30 for each dose group). Mean ± SD trough
levocarnitine concentrations (µmol/L) by dose after 12 and 24 weeks of therapy are summarized in the
table.
12 weeks
24 weeks
10 mg/kg
116 ± 69
148 ± 50
20 mg/kg
210 ± 58
240 ± 60
40 mg/kg
371 ± 111
456 ± 162
While the efficacy of CARNITOR® to increase carnitine concentrations in patients with ESRD undergoing
dialysis has been demonstrated, the effects of supplemental carnitine on the signs and symptoms of
carnitine deficiency and on clinical outcomes in this population have not been determined.
METABOLISM AND EXCRETION
In a pharmacokinetic study where five normal adult male volunteers received an oral dose of [3H-methyl]-
L-carnitine following 15 days of a high carnitine diet and additional carnitine supplement, 58 to 65% of the
administered radioactive dose was recovered in the urine and feces in 5 to 11 days. Maximum
concentration of [3H-methyl]-L-carnitine in serum occurred from 2.0 to 4.5 hr after drug administration.
Major metabolites found were trimethylamine N-oxide, primarily in urine (8% to 49% of the administered
dose) and [3H]- -butyrobetaine, primarily in feces (0.44% to 45% of the administered dose). Urinary
excretion of levocarnitine was about 4 to 8% of the dose. Fecal excretion of total carnitine was less than
1% of the administered dose.10
After attainment of steady state following 4 days of oral administration of CARNITOR® Tablets (1980 mg
q12h) or Oral Solution (2000 mg q12h) to 15 healthy male volunteers, the mean urinary excretion of
levocarnitine during a single dosing interval (12h) was about 9% of the orally administered dose
(uncorrected for endogenous urinary excretion).
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-948/S-022
NDA 19-257/S-010
NDA 20-182/S-008
Page 18
INDICATIONS AND USAGE
For the acute and chronic treatment of patients with an inborn error of metabolism which results in
secondary carnitine deficiency.
For the prevention and treatment of carnitine deficiency in patients with end stage renal disease who are
undergoing dialysis.
CONTRAINDICATIONS
None known.
WARNINGS
None.
PRECAUTIONS
The safety and efficacy of oral levocarnitine has not been evaluated in patients with renal insufficiency.
Chronic administration of high doses of oral levocarnitine in patients with severely compromised renal
function or in ESRD patients on dialysis may result in accumulation of the potentially toxic metabolites,
trimethylamine (TMA) and trimethylamine-N-oxide (TMAO), since these metabolites are normally
excreted in the urine.
Carcinogenesis, mutagenesis, impairment of fertility
Mutagenicity tests performed in Salmonella typhimurium, Saccharomyces cerevisiae, and
Schizosaccharomyces pombe indicate that levocarnitine is not mutagenic. No long-term animal studies
have been performed to evaluate the carcinogenic potential of levocarnitine.
Pregnancy
Pregnancy Category B.
Reproductive studies have been performed in rats and rabbits at doses up to 3.8 times the human dose on
the basis of surface area and have revealed no evidence of impaired fertility or harm to the fetus due to
CARNITOR®. There are, however, no adequate and well controlled studies in pregnant women.
Because animal reproduction studies are not always predictive of human response, this drug should be used
during pregnancy only if clearly needed.
Nursing Mothers
Levocarnitine supplementation in nursing mothers has not been specifically studied.
Studies in dairy cows indicate that the concentration of levocarnitine in milk is increased following
exogenous administration of levocarnitine. In nursing mothers receiving levocarnitine, any risks to the
child of excess carnitine intake need to be weighed against the benefits of levocarnitine supplementation to
the mother. Consideration may be given to discontinuation of nursing or of levocarnitine treatment.
Pediatric Use
See Dosage and Administration.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-948/S-022
NDA 19-257/S-010
NDA 20-182/S-008
Page 19
ADVERSE REACTIONS
Transient nausea and vomiting have been observed. Less frequent adverse reactions are body odor, nausea,
and gastritis. An incidence for these reactions is difficult to estimate due to the confounding effects of the
underlying pathology.
Seizures have been reported to occur in patients, with or without pre-existing seizure activity, receiving
either oral or intravenous levocarnitine. In patients with pre-existing seizure activity, an increase in seizure
frequency and/or severity has been reported.
The table below lists the adverse events that have been reported in two double-blind, placebo-controlled
trials in patients on chronic hemodialysis. Events occurring at ≥5% are reported without regard to
causality.
Adverse Events with a Frequency ≥5% Regardless of Causality by Body System
Pla
ceb
o
(n=
63)
Levoca
rnitine
10 mg
(n=34)
Levoca
rnitine
20 mg
(n=62)
Levoca
rnitine
40 mg
(n=34)
Levoca
rnitine
10, 20
&
40 mg
(n=130
)
Body as Whole
Abdominal
pain
17
21
5
6
9
Accidental
injury
10
12
8
12
10
Allergic
reaction
5
6
2
Asthenia
8
9
8
12
9
Back pain
10
9
8
6
8
Chest pain
14
6
15
12
12
Fever
5
6
5
12
7
Flu syndrome
40
15
27
29
25
Headache
16
12
37
3
22
Infection
17
15
10
24
15
Injection site
reaction
59
38
27
38
33
Pain
49
21
32
35
30
Cardiovascular
Arrhythmia
5
3
3
2
Atrial
fibrillation
2
6
2
Cardiovascula
r disorder
6
3
5
6
5
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-948/S-022
NDA 19-257/S-010
NDA 20-182/S-008
Page 20
Pla
ceb
o
(n=
63)
Levoca
rnitine
10 mg
(n=34)
Levoca
rnitine
20 mg
(n=62)
Levoca
rnitine
40 mg
(n=34)
Levoca
rnitine
10, 20
&
40 mg
(n=130
)
Electrocardiog
ram abnormal
3
6
2
Hemorrhage
6
9
2
3
4
Hypertension
14
18
21
21
20
Hypotension
19
15
19
3
14
Palpitations
3
8
5
Tachycardia
5
6
5
9
6
Vascular
disorder
2
2
6
2
Digestive
Anorexia
3
3
5
6
5
Constipation
6
3
3
3
3
Diarrhea
19
9
10
35
16
Dyspepsia
10
9
6
5
Gastrointestin
al disorder
2
3
6
2
Melena
3
6
2
Nausea
10
9
5
12
8
Stomach atony
5
Vomiting
16
9
16
21
15
Endocrine
System
Parathyroid
disorder
2
6
2
6
4
Hemic/Lympha
tic
Anemia
3
3
5
12
6
Metabolic/Nutr
itional
Hypercalcemia
3
15
8
6
9
Hyperkalemia
6
6
6
6
6
Hypervolemia
17
3
3
12
5
Peripheral
edema
3
6
5
3
5
Weight
decrease
3
3
8
3
5
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-948/S-022
NDA 19-257/S-010
NDA 20-182/S-008
Page 21
Pla
ceb
o
(n=
63)
Levoca
rnitine
10 mg
(n=34)
Levoca
rnitine
20 mg
(n=62)
Levoca
rnitine
40 mg
(n=34)
Levoca
rnitine
10, 20
&
40 mg
(n=130
)
Weight
increase
2
3
6
2
Musculo-
Skeletal
Leg cramps
13
8
4
Myalgia
6
Nervous
Anxiety
5
2
1
Depression
3
6
5
6
5
Dizziness
11
18
10
15
13
Drug
dependence
2
6
2
Hypertonia
5
3
1
Insomnia
6
3
6
4
Paresthesia
3
3
3
12
5
Vertigo
6
2
Respiratory
Bronchitis
5
3
3
Cough
increase
16
10
18
9
Dyspnea
19
3
11
3
7
Pharyngitis
33
24
27
15
23
Respiratory
disorder
5
Rhinitis
10
6
11
6
9
Sinusitis
5
2
3
2
Skin And
Appendages
Pruritus
13
8
3
5
Rash
3
5
3
3
Special Senses
Amblyopia
2
6
3
Eye disorder
3
6
3
3
Taste
perversion
2
9
3
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-948/S-022
NDA 19-257/S-010
NDA 20-182/S-008
Page 22
Pla
ceb
o
(n=
63)
Levoca
rnitine
10 mg
(n=34)
Levoca
rnitine
20 mg
(n=62)
Levoca
rnitine
40 mg
(n=34)
Levoca
rnitine
10, 20
&
40 mg
(n=130
)
Urogenital
Urinary tract
infect
6
3
3
2
Kidney failure
5
6
6
6
6
OVERDOSAGE
There have been no reports of toxicity from levocarnitine overdosage. Levocarnitine is easily removed
from plasma by dialysis. The intravenous LD50 of levocarnitine in rats is 5.4 g/kg and the oral LD50 of
levocarnitine in mice is 19.2 g/kg. Large doses of levocarnitine may cause diarrhea.
DOSAGE AND ADMINISTRATION
CARNITOR® Injection is administered intravenously.
Metabolic Disorders
The recommended dose is 50 mg/kg given as a slow 2-3 minute bolus injection or by infusion. Often a
loading dose is given in patients with severe metabolic crisis, followed by an equivalent dose over the
following 24 hours. It should be administered q3h or q4h, and never less than q6h either by infusion or by
intravenous injection. All subsequent daily doses are recommended to be in the range of 50 mg/kg or as
therapy may require. The highest dose administered has been 300 mg/kg.
It is recommended that a plasma carnitine concentration be obtained prior to beginning this parenteral
therapy. Weekly and monthly monitoring is recommended as well. This monitoring should include blood
chemistries, vital signs, plasma carnitine concentrations (the plasma free carnitine concentration should be
between 35 and 60 µmol/L) and overall clinical condition.
ESRD Patients on Hemodialysis
The recommended starting dose is 10-20 mg/kg dry body weight as a slow 2-3 minute bolus injection into
the venous return line after each dialysis session. Initiation of therapy may be prompted by trough (pre-
dialysis) plasma levocarnitine concentrations that are below normal (40-50 µmol/L). Dose adjustments
should be guided by trough (pre-dialysis) levocarnitine concentrations, and downward dose adjustments
(e.g. to 5 mg/kg after dialysis) may be made as early as the third or fourth week of therapy.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration, whenever solution and container permit.
COMPATIBILITY AND STABILITY
CARNITOR® Injection is compatible and stable when mixed in parenteral solutions of Sodium Chloride
0.9% or Lactated Ringer's in concentrations ranging from 250 mg/500 mL (0.5 mg/mL) to 4200 mg/500
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-948/S-022
NDA 19-257/S-010
NDA 20-182/S-008
Page 23
mL (8.0 mg/mL) and stored at room temperature (25°C) for up to 24 hours in PVC plastic bags.
HOW SUPPLIED
CARNITOR® (levocarnitine) Injection is available in 1 g per 5 mL single dose vials packaged 5 vials per
carton (NDC 54482-147-01). CARNITOR® (levocarnitine) Injection 5 mL vial is manufactured for Sigma-
Tau Pharmaceuticals, Inc. by Chesapeake Biological Laboratories, Inc. Baltimore, MD 21230-2591.
Store vials at controlled room temperature (25°C). See USP. Discard unused portion of an opened vial, as
the formulation does not contain a preservative.
CARNITOR® (levocarnitine) is also available in the following dosage forms:
CARNITOR® (levocarnitine) Injection is available in 1 g per 5 mL single dose ampoules packaged 5
ampoules per carton (NDC 54482-146-09). Made in Italy.
CARNITOR® (levocarnitine) Tablets are supplied as 330 mg tablets embossed with “CARNITOR ST” in
blister packages, in boxes of 90 tablets (NDC 54482-144-07). Made in Italy.
CARNITOR® (levocarnitine) Oral Solution is supplied in 118 mL (4 FL. OZ.) multiple-unit plastic
containers. The multiple-unit containers are packaged 24 per case (NDC 54482-145-08). CARNITOR®
(levocarnitine) Oral Solution is manufactured for Sigma-Tau Pharmaceuticals, Inc. by Alpharma USPD,
Inc., Baltimore, MD 21244-2654 and/or Hi-Tech Pharmacal Co., Inc., Amityville, NY 11701.
Rx only.
REFERENCES
1. Bohmer, T., Rydning, A. and Solberg, H.E. 1974. Carnitine levels in human serum in health and
disease. Clin. Chim. Acta 57:55-61.
2. Brooks, H., Goldberg, L., Holland, R. et al. 1977. Carnitine-induced effects on cardiac and
peripheral hemodynamics. J. Clin. Pharmacol. 17:561-568.
3. Christiansen, R., Bremer, J. 1976. Active transport of butyrobetaine and carnitine into isolated liver
cells.
Biochim. Biophys. Acta 448:562-577.
4. Lindstedt, S. and Lindstedt, G. 1961. Distribution and excretion of carnitine in the rat. Acta Chem.
Scand. 15:701-702.
5. Rebouche, C.J. and Engel, A.G. 1983. Carnitine metabolism and deficiency syndromes. Mayo Clin.
Proc. 58:533-540.
6. Rebouche, C.J. and Paulson, D.J. 1986. Carnitine metabolism and function in humans. Ann. Rev.
Nutr. 6:41-66.
7. Scriver, C.R., Beaudet, A.L., Sly, W.S. and Valle, D. 1989. The Metabolic Basis of Inherited
Disease. New York: McGraw-Hill.
8. Schaub, J., Van Hoof, F. and Vis, H.L. 1991. Inborn Errors of Metabolism. New York: Raven
Press.
9. Marzo, A., Arrigoni Martelli, E., Mancinelli, A., Cardace, G., Corbelletta, C., Bassani, E. and
Solbiati, M. 1991. Protein binding of L-carnitine family components. Eur. J. Drug Met.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-948/S-022
NDA 19-257/S-010
NDA 20-182/S-008
Page 24
Pharmacokin., Special Issue III: 364-368.
10. Rebouche, C.J. 1991. Quantitative estimation of absorption and degradation of a carnitine
supplement by human adults. Metabolism 40:1305-1310.
Manufactured by: Chesapeake
Biological
Laboratories,
Inc.
Baltimore, MD 21230-2591 for
Sigma-Tau Pharmaceuticals, Inc.
s i g m a - t a u
Pharmaceuticals, Inc.
Gaithersburg, MD 20877
PREVIOUS EDITION IS OBSOLETE
Date of Issue: 03/02 VPI-6-E
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
---------------------------------------------------------------------------------------------------------------------
This is a representation of an electronic record that was signed electronically and
this page is the manifestation of the electronic signature.
---------------------------------------------------------------------------------------------------------------------
/s/
---------------------
David Orloff
4/15/02 10:21:38 AM
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:47:00.361897
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2002/18948S22lbl.pdf', 'application_number': 20182, 'submission_type': 'SUPPL ', 'submission_number': 8}
|
12,306
|
NDA 20-184/S-011
Page 3
ACEON®
(perindopril erbumine) Tablets
500063/500064 Rev May 2005
USE IN PREGNANCY
When used in pregnancy during the second and third trimesters, ACE inhibitors can cause injury and
even death to the developing fetus. When pregnancy is detected, ACEON® Tablets should be
discontinued as soon as possible. See WARNINGS: Fetal/Neonatal Morbidity and Mortality.
DESCRIPTION
ACEON® (perindopril erbumine) Tablets is the tert-butylamine salt of perindopril, the ethyl ester of a
non-sulfhydryl angiotensin-converting enzyme (ACE) inhibitor. Perindopril erbumine is chemically
described as (2S,3∝S,7∝S)-1-[(S)-N-[(S)-1-Carboxy-butyl]alanyl]hexahydro-2-indolinecarboxylic
acid, 1-ethyl ester, compound with tert-butylamine (1:1). Its molecular formula is C19H32N2O5C4H11N.
Its structural formula is:
Perindopril erbumine is a white, crystalline powder with a molecular weight of 368.47 (free acid) or
441.61 (salt form). It is freely soluble in water (60% w/w), alcohol and chloroform.
Perindopril is the free acid form of perindopril erbumine, is a pro-drug and metabolized in vivo by
hydrolysis of the ester group to form perindoprilat, the biologically active metabolite.
ACEON® Tablets is available in 2 mg, 4 mg and 8 mg strengths for oral administration. In addition
to perindopril erbumine, each tablet contains the following inactive ingredients: colloidal silica
(hydrophobic), lactose, magnesium stearate and microcrystalline cellulose. The 4 and 8 mg tablets
also contain iron oxide.
CLINICAL PHARMACOLOGY
Mechanism of Action: ACEON® (perindopril erbumine) Tablets is a pro-drug for perindoprilat,
which inhibits ACE in human subjects and animals. The mechanism through which perindoprilat
lowers blood pressure is believed to be primarily inhibition of ACE activity. ACE is a peptidyl
dipeptidase that catalyzes conversion of the inactive decapeptide, angiotensin I, to the vasoconstrictor,
angiotensin II. Angiotensin II is a potent peripheral vasoconstrictor, which stimulates aldosterone
secretion by the adrenal cortex, and provides negative feedback on renin secretion. Inhibition of ACE
results in decreased plasma angiotensin II, leading to decreased vasoconstriction, increased plasma
renin activity and decreased aldosterone secretion. The latter results in diuresis and natriuresis and
may be associated with a small increase of serum potassium.
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ACE is identical to kininase II, an enzyme that degrades bradykinin. Whether increased levels of
bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effects of ACEON® Tablets
remains to be elucidated.
While the principal mechanism of perindopril in blood pressure reduction is believed to be through
the renin-angiotensin-aldosterone system, ACE inhibitors have some effect even in apparent low-renin
hypertension. Perindopril has been studied in relatively few black patients, usually a low-renin
population, and the average response of diastolic blood pressure to perindopril was about half the
response seen in nonblacks, a finding consistent with previous experience of other ACE inhibitors.
After administration of perindopril, ACE is inhibited in a dose and blood concentration-related
fashion, with the maximal inhibition of 80 to 90% attained by 8 mg persisting for 10 to 12 hours.
Twenty-four hour ACE inhibition is about 60% after these doses. The degree of ACE inhibition
achieved by a given dose appears to diminish over time (the ID50 increases). The pressor response to
an angiotensin I infusion is reduced by perindopril, but this effect is not as persistent as the effect on
ACE; there is about 35% inhibition at 24 hours after a 12 mg dose.
Pharmacokinetics: Oral administration of ACEON® (perindopril erbumine) Tablets results in its
rapid absorption with peak plasma concentrations occurring at approximately 1 hour. The absolute
oral bioavailability of perindopril is about 75%. Following absorption, approximately 30 to 50% of
systemically available perindopril is hydrolyzed to its active metabolite, perindoprilat, which has a
mean bioavailability of about 25%. Peak plasma concentrations of perindoprilat are attained 3 to 7
hours after perindopril administration. The presence of food in the gastrointestinal tract does not affect
the rate or extent of absorption of perindopril but reduces bioavailability of perindoprilat by about
35%. (See PRECAUTIONS: Food Interaction.)
With 4, 8 and 16 mg doses of ACEON® Tablets, Cmax and AUC of perindopril and perindoprilat
increase in a linear and dose-proportional manner following both single oral dosing and at steady state
during a once-a-day multiple dosing regimen.
Perindopril exhibits multiexponential pharmacokinetics following oral administration. The mean
half-life of perindopril associated with most of its elimination is approximately 0.8 to 1.0 hours. At
very low plasma concentrations of perindopril (<3 ng/mL), there is a prolonged terminal elimination
half-life, similar to that seen with other ACE inhibitors, that results from slow dissociation of
perindopril from plasma/tissue ACE binding sites. Perindopril does not accumulate with a once-a-day
multiple dosing regimen. Mean total body clearance of perindopril is 219 to 362 mL/min and its mean
renal clearance is 23.3 to 28.6 mL/min.
Perindopril is extensively metabolized following oral administration, with only 4 to 12% of the dose
recovered unchanged in the urine. Six metabolites resulting from hydrolysis, glucuronidation and
cyclization via dehydration have been identified. These include the active ACE inhibitor, perindoprilat
(hydrolyzed perindopril), perindopril and perindoprilat glucuronides, dehydrated perindopril and the
diastereoisomers of dehydrated perindoprilat. In humans, hepatic esterase appears to be responsible
for the hydrolysis of perindopril.
The active metabolite, perindoprilat, also exhibits multiexponential pharmacokinetics following the
oral administration of ACEON® Tablets. Formation of perindoprilat is gradual with peak plasma
concentrations occurring between 3 and 7 hours. The subsequent decline in plasma concentration
shows an apparent mean half-life of 3 to 10 hours for the majority of the elimination, with a prolonged
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terminal elimination half-life of 30 to 120 hours resulting from slow dissociation of perindoprilat from
plasma/tissue ACE binding sites. During repeated oral once-daily dosing with perindopril,
perindoprilat accumulates about 1.5 to 2.0 fold and attains steady state plasma levels in 3 to 6 days.
The clearance of perindoprilat and its metabolites is almost exclusively renal.
Approximately 60% of circulating perindopril is bound to plasma proteins, and only 10 to 20% of
perindoprilat is bound. Therefore, drug interactions mediated through effects on protein binding are
not anticipated.
At usual antihypertensive dosages, little radioactivity (<5% of the dose) was distributed to the brain
after administration of 14C-perindopril to rats.
Radioactivity was detectable in fetuses and in milk after administration of 14C-perindopril to
pregnant and lactating rats.
Elderly Patients: Plasma concentrations of both perindopril and perindoprilat in elderly patients (>70
yrs) are approximately twice those observed in younger patients, reflecting both increased conversion
of perindopril to perindoprilat and decreased renal excretion of perindoprilat. (See PRECAUTIONS:
Geriatric Use.)
Heart Failure Patients: Perindoprilat clearance is reduced in congestive heart failure patients,
resulting in a 40% higher dose interval AUC. (See DOSAGE AND ADMINISTRATION.)
Patients with Renal Insufficiency: With perindopril erbumine doses of 2 to 4 mg, perindoprilat AUC
increases with decreasing renal function. At creatinine clearances of 30 to 80 mL/min, AUC is about
double that of 100 mL/min. When creatinine clearance drops below 30 mL/min, AUC increases more
markedly.
In a limited number of patients studied, perindopril dialysis clearance ranged from 41.7 to 76.7
mL/min (mean 52.0 mL/min). Perindoprilat dialysis clearance ranged from 37.4 to 91.0 mL/min
(mean 67.2 mL/min). (See DOSAGE AND ADMINISTRATION.)
Patients with Hepatic Insufficiency: The bioavailability of perindoprilat is increased in patients with
impaired hepatic function. Plasma concentrations of perindoprilat in patients with impaired liver
function were about 50% higher than those observed in healthy subjects or hypertensive patients with
normal liver function.
Pharmacodynamics and Clinical Effects:
Stable Coronary Artery Disease
The EURopean trial On reduction of cardiac events with Perindopril in stable coronary Artery disease
(EUROPA) was a multicenter, randomized, double-blind and placebo-controlled study conducted in
12,218 patients who had evidence of stable coronary artery disease without clinical heart failure.
Patients had evidence of coronary artery disease documented by previous myocardial infarction more
than 3 months before screening, coronary revascularization more than 6 months before screening,
angiographic evidence of stenosis (at least 70% narrowing of one or more major coronary arteries), or
positive stress test in men with a history of chest pain. After a run-in period of 4 weeks during which
all patients received perindopril 2 mg to 8 mg, the patients were randomly assigned to perindopril 8 mg
once daily (n=6,110) or matching placebo (n=6,108). The mean follow-up was 4.2 years. The study
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examined the long-term effects of perindopril on time to first event of cardiovascular mortality, non-
fatal myocardial infarction, or cardiac arrest in patients with stable coronary artery disease.
The mean age of patients was 60 years; 85% were male, 92% were taking platelet inhibitors, 63%
were taking β blockers, and 56% were taking lipid-lowering therapy. The EUROPA study showed that
perindopril significantly reduced the relative risk for the primary endpoint events (Table 1). This
beneficial effect is largely attributable to a reduction in the risk of non-fatal myocardial infarction.
This beneficial effect of perindopril on the primary outcome was evident after about one year of
treatment (Figure 1).
Table 1. Primary Endpoint and Relative Risk Reduction
Perindopril
(N = 6,110)
Placebo
(N = 6,108)
RRR
(95% CI)
P
Combined Endpoint
Cardiovascular mortality, non-fatal MI
or cardiac arrest
Component Endpoint
Cardiovascular mortality
Non-fatal MI
Cardiac arrest
488 (8.0%)
215 (3.5%)
295 (4.8%)
6 (0.1%)
603 (9.9%)
249 (4.1%)
378 (6.2%)
11 (0.2%)
20% (9 to 29)
14% (-3 to 28)
22% (10 to 33)
46% (-47 to 80)
0.0003
0.107
0.001
0.22
RRR: relative risk reduction; MI: myocardial infarction
The outcome was similar across all predefined subgroups by age, underlying disease or concomitant
medication (Figure 2).
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Figure 1. Time to First Occurrence of Primary Endpoint
Proportion who had cardiovascular mortality,
non-fatal MI, or cardiac arrest
Proportion who had cardiovascular mortality,
non-fatal MI, or cardiac arrest
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Figure 2. Beneficial Effect of Perindopril Treatment on Primary Endpoint
in Predefined Subgroups
Previous revascularization
No previous revascularization
Favors
perindopril
Favors
placebo
Previous revascularization
No previous revascularization
Favors
perindopril
Favors
placebo
Size of squares proportional to the number of patients in that group. Dashed line indicates overall relative risk.
Hypertension
In placebo-controlled studies of perindopril monotherapy (2 to 16 mg q.d.) in patients with a mean
blood pressure of about 150/100 mm Hg, 2 mg had little effect, but doses of 4 to 16 mg lowered blood
pressure. The 8 and 16 mg doses were indistinguishable, and both had a greater effect than the 4 mg
dose. The magnitude of the blood pressure effect was similar in the standing and supine positions,
generally about 1 mm Hg greater on standing. In these studies, doses of 8 and 16 mg per day gave
supine, trough blood pressure reductions of 9 to 15/5 to 6 mm Hg. When once-daily and twice-daily
dosing were compared, the B.I.D. regimen was generally slightly superior, but by not more than about
0.5 to 1 mm Hg. After 2 to 16 mg doses of perindopril, the trough mean systolic and diastolic blood
pressure effects were approximately equal to the peak effects (measured 3 to 7 hours after dosing.).
Trough effects were about 75 to 100% of peak effects. When perindopril was given to patients
receiving 25 mg HCTZ, it had an added effect similar in magnitude to its effect as monotherapy, but 2
to 8 mg doses were approximately equal in effectiveness. In general, the effect of perindopril occurred
promptly, with effects increasing slightly over several weeks.
In hemodynamic studies carried out in animal models of hypertension, blood pressure reduction
after perindopril administration was accompanied by a reduction in peripheral arterial resistance and
improved arterial wall compliance. In studies carried out in patients with essential hypertension, the
reduction in blood pressure was accompanied by a reduction in peripheral resistance with no
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significant changes in heart rate or glomerular filtration rate. An increase in the compliance of large
arteries was also observed, suggesting a direct effect on arterial smooth muscle, consistent with the
results of animal studies.
Formal interaction studies of ACEON® Tablets have not been carried out with antihypertensive
agents other than thiazides. Limited experience in controlled and uncontrolled trials coadministering
ACEON® Tablets with a calcium channel blocker, a loop diuretic or triple therapy (beta-blocker,
vasodilator and a diuretic), does not suggest any unexpected interactions. In general, ACE inhibitors
have less than additive effects when given with beta-adrenergic blockers, presumably because both
work in part through the renin angiotensin system. A controlled pharmacokinetic study has shown no
effect on plasma digoxin concentrations when coadministered with ACEON® Tablets. (See
PRECAUTIONS: Drug Interactions.)
In uncontrolled studies in patients with insulin-dependent diabetes, perindopril did not appear to
affect glycemic control. In long-term use, no effect on urinary protein excretion was seen in these
patients.
The effectiveness of ACEON® Tablets was not influenced by sex and it was less effective in blacks
than in nonblacks. In elderly patients (≥60 years), the mean blood pressure effect was somewhat
smaller than in younger patients, although the difference was not significant.
INDICATIONS AND USAGE
Stable Coronary Artery Disease
ACEON® (perindopril erbumine) Tablets is indicated in patients with stable coronary artery disease to
reduce the risk of cardiovascular mortality or non-fatal myocardial infarction. ACEON® Tablets can
be used with conventional treatment for management of coronary artery disease, such as antiplatelet,
antihypertensive or lipid-lowering therapy.
Hypertension
ACEON® (perindopril erbumine) Tablets is indicated for the treatment of patients with essential
hypertension. ACEON® Tablets may be used alone or given with other classes of antihypertensives,
especially thiazide diuretics.
When using ACEON® Tablets, consideration should be given to the fact that another angiotensin
converting enzyme inhibitor (captopril) has caused agranulocytosis, particularly in patients with renal
impairment or collagen vascular disease. Available data are insufficient to determine whether
ACEON® Tablets has a similar potential. (See WARNINGS.)
In considering use of ACEON® Tablets, it should be noted that in controlled trials ACE inhibitors
have an effect on blood pressure that is less in black patients than in nonblacks. In addition, it should
be noted that black patients receiving ACE inhibitor monotherapy have been reported to have a higher
incidence of angioedema compared to nonblacks. (See WARNINGS: Head and Neck Angioedema.)
CONTRAINDICATIONS
ACEON® (perindopril erbumine) Tablets is contraindicated in patients known to be hypersensitive to
this product or to any other ACE inhibitor. ACEON® Tablets is also contraindicated in patients with a
history of angioedema related to previous treatment with an ACE inhibitor.
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WARNINGS
Anaphylactoid and Possibly Related Reactions: Presumably because angiotensin-converting
enzyme inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous
bradykinin, patients receiving ACE inhibitors (including ACEON® Tablets) may be subject to a
variety of adverse reactions, some of them serious.
Head and Neck Angioedema: Angioedema involving the face, extremities, lips, tongue, glottis and/or
larynx has been reported in patients treated with ACE inhibitors, including ACEON® (perindopril
erbumine) Tablets (0.1% of patients treated with ACEON® Tablets in U.S. clinical trials). In such
cases, ACEON® Tablets should be promptly discontinued and the patient carefully observed until the
swelling disappears. In instances where swelling has been confined to the face and lips, the condition
has generally resolved without treatment, although antihistamines have been useful in relieving
symptoms. Angioedema associated with involvement of the tongue, glottis or larynx may be fatal due
to airway obstruction. Appropriate therapy, such as subcutaneous epinephrine solution 1:1000 (0.3 to
0.5 mL), should be promptly administered. Patients with a history of angioedema unrelated to ACE
inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor.
Intestinal Angioedema: Intestinal angioedema has been reported in patients treated with ACE
inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in
some cases there was no prior history of facial angioedema and C-1 esterase levels were normal. The
angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at surgery,
and symptoms resolved after stopping the ACE inhibitor. Intestinal angioedema should be included in
the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain.
Anaphylactoid Reactions During Desensitization: Two patients undergoing desensitizing treatment
with hymenoptera venom while receiving ACE inhibitors sustained life-threatening anaphylactoid
reactions. In the same patients, these reactions were avoided when ACE inhibitors were temporarily
withheld, but they reappeared upon inadvertent rechallenge.
Anaphylactoid Reactions During Membrane Exposure: Anaphylactoid reactions have been reported
in patients dialyzed with high-flux membranes and treated concomitantly with an ACE inhibitor.
Anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein
apheresis with dextran sulfate absorption.
Hypotension: Like other ACE inhibitors, ACEON® Tablets can cause symptomatic hypotension.
ACEON® Tablets has been associated with hypotension in 0.3% of uncomplicated hypertensive
patients in U.S. placebo-controlled trials. Symptoms related to orthostatic hypotension were reported
in another 0.8% of patients.
Symptomatic hypotension associated with the use of ACE inhibitors is more likely to occur in
patients who have been volume and/or salt-depleted, as a result of prolonged diuretic therapy, dietary
salt restriction, dialysis, diarrhea or vomiting. Volume and/or salt depletion should be corrected before
initiating therapy with ACEON® Tablets. (See DOSAGE AND ADMINISTRATION.)
In patients with congestive heart failure, with or without associated renal insufficiency, ACE
inhibitors may cause excessive hypotension, and may be associated with oliguria or azotemia, and
rarely with acute renal failure and death. In patients with ischemic heart disease or cerebrovascular
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disease such an excessive fall in blood pressure could result in a myocardial infarction or a
cerebrovascular accident.
In patients at risk of excessive hypotension, ACEON® Tablets therapy should be started under very
close medical supervision. Patients should be followed closely for the first two weeks of treatment and
whenever the dose of ACEON® Tablets and/or diuretic is increased.
If excessive hypotension occurs, the patient should be placed immediately in a supine position and,
if necessary, treated with an intravenous infusion of physiological saline. ACEON® Tablets treatment
can usually be continued following restoration of volume and blood pressure.
Neutropenia/Agranulocytosis: Another ACE inhibitor, captopril, has been shown to cause
agranulocytosis and bone marrow depression, rarely in uncomplicated patients but more frequently in
patients with renal impairment, especially patients with a collagen vascular disease such as systemic
lupus erythematosus or scleroderma. Available data from clinical trials of ACEON® Tablets are
insufficient to show whether ACEON® Tablets causes agranulocytosis at similar rates.
Fetal/Neonatal Morbidity and Mortality: ACE inhibitors can cause fetal and neonatal morbidity
and death when administered to pregnant women. Several dozen cases have been reported in the world
literature. When pregnancy is detected, ACE inhibitors should be discontinued as soon as possible.
The use of ACE inhibitors during the second and third trimesters of pregnancy has been associated
with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or
irreversible renal failure and death. Oligohydramnios has also been reported, presumably resulting
from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb
contractures, craniofacial deformation and hypoplastic lung development. Prematurity, intrauterine
growth retardation and patent ductus arteriosus have also been reported, although it is not clear
whether these occurrences were due to the ACE-inhibitor exposure.
These adverse effects do not appear to have resulted from intrauterine ACE-inhibitor exposure that
has been limited to the first trimester. Mothers whose embryos and fetuses are exposed to ACE
inhibitors only during the first trimester should be so informed. Nonetheless, when patients become
pregnant, physicians should make every effort to discontinue the use of ACEON® Tablets as soon as
possible.
Rarely (probably less often than once in every thousand pregnancies), no alternative to ACE
inhibitors will be found. In these rare cases, the mothers should be apprised of the potential hazards to
their fetuses, and serial ultrasound examinations should be performed to assess the intra-amniotic
environment.
If oligohydramnios is observed, ACEON® Tablets should be discontinued unless it is considered
life-saving for the mother. Contraction stress testing (CST), a non-stress test (NST) or biophysical
profiling (BPP) may be appropriate, depending upon the week of pregnancy. Patients and physicians
should be aware, however, that oligohydramnios may not appear until after the fetus has sustained
irreversible injury.
Infants with histories of in utero exposure to ACE inhibitors should be closely observed for
hypotension, oliguria and hyperkalemia. If oliguria occurs, attention should be directed toward support
of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as means of
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reversing hypotension and/or substituting for disordered renal function. Perindopril, which crosses the
placenta, can theoretically be removed from the neonatal circulation by these means, but limited
experience has not shown that such removal is central to the treatment of these infants.
No teratogenic effects of perindopril were seen in studies of pregnant rats, mice, rabbits and
cynomolgus monkeys. On a mg/m2 basis, the doses used in these studies were 6 times (in mice), 670
times (in rats), 50 times (in rabbits) and 17 times (in monkeys) the maximum recommended human
dose (assuming a 50 kg adult). On a mg/kg basis, these multiples are 60 times (in mice), 3,750 times
(in rats), 150 times (in rabbits) and 50 times (in monkeys) the maximum recommended human dose.
Hepatic Failure: Rarely, ACE inhibitors have been associated with a syndrome that starts with
cholestatic jaundice and progresses to fulminant hepatic necrosis and (sometimes) death. The
mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop
jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive
appropriate medical follow-up.
PRECAUTIONS
General: Impaired Renal Function: As a consequence of inhibiting the renin-angiotensin-
aldosterone system, changes in renal function may be anticipated in susceptible individuals.
Hypertensive Patients with Congestive Heart Failure: In patients with severe congestive heart
failure, where renal function may depend on the activity of the renin-angiotensin-aldosterone system,
treatment with ACE inhibitors, including ACEON® Tablets, may be associated with oliguria and/or
progressive azotemia, and rarely with acute renal failure and/or death.
Hypertensive Patients with Renal Artery Stenosis: In hypertensive patients with unilateral or bilateral
renal artery stenosis, increases in blood urea nitrogen and serum creatinine may occur. Experience
with ACE inhibitors suggests that these increases are usually reversible upon discontinuation of the
drug. In such patients, renal function should be monitored during the first few weeks of therapy.
Some hypertensive patients without apparent pre-existing renal vascular disease have developed
increases in blood urea nitrogen and serum creatinine, usually minor and transient. These increases are
more likely to occur in patients treated concomitantly with a diuretic and in patients with pre-existing
renal impairment. Reduction of dosages of ACEON® Tablets, the diuretic or both may be required.
In some cases, discontinuation of either or both drugs may be necessary.
Evaluation of hypertensive patients should always include an assessment of renal function. (See
DOSAGE AND ADMINISTRATION.)
Hyperkalemia: Elevations of serum potassium have been observed in some patients treated with ACE
inhibitors, including ACEON® Tablets. In U.S. controlled clinical trials, 1.4% of the patients
receiving ACEON® Tablets and 2.3% of patients receiving placebo showed increased serum
potassium levels to greater than 5.7 mEq/L. Most cases were isolated single values that did not appear
clinically relevant and were rarely a cause for withdrawal. Risk factors for the development of
hyperkalemia include renal insufficiency, diabetes mellitus and the concomitant use of agents such as
potassium-sparing diuretics, potassium supplements and/or potassium-containing salt substitutes.
Drugs associated with increases in serum potassium should be used cautiously, if at all, with ACEON®
Tablets. (See PRECAUTIONS: Drug Interactions.)
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Cough: Presumably due to the inhibition of the degradation of endogenous bradykinin, persistent
nonproductive cough has been reported with all ACE inhibitors, always resolving after discontinuation
of therapy. ACE inhibitor-induced cough should be considered in the differential diagnosis of cough.
In controlled trials with perindopril, cough was present in 12% of perindopril patients and 4.5% of
patients given placebo.
Surgery/Anesthesia: In patients undergoing surgery or during anesthesia with agents that produce
hypotension, ACEON® Tablets may block angiotensin II formation that would otherwise occur
secondary to compensatory renin release. Hypotension attributable to this mechanism can be corrected
by volume expansion.
Information for Patients: Angioedema: Angioedema, including laryngeal edema, can occur with
ACE inhibitor therapy, especially following the first dose. Patients should be told to report
immediately signs or symptoms suggesting angioedema (swelling of face, extremities, eyes, lips,
tongue, hoarseness or difficulty in swallowing or breathing) and to take no more drug before
consulting a physician.
Symptomatic Hypotension: As with any antihypertensive therapy, patients should be cautioned that
lightheadedness can occur, especially during the first few days of therapy and that it should be reported
promptly. Patients should be told that if fainting occurs, ACEON® Tablets should be discontinued and
a physician consulted.
All patients should be cautioned that inadequate fluid intake or excessive perspiration, diarrhea or
vomiting can lead to an excessive fall in blood pressure in association with ACE inhibitor therapy.
Hyperkalemia: Patients should be advised not to use potassium supplements or salt substitutes
containing potassium without a physician’s advice.
Neutropenia: Patients should be told to report promptly any indication of infection (e.g., sore throat,
fever) which could be a sign of neutropenia.
Pregnancy: Female patients of childbearing age should be told about the consequences of second and
third trimester exposure to ACE inhibitors, and they should also be told that these consequences do not
appear to have resulted from intrauterine ACE-inhibitor exposure that has been limited to the first
trimester. These patients should be asked to report pregnancies to their physicians as soon as possible.
Drug Interactions: Diuretics: Patients on diuretics, and especially those started recently, may
occasionally experience an excessive reduction of blood pressure after initiation of ACEON® Tablets
therapy. The possibility of hypotensive effects can be minimized by either discontinuing the diuretic
or increasing the salt intake prior to initiation of treatment with perindopril. If diuretics cannot be
interrupted, close medical supervision should be provided with the first dose of ACEON® Tablets, for
at least two hours and until blood pressure has stabilized for another hour. (See WARNINGS and
DOSAGE AND ADMINISTRATION.)
The rate and extent of perindopril absorption and elimination are not affected by concomitant
diuretics. The bioavailability of perindoprilat was reduced by diuretics, however, and this was
associated with a decrease in plasma ACE inhibition.
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Potassium Supplements and Potassium-Sparing Diuretics: ACEON® Tablets may increase serum
potassium because of its potential to decrease aldosterone production. Use of potassium-sparing
diuretics (spironolactone, amiloride, triamterene and others), potassium supplements or other drugs
capable of increasing serum potassium (indomethacin, heparin, cyclosporine and others) can increase
the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be
given with caution and the patient’s serum potassium should be monitored frequently.
Lithium: Increased serum lithium and symptoms of lithium toxicity have been reported in patients
receiving concomitant lithium and ACE inhibitor therapy. These drugs should be coadministered with
caution and frequent monitoring of serum lithium concentration is recommended. Use of a diuretic
may further increase the risk of lithium toxicity.
Digoxin: A controlled pharmacokinetic study has shown no effect on plasma digoxin concentrations
when coadministered with ACEON® Tablets, but an effect of digoxin on the plasma concentration of
perindopril/perindoprilat has not been excluded.
Gentamicin: Animal data have suggested the possibility of interaction between perindopril and
gentamicin. However, this has not been investigated in human studies. Coadministration of both
drugs should proceed with caution.
Food Interaction: Oral administration of ACEON® Tablets with food does not significantly lower the
rate or extent of perindopril absorption relative to the fasted state. However, the extent of
biotransformation of perindopril to the active metabolite, perindoprilat, is reduced approximately 43%,
resulting in a reduction in the plasma ACE inhibition curve of approximately 20%, probably clinically
insignificant. In clinical trials, perindopril was generally administered in a non-fasting state.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenesis: No evidence of
carcinogenic effect was observed in studies in rats and mice when perindopril was administered at
dosages up to 20 times (mg/kg) or 2 to 4 times (mg/m2) the maximum proposed clinical doses (16
mg/day) for 104 weeks.
Mutagenesis: No genotoxic potential was detected for ACEON® Tablets, perindoprilat and other
metabolites in various in vitro and in vivo investigations, including the Ames test, the Saccharomyces
cerevisiae D4 test, cultured human lymphocytes, TK ± mouse lymphoma assay, mouse and rat
micronucleus tests and Chinese hamster bone marrow assay.
Impairment of Fertility: There was no meaningful effect on reproductive performance or fertility in
the rat given up to 30 times (mg/kg) or 6 times (mg/m2) the proposed maximum clinical dosage of
ACEON® Tablets during the period of spermatogenesis in males or oogenesis and gestation in
females.
Pregnancy: Pregnancy Categories C (first trimester) and D (second and third trimesters). (See
WARNINGS: Fetal/Neonatal Morbidity and Mortality.)
Nursing Mothers: Milk of lactating rats contained radioactivity following administration 14C-
perindopril. It is not known whether perindopril is secreted in human milk. Because many drugs are
secreted in human milk, caution should be exercised when ACEON® Tablets is given to nursing
mothers.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-184/S-011
Page 15
Pediatric Use: Safety and effectiveness of ACEON® Tablets in pediatric patients have not been
established.
Geriatric Use: The mean blood pressure effect of perindopril was somewhat smaller in patients over
60 than in younger patients, although the difference was not significant. Plasma concentrations of both
perindopril and perindoprilat were increased in elderly patients compared to concentrations in younger
patients. No adverse effects were clearly increased in older patients with the exception of dizziness
and possibly rash. Experience with ACEON® Tablets in elderly patients at daily doses exceeding 8
mg is limited.
ADVERSE REACTIONS
Hypertension
ACEON® (perindopril erbumine) Tablets has been evaluated for safety in approximately 3,400
patients with hypertension in U.S. and foreign clinical trials. ACEON® Tablets was in general well-
tolerated in the patient populations studied, the side effects were usually mild and transient. Although
dizziness was reported more frequently in placebo patients (8.5%) than in perindopril patients (8.2%),
the incidence appeared to increase with an increase in perindopril dose.
The data presented here are based on results from the 1,417 ACEON® Tablets-treated patients who
participated in the U.S. clinical trials. Over 220 of these patients were treated with ACEON® Tablets
for at least one year.
In placebo-controlled U.S. clinical trials, the incidence of premature discontinuation of therapy due
to adverse events was 6.5% in patients treated with ACEON® Tablets and 6.7% in patients treated
with placebo. The most common causes were cough, headache, asthenia and dizziness.
Among 1,012 patients in placebo-controlled U.S. trials, the overall frequency of reported adverse
events was similar in patients treated with ACEON® Tablets and in those treated with placebo
(approximately 75% in each group). Adverse events that occurred in 1% or greater of the patients and
that were more common for perindopril than placebo by at least 1% (regardless of whether they were
felt to be related to study drug) are shown in the first two columns below. Of these adverse events,
those considered possibly or probably related to study drug are shown in the last two columns.
Table 3.
Frequency of Adverse Events (%)
All Adverse Events
Possibly – or Probably –
Related Adverse Events
Perindopril
n=789
Placebo
n=223
Perindopril
n=789
Placebo
n=223
Cough
12.0
4.5
6.0
1.8
Back Pain
5.8
3.1
0.0
0.0
Sinusitis
5.2
3.6
0.6
0.0
Viral Infection
3.4
1.6
0.3
0.0
Upper Extremity Pain
2.8
1.4
0.2
0.0
Hypertonia
2.7
1.4
0.2
0.0
Dyspepsia
1.9
0.9
0.3
0.0
Fever
1.5
0.5
0.3
0.0
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-184/S-011
Page 16
Proteinuria
1.5
0.5
1.0
0.5
Ear Infection
1.3
0.0
0.0
0.0
Palpitation
1.1
0.0
0.9
0.0
Of these, cough was the reason for withdrawal in 1.3% of perindopril and 0.4% of placebo patients.
While dizziness was not reported more frequently in the perindopril group (8.2%) than in the placebo
group (8.5%), it was clearly increased with dose, suggesting a causal relationship with perindopril.
Other commonly reported complaints (1% or greater), regardless of causality, include: headache
(23.8%), upper respiratory infection (8.6%), asthenia (7.9%), rhinitis (4.8%), low extremity pain
(4.7%), diarrhea (4.3%), edema (3.9%), pharyngitis (3.3%), urinary tract infection (2.8%), abdominal
pain (2.7%), sleep disorder (2.5%), chest pain (2.4%), injury, paresthesia, nausea, rash (each 2.3%),
seasonal allergy, depression (each 2.0%), abnormal ECG (1.8%), ALT increase (1.7%), tinnitus,
vomiting (each 1.5%), neck pain, male sexual dysfunction (each 1.4%), triglyceride increase,
somnolence (each 1.3%), joint pain, nervousness, myalgia, menstrual disorder (each 1.1%), flatulence
and arthritis (each 1.0%), but none of those was more frequent by at least 1% on perindopril than on
placebo. Depending on the specific adverse event, approximately 30 to 70% of the common
complaints were considered possibly or probably related to treatment.
Stable Coronary Artery Disease
Perindopril has been evaluated for safety in EUROPA, a double-blind, placebo-controlled study in
12,218 patients with stable coronary artery disease. The overall rate of discontinuation was about 22%
on drug and placebo. The most common medical reasons for discontinuation that were more frequent
on perindopril than placebo were cough, drug intolerance and hypotension.
Below is a list (by body system) of adverse experiences reported in 0.3 to 1% of patients in U.S.
placebo-controlled studies in hypertensive patients without regard to attribution to therapy. Less
frequent but medically important adverse events are also included; the incidence of these events is
given in parentheses.
Body as a Whole: malaise, pain, cold/hot sensation, chills, fluid retention, orthostatic symptoms,
anaphylactic reaction, facial edema, angioedema (0.1%).
Gastrointestinal: constipation, dry mouth, dry mucous membrane, appetite increased, gastroenteritis.
Respiratory: posterior nasal drip, bronchitis, rhinorrhea, throat disorder, dyspnea, sneezing, epistaxis,
hoarseness, pulmonary fibrosis (<0.1%).
Urogenital: vaginitis, kidney stone, flank pain, urinary frequency, urinary retention.
Cardiovascular: hypotension, ventricular extrasystole, myocardial infarction, vasodilation, syncope,
abnormal conduction, heart murmur, orthostatic hypotension.
Endocrine: gout.
Hematology: hematoma, ecchymosis.
Musculoskeletal: arthralgia, myalgia.
CNS: migraine, amnesia, vertigo, cerebral vascular accident (0.2%).
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Page 17
Psychiatric: anxiety, psychosexual disorder.
Dermatology: sweating, skin infection, tinea, pruritus, dry skin, erythema, fever blisters, purpura
(0.1%).
Special Senses: conjunctivitis, earache.
Laboratory: potassium decrease, uric acid increase, alkaline phosphatase increase, cholesterol
increase, AST increase, creatinine increase, hematuria, glucose increase.
When ACEON® Tablets was given concomitantly with thiazide diuretics, adverse events were
generally reported at the same rate as those for ACEON® Tablets alone, except for a higher incidence
of abnormal laboratory findings known to be related to treatment with thiazide diuretics alone (e.g.,
increases in serum uric acid, triglycerides and cholesterol and decreases in serum potassium).
Potential Adverse Effects Reported with ACE Inhibitors: Other medically important adverse
effects reported with other available ACE inhibitors include: cardiac arrest, eosinophilic pneumonitis,
neutropenia/agranulocytosis, pancytopenia, anemia (including hemolytic and aplastic),
thrombocytopenia, acute renal failure, nephritis, hepatic failure, jaundice (hepatocellular or
cholestatic), symptomatic hyponatremia, bullous pemphigus, acute pancreatitis, exfoliative dermatitis
and a syndrome which may include: arthralgia/arthritis, vasculitis, serositis, myalgia, fever, rash or
other dermatologic manifestations, a positive ANA, leukocytosis, eosinophilia or an elevated ESR.
Many of these adverse effects have also been reported for perindopril.
Fetal/Neonatal Morbidity and Mortality: See WARNINGS: Fetal/Neonatal Morbidity and
Mortality.
Clinical Laboratory Test Findings
Hypertension
Hematology, clinical chemistry and urinalysis parameters have been evaluated in U.S. placebo-
controlled trials. In general, there were no clinically significant trends in laboratory test findings.
Hyperkalemia: In clinical trials, 1.4% of the patients receiving ACEON® Tablets and 2.3% of the
patients receiving placebo showed serum potassium levels greater than 5.7 mEq/L. (See
PRECAUTIONS.)
BUN/Serum Creatinine Elevations: Elevations, usually transient and minor, of BUN and serum
creatinine have been observed. In placebo-controlled clinical trials, the proportion of patients
experiencing increases in serum creatinine were similar in the ACEON® Tablets and placebo
treatment groups. Rapid reduction of long-standing or markedly elevated blood pressure by any
antihypertensive therapy can result in decreases in the glomerular filtration rate and, in turn, lead to
increases in BUN or serum creatinine. (See PRECAUTIONS.)
Hematology: Small decreases in hemoglobin and hematocrit occur frequently in hypertensive patients
treated with ACEON® Tablets, but are rarely of clinical importance. In controlled clinical trials, no
patient was discontinued from therapy due to the development of anemia. Leukopenia (including
neutropenia) was observed in 0.1% of patients in U.S. clinical trials (See WARNINGS.)
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For current labeling information, please visit https://www.fda.gov/drugsatfda
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Page 18
Liver Function Tests: Elevations in ALT (1.6% ACEON® Tablets vs 0.9% placebo) and AST (0.5%
ACEON® Tablets vs 0.4% placebo) have been observed in U.S. placebo-controlled clinical trials. The
elevations were generally mild and transient and resolved after discontinuation of therapy.
OVERDOSAGE
In animals, doses of perindopril up to 2,500 mg/kg in mice, 3,000 mg/kg in rats and 1,600 mg/kg in
dogs were non-lethal. Past experiences were scant but suggested that overdosage with other ACE
inhibitors was also fairly well tolerated by humans. The most likely manifestation is hypotension, and
treatment should be symptomatic and supportive. Therapy with the ACE inhibitor should be
discontinued, and the patient should be observed. Dehydration, electrolyte imbalance and hypotension
should be treated by established procedures.
However, of the reported cases of perindopril overdosage, one (dosage unknown) required assisted
ventilation and the other developed hypothermia, circulatory arrest and died following ingestion of up
to 180 mg of perindopril. The intervention for perindopril overdose may require vigorous support (see
below).
Laboratory determinations of serum levels of perindopril and its metabolites are not widely
available, and such determinations have, in any event, no established role in the management of
perindopril overdose.
No data are available to suggest physiological maneuvers (e.g., maneuvers to change the pH of the
urine) that might accelerate elimination of perindopril and its metabolites. Perindopril can be removed
by hemodialysis, with clearance of 52 mL/min for perindopril and 67 mL/min for perindoprilat.
Angiotensin II could presumably serve as a specific antagonist-antidote in the settling of perindopril
overdose, but angiotensin II is essentially unavailable outside of scattered research facilities. Because
the hypotensive effect of perindopril is achieved through vasodilation and effective hypovolemia, it is
reasonable to treat perindopril overdose by infusion of normal saline solution.
DOSAGE AND ADMINISTRATION
Stable Coronary Artery Disease
In patients with stable coronary artery disease, ACEON® Tablets should be given at an initial dose of
4 mg once daily for 2 weeks, and then increased as tolerated, to a maintenance dose of 8 mg once
daily. In elderly patients (>70 yrs), ACEON® Tablets should be given as a 2 mg dose once daily in
the first week, followed by 4 mg once daily in the second week and 8 mg once daily for maintenance
dose if tolerated.
Hypertension
Use in Uncomplicated Hypertensive Patients: In patients with essential hypertension, the
recommended initial dose is 4 mg once a day. The dosage may be titrated upward until blood pressure,
when measured just before the next dose, is controlled or to a maximum of 16 mg per day. The usual
maintenance dose range is 4 to 8 mg administered as a single daily dose. ACEON® Tablets may also
be administered in two divided doses. When once-daily dosing was compared to twice-daily dosing in
clinical studies, the B.I.D. regimen was generally slightly superior, but not by more than about 0.5 to
1.0 mm Hg.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-184/S-011
Page 19
Use in the Elderly Patients: As in younger patients, the recommended initial daily dosage of
ACEON® Tablets for the elderly (>65 years) is 4 mg daily, given in one or two divided doses. The
daily dosage may be titrated upward until blood pressure, when measured just before the next dose, is
controlled, but experience with ACEON® Tablets is limited in the elderly at doses exceeding 8 mg.
Dosages above 8 mg should be administered with caution and under close medical supervision. (See
PRECAUTIONS: Geriatric Use.)
Use in Concomitant Diuretics: If blood pressure is not adequately controlled with perindopril alone,
a diuretic may be added. In patients currently being treated with a diuretic, symptomatic hypotension
occasionally can occur following the initial dose of perindopril. To reduce likelihood of such reaction,
the diuretic should, if possible, be discontinued 2 to 3 days prior to the beginning of ACEON® Tablets
therapy. (See WARNINGS.) Then, if blood pressure is not controlled with ACEON® Tablets alone,
the diuretic should be resumed.
If the diuretic cannot be discontinued, an initial dose of 2 to 4 mg daily in one or in two divided
doses should be used with careful medical supervision for several hours and until blood pressure has
stabilized. The dosage should then be titrated as described above. (See WARNINGS and
PRECAUTIONS: Drug Interactions.)
After the first dose of ACEON® Tablets, the patient should be followed closely for the first two
weeks of treatment and whenever the dose of ACEON® Tablets and/or diuretics is increased (See
WARNINGS and PRECAUTIONS, Drug Interactions.) In patients who are currently being treated
with a diuretic, symptomatic hypotension occasionally can occur following the initial dose of
ACEON® Tablets. To reduce the likelihood of hypotension, the dose of diuretic, if possible, can be
adjusted which may diminish the likelihood of hypotension. The appearance of hypotension after the
initial dose of ACEON® Tablets does not preclude subsequent careful dose titration with the drug,
following effective management of the hypotension.
Dose Adjustment in Renal Impairment
Kinetic data indicate that perindoprilat elimination is decreased in renally impaired patients, with a
marked increase in accumulation when creatinine clearance drops below 30 mL/min. In such patients
(creatinine clearance <30 mL/min), safety and efficacy of ACEON® Tablets have not been
established. For patients with lesser degrees of impairment (creatinine clearance above 30 mL/min),
the initial dosage should be 2 mg/day and dosage should not exceed 8 mg/day due to limited clinical
experience. During dialysis, perindopril is removed with the same clearance as in patients with normal
renal function.
HOW SUPPLIED
Tablets 2 mg:
Scored one side, white, oblong (debossed “ACN 2” on one side and debossed with
“SLV” on both sides of score on the other side)
Bottles of 100.....................................................................................................NDC 0032-1101-01
Tablets 4 mg:
Scored one side, pink, oblong (debossed “ACN 4” on one side and debossed with
“SLV” on both sides of score on the other side)
Bottles of 100.....................................................................................................NDC 0032-1102-01
Tablets 8 mg:
Scored one side, salmon-colored, oblong (debossed “ACN 8” on one side and
debossed with “SLV” on both sides of score on the other side)
Bottles of 100.....................................................................................................NDC 0032-1103-01
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-184/S-011
Page 20
Storage Conditions: Store at controlled room temperature 20° to 25°C (68° to 77°F) [see USP].
Protect from moisture.
Keep out of the reach of children.
Manufactured by:
Patheon Pharmaceuticals, Inc.
Cincinnati, OH 45237 USA
Marketed by:
Solvay Pharmaceuticals, Inc.
Marietta, GA 30062
© 2005 Solvay Pharmaceuticals, Inc.
500063/500064 Rev May 2005
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:47:00.479789
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/020184s011lbl.pdf', 'application_number': 20184, 'submission_type': 'SUPPL ', 'submission_number': 11}
|
12,307
|
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to
use ACEON® safely and effectively. See full prescribing
information for ACEON.
ACEON (perindopril erbumine) 2, 4 and 8 mg Tablets
Initial U.S. Approval: 1993
WARNING: AVOID USE IN PREGNANCY
When pregnancy is detected, ACEON should be discontinued as
soon as possible. Drugs that act directly on the renin-angiotensin
system can cause injury to or death of the developing fetus. (5.4)
---------------------- INDICATIONS AND USAGE------------------
• ACEON is indicated for the treatment of patients with essential
hypertension (1.1)
• ACEON is indicated for treatment of patients with stable
coronary artery disease to reduce the risk of cardiovascular
mortality or nonfatal myocardial infarction (1.2)
------------------DOSAGE AND ADMINISTRATION -------------
Hypertension
• The recommended initial dose is 4 mg once a day. The dosage
may be titrated upward until blood pressure, when measured
just before the next dose, is controlled or to a maximum of 16
mg per day (2.1)
Stable Coronary Artery Disease
• ACEON should be given at an initial dose of 4 mg once daily
for 2 weeks, and then increased, as tolerated, to a maintenance
dose of 8 mg once daily (2.2)
---------------- DOSAGE FORMS AND STRENGTHS------------
• Tablets: 2, 4 and 8 mg (3)
------------------------- CONTRAINDICATIONS -----------------
• Angioedema related to previous treatment with an ACE
inhibitor, or a history of hereditary or idiopathic angioedema
(4.0, 5.1)
-------------------WARNINGS AND PRECAUTIONS -------------
• Watch for anaphylactoid reactions, including angioedema (5.1)
• Monitor renal function during therapy (5.8)
• Assess for hypotension and hyperkalemia (5.2, 5.6)
--------------------------ADVERSE REACTIONS --------------------
• Hypertension: Most common adverse events (incidence
greater than or equal to 5%) are cough, dizziness and back pain
(6.1)
• Stable Coronary Artery Disease: Most common adverse
events leading to discontinuation were cough, drug intolerance,
and hypotension (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact
Abbott Laboratories at 1-800-354-0026 (ext. 7530) or FDA at 1
800-FDA-1088 or www.FDA.gov/Medwatch.
--------------------------DRUG INTERACTIONS --------------------
• Diuretics: Excessive drop in blood pressure (7.1)
• Potassium-sparing diuretics/potassium supplements:
Hyperkalemia (7.2)
• Lithium: Increase serum lithium levels, symptoms of lithium
toxicity (7.3)
• Injectable gold: Nitritoid reactions (facial flushing, nausea,
vomiting, and hypotension) (7.4)
• NSAID use may lead to increased risk of renal impairment and
loss of antihypertensive effect (7.7)
-------------------USE IN SPECIFIC POPULATIONS -------------
• Geriatrics: Start at low daily dose (4 mg or less) and titrate
slowly as needed. Experience with doses exceeding 8 mg is
limited (8.5)
• Dosage adjustment may be necessary in renally impaired
patients (8.7)
SEE 17 FOR PATIENT COUNSELING INFORMATION.
Revised: 06/2011
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: AVOID USE IN PREGNANCY
1
INDICATIONS AND USAGE
1.1 Hypertension
1.2 Stable Coronary Artery Disease
2
DOSAGE AND ADMINISTRATION
2.1 Hypertension
2.2 Stable Coronary Artery Disease
2.3 Dose Adjustment in Renal Impairment and Dialysis
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1 Anaphylactoid and Possibly Related Reactions
5.2 Hypotension
5.3 Neutropenia and Agranulocytosis
5.4 Fetal/Neonatal Morbidity and Mortality
5.5 Impaired Renal Function
5.6 Hyperkalemia
5.7 Cough
5.8 Hepatic Failure
5.9 Surgery/Anesthesia
6
ADVERSE REACTIONS
6.1 Clinical Trials Experience
6.2 Postmarketing Experience
6.3 linical Laboratory Test Findings
7
DRUG INTERACTIONS
7.1 Diuretics
7.2 Potassium Supplements and Potassium-Sparing
Diuretics
7.3 Lithium
7.4 Gold
7.5 Digoxin
7.6 Gentamicin
7.7 Non-Steroidal Anti-inflammatory Agents including
Selective Cyclooxygenase-2 Inhibitors (COX-2
Inhibitors)
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Renal Impairment
8.7 Hepatic Impairment
10
OVERDOSAGE
11
DESCRIPTION
12
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Phamacodynamics
12.3 Pharmacokinetics
13
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14
CLINICAL STUDIES
14.1 Hypertension
14.2 Stable Coronary Artery Disease
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing
information are not listed.
Reference ID: 3004831
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
500063 5E Rev Jun 2011
23
FULL PRESCRIBING INFORMATION
WARNING: AVOID USE IN PREGNANCY
When pregnancy is detected, discontinue ACEON as soon as possible. Drugs that act directly on the renin-angiotensin system can cause injury to
or death of the developing fetus (5.4)
4
1
INDICATIONS AND USAGE
5
1.1 Hypertension
6
ACEON is indicated for the treatment of patients with essential hypertension. ACEON may be used alone or given with other classes of
7
antihypertensives, especially thiazide diuretics.
8
1.2 Stable Coronary Artery Disease
9
ACEON is indicated for treatment of patients with stable coronary artery disease to reduce the risk of cardiovascular mortality or nonfatal
10
myocardial infarction. ACEON can be used with conventional treatment for management of coronary artery disease, such as antiplatelet,
11
antihypertensive or lipid-lowering therapy.
12
2
DOSAGE AND ADMINISTRATION
13
2.1 Hypertension
14
Use in Uncomplicated Hypertensive Patients: In patients with essential hypertension, the recommended initial dose is 4 mg once a day.
15
The dose may be titrated, as needed to a maximum of 16 mg per day. The usual maintenance dose range is 4 mg to 8 mg administered as a single
16
daily dose or in two divided doses.
17
Use in Elderly Patients: The recommended initial daily dosage of ACEON for the elderly is 4 mg daily, given in one or two divided doses.
18
Experience with ACEON is limited in the elderly at doses exceeding 8 mg. Dosages above 8 mg should be administered with careful blood
19
pressure monitoring and dose titration [see Use in Specific Populations (8.5)].
20
Use with Diuretics: In patients who are currently being treated with a diuretic, symptomatic hypotension can occur following the initial dose of
21
ACEON. Consider reducing the dose of diuretic prior to starting ACEON [see Drug Interactions (7.1)].
22
2.2 Stable Coronary Artery Disease
23
In patients with stable coronary artery disease, ACEON should be given at an initial dose of 4 mg once daily for 2 weeks, and then
24
increased as tolerated, to a maintenance dose of 8 mg once daily. In elderly patients (greater than 70 years), ACEON should be given as a 2 mg
25
dose once daily in the first week, followed by 4 mg once daily in the second week and 8 mg once daily for maintenance dose if tolerated.
26
2.3 Dose Adjustment in Renal Impairment and Dialysis
27
Perindoprilat elimination is decreased in renally impaired patients. ACEON is not recommended in patients with creatinine clearance <30
28
mL/min.For patients with lesser degrees of impairment, the initial dosage should be 2 mg/day and dosage should not exceed 8 mg/day. During
29
dialysis, perindopril is removed with the same clearance as in patients with normal renal function.
30
3
DOSAGE FORMS AND STRENGTHS
31
Tablets are oblong with a score on one side.
32
2 mg tablet is white and debossed on the unscored side with “ACN 2”.
33
4 mg tablet is pink and debossed on the unscored side with “ACN 4”.
34
8 mg tablet is salmon and debossed on the unscored side with “ACN 8”.
35
4
CONTRAINDICATIONS
36
ACEON is contraindicated in patients known to be hypersensitive (including angioedema) to this product or to any other ACE inhibitor.
37
ACEON is also contraindicated in patients with hereditary or idiopathic angioedema.
38
5
WARNINGS AND PRECAUTIONS
39
5.1 Anaphylactoid and Possibly Related Reactions
40
Presumably because angiotensin-converting enzyme inhibitors affect the metabolism of eicosanoids and polypeptides, including
41
endogenous bradykinin, patients receiving ACE inhibitors (including ACEON) may be subject to a variety of adverse events, some of them
42
serious. Black patients receiving ACE inhibitors have a higher incidence of angioedema compared to nonblacks.
43
Head and Neck Angioedema: Angioedema of the face, extremities, lips, tongue, glottis, or larynx has been reported in patients treated with
44
ACE inhibitors, including ACEON (0.1% of patients treated with ACEON in U.S. clinical trials). Angioedema associated with involvement of the
45
tongue, glottis or larynx may be fatal. In such cases, discontinue ACEON treatment immediately and observe until the swelling disappears. When
46
involvement of the tongue, glottis, or larynx appears likely to cause airway obstruction, administer appropriate therapy, such as subcutaneous
47
epinephrine solution 1:1000 (0.3 to 0.5 mL), promptly.
Reference ID: 3004831
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
48
Intestinal Angioedema: Intestinal angioedema has been reported in patients treated with ACE inhibitors. These patients presented with
49
abdominal pain (with or without nausea or vomiting); in some cases there was no prior history of facial angioedema and C-1 esterase levels were
50
normal. The angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at surgery, and symptoms resolved after
51
stopping the ACE inhibitor. Intestinal angioedema should be included in the differential diagnosis of patients on ACE inhibitors presenting with
52
abdominal pain.
53
5.2 Hypotension
54
ACEON can cause symptomatic hypotension. ACEON has been associated with hypotension in 0.3% of uncomplicated hypertensive
55
patients in U.S. placebo-controlled trials. Symptoms related to orthostatic hypotension were reported in another 0.8% of patients.
56
Symptomatic hypotension is most likely to occur in patients who have been volume or salt-depleted as a result of prolonged diuretic
57
therapy, dietary salt restriction, dialysis, diarrhea or vomiting [see Dosage and Administration (2.1)].
58
ACE inhibitors may cause excessive hypotension, and may be associated with oliguria or azotemia, and rarely with acute renal failure and
59
death. In patients with ischemic heart disease or cerebrovascular disease, an excessive fall in blood pressure could result in a myocardial
60
infarction or a cerebrovascular accident.
61
In patients at risk of excessive hypotension, ACEON therapy should be started under very close medical supervision. Patients should be
62
followed closely for the first two weeks of treatment and whenever the dose of ACEON and/or diuretic is increased.
63
If excessive hypotension occurs, the patient should be placed immediately in a supine position and, if necessary, treated with an
64
intravenous infusion of physiological saline. ACEON treatment can usually be continued following restoration of volume and blood pressure.
65
5.3 Neutropenia/Agranulocytosis
66
ACE inhibitors have been associated with agranulocytosis and bone marrow depression, most frequently in patients with renal impairment,
67
especially patients with a collagen vascular disease such as systemic lupus erythematosus or scleroderma.
68
5.4 Fetal/Neonatal Morbidity and Mortality
69
ACE inhibitors can cause fetal and neonatal morbidity and death when administered to pregnant women. Several dozen cases have been
70
reported in the world literature. When pregnancy is detected, ACE inhibitors should be discontinued as soon as possible.
71
The use of ACE inhibitors during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury,
72
including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure and death. Oligohydramnios has also been
73
reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb
74
contractures, craniofacial deformation and hypoplastic lung development.
75
Prematurity, intrauterine growth retardation, patent ductus arteriosus, and other structural cardiac malformations, as well as neurologic
76
malformations, have been reported following exposure to ACE inhibitors during the first trimester of pregnancy.
77
When patients become pregnant, healthcare providers should make every effort to discontinue the use of ACEON as soon as possible.
78
Rarely (probably less often than once in every thousand pregnancies), no alternative to ACE inhibitors will be found. In these rare cases, the
79
mothers should be apprised of the potential hazards to their fetuses, and serial ultrasound examinations should be performed to assess the intra
80
amniotic environment.
81
If oligohydramnios is observed, ACEON should be discontinued unless it is considered life-saving for the mother. Contraction stress
82
testing (CST), a non-stress test (NST) or biophysical profiling (BPP) may be appropriate, depending upon the week of pregnancy. Patients and
83
healthcare providers should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury.
84
Infants with histories of in utero exposure to ACE inhibitors should be closely observed for hypotension, oliguria and hyperkalemia. If
85
oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be
86
required as a means of reversing hypotension and/or substituting for disordered renal function. Perindopril, which crosses the placenta, can
87
theoretically be removed from the neonatal circulation by these means, but limited experience has not shown that such removal is central to the
88
treatment of these infants.
89
5.5 Impaired Renal Function
90
As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible
91
individuals. Renal function should be monitored periodically in patients receiving ACEON. [see Dosage and Administration (2.3)].
92
In patients with severe congestive heart failure, where renal function may depend on the activity of the renin-angiotensin-aldosterone
93
system, treatment with ACE inhibitors, including ACEON, may be associated with oliguria, progressive azotemia, and, rarely, acute renal failure
94
and death.
95
In hypertensive patients with unilateral or bilateral renal artery stenosis, increases in blood urea nitrogen and serum creatinine may occur;
96
usually reversible upon discontinuation of the ACE inhibitor . In such patients, renal function should be monitored during the first few weeks of
97
therapy.
98
Some ACEON-treated patients have developed minor and transient increases in blood urea nitrogen and serum creatinine especially in
99
those concomitantly treated with a diuretic.
100
5.6 Hyperkalemia
101
Elevations of serum potassium have been observed in some patients treated with ACE inhibitors, including ACEON. Most cases were
102
isolated single values that did not appear clinically relevant and were rarely a cause for withdrawal. Risk factors for the development of
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103
hyperkalemia include renal insufficiency, diabetes mellitus and the concomitant use of agents such as potassium-sparing diuretics, potassium
104
supplements and/or potassium-containing salt substitutes [see Drug Interactions (7.2)].
105
Serum potassium should be monitored periodically in patients receiving ACEON.
106
5.7 Cough
107
Presumably because of the inhibition of the degradation of endogenous bradykinin, persistent nonproductive cough has been reported with
108
all ACE inhibitors, generally resolving after discontinuation of therapy. Consider ACE inhibitor-induced cough in the differential diagnosis of
109
cough.
110
5.8 Hepatic Failure
111
Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic
112
necrosis and sometimes death. The mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice or
113
marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up.
114
5.9 Surgery/Anesthesia
115
In patients undergoing surgery or during anesthesia with agents that produce hypotension, ACEON may block angiotensin II formation
116
that would otherwise occur secondary to compensatory renin release. Hypotension attributable to this mechanism can be corrected by volume
117
expansion.
118
6
ADVERSE REACTIONS
119
Because clinical trials are conducted under widely varying conditions, adverse event rates observed in the clinical trials of a drug cannot be
120
directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
121
6.1 Clinical Trials Experience
122
The following adverse reactions are discussed elsewhere in labeling:
123
•
Anaphylactoid reactions, including angioedema [see Warnings and Precautions (5.1)]
124
•
Hypotension [see Warnings and Precautions (5.2)]
125
•
Neutropenia and agranulocytosis [see Warnings and Precautions (5.3)]
126
•
Impaired renal function [see Warnings and Precautions (5.5)]
127
•
Hyperkalemia [see Warnings and Precautions (5.6)]
128
•
Cough [see Warnings and Precautions (5.7)]
129
Hypertension
130
ACEON has been evaluated for safety in approximately 3,400 patients with hypertension in U.S. and foreign clinical trials. The data presented
131
here are based on results from the 1,417 ACEON-treated patients who participated in the U.S. clinical trials. Over 220 of these patients were
132
treated with ACEON for at least one year.
133
In placebo-controlled U.S. clinical trials, the incidence of premature discontinuation of therapy due to adverse events was 6.5% in patients
134
treated with ACEON and 6.7% in patients treated with placebo. The most common causes were cough, headache, asthenia and dizziness.
135
Among 1,012 patients in placebo-controlled U.S. trials, the overall frequency of reported adverse events was similar in patients treated
136
with ACEON and in those treated with placebo (approximately 75% in each group). The only adverse events whose incidence on ACEON was at
137
least 2% greater than on placebo were cough (12% vs. 4.5%) and back pain (5.8% vs. 3.1%).
138
Dizziness was not reported more frequently in the perindopril group (8.2%) than in the placebo group (8.5%), but its likelihood increased
139
with dose, suggesting a causal relationship with perindopril.
140
Stable Coronary Artery Disease
141
Perindopril has been evaluated for safety in EUROPA, a double-blind, placebo-controlled study in 12,218 patients with stable coronary
142
artery disease. The overall rate of discontinuation was about 22% on drug and placebo. The most common medical reasons for discontinuation
143
that were more frequent on perindopril than placebo were cough, drug intolerance and hypotension.
144
6.2 Postmarketing Experience
145
Voluntary reports of adverse events in patients taking ACEON that have been received since market introduction and are of unknown
146
causal relationship to ACEON include: cardiac arrest, eosinophilic pneumonitis, neutropenia/agranulocytosis, pancytopenia, anemia (including
147
hemolytic and aplastic), thrombocytopenia, acute renal failure, nephritis, hepatic failure, jaundice (hepatocellular or cholestatic), symptomatic
148
hyponatremia, bullous pemphigoid, pemphigus, acute pancreatitis, falls, psoriasis, exfoliative dermatitis and a syndrome which may include:
149
arthralgia/arthritis, vasculitis, serositis, myalgia, fever, rash or other dermatologic manifestations, a positive antinuclear antibody (ANA),
150
leukocytosis, eosinophilia or an elevated erythrocyte sedimentation rate (ESR).
151
6.3 Clinical Laboratory Test Findings
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152
Hematology: Small decreases in hemoglobin and hematocrit occur frequently in hypertensive patients treated with ACEON, but are rarely of
153
clinical importance. In controlled clinical trials, no patient was discontinued from therapy due to the development of anemia. Leukopenia
154
(including neutropenia) was observed in 0.1% of patients in U.S. clinical trials [see Warnings and Precautions (5.3)].
155
Liver Function Tests: Elevations in ALT (1.6% ACEON versus 0.9% placebo) and AST (0.5% ACEON versus 0.4% placebo) have been
156
observed in placebo-controlled clinical trials. The elevations were generally mild and transient and resolved after discontinuation of therapy.
157
7
DRUG INTERACTIONS
158
7.1 Diuretics
159
Patients on diuretics, and especially those started recently, may occasionally experience an excessive reduction of blood pressure after
160
initiation of ACEON therapy. The possibility of hypotensive effects can be minimized by either decreasing the dose of or discontinuing the
161
diuretic or increasing the salt intake prior to initiation of treatment with perindopril. If diuretic therapy cannot be altered, provide close medical
162
supervision with the first dose of ACEON, for at least two hours and until blood pressure has stabilized for another hour [see Warnings and
163
Precautions (5.2)].
164
The rate and extent of perindopril absorption and elimination are not affected by concomitant diuretics. The bioavailability of perindoprilat
165
was reduced by diuretics, however, and this was associated with a decrease in plasma ACE inhibition.
166
7.2 Potassium Supplements and Potassium-Sparing Diuretics
167
ACEON may increase serum potassium because of its potential to decrease aldosterone production. Use of potassium-sparing diuretics
168
(spironolactone, amiloride, triamterene and others), potassium supplements or other drugs capable of increasing serum potassium (indomethacin,
169
heparin, cyclosporine and others) can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, monitor the
170
patient’s serum potassium frequently.
171
7.3 Lithium
172
Increased serum lithium and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor
173
therapy. Frequent monitoring of serum lithium concentration is recommended. Use of a diuretic may further increase the risk of lithium toxicity.
174
7.4 Gold
175
Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have been reported rarely in patients on therapy
176
with injectable gold (sodium aurothiomalate) and concomitant ACE Inhibitor therapy including ACEON.
177
7.5 Digoxin
178
A controlled pharmacokinetic study has shown no effect on plasma digoxin concentrations when coadministered with ACEON, but an
179
effect of digoxin on the plasma concentration of perindopril/perindoprilat has not been excluded.
180
7.6 Gentamicin
181
Animal data have suggested the possibility of interaction between perindopril and gentamicin. However, this has not been investigated in
182
human studies.
183
7.7
Non-Steroidal Anti-flammatory Agents including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors)
184
In patients who are elderly, volume-depleted (including those on diuretic therapy), or with copromised renal function, co-administration of
185
NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors, including perindopril, may result in deterioration of renal function,
186
including possible actue renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving perindopril
187
and NSAID therapy.
188
The antihypertensive effect of ACE inhibitors, including perindopril, may be attenuated by NSAIDs including selective COX-2 inhibitors.
189
8
USE IN SPECIFIC POPULATIONS
190
8.1 Pregnancy
191
Pregnancy Category D [see Boxed Warning and Warnings and Precautions (5.4)]. Radioactivity was detectable in fetuses after
192
administration of 14C-perindopril to pregnant rats.
193
8.3 Nursing Mothers
194
Milk of lactating rats contained radioactivity following administration of 14C-perindopril. It is not known whether perindopril is secreted
195
in human milk. Because many drugs are secreted in human milk, caution should be exercised when ACEON is given to nursing mothers.
196
8.4 Pediatric Use
197
Safety and effectiveness of ACEON in pediatric patients have not been established.
198
8.5 Geriatric Use
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199
The mean blood pressure effect of perindopril was somewhat smaller in patients over 60 than in younger patients, although the difference
200
was not significant. Plasma concentrations of both perindopril and perindoprilat were increased in elderly patients compared to concentrations
201
in younger patients. No adverse effects were clearly increased in older patients with the exception of dizziness and possibly rash.
202
Start at a low dose and titrate slowly as needed. Monitor for dizziness because of potential for falls.
203
Experience with ACEON in elderly patients at daily doses exceeding 8 mg is limited.
204
8.6 Renal Impairment
205
Dosage adjustment may be necessary in renally impaired patients [see Dosage and Administration (2.3) and Clinical Pharmacology
206
(12.3)].
207
8.7 Hepatic Impairment
208
The bioavailability of perindoprilat is increased in patients with impaired hepatic function [see Clinical Pharmacology (12.3)].
209
10
OVERDOSAGE
210
In animals, doses of perindopril up to 2,500 mg/kg in mice, 3,000 mg/kg in rats and 1,600 mg/kg in dogs were non-lethal. Past experiences
211
were scant but suggested that overdosage with other ACE inhibitors was also fairly well tolerated by humans. The most likely manifestation is
212
hypotension, and treatment should be symptomatic and supportive. Therapy with the ACE inhibitor should be discontinued, and the patient
213
should be observed. Dehydration, electrolyte imbalance and hypotension should be treated by established procedures.
214
Among the reported cases of perindopril overdosage, patients who were known to have ingested a dose of 80 mg to 120 mg required
215
assisted ventilation and circulatory support. One additional patient developed hypothermia, circulatory arrest and died following ingestion of up
216
to 180 mg of perindopril. The intervention for perindopril overdose may require vigorous support.
217
Laboratory determinations of serum levels of perindopril and its metabolites are not widely available, and such determinations have, in any
218
event, no established role in the management of perindopril overdose.
219
No data are available to suggest physiological maneuvers (e.g., maneuvers to change the pH of the urine) that might accelerate elimination
220
of perindopril and its metabolites. Perindopril can be removed by hemodialysis, with clearance of 52 mL/min for perindopril and 67 mL/min for
221
perindoprilat.
222
Angiotensin II could presumably serve as a specific antagonist-antidote in the settling of perindopril overdose, but angiotensin II is
223
essentially unavailable outside of scattered research facilities. Because the hypotensive effect of perindopril is achieved through vasodilation and
224
effective hypovolemia, it is reasonable to treat perindopril overdose by infusion of normal saline solution.
225
11
DESCRIPTION
226
ACEON® (perindopril erbumine) Tablets contain the tert-butylamine salt of perindopril, the ethyl ester of a non-sulfhydryl angiotensin
227
converting enzyme (ACE) inhibitor. Perindopril erbumine is chemically described as (2S,3∝S,7∝S)-1-[(S)-N-[(S)-1-Carboxy
228
butyl]alanyl]hexahydro-2-indolinecarboxylic acid, 1-ethyl ester, compound with tert-butylamine (1:1). Its molecular formula is
229
C19H32N2O5C4H11N. Its structural formula is: structural formula
230
231
Perindopril erbumine is a white, crystalline powder with a molecular weight of 368.47 (free acid) or 441.61 (salt form). It is freely soluble
232
in water (60% w/w), alcohol and chloroform.
233
Perindopril is the free acid form of perindopril erbumine, is a pro-drug and metabolized in vivo by hydrolysis of the ester group to form
234
perindoprilat, the biologically active metabolite.
235
ACEON is available in 2 mg, 4 mg and 8 mg strengths for oral administration. In addition to perindopril erbumine, each tablet contains the
236
following inactive ingredients: colloidal silica (hydrophobic), lactose, magnesium stearate and microcrystalline cellulose. The 4 mg and 8 mg
237
tablets also contain iron oxide.
238
12
CLINICAL PHARMACOLOGY
239
12.1 Mechanism of Action
240
ACEON is a pro-drug for perindoprilat, which inhibits ACE in human subjects and animals. The mechanism through which perindoprilat
241
lowers blood pressure is believed to be primarily inhibition of ACE activity. ACE is a peptidyl dipeptidase that catalyzes conversion of the
242
inactive decapeptide, angiotensin I, to the vasoconstrictor, angiotensin II. Angiotensin II is a potent peripheral vasoconstrictor, which stimulates
243
aldosterone secretion by the adrenal cortex, and provides negative feedback on renin secretion. Inhibition of ACE results in decreased plasma
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244
angiotensin II, leading to decreased vasoconstriction, increased plasma renin activity and decreased aldosterone secretion. The latter results in
245
diuresis and natriuresis and may be associated with a small increase of serum potassium.
246
ACE is identical to kininase II, an enzyme that degrades bradykinin. Whether increased levels of bradykinin, a potent vasodepressor
247
peptide, play a role in the therapeutic effects of ACEON remains to be elucidated.
248
While the principal mechanism of perindopril in blood pressure reduction is believed to be through the renin-angiotensin-aldosterone
249
system, ACE inhibitors have some effect even in apparent low-renin hypertension. Perindopril has been studied in relatively few black patients,
250
usually a low-renin population, and the average response of diastolic blood pressure to perindopril was about half the response seen in nonblack
251
patients, a finding consistent with previous experience of other ACE inhibitors.
252
12.2 Pharmacodynamics
253
After administration of perindopril, ACE is inhibited in a dose and blood concentration-related fashion, with the maximal inhibition of 80
254
to 90% attained by 8 mg persisting for 10 to 12 hours. Twenty-four hour ACE inhibition is about 60% after these doses. The degree of ACE
255
inhibition achieved by a given dose appears to diminish over time (the ID50 increases). The pressor response to an angiotensin I infusion is
256
reduced by perindopril, but this effect is not as persistent as the effect on ACE; there is about 35% inhibition at 24 hours after a 12 mg dose.
257
12.3 Pharmacokinetics
258
Absorption: Oral administration of ACEON results in peak plasma concentrations that occur at approximately 1 hour. The absolute oral
259
bioavailability of perindopril is about 75%. Following absorption, approximately 30 to 50% of systemically available perindopril is hydrolyzed to
260
its active metabolite, perindoprilat, which has a mean bioavailability of about 25%. Peak plasma concentrations of perindoprilat are attained 3 to
261
7 hours after perindopril administration. Oral administration of ACEON with food does not significantly lower the rate or extent of perindopril
262
absorption relative to the fasted state. However, the extent of biotransformation of perindopril to the active metabolite, perindoprilat, is reduced
263
approximately 43%, resulting in a reduction in the plasma ACE inhibition curve of approximately 20%, probably clinically insignificant. In
264
clinical trials, perindopril was generally administered in a non-fasting state.
265
With 4 mg, 8 mg and 16 mg doses of ACEON, Cmax and AUC of perindopril and perindoprilat increase in a dose-proportional manner
266
following both single oral dosing and at steady state during a once-a-day multiple dosing regimen.
267
Distribution: Approximately 60% of circulating perindopril is bound to plasma proteins, and only 10 to 20% of perindoprilat is bound.
268
Therefore, drug interactions mediated through effects on protein binding are not anticipated.
269
Metabolism and Elimination: Following oral administration perindopril exhibits multicompartment pharmacokinetics including a deep tissue
270
compartment (ACE binding sites). The mean half-life of perindopril associated with most of its elimination is approximately 0.8 to 1 hours.
271
Perindopril is extensively metabolized following oral administration, with only 4 to 12% of the dose recovered unchanged in the urine. Six
272
metabolites resulting from hydrolysis, glucuronidation and cyclization via dehydration have been identified. These include the active ACE
273
inhibitor, perindoprilat (hydrolyzed perindopril), perindopril and perindoprilat glucuronides, dehydrated perindopril and the diastereoisomers of
274
dehydrated perindoprilat. In humans, hepatic esterase appears to be responsible for the hydrolysis of perindopril.
275
The active metabolite, perindoprilat, also exhibits multicompartment pharmacokinetics following the oral administration of ACEON.
276
Formation of perindoprilat is gradual with peak plasma concentrations occurring between 3 and 7 hours. The subsequent decline in plasma
277
concentration shows an apparent mean half-life of 3 to 10 hours for the majority of the elimination, with a prolonged terminal elimination half
278
life of 30 to 120 hours resulting from slow dissociation of perindoprilat from plasma/tissue ACE binding sites. During repeated oral once daily
279
dosing with perindopril, perindoprilat accumulates about 1.5- to 2-fold and attains steady state plasma levels in 3 to 6 days. The clearance of
280
perindoprilat and its metabolites is almost exclusively renal.
281
Elderly: Plasma concentrations of both perindopril and perindoprilat in elderly patients (greater than 70 years) are approximately twice those
282
observed in younger patients, reflecting both increased conversion of perindopril to perindoprilat and decreased renal excretion of perindoprilat.
283
[see Dosage and Administration (2.1) and Use In Specific Populations (8.5)].
284
Heart Failure: Perindoprilat clearance is reduced in congestive heart failure patients, resulting in a 40% higher dose interval AUC.
285
Renal Impairment: With perindopril doses of 2 mg to 4 mg, perindoprilat AUC increases with decreasing renal function. At creatinine
286
clearances of 30 to 80 mL/min, AUC is about double that at 100 mL/min. When creatinine clearance drops below 30 mL/min, AUC increases
287
more markedly.
288
In a limited number of patients studied, perindopril clearance by dialysis ranged from about 40 to 80 mL/min. Perindoprilat clearance by
289
dialysis ranged from about 40 to 90 mL/min [see Dosage and Administration (2.3)].
290
Hepatic Impairment: The bioavailability of perindoprilat is increased in patients with impaired hepatic function. Plasma concentrations of
291
perindoprilat in patients with impaired liver function were about 50% higher than those observed in healthy subjects or hypertensive patients
292
with normal liver function.
293
13
NONCLINICAL TOXICOLOGY
294
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
295
Carcinogenicity: No evidence of carcinogenic effect was observed in studies in rats and mice when perindopril was administered at dosages
296
up to 20 times (mg/kg) or 2 to 4 times (mg/m2) the maximum proposed clinical doses (16 mg/day) for 104 weeks.
297
Mutagenesis: No genotoxic potential was detected for ACEON, perindoprilat and other metabolites in various in vitro and in vivo
298
investigations, including the Ames test, the Saccharomyces cerevisiae D4 test, cultured human lymphocytes, TK ± mouse lymphoma assay,
299
mouse and rat micronucleus tests and Chinese hamster bone marrow assay.
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300
Impairment of Fertility: There was no meaningful effect on reproductive performance or fertility in the rat given up to 30 times (mg/kg) or 6
301
times (mg/m2) the proposed maximum clinical dosage of ACEON during the period of spermatogenesis in males or oogenesis and gestation in
302
females.
303
14 CLINICAL STUDIES
304
14.1 Hypertension
305
In placebo-controlled studies of perindopril monotherapy (2 mg to 16 mg once daily) in patients with a mean blood pressure of about
306
150/100 mm Hg, 2 mg had little effect, but doses of 4 mg to 16 mg lowered blood pressure. The 8 mg and 16 mg doses were indistinguishable,
307
and both had a greater effect than the 4 mg dose. In these studies, doses of 8 mg and 16 mg per day gave supine, trough blood pressure reductions
308
of 9 to 15/5 to 6 mm Hg. When once daily and twice daily dosing were compared, the twice daily dosing regimen was generally slightly superior,
309
but by not more than about 0.5 mm Hg to 1 mm Hg. After 2 mg to 16 mg doses of perindopril, the trough mean systolic and diastolic blood
310
pressure effects were about 75 to 100% of peak effects.
311
Perindopril’s effects on blood pressure were similar when given alone or on a background of 25 mg hydrochlorothiazide In general, the
312
effect of perindopril occurred promptly, with effects increasing slightly over several weeks.
313
Formal interaction studies of ACEON have not been carried out with antihypertensive agents other than thiazides. Limited experience in
314
controlled and uncontrolled trials coadministering ACEON with a calcium channel blocker, a loop diuretic or triple therapy (beta-blocker,
315
vasodilator and a diuretic), does not suggest any unexpected interactions. In general, ACE inhibitors have less than additive effects when given
316
with beta-adrenergic blockers, presumably because both work in part through the renin angiotensin system.
317
In uncontrolled studies in patients with insulin-dependent diabetes, perindopril did not appear to affect glycemic control. In long-term use,
318
no effect on urinary protein excretion was seen in these patients.
319
The effectiveness of ACEON was not influenced by sex and it was less effective in black patients than in nonblack patients. In elderly
320
patients (greater than or equal to 60 years), the mean blood pressure effect was somewhat smaller than in younger patients, although the
321
difference was not significant.
322
14.2 Stable Coronary Artery Disease
323
The EURopean trial On reduction of cardiac events with Perindopril in stable coronary Artery disease (EUROPA) was a multicenter,
324
randomized, double-blind and placebo-controlled study conducted in 12,218 patients who had evidence of stable coronary artery disease without
325
clinical heart failure. Patients had evidence of coronary artery disease documented by previous myocardial infarction more than 3 months before
326
screening, coronary revascularization more than 6 months before screening, angiographic evidence of stenosis (at least 70% narrowing of one or
327
more major coronary arteries), or positive stress test in men with a history of chest pain. After a run-in period of 4 weeks during which all patients
328
received perindopril 2 mg to 8 mg, the patients were randomly assigned to perindopril 8 mg once daily (n=6,110) or matching placebo (n=6,108).
329
The mean follow-up was 4.2 years. The study examined the long-term effects of perindopril on time to first event of cardiovascular mortality,
330
nonfatal myocardial infarction, or cardiac arrest in patients with stable coronary artery disease.
331
The mean age of patients was 60 years; 85% were male, 92% were taking platelet inhibitors, 63% were taking β blockers, and 56% were
332
taking lipid-lowering therapy. The EUROPA study showed that perindopril significantly reduced the relative risk for the primary endpoint events
333
(Table 1). This beneficial effect is largely attributable to a reduction in the risk of nonfatal myocardial infarction. This beneficial effect of
334
perindopril on the primary outcome was evident after about one year of treatment (Figure 1). The outcome was similar across all predefined
335
subgroups by age, underlying disease or concomitant medication (Figure 2).
336
Table 1. Primary Endpoint and Relative Risk Reduction
Perindopril
Placebo
RRR
P
(N = 6,110)
(N = 6,108)
(95% CI)
Combined Endpoint
Cardiovascular mortality, nonfatal MI or
488 (8%)
603 (9.9%)
20% (9 to 29)
0.0003
cardiac arrest
Component Endpoint
Cardiovascular mortality
215 (3.5%)
249 (4.1%)
14% (-3 to 28)
0.107
Nonfatal MI
295 (4.8%)
378 (6.2%)
22% (10 to 33)
0.001
Cardiac arrest
6 (0.1%)
11 (0.2%)
46% (-47 to 80)
0.22
CI=confidence interval; RRR: relative risk reduction; MI: myocardial infarction
337
Figure 1. Time to First Occurrence of Primary Endpoint
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graph
338
339
Figure 2. Beneficial Effect of Perindopril Treatment on Primary Endpoint
340
in Predefined Subgroups
341
342
Size of squares proportional to the number of patients in that group. Dashed line indicates overall relative risk.
343
16
HOW SUPPLIED/STORAGE AND HANDLING
344
Tablets are oblong with a score on one side.
Tablets
Appearance
NDC (Bottles of 100)
2 mg
White, debossed “ACN 2” on
unscored side
NDC 0032-1101-01
4 mg
Pink, debossed “ACN 4” on
unscored side
NDC 0032-1102-01
8 mg
Salmon-colored, debossed
“ACN 8” on unscored side
NDC 0032-1103-01
345
Keep out of the reach of children.
346
Store at controlled room temperature 20° to 25°C (68° to 77°F) [see USP]. Protect from moisture. logo
For further information, please call our medical communications department
toll-free 1-800-241-1643.
347
17
PATIENT COUNSELING INFORMATION
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348
349
350
351
352
353
354
355
356
357
358
359
360
361
362
Inform female patients of childbearing age that use of drugs, such as ACEON, that act on the renin-angiotensin system during pregnancy
may cause serious problems in the fetus and infant. Patients taking ACEON who are or plan to become pregnant should immediately notify
their healthcare provider.
Tell patients to report immediately signs or symptoms suggesting angioedema (swelling of face, extremities, eyes, lips, tongue, hoarseness
or difficulty in swallowing or breathing) and to take no more drug before consulting a healthcare provider.
Tell patients to report promptly any indication of infection (e.g., sore throat, fever) which could be a sign of neutropenia.
Manufactured by:
Patheon Pharmaceuticals, Inc.
Cincinnati, OH 45237 USA
Marketed by:
Abbott Laboratories
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Reference ID: 3004831
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HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
®
ACEON safely and effectively. See full prescribing information for
ACEON.
ACEON (perindopril erbumine) 2, 4 and 8 mg Tablets
Initial U.S. Approval: 1993
WARNING: FETAL TOXICITY
See full prescribing information for complete boxed warning.
When pregnancy is detected, discontinue ACEON as soon as
possible. (5.4)
Drugs that act directly on the renin-angiotensin system can cause injury
and death to the developing fetus. (5.4)
-------INDICATIONS AND USAGE -------
ACEON is indicated for the treatment of patients with essential
hypertension (1.1)
ACEON is indicated for treatment of patients with stable coronary
artery disease to reduce the risk of cardiovascular mortality or
nonfatal myocardial infarction (1.2)
-------DOSAGE AND ADMINISTRATION -------
Hypertension
The recommended initial dose is 4 mg once a day. The dosage may
be titrated upward until blood pressure, when measured just before
the next dose, is controlled or to a maximum of 16 mg per day (2.1)
Stable Coronary Artery Disease
ACEON should be given at an initial dose of 4 mg once daily for 2
weeks, and then increased, as tolerated, to a maintenance dose of 8
mg once daily (2.2)
-------DOSAGE FORMS AND STRENGTHS -------
Tablets: 2, 4 and 8 mg (3)
-------CONTRAINDICATIONS -------
Angioedema related to previous treatment with an ACE inhibitor, or
a history of hereditary or idiopathic angioedema (4.0, 5.1)
-------WARNINGS AND PRECAUTIONS -------
Watch for anaphylactoid reactions, including angioedema (5.1)
Monitor renal function during therapy (5.8)
Assess for hypotension and hyperkalemia (5.2, 5.6)
-------ADVERSE REACTIONS-------
Hypertension: Most common adverse events (incidence greater
than or equal to 5%) are cough, dizziness and back pain (6.1)
Stable Coronary Artery Disease: Most common adverse events
leading to discontinuation were cough, drug intolerance, and
hypotension (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact XOMA
(US) LLC at 1-800-718-9884 or FDA at 1-800-FDA-1088 or
www.FDA.gov/Medwatch.
-------DRUG INTERACTIONS -------
Diuretics: Excessive drop in blood pressure (7.1)
Potassium-sparing diuretics/potassium supplements: Hyperkalemia
(7.2)
Lithium: Increase serum lithium levels, symptoms of lithium
toxicity (7.3)
Injectable gold: Nitritoid reactions (facial flushing, nausea,
vomiting, and hypotension) (7.4)
NSAID use may lead to increased risk of renal impairment and loss
of antihypertensive effect (7.7)
-------USE IN SPECIFIC POPULATIONS -------
Geriatrics: Start at low daily dose (4 mg or less) and titrate slowly
as needed. Experience with doses exceeding 8 mg is limited (8.5)
Dosage adjustment may be necessary in renally impaired patients
(8.7)
See 17 for PATIENT COUNSELING INFORMATION
Revised: 03/2012
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: AVOID USE IN PREGNANCY
1 INDICATIONS AND USAGE
1.1 Hypertension
1.2 Stable Coronary Artery Disease
2 DOSAGE AND ADMINISTRATION
2.1 Hypertension
2.2 Stable Coronary Artery Disease
2.3 Dose Adjustment in Renal Impairment and Dialysis
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Anaphylactoid and Possibly Related Reactions
5.2 Hypotension
5.3 Neutropenia/Agranulocytosis
5.4 Fetal Toxicity
5.5 Impaired Renal Function
5.6 Hyperkalemia
5.7 Cough
5.8 Hepatic Failure
5.9 Surgery/Anesthesia
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
6.2 Postmarketing Experience
6.3 Clinical Laboratory Test Findings
7 DRUG INTERACTIONS
7.1 Diuretics
7.2 Potassium Supplements and Potassium-Sparing Diuretics
7.3 Lithium
7.4 Gold
7.5 Digoxin
7.6 Gentamicin
7.7 Non-Steroidal Anti-Inflammatory Agents including Selective
Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors)
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Renal Impairment
8.7 Hepatic Impairment
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
14.1 Hypertension
14.2 Stable Coronary Artery Disease
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
* Sections or subsections omitted from the full prescribing information are not
listed
Reference ID: 3114775
FULL PRESCRIBING INFORMATION
WARNING: FETAL TOXICITY
When pregnancy is detected, discontinue ACEON as soon as possible. (5.4)
Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus. (5.4)
1 INDICATIONS AND USAGE
1.1 Hypertension
ACEON is indicated for the treatment of patients with essential hypertension. ACEON may be used alone or
given with other classes of antihypertensives, especially thiazide diuretics.
1.2 Stable Coronary Artery Disease
ACEON is indicated for treatment of patients with stable coronary artery disease to reduce the risk of
cardiovascular mortality or nonfatal myocardial infarction. ACEON can be used with conventional treatment for
management of coronary artery disease, such as antiplatelet, antihypertensive or lipid-lowering therapy.
2 DOSAGE AND ADMINISTRATION
2.1 Hypertension
Use in Uncomplicated Hypertensive Patients: In patients with essential hypertension, the recommended initial
dose is 4 mg once a day. The dose may be titrated, as needed to a maximum of 16 mg per day. The usual
maintenance dose range is 4 mg to 8 mg administered as a single daily dose or in two divided doses.
Use in Elderly Patients: The recommended initial daily dosage of ACEON for the elderly is 4 mg daily, given
in one or two divided doses. Experience with ACEON is limited in the elderly at doses exceeding 8 mg.
Dosages above 8 mg should be administered with careful blood pressure monitoring and dose titration [see Use
in Specific Populations (8.5)].
Use with Diuretics: In patients who are currently being treated with a diuretic, symptomatic hypotension can
occur following the initial dose of ACEON. Consider reducing the dose of diuretic prior to starting ACEON
[see Drug Interactions (7.1)].
2.2 Stable Coronary Artery Disease
In patients with stable coronary artery disease, ACEON should be given at an initial dose of 4 mg once daily for
2 weeks, and then increased as tolerated, to a maintenance dose of 8 mg once daily. In elderly patients (greater
than 70 years), ACEON should be given as a 2 mg dose once daily in the first week, followed by 4 mg once
daily in the second week and 8 mg once daily for maintenance dose if tolerated.
Reference ID: 3114775
2.3 Dose Adjustment in Renal Impairment and Dialysis
Perindoprilat elimination is decreased in renally impaired patients. ACEON is not recommended in patients
with creatinine clearance <30 mL/min. For patients with lesser degrees of impairment, the initial dosage should
be 2 mg/day and dosage should not exceed 8 mg/day. During dialysis, perindopril is removed with the same
clearance as in patients with normal renal function.
3 DOSAGE FORMS AND STRENGTHS
Tablets are oblong with a score on one side.
2 mg tablet is white and debossed on the unscored side with “ACN 2”.
4 mg tablet is pink and debossed on the unscored side with “ACN 4”.
8 mg tablet is salmon and debossed on the unscored side with “ACN 8”.
4 CONTRAINDICATIONS
ACEON® (perindopril erbumine) is contraindicated in patients known to be hypersensitive (including
angioedema) to this product or to any other ACE inhibitor. ACEON is also contraindicated in patients with
hereditary or idiopathic angioedema.
5 WARNINGS AND PRECAUTIONS
5.1 Anaphylactoid and Possibly Related Reactions
Presumably because angiotensin-converting enzyme inhibitors affect the metabolism of eicosanoids and
polypeptides, including endogenous bradykinin, patients receiving ACE inhibitors (including ACEON) may be
subject to a variety of adverse events, some of them serious. Black patients receiving ACE inhibitors have a
higher incidence of angioedema compared to nonblacks.
Head and Neck Angioedema: Angioedema of the face, extremities, lips, tongue, glottis, or larynx has been
reported in patients treated with ACE inhibitors, including ACEON (0.1% of patients treated with ACEON in
U.S. clinical trials). Angioedema associated with involvement of the tongue, glottis or larynx may be fatal. In
such cases, discontinue ACEON treatment immediately and observe until the swelling disappears. When
involvement of the tongue, glottis, or larynx appears likely to cause airway obstruction, administer appropriate
therapy, such as subcutaneous epinephrine solution 1:1000 (0.3 to 0.5 mL), promptly.
Intestinal Angioedema: Intestinal angioedema has been reported in patients treated with ACE inhibitors. These
patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior
history of facial angioedema and C-1 esterase levels were normal. The angioedema was diagnosed by
procedures including abdominal CT scan or ultrasound, or at surgery, and symptoms resolved after stopping the
ACE inhibitor. Intestinal angioedema should be included in the differential diagnosis of patients on ACE
inhibitors presenting with abdominal pain.
Reference ID: 3114775
5.2 Hypotension
ACEON can cause symptomatic hypotension. ACEON has been associated with hypotension in 0.3% of
uncomplicated hypertensive patients in U.S. placebo-controlled trials. Symptoms related to orthostatic
hypotension were reported in another 0.8% of patients.
Symptomatic hypotension is most likely to occur in patients who have been volume or salt-depleted as a result
of prolonged diuretic therapy, dietary salt restriction, dialysis, diarrhea or vomiting [see Dosage and
Administration (2.1)].
ACE inhibitors may cause excessive hypotension, and may be associated with oliguria or azotemia, and rarely
with acute renal failure and death. In patients with ischemic heart disease or cerebrovascular disease, an
excessive fall in blood pressure could result in a myocardial infarction or a cerebrovascular accident.
In patients at risk of excessive hypotension, ACEON therapy should be started under very close medical
supervision. Patients should be followed closely for the first two weeks of treatment and whenever the dose of
ACEON and/or diuretic is increased.
If excessive hypotension occurs, the patient should be placed immediately in a supine position and, if necessary,
treated with an intravenous infusion of physiological saline. ACEON treatment can usually be continued
following restoration of volume and blood pressure.
5.3 Neutropenia/Agranulocytosis
ACE inhibitors have been associated with agranulocytosis and bone marrow depression, most frequently in
patients with renal impairment, especially patients with a collagen vascular disease such as systemic lupus
erythematosus or scleroderma.
5.4 Fetal Toxicity
Pregnancy Category D
Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy
reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios
can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects
include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected discontinue
ACEON as soon as possible [see Use in specific Populations (8.1)].
5.5 Impaired Renal Function
As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be
anticipated in susceptible individuals. Renal function should be monitored periodically in patients receiving
ACEON [see Dosage and Administration (2.3)].
Reference ID: 3114775
In patients with severe congestive heart failure, where renal function may depend on the activity of the renin
angiotensin-aldosterone system, treatment with ACE inhibitors, including ACEON, may be associated with
oliguria, progressive azotemia, and, rarely, acute renal failure and death.
In hypertensive patients with unilateral or bilateral renal artery stenosis, increases in blood urea nitrogen and
serum creatinine may occur; usually reversible upon discontinuation of the ACE inhibitor . In such patients,
renal function should be monitored during the first few weeks of therapy.
Some ACEON-treated patients have developed minor and transient increases in blood urea nitrogen and serum
creatinine especially in those concomitantly treated with a diuretic.
5.6 Hyperkalemia
Elevations of serum potassium have been observed in some patients treated with ACE inhibitors, including
ACEON. Most cases were isolated single values that did not appear clinically relevant and were rarely a cause
for withdrawal. Risk factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus
and the concomitant use of agents such as potassium-sparing diuretics, potassium supplements and/or
potassium-containing salt substitutes [see Drug Interactions (7.2)].
Serum potassium should be monitored periodically in patients receiving ACEON.
5.7 Cough
Presumably because of the inhibition of the degradation of endogenous bradykinin, persistent nonproductive
cough has been reported with all ACE inhibitors, generally resolving after discontinuation of therapy. Consider
ACE inhibitor-induced cough in the differential diagnosis of cough.
5.8 Hepatic Failure
Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and
progresses to fulminant hepatic necrosis and sometimes death. The mechanism of this syndrome is not
understood. Patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes
should discontinue the ACE inhibitor and receive appropriate medical follow-up.
5.9 Surgery/Anesthesia
In patients undergoing surgery or during anesthesia with agents that produce hypotension, ACEON may block
angiotensin II formation that would otherwise occur secondary to compensatory renin release. Hypotension
attributable to this mechanism can be corrected by volume expansion.
6 ADVERSE REACTIONS
Because clinical trials are conducted under widely varying conditions, adverse event rates observed in the
clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not
reflect the rates observed in practice.
Reference ID: 3114775
6.1 Clinical Trials Experience
The following adverse reactions are discussed elsewhere in labeling:
• Anaphylactoid reactions, including angioedema [see Warnings and Precautions (5.1)]
• Hypotension [see Warnings and Precautions (5.2)]
• Neutropenia and agranulocytosis [see Warnings and Precautions (5.3)]
• Impaired renal function [see Warnings and Precautions (5.5)]
• Hyperkalemia [see Warnings and Precautions (5.6)]
• Cough [see Warnings and Precautions (5.7)]
Hypertension
ACEON has been evaluated for safety in approximately 3,400 patients with hypertension in U.S. and foreign
clinical trials. The data presented here are based on results from the 1,417 ACEON-treated patients who
participated in the U.S. clinical trials. Over 220 of these patients were treated with ACEON® (perindopril
erbumine) for at least one year.
In placebo-controlled U.S. clinical trials, the incidence of premature discontinuation of therapy due to adverse
events was 6.5% in patients treated with ACEON and 6.7% in patients treated with placebo. The most common
causes were cough, headache, asthenia and dizziness.
Among 1,012 patients in placebo-controlled U.S. trials, the overall frequency of reported adverse events was
similar in patients treated with ACEON and in those treated with placebo (approximately 75% in each group).
The only adverse events whose incidence on ACEON was at least 2% greater than on placebo were cough (12%
vs. 4.5%) and back pain (5.8% vs. 3.1%).
Dizziness was not reported more frequently in the perindopril group (8.2%) than in the placebo group (8.5%),
but its likelihood increased with dose, suggesting a causal relationship with perindopril.
Stable Coronary Artery Disease
Perindopril has been evaluated for safety in EUROPA, a double-blind, placebo-controlled study in 12,218
patients with stable coronary artery disease. The overall rate of discontinuation was about 22% on drug and
placebo. The most common medical reasons for discontinuation that were more frequent on perindopril than
placebo were cough, drug intolerance and hypotension.
6.2 Postmarketing Experience
Voluntary reports of adverse events in patients taking ACEON that have been received since market
introduction and are of unknown causal relationship to ACEON include: cardiac arrest, eosinophilic
pneumonitis, neutropenia/agranulocytosis, pancytopenia, anemia (including hemolytic and aplastic),
Reference ID: 3114775
thrombocytopenia, acute renal failure, nephritis, hepatic failure, jaundice (hepatocellular or cholestatic),
symptomatic hyponatremia, bullous pemphigoid, pemphigus, acute pancreatitis, falls, psoriasis, exfoliative
dermatitis and a syndrome which may include: arthralgia/arthritis, vasculitis, serositis, myalgia, fever, rash or
other dermatologic manifestations, a positive antinuclear antibody (ANA), leukocytosis, eosinophilia or an
elevated erythrocyte sedimentation rate (ESR).
6.3 Clinical Laboratory Test Findings
Hematology: Small decreases in hemoglobin and hematocrit occur frequently in hypertensive patients treated
with ACEON, but are rarely of clinical importance. In controlled clinical trials, no patient was discontinued
from therapy due to the development of anemia. Leukopenia (including neutropenia) was observed in 0.1% of
patients in U.S. clinical trials [see Warnings and Precautions (5.3)].
Liver Function Tests: Elevations in ALT (1.6% ACEON versus 0.9% placebo) and AST (0.5% ACEON versus
0.4% placebo) have been observed in placebo-controlled clinical trials. The elevations were generally mild and
transient and resolved after discontinuation of therapy.
7 DRUG INTERACTIONS
7.1 Diuretics
Patients on diuretics, and especially those started recently, may occasionally experience an excessive reduction
of blood pressure after initiation of ACEON therapy. The possibility of hypotensive effects can be minimized
by either decreasing the dose of or discontinuing the diuretic or increasing the salt intake prior to initiation of
treatment with perindopril. If diuretic therapy cannot be altered, provide close medical supervision with the first
dose of ACEON, for at least two hours and until blood pressure has stabilized for another hour [see Warnings
and Precautions (5.2)].
The rate and extent of perindopril absorption and elimination are not affected by concomitant diuretics. The
bioavailability of perindoprilat was reduced by diuretics, however, and this was associated with a decrease in
plasma ACE inhibition.
7.2 Potassium Supplements and Potassium-Sparing Diuretics
ACEON may increase serum potassium because of its potential to decrease aldosterone production. Use of
potassium-sparing diuretics (spironolactone, amiloride, triamterene and others), potassium supplements or other
drugs capable of increasing serum potassium (indomethacin, heparin, cyclosporine and others) can increase the
risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, monitor the patient's serum
potassium frequently.
7.3 Lithium
Increased serum lithium and symptoms of lithium toxicity have been reported in patients receiving concomitant
lithium and ACE inhibitor therapy. Frequent monitoring of serum lithium concentration is recommended. Use
of a diuretic may further increase the risk of lithium toxicity.
Reference ID: 3114775
7.4 Gold
Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have been reported
rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE Inhibitor
therapy including ACEON.
7.5 Digoxin
A controlled pharmacokinetic study has shown no effect on plasma digoxin concentrations when
coadministered with ACEON, but an effect of digoxin on the plasma concentration of perindopril/perindoprilat
has not been excluded.
7.6 Gentamicin
Animal data have suggested the possibility of interaction between perindopril and gentamicin. However, this
has not been investigated in human studies.
7.7 Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors (COX-2
Inhibitors)
In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal
function, co-administration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors, including
perindopril, may result in deterioration of renal function, including possible acute renal failure. These effects are
usually reversible. Monitor renal function periodically in patients receiving perindopril and NSAID therapy.
The antihypertensive effect of ACE inhibitors, including perindopril, may be attenuated by NSAIDs including
selective COX-2 inhibitors.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category D [see Boxed Warning and Warnings and Precautions (5.4)].
Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy
reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios
can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects
include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue
ACEON as soon as possible. These adverse outcomes are usually associated with use of these drugs in the
second and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after
exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin
angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension
during pregnancy is important to optimize outcomes for both mother and fetus.
In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin
system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound
examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue ACEON,
Reference ID: 3114775
unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of
pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after
the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to ACEON
for hypotension, oliguria, and hyperkalemia. [see Use in Specific Populations(8.4)]
Radioactivity was detectable in fetuses after administration of 14C-perindopril to pregnant rats.
8.3 Nursing Mothers
Milk of lactating rats contained radioactivity following administration of 14C-perindopril. It is not known
whether perindopril is secreted in human milk. Because many drugs are secreted in human milk, caution should
be exercised when ACEON is given to nursing mothers.
8.4 Pediatric Use
Neonates with a history of in utero exposure to ACEON:
If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion.
Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for
disordered renal function. Perindopril, which crosses the placenta, can theoretically be removed from the
neonatal circulation by these means, but limited experience has not shown that such removal is central to the
treatment of these infants.
Safety and effectiveness of ACEON in pediatric patients have not been established.
8.5 Geriatric Use
The mean blood pressure effect of perindopril was somewhat smaller in patients over 60 than in younger
patients, although the difference was not significant. Plasma concentrations of both perindopril and
perindoprilat were increased in elderly patients compared to concentrations in younger patients. No adverse
effects were clearly increased in older patients with the exception of dizziness and possibly rash.
Start at a low dose and titrate slowly as needed. Monitor for dizziness because of potential for falls.
Experience with ACEON in elderly patients at daily doses exceeding 8 mg is limited.
8.6 Renal Impairment
Dosage adjustment may be necessary in renally impaired patients [see Dosage and Administration (2.3) and
Clinical Pharmacology (12.3)].
8.7 Hepatic Impairment
The bioavailability of perindoprilat is increased in patients with impaired hepatic function [see Clinical
Pharmacology (12.3)].
Reference ID: 3114775
10 OVERDOSAGE
In animals, doses of perindopril up to 2,500 mg/kg in mice, 3,000 mg/kg in rats and 1,600 mg/kg in dogs were
non-lethal. Past experiences were scant but suggested that overdosage with other ACE inhibitors was also fairly
well tolerated by humans. The most likely manifestation is hypotension, and treatment should be symptomatic
and supportive. Therapy with the ACE inhibitor should be discontinued, and the patient should be observed.
Dehydration, electrolyte imbalance and hypotension should be treated by established procedures.
Among the reported cases of perindopril overdosage, patients who were known to have ingested a dose of 80
mg to 120 mg required assisted ventilation and circulatory support. One additional patient developed
hypothermia, circulatory arrest and died following ingestion of up to 180 mg of perindopril. The intervention
for perindopril overdose may require vigorous support.
Laboratory determinations of serum levels of perindopril and its metabolites are not widely available, and such
determinations have, in any event, no established role in the management of perindopril overdose.
No data are available to suggest physiological maneuvers (e.g., maneuvers to change the pH of the urine) that
might accelerate elimination of perindopril and its metabolites. Perindopril can be removed by hemodialysis,
with clearance of 52 mL/min for perindopril and 67 mL/min for perindoprilat.
Angiotensin II could presumably serve as a specific antagonist-antidote in the settling of perindopril overdose,
but angiotensin II is essentially unavailable outside of scattered research facilities. Because the hypotensive
effect of perindopril is achieved through vasodilation and effective hypovolemia, it is reasonable to treat
perindopril overdose by infusion of normal saline solution.
11 DESCRIPTION
ACEON® (perindopril erbumine) Tablets contain the tert-butylamine salt of perindopril, the ethyl ester of a
non-sulfhydryl angiotensin-converting enzyme (ACE) inhibitor. Perindopril erbumine is chemically described
as (2S,3∝S,7∝S)-1-[(S)-N-[(S)-1-Carboxy-butyl]alanyl]hexahydro-2-indolinecarboxylic acid, 1-ethyl ester,
compound with tert-butylamine (1:1). Its molecular formula is C19H32N2O5C4H11N. Its structural formula is: structural formula
Perindopril erbumine is a white, crystalline powder with a molecular weight of 368.47 (free acid) or 441.61 (salt
form). It is freely soluble in water (60% w/w), alcohol and chloroform.
Perindopril is the free acid form of perindopril erbumine, is a pro-drug and metabolized in vivo by hydrolysis of
the ester group to form perindoprilat, the biologically active metabolite.
Reference ID: 3114775
ACEON is available in 2 mg, 4 mg and 8 mg strengths for oral administration. In addition to perindopril
erbumine, each tablet contains the following inactive ingredients: colloidal silica (hydrophobic), lactose,
magnesium stearate and microcrystalline cellulose. The 4 mg and 8 mg tablets also contain iron oxide.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
ACEON® (perindopril erbumine) is a pro-drug for perindoprilat, which inhibits ACE in human subjects and
animals. The mechanism through which perindoprilat lowers blood pressure is believed to be primarily
inhibition of ACE activity. ACE is a peptidyl dipeptidase that catalyzes conversion of the inactive decapeptide,
angiotensin I, to the vasoconstrictor, angiotensin II. Angiotensin II is a potent peripheral vasoconstrictor, which
stimulates aldosterone secretion by the adrenal cortex, and provides negative feedback on renin secretion.
Inhibition of ACE results in decreased plasma angiotensin II, leading to decreased vasoconstriction, increased
plasma renin activity and decreased aldosterone secretion. The latter results in diuresis and natriuresis and may
be associated with a small increase of serum potassium.
ACE is identical to kininase II, an enzyme that degrades bradykinin. Whether increased levels of bradykinin, a
potent vasodepressor peptide, play a role in the therapeutic effects of ACEON remains to be elucidated.
While the principal mechanism of perindopril in blood pressure reduction is believed to be through the renin
angiotensin-aldosterone system, ACE inhibitors have some effect even in apparent low-renin hypertension.
Perindopril has been studied in relatively few black patients, usually a low-renin population, and the average
response of diastolic blood pressure to perindopril was about half the response seen in nonblack patients, a
finding consistent with previous experience of other ACE inhibitors.
12.2 Pharmacodynamics
After administration of perindopril, ACE is inhibited in a dose and blood concentration-related fashion, with the
maximal inhibition of 80 to 90% attained by 8 mg persisting for 10 to 12 hours. Twenty-four hour ACE
inhibition is about 60% after these doses. The degree of ACE inhibition achieved by a given dose appears to
diminish over time (the ID50 increases). The pressor response to an angiotensin I infusion is reduced by
perindopril, but this effect is not as persistent as the effect on ACE; there is about 35% inhibition at 24 hours
after a 12 mg dose.
12.3 Pharmacokinetics
Absorption: Oral administration of ACEON results in peak plasma concentrations that occur at approximately 1
hour. The absolute oral bioavailability of perindopril is about 75%. Following absorption, approximately 30 to
50% of systemically available perindopril is hydrolyzed to its active metabolite, perindoprilat, which has a
mean bioavailability of about 25%. Peak plasma concentrations of perindoprilat are attained 3 to 7 hours after
perindopril administration. Oral administration of ACEON with food does not significantly lower the rate or
extent of perindopril absorption relative to the fasted state. However, the extent of biotransformation of
perindopril to the active metabolite, perindoprilat, is reduced approximately 43%, resulting in a reduction in the
Reference ID: 3114775
plasma ACE inhibition curve of approximately 20%, probably clinically insignificant. In clinical trials,
perindopril was generally administered in a non-fasting state.
With 4 mg, 8 mg and 16 mg doses of ACEON, Cmax and AUC of perindopril and perindoprilat increase in a
dose-proportional manner following both single oral dosing and at steady state during a once-a-day multiple
dosing regimen.
Distribution: Approximately 60% of circulating perindopril is bound to plasma proteins, and only 10 to 20% of
perindoprilat is bound. Therefore, drug interactions mediated through effects on protein binding are not
anticipated.
Metabolism and Elimination: Following oral administration perindopril exhibits multicompartment
pharmacokinetics including a deep tissue compartment (ACE binding sites). The mean half-life of perindopril
associated with most of its elimination is approximately 0.8 to 1 hours.
Perindopril is extensively metabolized following oral administration, with only 4 to 12% of the dose recovered
unchanged in the urine. Six metabolites resulting from hydrolysis, glucuronidation and cyclization via
dehydration have been identified. These include the active ACE inhibitor, perindoprilat (hydrolyzed
perindopril), perindopril and perindoprilat glucuronides, dehydrated perindopril and the diastereoisomers of
dehydrated perindoprilat. In humans, hepatic esterase appears to be responsible for the hydrolysis of
perindopril.
The active metabolite, perindoprilat, also exhibits multicompartment pharmacokinetics following the oral
administration of ACEON. Formation of perindoprilat is gradual with peak plasma concentrations occurring
between 3 and 7 hours. The subsequent decline in plasma concentration shows an apparent mean half-life of 3
to 10 hours for the majority of the elimination, with a prolonged terminal elimination half-life of 30 to 120
hours resulting from slow dissociation of perindoprilat from plasma/tissue ACE binding sites. During repeated
oral once daily dosing with perindopril, perindoprilat accumulates about 1.5 to 2 fold and attains steady state
plasma levels in 3 to 6 days. The clearance of perindoprilat and its metabolites is almost exclusively renal.
Elderly: Plasma concentrations of both perindopril and perindoprilat in elderly patients (greater than 70 years)
are approximately twice those observed in younger patients, reflecting both increased conversion of perindopril
to perindoprilat and decreased renal excretion of perindoprilat [see Dosage and Administration (2.1) and Use In
Specific Populations (8.5)].
Heart Failure: Perindoprilat clearance is reduced in congestive heart failure patients, resulting in a 40% higher
dose interval AUC.
Renal Impairment: With perindopril doses of 2 mg to 4 mg, perindoprilat AUC increases with decreasing renal
function. At creatinine clearances of 30 to 80 mL/min, AUC is about double that at 100 mL/min. When
creatinine clearance drops below 30 mL/min, AUC increases more markedly.
In a limited number of patients studied, perindopril clearance by dialysis ranged from about 40 to 80 mL/min.
Perindoprilat clearance by dialysis ranged from about 40 to 90 mL/min [see Dosage and Administration (2.3)].
Reference ID: 3114775
Hepatic Impairment: The bioavailability of perindoprilat is increased in patients with impaired hepatic
function. Plasma concentrations of perindoprilat in patients with impaired liver function were about 50% higher
than those observed in healthy subjects or hypertensive patients with normal liver function.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity: No evidence of carcinogenic effect was observed in studies in rats and mice when perindopril
was administered at dosages up to 20 times (mg/kg) or 2 to 4 times (mg/m2) the maximum proposed clinical
doses (16 mg/day) for 104 weeks.
Mutagenesis: No genotoxic potential was detected for ACEON, perindoprilat and other metabolites in various
in vitro and in vivo investigations, including the Ames test, the Saccharomyces cerevisiae D4 test, cultured
human lymphocytes, TK ± mouse lymphoma assay, mouse and rat micronucleus tests and Chinese hamster
bone marrow assay.
Impairment of Fertility: There was no meaningful effect on reproductive performance or fertility in the rat
given up to 30 times (mg/kg) or 6 times (mg/m2) the proposed maximum clinical dosage of ACEON during the
period of spermatogenesis in males or oogenesis and gestation in females.
14 CLINICAL STUDIES
14.1 Hypertension
In placebo-controlled studies of perindopril monotherapy (2 mg to 16 mg once daily) in patients with a mean
blood pressure of about 150/100 mm Hg, 2 mg had little effect, but doses of 4 mg to 16 mg lowered blood
pressure. The 8 mg and 16 mg doses were indistinguishable, and both had a greater effect than the 4 mg dose. In
these studies, doses of 8 mg and 16 mg per day gave supine, trough blood pressure reductions of 9 to 15/5 to 6
mm Hg. When once daily and twice daily dosing were compared, the twice daily dosing regimen was generally
slightly superior, but by not more than about 0.5 mm Hg to 1 mm Hg. After 2 mg to 16 mg doses of perindopril,
the trough mean systolic and diastolic blood pressure effects were about 75 to 100% of peak effects.
Perindopril's effects on blood pressure were similar when given alone or on a background of 25 mg
hydrochlorothiazide In general, the effect of perindopril occurred promptly, with effects increasing slightly over
several weeks.
Formal interaction studies of ACEON® (perindopril erbumine) have not been carried out with antihypertensive
agents other than thiazides. Limited experience in controlled and uncontrolled trials coadministering ACEON
with a calcium channel blocker, a loop diuretic or triple therapy (beta-blocker, vasodilator and a diuretic), does
not suggest any unexpected interactions. In general, ACE inhibitors have less than additive effects when given
with beta-adrenergic blockers, presumably because both work in part through the renin angiotensin system.
In uncontrolled studies in patients with insulin-dependent diabetes, perindopril did not appear to affect glycemic
control. In long-term use, no effect on urinary protein excretion was seen in these patients.
Reference ID: 3114775
The effectiveness of ACEON was not influenced by sex and it was less effective in black patients than in
nonblack patients. In elderly patients (greater than or equal to 60 years), the mean blood pressure effect was
somewhat smaller than in younger patients, although the difference was not significant.
14.2 Stable Coronary Artery Disease
The EURopean trial On reduction of cardiac events with Perindopril in stable coronary Artery disease
(EUROPA) was a multicenter, randomized, double-blind and placebo-controlled study conducted in 12,218
patients who had evidence of stable coronary artery disease without clinical heart failure. Patients had evidence
of coronary artery disease documented by previous myocardial infarction more than 3 months before screening,
coronary revascularization more than 6 months before screening, angiographic evidence of stenosis (at least
70% narrowing of one or more major coronary arteries), or positive stress test in men with a history of chest
pain. After a run-in period of 4 weeks during which all patients received perindopril 2 mg to 8 mg, the patients
were randomly assigned to perindopril 8 mg once daily (n=6,110) or matching placebo (n=6,108). The mean
follow-up was 4.2 years. The study examined the long-term effects of perindopril on time to first event of
cardiovascular mortality, nonfatal myocardial infarction, or cardiac arrest in patients with stable coronary artery
disease.
The mean age of patients was 60 years; 85% were male, 92% were taking platelet inhibitors, 63% were taking β
blockers, and 56% were taking lipid-lowering therapy. The EUROPA study showed that perindopril
significantly reduced the relative risk for the primary endpoint events (Table 1). This beneficial effect is largely
attributable to a reduction in the risk of nonfatal myocardial infarction. This beneficial effect of perindopril on
the primary outcome was evident after about one year of treatment (Figure 1). The outcome was similar across
all predefined subgroups by age, underlying disease or concomitant medication (Figure 2).
Table 1. Primary Endpoint and Relative Risk Reduction
Perindopril
Placebo
RRR
P
(N = 6,110)
(N = 6,108) (95% CI)
Combined Endpoint
Cardiovascular mortality, nonfatal MI or
cardiac arrest
488 (8%)
603 (9.9%)
20% (9 to
29)
0.0003
Component Endpoint
Cardiovascular mortality
215 (3.5%)
249 (4.1%)
14% (-3
0.107
to 28)
Nonfatal MI
295 (4.8%)
378 (6.2%)
22% (10
0.001
to 33)
Cardiac arrest
6 (0.1%)
11 (0.2%)
46% (-47
0.22
to 80)
CI=confidence interval; RRR: relative risk reduction; MI: myocardial infarction
Figure 1. Time to First Occurrence of Primary Endpoint
Reference ID: 3114775
graph
Figure 2. Beneficial Effect of Perindopril Treatment on Primary Endpoint
in Predefined Subgroups
Reference ID: 3114775
Tablets
Appearance
NDC (Bottles of 100)
2 mg
White, debossed “ACN 2” on unscored side
NDC 76234-000-01
4 mg
Pink, debossed “ACN 4” on unscored side
NDC 76234-001-01
8 mg
Salmon-colored, debossed “ACN 8” on unscored side
NDC 76234-002-01
16 HOW SUPPLIED/STORAGE AND HANDLING
Tablets are oblong with a score on one side.
Keep out of the reach of children.
Store at controlled room temperature 20° to 25°C (68° to 77°F) [see USP]. Protect from moisture.
For further information, please call our medical communications
department toll-free 1-800-718-9884.
Reference ID: 3114775
17 PATIENT COUNSELING INFORMATION
Female patients of childbearing age should be told about the consequences of exposure to ACEON during
pregnancy. Discuss treatment options with women planning to become pregnant. Patients should be asked to
report pregnancies to their physicians as soon as possible.
Tell patients to report promptly any indication of infection (e.g., sore throat, fever) which could be a sign of
neutropenia.
Manufactured by:
Patheon Pharmaceuticals, Inc.
Cincinnati, OH 45237 USA
Marketed by:
XOMA (US) LLC
Berkeley, CA 94710 USA
100008 1E Rev Mar 2012
Formatted: English (U.S.)
Revised: March, 2012 company logo
Reference ID: 3114775
|
custom-source
|
2025-02-12T13:47:00.772911
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/020184s019lbl.pdf', 'application_number': 20184, 'submission_type': 'SUPPL ', 'submission_number': 19}
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12,309
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ZIAC(R) - bisoprolol fumarate and hydrochlorothiazide tablet, film coated
Rx only
Revised MAY 2007
11001233
DESCRIPTION
ZIAC (bisoprolol fumarate and hydrochlorothiazide) is indicated for the treatment of hypertension. It combines two antihypertensive
agents in a once-daily dosage: a synthetic beta1-selective (cardioselective) adrenoceptor blocking agent (bisoprolol fumarate) and a
benzothiadiazine diuretic (hydrochlorothiazide).
Bisoprolol fumarate is chemically described as (±)-1-[4-[[2-(1-methylethoxy)ethoxy]methyl]phenoxy]-3-[(1-methylethyl)amino]-2
propanol(E)-2-butenedioate (2:1) (salt). It possesses an asymmetric carbon atom in its structure and is provided as a racemic mixture.
The S(-) enantiomer is responsible for most of the beta-blocking activity. Its empirical formula is (C18H31NO4)2•C4H4O4 and it has a
molecular weight of 766.97. Its structural formula is: Chemical structure of ziac
Bisoprolol fumarate is a white crystalline powder, approximately equally hydrophilic and lipophilic, and readily soluble in water,
methanol, ethanol, and chloroform.
Hydrochlorothiazide (HCTZ) is 6-Chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. It is a white, or
practically white, practically odorless crystalline powder. It is slightly soluble in water, sparingly soluble in dilute sodium hydroxide
solution, freely soluble in n-butylamine and dimethylformamide, sparingly soluble in methanol, and insoluble in ether, chloroform,
and dilute mineral acids. Its empirical formula is C7H8ClN3O4S2 and it has a molecular weight of 297.73. Its structural formula is: Chemical structure of bisoprolol fumarate
Each ZIAC®-2.5 mg/6.25 mg tablet for oral administration contains:
Bisoprolol fumarate…………………………………………..2.5 mg
Hydrochlorothiazide………………………………………..6.25 mg
Each ZIAC®-5 mg/6.25 mg tablet for oral administration contains:
Bisoprolol fumarate……………………………………………5 mg
Hydrochlorothiazide………………………………………..6.25 mg
Each ZIAC®-10 mg/6.25 mg tablet for oral administration contains:
Bisoprolol fumarate…………………………………………...10 mg
Hydrochlorothiazide………………………………………..6.25 mg
Inactive ingredients include Corn Starch, Dibasic Calcium Phosphate, Hypromellose, Magnesium Stearate, Microcrystalline Cellulose,
Polyethylene Glycol, Polysorbate 80, and Titanium Dioxide. The 10 mg/6.25mg tablet also contains Colloidal Silicon Dioxide. The 5
mg/6.25 mg tablet also contains Colloidal Silicon Dioxide, and Red and Yellow Iron Oxide. The 2.5 mg/6.25 mg tablet also contains
Crospovidone, Pregelatinized Starch, and Yellow Iron Oxide.
page 1 of 13
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
CLINICAL PHARMACOLOGY
Bisoprolol fumarate and HCTZ have been used individually and in combination for the treatment of hypertension. The
antihypertensive effects of these agents are additive; HCTZ 6.25 mg significantly increases the antihypertensive effect of bisoprolol
fumarate. The incidence of hypokalemia with the bisoprolol fumarate and HCTZ 6.25 mg combination (B/H) is significantly lower
than with HCTZ 25 mg. In clinical trials of ZIAC, mean changes in serum potassium for patients treated with ZIAC 2.5/6.25 mg,
5/6.25 mg or 10/6.25 mg or placebo were less than ± 0.1 mEq/L. Mean changes in serum potassium for patients treated with any dose
of bisoprolol in combination with HCTZ 25 mg ranged from -0.1 to -0.3 mEq/L.
Bisoprolol fumarate is a beta1-selective (cardioselective) adrenoceptor blocking agent without significant membrane stabilizing or
intrinsic sympathomimetic activities in its therapeutic dose range. At higher doses (≥ 20 mg) bisoprolol fumarate also inhibits beta2
adrenoreceptors located in bronchial and vascular musculature. To retain relative selectivity, it is important to use the lowest effective
dose.
Hydrochlorothiazide is a benzothiadiazine diuretic. Thiazides affect renal tubular mechanisms of electrolyte reabsorption and increase
excretion of sodium and chloride in approximately equivalent amounts. Natriuresis causes a secondary loss of potassium.
Pharmacokinetics and Metabolism
ZIAC:
In healthy volunteers, both bisoprolol fumarate and hydrochlorothiazide are well absorbed following oral administration of ZIAC.
No change is observed in the bioavailability of either agent when given together in a single tablet. Absorption is not affected whether
ZIAC is taken with or without food. Mean peak bisoprolol fumarate plasma concentrations of about 9.0 ng/mL, 19 ng/mL and 36
ng/mL occur approximately 3 hours after the administration of the 2.5 mg/6.25 mg, 5 mg/6.25 mg and 10 mg/6.25 mg combination
tablets, respectively. Mean peak plasma hydrochlorothiazide concentrations of 30 ng/mL occur approximately 2.5 hours following
the administration of the combination. Dose proportional increases in plasma bisoprolol concentrations are observed between the
2.5 and 5, as well as between the 5 and 10 mg doses. The elimination T1/2 of bisoprolol ranges from 7 to 15 hours, and that of
hydrochlorothiazide ranges from 4 to 10 hours. The percent of dose excreted unchanged in urine is about 55% for bisoprolol and about
60% for hydrochlorothiazide.
Bisoprolol Fumarate:
The absolute bioavailability after a 10 mg oral dose of bisoprolol fumarate is about 80%. The first pass metabolism of bisoprolol
fumarate is about 20%.
The pharmacokinetic profile of bisoprolol fumarate has been examined following single doses and at steady state. Binding to serum
proteins is approximately 30%. Peak plasma concentrations occur within 2-4 hours of dosing with 2.5 to 20 mg, and mean peak
values range from 9.0 ng/mL at 2.5 mg to 70 ng/mL at 20 mg. Once-daily dosing with bisoprolol fumarate results in less than
twofold intersubject variation in peak plasma concentrations. Plasma concentrations are proportional to the administered dose in
the range of 2.5 to 20 mg. The plasma elimination half-life is 9-12 hours and is slightly longer in elderly patients, in part because of
decreased renal function. Steady state is attained within 5 days with once-daily dosing. In both young and elderly populations, plasma
accumulation is low; the accumulation factor ranges from 1.1 to 1.3, and is what would be expected from the half-life and once-daily
dosing. Bisoprolol is eliminated equally by renal and nonrenal pathways with about 50% of the dose appearing unchanged in the urine
and the remainder in the form of inactive metabolites. In humans, the known metabolites are labile or have no known pharmacologic
activity. Less than 2% of the dose is excreted in the feces. The pharmacokinetic characteristics of the two enantiomers are similar.
Bisoprolol is not metabolized by cytochrome P450 II D6 (debrisoquin hydroxylase).
In subjects with creatinine clearance less than 40 mL/min, the plasma half-life is increased approximately threefold compared to
healthy subjects.
In patients with liver cirrhosis, the rate of elimination of bisoprolol is more variable and significantly slower than that in healthy
subjects, with a plasma half-life ranging from 8 to 22 hours.
In elderly subjects, mean plasma concentrations at steady state are increased, in part attributed to lower creatinine clearance. However,
no significant differences in the degree of bisoprolol accumulation is found between young and elderly populations.
Hydrochlorothiazide:
Hydrochlorothiazide is well absorbed (65%-75%) following oral administration. Absorption of hydrochlorothiazide is reduced in
patients with congestive heart failure.
Peak plasma concentrations are observed within 1-5 hours of dosing, and range from 70-490 ng/mL following oral doses of 12.5-100
mg. Plasma concentrations are linearly related to the administered dose. Concentrations of hydrochlorothiazide are 1.6-1.8 times
higher in whole blood than in plasma. Binding to serum proteins has been reported to be approximately 40% to 68%. The plasma
elimination half-life has been reported to be 6-15 hours. Hydrochlorothiazide is eliminated primarily by renal pathways. Following
oral doses of 12.5-100 mg, 55%-77% of the administered dose appears in urine and greater than 95% of the absorbed dose is excreted
page 2 of 13
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
in urine as unchanged drug. Plasma concentrations of hydrochlorothiazide are increased and the elimination half-life is prolonged in
patients with renal disease.
Pharmacodynamics
Bisoprolol Fumarate:
Findings in clinical hemodynamics studies with bisoprolol fumarate are similar to those observed with other beta-blockers. The most
prominent effect is the negative chronotropic effect, giving a reduction in resting and exercise heart rate. There is a fall in resting and
exercise cardiac output with little observed change in stroke volume, and only a small increase in right atrial pressure, or pulmonary
capillary wedge pressure at rest or during exercise.
In normal volunteers, bisoprolol fumarate therapy resulted in a reduction of exercise- and isoproterenol-induced tachycardia. The
maximal effect occurred within 1-4 hours post-dosing. Effects generally persisted for 24 hours at doses of 5 mg or greater.
In controlled clinical trials, bisoprolol fumarate given as a single daily dose has been shown to be an effective antihypertensive agent
when used alone or concomitantly with thiazide diuretics (see CLINICAL STUDIES).
The mechanism of bisoprolol fumarate’s antihypertensive effect has not been completely established. Factors that may be involved
include:
1) Decreased cardiac output,
2) Inhibition of renin release by the kidneys,
3) Diminution of tonic sympathetic outflow from vasomotor centers in the brain.
Beta1-selectivity of bisoprolol fumarate has been demonstrated in both animal and human studies. No effects at therapeutic doses on
beta2-adrenoreceptor density have been observed. Pulmonary function studies have been conducted in healthy volunteers, asthmatics,
and patients with chronic obstructive pulmonary disease (COPD). Doses of bisoprolol fumarate ranged from 5 to 60 mg, atenolol from
50 to 200 mg, metoprolol from 100 to 200 mg, and propranolol from 40 to 80 mg. In some studies, slight, asymptomatic increases
in airway resistance (AWR) and decreases in forced expiratory volume (FEV1) were observed with doses of bisoprolol fumarate 20
mg and higher, similar to the small increases in AWR noted with other cardioselective beta-blocking agents. The changes induced by
beta-blockade with all agents were reversed by bronchodilator therapy.
Electrophysiology studies in man have demonstrated that bisoprolol fumarate significantly decreases heart rate, increases sinus node
recovery time, prolongs AV node refractory periods, and, with rapid atrial stimulation, prolongs AV nodal conduction.
Hydrochlorothiazide
Acute effects of thiazides are thought to result from a reduction in blood volume and cardiac output, secondary to a natriuretic effect,
although a direct vasodilatory mechanism has also been proposed. With chronic administration, plasma volume returns toward normal,
but peripheral vascular resistance is decreased.
Thiazides do not affect normal blood pressure. Onset of action occurs within 2 hours of dosing, peak effect is observed at about 4
hours, and activity persists for up to 24 hours.
CLINICAL STUDIES
In controlled clinical trials, bisoprolol fumarate/hydrochlorothiazide 6.25 mg has been shown to reduce systolic and diastolic blood
pressure throughout a 24-hour period when administered once daily. The effects on systolic and diastolic blood pressure reduction of
the combination of bisoprolol fumarate and hydrochlorothiazide were additive. Further, treatment effects were consistent across age
groups (<60, ≥ 60 years), racial groups (black, nonblack), and gender (male, female).
In two randomized, double-blind, placebo-controlled trials conducted in the U.S., reductions in systolic and diastolic blood pressure
and heart rate 24 hours after dosing in patients with mild-to-moderate hypertension are shown below. In both studies mean systolic/
diastolic blood pressure and heart rate at baseline were approximately 151/101 mm Hg and 77 bpm.
Sitting Systolic/Diastolic Pressure (BP) and Heart Rate (HR)
Mean Decrease (Δ) After 3-4 Weeks
Study 1
Study 2
Placebo
B5/H6.25 mg
Placebo
H6.25 mg
B2.5/ H6.25 mg
B10/ H6.25 mg
n=
75
150
56
23
28
25
page 3 of 13
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Total ΔBP (mm
Hg)
-2.9/-3.9
-15.8/-12.6
-3.0/-3.7
-6.6/-5.8
-14.1/-10.5
-15.3/-14.3
Drug Effect *
-/
-12.9/-8.7
-/
-3.6/-2.1
-11.1/-6.8
-12.3/-10.6
Total ΔHR
(bpm)
-0.3
-6.9
-1.6
-0.8
-3.7
-9.8
Drug Effect *
-
-6.6
-
+0.8
-2.1
-8.2
*Observed mean change from baseline minus placebo.
Blood pressure responses were seen within 1 week of treatment but the maximum effect was apparent after 2 to 3 weeks of treatment.
Overall, significantly greater blood pressure reductions were observed on ZIAC than on placebo. Further, blood pressure reductions
were significantly greater for each of the bisoprolol fumarate plus hydrochlorothiazide combinations than for either of the components
used alone regardless of race, age, or gender. There were no significant differences in response between black and nonblack patients.
INDICATIONS AND USAGE
ZIAC (bisoprolol fumarate and hydrochlorothiazide) is indicated in the management of hypertension.
CONTRAINDICATIONS
ZIAC is contraindicated in patients in cardiogenic shock, overt cardiac failure (see WARNINGS), second or third degree AV block,
marked sinus bradycardia, anuria, and hypersensitivity to either component of this product or to other sulfonamide-derived drugs.
WARNINGS
Cardiac Failure
In general, beta-blocking agents should be avoided in patients with overt congestive failure. However, in some patients with
compensated cardiac failure, it may be necessary to utilize these agents. In such situations, they must be used cautiously.
Patients Without a History of Cardiac Failure
Continued depression of the myocardium with beta-blockers can, in some patients, precipitate cardiac failure. At the first signs or
symptoms of heart failure, discontinuation of ZIAC should be considered. In some cases ZIAC therapy can be continued while heart
failure is treated with other drugs.
Abrupt Cessation of Therapy
Exacerbations of angina pectoris and, in some instances, myocardial infarction or ventricular arrhythmia, have been observed in
patients with coronary artery disease following abrupt cessation of therapy with beta-blockers. Such patients should, therefore, be
cautioned against interruption or discontinuation of therapy without the physician’s advice. Even in patients without overt coronary
artery disease, it may be advisable to taper therapy with ZIAC (bisoprolol fumarate and hydrochlorothiazide) over approximately 1
week with the patient under careful observation. If withdrawal symptoms occur, beta-blocking agent therapy should be reinstituted, at
least temporarily.
Peripheral Vascular Disease
Beta-blockers can precipitate or aggravate symptoms of arterial insufficiency in patients with peripheral vascular disease. Caution
should be exercised in such individuals.
Bronchospastic Disease
PATIENTS WITH BRONCHOSPASTIC PULMONARY DISEASE SHOULD, IN GENERAL, NOT RECEIVE BETA
BLOCKERS. Because of the relative beta1-selectivity of bisoprolol fumarate, ZIAC may be used with caution in patients with
bronchospastic disease who do not respond to, or who cannot tolerate other antihypertensive treatment. Since beta1-selectivity
is not absolute, the lowest possible dose of ZIAC should be used. A beta2 agonist (bronchodilator) should be made available.
Anesthesia and Major Surgery
If ZIAC treatment is to be continued perioperatively, particular care should be taken when anesthetic agents that depress myocardial
function, such as ether, cyclopropane, and trichloroethylene, are used. See OVERDOSAGE for information on treatment of
bradycardia and hypotension.
Diabetes and Hyopglycemia
Beta-blockers may mask some of the manifestations of hypoglycemia, particularly tachycardia. Nonselective beta-blockers may
potentiate insulin-induced hypoglycemia and delay recovery of serum glucose levels. Because of its beta1-selectivity, this is less
likely with bisoprolol fumarate. However, patients subject to spontaneous hypoglycemia, or diabetic patients receiving insulin or oral
hypoglycemic agents, should be cautioned about these possibilities. Also, latent diabetes mellitus may become manifest and diabetic
page 4 of 13
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
patients given thiazides may require adjustment of their insulin dose. Because of the very low dose of HCTZ employed, this may be
less likely with ZIAC.
Thyrotoxicosis
Beta-adrenergic blockade may mask clinical signs of hyperthyroidism, such as tachycardia. Abrupt withdrawal of beta-blockade may
be followed by an exacerbation of the symptoms of hyperthyroidism or may precipitate thyroid storm.
Renal Disease
Cumulative effects of the thiazides may develop in patients with impaired renal function. In such patients, thiazides may precipitate
azotemia. In subjects with creatinine clearance less than 40 mL/min, the plasma half-life of bisoprolol fumarate is increased up to
threefold, as compared to healthy subjects. If progressive renal impairment becomes apparent, ZIAC should be discontinued. (See
Pharmacokinetics and Metabolism.)
Hepatic Disease
ZIAC should be used with caution in patients with impaired hepatic function or progressive liver disease. Thiazides may alter fluid
and electrolyte balance, which may precipitate hepatic coma. Also, elimination of bisoprolol fumarate is significantly slower in
patients with cirrhosis than in healthy subjects. (See Pharmacokinetics and Metabolism.)
PRECAUTIONS
General
Electrolyte and Fluid Balance Status:
Although the probability of developing hypokalemia is reduced with ZIAC because of the very low dose of HCTZ employed, periodic
determination of serum electrolytes should be performed, and patients should be observed for signs of fluid or electrolyte disturbances,
i.e., hyponatremia, hypochloremic alkalosis, hypokalemia, and hypomagnesemia. Thiazides have been shown to increase the urinary
excretion of magnesium; this may result in hypomagnesemia.
Warning signs or symptoms of fluid and electrolyte imbalance include dryness of mouth, thirst, weakness, lethargy, drowsiness,
restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as
nausea and vomiting.
Hypokalemia may develop, especially with brisk diuresis when severe cirrhosis is present, during concomitant use of corticosteroids
or adrenocorticotropic hormone (ACTH) or after prolonged therapy. Interference with adequate oral electrolyte intake will also
contribute to hypokalemia. Hypokalemia and hypomagnesemia can provoke ventricular arrhythmias or sensitize or exaggerate the
response of the heart to the toxic effects of digitalis. Hypokalemia may be avoided or treated by potassium supplementation or
increased intake of potassium-rich foods.
Dilutional hyponatremia may occur in edematous patients in hot weather; appropriate therapy is water restriction rather than salt
administration, except in rare instances when the hyponatremia is life threatening. In actual salt depletion, appropriate replacement is
the therapy of choice.
Parathyroid Disease:
Calcium excretion is decreased by thiazides, and pathologic changes in the parathyroid glands, with hypercalcemia and
hypophosphatemia, have been observed in a few patients on prolonged thiazide therapy.
Hyperuricemia:
Hyperuricemia or acute gout may be precipitated in certain patients receiving thiazide diuretics. Bisoprolol fumarate, alone or in
combination with HCTZ, has been associated with increases in uric acid. However, in U.S. clinical trials, the incidence of treatment-
related increases in uric acid was higher during therapy with HCTZ 25 mg (25%) than with B/H 6.25 mg (10%). Because of the very
low dose of HCTZ employed, hyperuricemia may be less likely with ZIAC.
Drug Interactions:
ZIAC may potentiate the action of other antihypertensive agents used concomitantly. ZIAC should not be combined with other beta-
blocking agents. Patients receiving catecholamine-depleting drugs, such as reserpine or guanethidine, should be closely monitored
because the added beta-adrenergic blocking action of bisoprolol fumarate may produce excessive reduction of sympathetic activity.
In patients receiving concurrent therapy with clonidine, if therapy is to be discontinued, it is suggested that ZIAC be discontinued for
several days before the withdrawal of clonidine.
ZIAC should be used with caution when myocardial depressants or inhibitors of AV conduction, such as certain calcium antagonists
(particularly of the phenylalkylamine [verapamil] and benzothiazepine [diltiazem] classes), or antiarrhythmic agents, such as
disopyramide, are used concurrently.
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Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the
risk of bradycardia.
Bisoprolol Fumarate
Concurrent use of rifampin increases the metabolic clearance of bisoprolol fumarate, shortening its elimination half-life. However,
initial dose modification is generally not necessary.
Pharmacokinetic studies document no clinically relevant interactions with other agents given concomitantly, including thiazide
diuretics and cimetidine. There was no effect of bisoprolol fumarate on prothrombin times in patients on stable doses of warfarin.
Risk of Anaphylactic Reaction:
While taking beta-blockers, patients with a history of severe anaphylactic reaction to a variety of allergens may be more reactive to
repeated challenge, either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine
used to treat allergic reactions.
Hydrochlorothiazide
When given concurrently the following drugs may interact with thiazide diuretics.
Alcohol, barbiturates, or narcotics - potentiation of orthostatic hypotension may occur.
Antidiabetic drugs (oral agents and insulin) - dosage adjustment of the antidiabetic drug may be required.
Other antihypertensive drugs - additive effect or potentiation.
Cholestyramine and colestipol resins - Absorption of hydrochlorothiazide is impaired in the presence of anionic exchange resins.
Single doses of cholestyramine and colestipol resins bind the hydrochlorothiazide and reduce its absorption in the gastrointestinal tract
by up to 85 percent and 43 percent, respectively.
Corticosteroids, ACTH - Intensified electrolyte depletion, particularly hypokalemia.
Pressor amines (e.g., norepinephrine) - possible decreased response to pressor amines but not sufficient to preclude their use.
Skeletal muscle relaxants, nondepolarizing (e.g., tubocurarine) - possible increased responsiveness to the muscle relaxant.
Lithium - generally should not be given with diuretics. Diuretic agents reduce the renal clearance of lithium and add a high risk of
lithium toxicity. Refer to the package insert for lithium preparations before use of such preparations with ZIAC.
Nonsteroidal anti-inflammatory drugs - In some patients, the administration of a nonsteroidal anti-inflammatory agent can reduce
the diuretic, natriuretic, and antihypertensive effects of loop, potassium sparing, and thiazide diuretics. Therefore, when ZIAC and
nonsteroidal anti-inflammatory agents are used concomitantly, the patient should be observed closely to determine if the desired effect
of the diuretic is obtained.
In patients receiving thiazides, sensitivity reactions may occur with or without a history of allergy or bronchial asthma.
Photosensitivity reactions and possible exacerbation or activation of systemic lupus erythematosus have been reported in patients
receiving thiazides. The antihypertensive effects of thiazides may be enhanced in the post-sympathectomy patient.
Laboratory Test Interactions:
Based on reports involving thiazides, ZIAC (bisoprolol fumarate and hydrochlorothiazide) may decrease serum levels of protein-
bound iodine without signs of thyroid disturbance.
Because it includes a thiazide, ZIAC should be discontinued before carrying out tests for parathyroid function (see PRECAUTIONS
Parathyroid Disease).
INFORMATION FOR PATIENTS
Patients, especially those with coronary artery disease, should be warned against discontinuing use of ZIAC without a physician’s
supervision. Patients should also be advised to consult a physician if any difficulty in breathing occurs, or if they develop other signs
or symptoms of congestive heart failure or excessive bradycardia.
Patients subject to spontaneous hypoglycemia, or diabetic patients receiving insulin or oral hypoglycemic agents, should be cautioned
that beta-blockers may mask some of the manifestations of hypoglycemia, particularly tachycardia, and bisoprolol fumarate should be
used with caution.
Patients should know how they react to this medicine before they operate automobiles and machinery or engage in other tasks
requiring alertness. Patients should be advised that photosensitivity reactions have been reported with thiazides.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
ZIAC:
Long-term studies have not been conducted with the bisoprolol fumarate/hydrochlorothiazide combination.
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Bisoprolol Fumarate:
Long-term studies were conducted with oral bisoprolol fumarate administered in the feed of mice (20 and 24 months) and rats (26
months). No evidence of carcinogenic potential was seen in mice dosed up to 250 mg/kg/day or rats dosed up to 125 mg/kg/day. On
a body weight basis, these doses are 625 and 312 times, respectively, the maximum recommended human dose (MRHD) of 20 mg,
or 0.4 mg/kg/day, based on 50 kg individuals; on a body surface area basis, these doses are 59 times (mice) and 64 times (rats) the
MRHD.
Hydrochlorothiazide:
Two-year feeding studies in mice and rats, conducted under the auspices of the National Toxicology Program (NTP), treated mice
and rats with doses of hydrochlorothiazide up to 600 and 100 mg/kg/day, respectively. On a body weight basis, these doses are
2400 times (in mice) and 400 times (in rats) the MRHD of hydrochlorothiazide (12.5 mg/day) in ZIAC® (bisoprolol fumarate and
hydrochlorothiazide). On a body surface area basis, these doses are 226 times (in mice) and 82 times (in rats) the MRHD. These
studies uncovered no evidence of carcinogenic potential of hydrochlorothiazide in rats or female mice, but there was equivocal
evidence of hepatocarcinogenicity in male mice.
Mutagenesis
ZIAC:
The mutagenic potential of the bisoprolol fumarate/hydrochlorothiazide combination was evaluated in the microbial mutagenicity
(Ames) test, the point mutation and chromosomal aberration assays in Chinese hamster V79 cells, and the micronucleus test in mice.
There was no evidence of mutagenic potential in these in vitro and in vivo assays.
Bisoprolol Fumarate:
The mutagenic potential of bisoprolol fumarate was evaluated in the microbial mutagenicity (Ames) test, the point mutation and
chromosome aberration assays in Chinese hamster V79 cells, the unscheduled DNA synthesis test, the micronucleus test in mice, and
the cytogenetics assay in rats. There was no evidence of mutagenic potential in these in vitro and in vivo assays.
Hydrochlorothiazide:
Hydrochlorothiazide was not genotoxic in in vitro assays using strains TA 98, TA 100, TA 1535, TA 1537 and TA 1538 of
Salmonella typhimurium (the Ames test); in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations; or in in vivo assays
using mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, and the Drosophila sex-linked recessive lethal
trait gene. Positive test results were obtained in the in vitro CHO Sister Chromatid Exchange (clastogenicity) test and in the mouse
Lymphoma Cell (mutagenicity) assays, using concentrations of hydrochlorothiazide of 43-1300 µg/mL. Positive test results were also
obtained in the Aspergillus nidulans non-disjunction assay, using an unspecified concentration of hydrochlorothiazide.
Impairment of Fertility
ZIAC:
Reproduction studies in rats did not show any impairment of fertility with the bisoprolol fumarate/hydrochlorothiazide combination
doses containing up to 30 mg/kg/day of bisoprolol fumarate in combination with 75 mg/kg/day of hydrochlorothiazide. On a body
weight basis, these doses are 75 and 300 times, respectively, the MRHD of bisoprolol fumarate and hydrochlorothiazide. On a body
surface area basis, these study doses are 15 and 62 times, respectively, MRHD.
Bisoprolol Fumarate:
Reproduction studies in rats did not show any impairment of fertility at doses up to 150 mg/kg/day of bisoprolol fumarate, or 375 and
77 times the MRHD on the basis of body weight and body surface area, respectively.
Hydrochlorothiazide:
Hydrochlorothiazide had no adverse effects on the fertility of mice and rats of either sex in studies wherein these species were
exposed, via their diet, to doses of up to 100 and 4 mg/kg/day, respectively, prior to mating and throughout gestation. Corresponding
multiples of maximum recommended human doses are 400 (mice) and 16 (rats) on the basis of body weight and 38 (mice) and 3.3
(rats) on the basis of body surface area.
Pregnancy
Teratogenic Effects-Pregnancy Category C
ZIAC:
In rats, the bisoprolol fumarate/hydrochlorothiazide (B/H) combination was not teratogenic at doses up to 51.4 mg/kg/day of
bisoprolol fumarate in combination with 128.6 mg/kg/day of hydrochlorothiazide. Bisoprolol fumarate and hydrochlorothiazide
doses used in the rat study are, as multiples of the MRHD in the combination, 129 and 514 times greater, respectively, on a body
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weight basis, and 26 and 106 times greater, respectively, on the basis of body surface area. The drug combination was maternotoxic
(decreased body weight and food consumption) at B5.7/H14.3 (mg/kg/day) and higher, and fetotoxic (increased late resorptions) at
B17.1/H42.9 (mg/kg/day) and higher. Maternotoxicity was present at 14/57 times the MRHD of B/H, respectively, on a body weight
basis, and 3/12 times the MRHD of B/H doses, respectively, on the basis of body surface area. Fetotoxicity was present at 43/172
times the MRHD of B/H, respectively, on a body weight basis, and 9/35 times the MRHD of B/H doses, respectively, on the basis of
body surface area. In rabbits, the B/H combination was not teratogenic at doses of B10/H25 (mg/kg/day). Bisoprolol fumarate and
hydrochlorothiazide used in the rabbit study were not teratogenic at 25/100 times the B/H MRHD, respectively, on a body weight
basis, and 10/40 times the B/H MRHD, respectively, on the basis of body surface area. The drug combination was maternotoxic
(decreased body weight) at B1/H2.5 (mg/kg/day) and higher, and fetotoxic (increased resorptions) at B10/H25 (mg/kg/day). The
multiples of the MRHD for the B/H combination that were maternotoxic are, respectively, 2.5/10 (on the basis of body weight) and
1/4 (on the basis of body surface area), and for fetotoxicity were, respectively 25/100 (on the basis of body weight) and 10/40 (on the
basis of body surface area).
There are no adequate and well-controlled studies with ZIAC in pregnant women. ZIAC (bisoprolol fumarate and
hydrochlorothiazide) should be used during pregnancy only if the potential benefit justifies the risk to the fetus.
Bisoprolol Fumarate:
In rats, bisoprolol fumarate was not teratogenic at doses up to 150 mg/kg/day, which were 375 and 77 times the MRHD on the basis
of body weight and body surface area, respectively. Bisoprolol fumarate was fetotoxic (increased late resorptions) at 50 mg/kg/day
and maternotoxic (decreased food intake and body weight gain) at 150 mg/kg/day. The fetotoxicity in rats occurred at 125 times the
MRHD on a body weight basis and 26 times the MRHD on the basis of body surface area. The maternotoxicity occurred at 375 times
the MRHD on a body weight basis and 77 times the MRHD on the basis of body surface area. In rabbits, bisoprolol fumarate was
not teratogenic at doses up to 12.5 mg/kg/day, which is 31 and 12 times the MRHD based on body weight and body surface area,
respectively, but was embryolethal (increased early resorptions) at 12.5 mg/kg/day.
Hydrochlorothiazide:
Hydrochlorothiazide was orally administered to pregnant mice and rats during respective periods of major organogenesis at doses up
to 3000 and 1000 mg/kg/day, respectively. At these doses, which are multiples of the MRHD equal to 12,000 for mice and 4000 for
rats, based on body weight, and equal to 1129 for mice and 824 for rats, based on body surface area, there was no evidence of harm to
the fetus. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are
not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Nonteratogenic Effects
Thiazides cross the placental barrier and appear in the cord blood. The use of thiazides in pregnant women requires that the
anticipated benefit be weighed against possible hazards to the fetus. These hazards include fetal or neonatal jaundice, pancreatitis,
thrombocytopenia, and possibly other adverse reactions that have occurred in the adult.
Nursing Mothers
Bisoprolol fumarate alone or in combination with HCTZ has not been studied in nursing mothers. Thiazides are excreted in human
breast milk. Small amounts of bisoprolol fumarate (<2% of the dose) have been detected in the milk of lactating rats. Because of the
potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue
the drug, taking into account the importance of the drug to the mother.
Pediatric Use
Safety and effectiveness of ZIAC in pediatric patients have not been established.
Geriatric Use
In clinical trials, at least 270 patients treated with bisoprolol fumarate plus HCTZ were 60 years of age or older. HCTZ added
significantly to the antihypertensive effect of bisoprolol in elderly hypertensive patients. No overall differences in effectiveness or
safety were observed between these patients and younger patients. Other reported clinical experience has not identified differences in
responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
ADVERSE REACTIONS
ZIAC
Bisoprolol fumarate/HCTZ 6.25 mg is well tolerated in most patients. Most adverse effects (AEs) have been mild and transient. In
more than 65,000 patients treated worldwide with bisoprolol fumarate, occurrences of bronchospasm have been rare. Discontinuation
rates for AEs were similar for bisoprolol fumarate/HCTZ 6.25 mg and placebo-treated patients.
In the United States, 252 patients received bisoprolol fumarate (2.5, 5, 10, or 40 mg)/HCTZ 6.25 mg and 144 patients received
placebo in two controlled trials. In Study 1, bisoprolol fumarate 5/HCTZ 6.25 mg was administered for 4 weeks. In Study 2, bisoprolol
fumarate 2.5, 10, or 40/HCTZ 6.25 mg was administered for 12 weeks. All adverse experiences, whether drug related or not, and drug
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related adverse experiences in patients treated with bisoprolol fumarate 2.5-10/HCTZ 6.25 mg, reported during comparable, 4 week
treatment periods by at least 2% of bisoprolol fumarate/HCTZ 6.25 mg-treated patients (plus additional selected adverse experiences)
are presented in the following table:
% of Patients with Adverse Experiences *
Body System/ Adverse Experience
All Adverse Experiences
Drug Related Adverse Experiences
Placebo†
B2.5-40/H6.25†
Placebo†
B2.5-10/H6.25†
(n=144)
(n=252)
(n=144)
(n=221)
%
%
%
%
Cardiovascular
bradycardia
0.7
1.1
0.7
0.9
arrhythmia
1.4
0.4
0.0
0.0
peripheral ischemia
0.9
0.7
0.99
0.4
chest pain
0.7
1.8
0.7
0.9
Respiratory
bronchospasm
0.0
0.0
0.0
0.0
cough
1.0
2.2
0.7
1.5
rhinitis
2.0
0.7
0.7
0.9
URI
2.3
2.1
0.0
0.0
Body as a Whole
asthenia
0.0
0.0
0.0
0.0
fatigue
2.7
4.6
1.7
3.0
peripheral edema
0.7
1.1
0.7
0.9
Central Nervous System
dizziness
1.8
5.1
1.8
3.2
headache
4.7
4.5
2.7
0.4
Musculoskeletal
muscle cramps
0.7
1.2
0.7
1.1
myalgia
1.4
2.4
0.0
0.0
Psychiatric
insomnia
2.4
1.1
2.0
1.2
somnolence
0.7
1.1
0.7
0.9
loss of libido
1.2
0.4
1.2
0.4
impotence
0.7
1.1
0.7
1.1
Gastrointestinal
diarrhea
1.4
4.3
1.2
1.1
nausea
0.9
1.1
0.9
0.9
dyspepsia
0.7
1.2
0.7
0.9
*Averages adjusted to combine across studies.
†Combined across studies.
Other adverse experiences that have been reported with the individual components are listed below.
Bisoprolol Fumarate
In clinical trials worldwide, or in postmarketing experience, a variety of other AEs, in addition to those listed above, have been
reported. While in many cases it is not known whether a causal relationship exists between bisoprolol and these AEs, they are listed to
alert the physician to a possible relationship.
Central Nervous System:
Unsteadiness, dizziness, vertigo, headache, syncope, paresthesia, hypoesthesia, hyperesthesia, sleep disturbance/vivid dreams,
insomnia, somnolence, depression, anxiety/restlessness, decreased concentration/memory.
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Cardiovascular:
Bradycardia, palpitations and other rhythm disturbances, cold extremities, claudication, hypotension, orthostatic hypotension, chest
pain, congestive heart failure, dyspnea on exertion.
Gastrointestinal:
Gastric/epigastric/abdominal pain, peptic ulcer, gastritis, dyspepsia, nausea, vomiting, diarrhea, constipation, dry mouth.
Musculoskeletal:
Arthralgia, muscle/joint pain, back/neck pain, muscle cramps, twitching/tremor.
Skin:
Rash, acne, eczema, psoriasis, skin irritation, pruritus, purpura, flushing, sweating, alopecia, dermatitis, exfoliative dermatitis (very
rarely), cutaneous vaculitis.
Special Senses:
Visual disturbances, ocular pain/pressure, abnormal lacrimation, tinnitus, decreased hearing, earache, taste abnormalities.
Metabolic:
Gout.
Respiratory:
Asthma, bronchospasm, bronchitis, dyspnea, pharyngitis, rhinitis, sinusitis, URI (upper respiratory infection).
Genitourinary:
Decreased libido/impotence, Peyronie’s disease (very rarely), cystitis, renal colic, polyuria.
General:
Fatigue, asthenia, chest pain, malaise, edema, weight gain, angioedema.
In addition, a variety of adverse effects have been reported with other beta-adrenergic blocking agents and should be considered
potential adverse effects:
Central Nervous System:
Reversible mental depression progressing to catatonia, hallucinations, an acute reversible syndrome characterized by disorientation to
time and place, emotional lability, slightly clouded sensorium.
Allergic:
Fever, combined with aching and sore throat, laryngospasm, and respiratory distress.
Hematologic:
Agranulocytosis, thrombocytopenia.
Gastrointestinal:
Mesenteric arterial thrombosis and ischemic colitis.
Miscellaneous:
The oculomucocutaneous syndrome associated with the beta-blocker practolol has not been reported with bisoprolol fumarate during
investigational use or extensive foreign marketing experience.
Hydrochlorothiazide
The following adverse experiences, in addition to those listed in the above table, have been reported with hydrochlorothiazide
(generally with doses of 25 mg or greater).
General:
Weakness.
Central Nervous System:
Vertigo, paresthesia, restlessness.
Cardiovascular:
Orthostatic hypotension (may be potentiated by alcohol, barbiturates, or narcotics).
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Gastrointestinal:
Anorexia, gastric irritation, cramping, constipation, jaundice (intrahepatic cholestatic jaundice), pancreatitis, cholecystitis, sialadenitis,
dry mouth.
Musculoskeletal:
Muscle spasm.
Hypersensitive Reactions:
Purpura, photosensitivity, rash, urticaria, necrotizing angiitis (vasculitis and cutaneous vasculitis), fever, respiratory distress including
pneumonitis and pulmonary edema, anaphylactic reactions.
Special Senses:
Transient blurred vision, xanthopsia.
Metabolic:
Gout.
Genitourinary:
Sexual dysfunction, renal failure, renal dysfunction, interstitial nephritis.
Laboratory Abnormalities
ZIAC
Because of the low dose of hydrochlorothiazide in ZIAC (bisoprolol fumarate and hydrochlorothiazide), adverse metabolic effects
with bisoprolol fumarate/HCTZ 6.25 mg are less frequent and of smaller magnitude than with HCTZ 25 mg. Laboratory data on serum
potassium from the U.S. placebo-controlled trials are shown in the following table:
Serum Potassium Data from U.S. Controlled Studies
Placebo*
B2.5/ H6.25 mg
B5/ H6.25 mg
B10/ H6.25 mg
HCTZ 25 mg*
(N=130†)
(N=28†)
(N=149†)
(N=28†)
(N=142†)
Potassium
Mean Change‡ (mEq/L)
+0.04
+0.11
-0.08
0.00
-0.30%
Hypokalemia§
0.0%
0.0%
0.7%
0.0%
5.5%
*Combined across studies.
†Patients with normal serum potassium at baseline.
‡Mean change from baseline at Week 4.
§Percentage of patients with abnormality at Week 4.
Treatment with both beta blockers and thiazide diuretics is associated with increases in uric acid. However, the magnitude of the
change in patients treated with B/H 6.25 mg was smaller than in patients treated with HCTZ 25 mg. Mean increases in serum
triglycerides were observed in patients treated with bisoprolol fumarate and hydrochlorothiazide 6.25 mg. Total cholesterol was
generally unaffected, but small decreases in HDL cholesterol were noted.
Other laboratory abnormalities that have been reported with the individual components are listed below.
Bisoprolol Fumarate
In clinical trials, the most frequently reported laboratory change was an increase in serum triglycerides, but this was not a consistent
finding.
Sporadic liver test abnormalities have been reported. In the U.S. controlled trials experience with bisoprolol fumarate treatment for
4-12 weeks, the incidence of concomitant elevations in SGOT and SGPT from 1 to 2 times normal was 3.9%, compared to 2.5% for
placebo. No patient had concomitant elevations greater than twice normal.
In the long-term, uncontrolled experience with bisoprolol fumarate treatment for 6-18 months, the incidence of one or more
concomitant elevations in SGOT and SGPT from 1 to 2 times normal was 6.2%. The incidence of multiple occurrences was 1.9%.
For concomitant elevations in SGOT and SGPT of greater than twice normal, the incidence was 1.5%. The incidence of multiple
occurrences was 0.3%. In many cases these elevations were attributed to underlying disorders, or resolved during continued treatment
with bisoprolol fumarate.
Other laboratory changes included small increases in uric acid, creatinine, BUN, serum potassium, glucose, and phosphorus and
decreases in WBC and platelets. There have been occasional reports of eosinophilia. These were generally not of clinical importance
and rarely resulted in discontinuation of bisoprolol fumarate.
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As with other beta-blockers, ANA conversions have also been reported on bisoprolol fumarate. About 15% of patients in long-term
studies converted to a positive titer, although about one-third of these patients subsequently reconverted to a negative titer while on
continued therapy.
Hydrochlorothiazide
Hyperglycemia, glycosuria, hyperuricemia, hypokalemia and other electrolyte imbalances (see PRECAUTIONS), hyperlipidemia,
hypercalcemia, leukopenia, agranulocytosis, thrombocytopenia, aplastic anemia, and hemolytic anemia have been associated with
HCTZ therapy.
OVERDOSAGE
There are limited data on overdose with ZIAC. However, several cases of overdose with bisoprolol fumarate have been reported
(maximum: 2000 mg). Bradycardia and/or hypotension were noted. Sympathomimetic agents were given in some cases, and all
patients recovered.
The most frequently observed signs expected with overdosage of a beta-blocker are bradycardia and hypotension. Lethargy is also
common, and with severe overdoses, delirium, coma, convulsions, and respiratory arrest have been reported to occur. Congestive
heart failure, bronchospasm, and hypoglycemia may occur, particularly in patients with underlying conditions. With thiazide diuretics,
acute intoxication is rare. The most prominent feature of overdose is acute loss of fluid and electrolytes. Signs and symptoms include
cardiovascular (tachycardia, hypotension, shock), neuromuscular (weakness, confusion, dizziness, cramps of the calf muscles,
paresthesia, fatigue, impairment of consciousness), gastrointestinal (nausea, vomiting, thirst), renal (polyuria, oliguria, or anuria [due
to hemoconcentration]), and laboratory findings (hypokalemia, hyponatremia, hypochloremia, alkalosis, increased BUN [especially in
patients with renal insufficiency]).
If overdosage of ZIAC (bisoprolol fumarate and hydrochlorothiazide) is suspected, therapy with ZIAC should be discontinued and
the patient observed closely. Treatment is symptomatic and supportive; there is no specific antidote. Limited data suggest bisoprolol
fumarate is not dialyzable; similarly, there is no indication that hydrochlorothiazide is dialyzable. Suggested general measures include
induction of emesis and/or gastric lavage, administration of activated charcoal, respiratory support, correction of fluid and electrolyte
imbalance, and treatment of convulsions. Based on the expected pharmacologic actions and recommendations for other beta-blockers
and hydrochlorothiazide, the following measures should be considered when clinically warranted:
Bradycardia
Administer IV atropine. If the response is inadequate, isoproterenol or another agent with positive chronotropic properties may be
given cautiously. Under some circumstances, transvenous pacemaker insertion may be necessary.
Hypotension, Shock
The patient’s legs should be elevated. IV fluids should be administered and lost electrolytes (potassium, sodium) replaced. Intravenous
glucagon may be useful. Vasopressors should be considered.
Heart Block (second or third degree)
Patients should be carefully monitored and treated with isoproterenol infusion or transvenous cardiac pacemaker insertion, as
appropriate.
Congestive Heart Failure
Initiate conventional therapy (ie, digitalis, diuretics, vasodilating agents, inotropic agents).
Bronchospasm
Administer a bronchodilator such as isoproterenol and/or aminophylline.
Hypoglycemia
Administer IV glucose.
Surveillance
Fluid and electrolyte balance (especially serum potassium) and renal function should be monitored until normalized.
DOSAGE AND ADMINISTRATION
Bisoprolol is an effective treatment of hypertension in once-daily doses of 2.5 to 40 mg, while hydrochlorothiazide is effective in
doses of 12.5 to 50 mg. In clinical trials of bisoprolol/hydrochlorothiazide combination therapy using bisoprolol doses of 2.5 to 20 mg
and hydrochlorothiazide doses of 6.25 to 25 mg, the antihypertensive effects increased with increasing doses of either component.
The adverse effects (see WARNINGS) of bisoprolol are a mixture of dose-dependent phenomena (primarily bradycardia, diarrhea,
asthenia, and fatigue) and dose-independent phenomena (eg, occasional rash); those of hydrochlorothiazide are a mixture of dose-
dependent phenomena (primarily hypokalemia) and dose-independent phenomena (eg, possibly pancreatitis); the dose-dependent
phenomena for each being much more common than the dose-independent phenomena. The latter consist of those few that are truly
idiosyncratic in nature or those that occur with such low frequency that a dose relationship may be difficult to discern. Therapy with
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a combination of bisoprolol and hydrochlorothiazide will be associated with both sets of dose-independent adverse effects, and to
minimize these, it may be appropriate to begin combination therapy only after a patient has failed to achieve the desired effect with
monotherapy. On the other hand, regimens that combine low doses of bisoprolol and hydrochlorothiazide should produce minimal
dose-dependent adverse effects, eg, bradycardia, diarrhea, asthenia and fatigue, and minimal dose-dependent adverse metabolic
effects, ie, decreases in serum potassium (see CLINICAL PHARMACOLOGY).
Therapy Guided by Clinical Effect
A patient whose blood pressure is not adequately controlled with 2.5-20 mg bisoprolol daily may instead be given ZIAC. Patients
whose blood pressures are adequately controlled with 50 mg of hydrochlorothiazide daily, but who experience significant potassium
loss with this regimen, may achieve similar blood pressure control without electrolyte disturbance if they are switched to ZIAC.
Initial Therapy
Antihypertensive therapy may be initiated with the lowest dose of ZIAC, one 2.5/6.25 mg tablet once daily. Subsequent titration (14
day intervals) may be carried out with ZIAC tablets up to the maximum recommended dose 20/12.5 mg (two 10/6.25 mg tablets) once
daily, as appropriate.
Replacement Therapy
The combination may be substituted for the titrated individual components.
Cessation of Therapy
If withdrawal of ZIAC therapy is planned, it should be achieved gradually over a period of about 2 weeks. Patients should be carefully
observed.
Patients with Renal or Hepatic Impairment: As noted in the WARNINGS section, caution must be used in dosing/titrating patients
with hepatic impairment or renal dysfunction. Since there is no indication that hydrochlorothiazide is dialyzable, and limited data
suggest that bisoprolol is not dialyzable, drug replacement is not necessary in patients undergoing dialysis.
Geriatric Patients: Dosage adjustment on the basis of age is not usually necessary, unless there is also significant renal or hepatic
dysfunction (see above and WARNINGS section).
Pediatric Patients: There is no pediatric experience with ZIAC.
HOW SUPPLIED
ZIAC®-2.5 mg/6.25 mg Tablets (bisoprolol fumarate 2.5 mg and hydrochlorothiazide 6.25 mg): Yellow, round, film-coated, unscored
tablet. Debossed with stylized b within an engraved heart shape on one side and 47 on the other side, supplied as follows:
Bottle of 100 Tablets
NDC 51285-047-02
ZIAC®-5 mg/6.25 mg Tablets (bisoprolol fumarate 5 mg and hydrochlorothiazide 6.25 mg) are pink, round, film-coated, unscored
tablets. Debossed with stylized b within an engraved heart shape on one side and 50 on the other side, supplied as follows:
Bottle of 100 Tablets
NDC 51285-050-02
ZIAC®-10 mg/6.25 mg Tablets (bisoprolol fumarate 10 mg and hydrochlorothiazide 6.25 mg) are white, round, film-coated, unscored
tablets. Debossed with stylized b within an engraved heart shape on one side and 40 on the other side, supplied as follows:
Bottle of 30 Tablets with child resistant closure
NDC 51285-040-01
Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].
Dispense in a tight container.
DURAMED PHARMACEUTICALS, INC.
Subsidiary of Barr Pharmaceuticals, Inc.
Pomona, New York 10970
Revised MAY 2007
BR-0047, 0050, 0040
page 13 of 13
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/020186s023lbl.pdf', 'application_number': 20186, 'submission_type': 'SUPPL ', 'submission_number': 23}
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NDA 020189/S-027
FDA Approved Labeling Text dated 8/27/2012
Page 1
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FELBATOL® (felbamate)
2
Tablets 400 mg and 600 mg, Oral Suspension 600 mg/5 mL
3
IN-00431-18
Rev. 7/11
4
Before Prescribing Felbatol® (felbamate), the physician should be thoroughly familiar with the
6
details of this prescribing information.
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8
FELBATOL® SHOULD NOT BE USED BY PATIENTS UNTIL THERE HAS BEEN A
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COMPLETE DISCUSSION OF THE RISKS AND THE PATIENT, PARENT, OR GUARDIAN
HAS BEEN PROVIDED THE FELBATOL WRITTEN ACKNOWLEDGEMENT (SEE
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PATIENT/PHYSICIAN ACKNOWLEDGMENT FORM).
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WARNING
1. APLASTIC ANEMIA
THE USE OF FELBATOL® (felbamate) IS ASSOCIATED WITH A MARKED INCREASE IN THE
INCIDENCE OF APLASTIC ANEMIA. ACCORDINGLY, FELBATOL® SHOULD ONLY BE USED
IN PATIENTS WHOSE EPILEPSY IS SO SEVERE THAT THE RISK OF APLASTIC ANEMIA IS
DEEMED ACCEPTABLE IN LIGHT OF THE BENEFITS CONFERRED BY ITS USE (SEE
INDICATIONS). ORDINARILY, A PATIENT SHOULD NOT BE PLACED ON AND/OR
CONTINUED ON FELBATOL® WITHOUT CONSIDERATION OF APPROPRIATE EXPERT
HEMATOLOGIC CONSULTATION.
AMONG FELBATOL® TREATED PATIENTS, APLASTIC ANEMIA (PANCYTOPENIA IN THE
PRESENCE OF A BONE MARROW LARGELY DEPLETED OF HEMATOPOIETIC PRECURSORS)
OCCURS AT AN INCIDENCE THAT MAY BE MORE THAN A 100 FOLD GREATER THAN THAT
SEEN IN THE UNTREATED POPULATION (I.E., 2 TO 5 PER MILLION PERSONS PER YEAR).
THE RISK OF DEATH IN PATIENTS WITH APLASTIC ANEMIA GENERALLY VARIES AS A
FUNCTION OF ITS SEVERITY AND ETIOLOGY; CURRENT ESTIMATES OF THE OVERALL
CASE FATALITY RATE ARE IN THE RANGE OF 20 TO 30%, BUT RATES AS HIGH AS 70%
HAVE BEEN REPORTED IN THE PAST.
THERE ARE TOO FEW FELBATOL® ASSOCIATED CASES, AND TOO LITTLE KNOWN ABOUT
THEM TO PROVIDE A RELIABLE ESTIMATE OF THE SYNDROME'S INCIDENCE OR ITS CASE
FATALITY RATE OR TO IDENTIFY THE FACTORS, IF ANY, THAT MIGHT CONCEIVABLY BE
USED TO PREDICT WHO IS AT GREATER OR LESSER RISK.
IN MANAGING PATIENTS ON FELBATOL®, IT SHOULD BE BORNE IN MIND THAT THE
CLINICAL MANIFESTATION OF APLASTIC ANEMIA MAY NOT BE SEEN UNTIL AFTER A
PATIENT HAS BEEN ON FELBATOL® FOR SEVERAL MONTHS (E.G., ONSET OF APLASTIC
ANEMIA AMONG FELBATOL® EXPOSED PATIENTS FOR WHOM DATA ARE AVAILABLE
HAS RANGED FROM 5 TO 30 WEEKS). HOWEVER, THE INJURY TO BONE MARROW STEM
CELLS THAT IS HELD TO BE ULTIMATELY RESPONSIBLE FOR THE ANEMIA MAY OCCUR
WEEKS TO MONTHS EARLIER. ACCORDINGLY, PATIENTS WHO ARE DISCONTINUED
FROM FELBATOL® REMAIN AT RISK FOR DEVELOPING ANEMIA FOR A VARIABLE, AND
UNKNOWN, PERIOD AFTERWARDS.
IT IS NOT KNOWN WHETHER OR NOT THE RISK OF DEVELOPING APLASTIC ANEMIA
CHANGES WITH DURATION OF EXPOSURE. CONSEQUENTLY, IT IS NOT SAFE TO ASSUME
THAT A PATIENT WHO HAS BEEN ON FELBATOL® WITHOUT SIGNS OF HEMATOLOGIC
ABNORMALITY FOR LONG PERIODS OF TIME IS WITHOUT RISK.
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IT IS NOT KNOWN WHETHER OR NOT THE DOSE OF FELBATOL® AFFECTS THE
INCIDENCE OF APLASTIC ANEMIA.
IT IS NOT KNOWN WHETHER OR NOT CONCOMITANT USE OF ANTIEPILEPTIC DRUGS
AND/OR OTHER DRUGS AFFECTS THE INCIDENCE OF APLASTIC ANEMIA.
APLASTIC ANEMIA TYPICALLY DEVELOPS WITHOUT PREMONITORY CLINICAL OR
LABORATORY SIGNS, THE FULL BLOWN SYNDROME PRESENTING WITH SIGNS OF
INFECTION, BLEEDING, OR ANEMIA. ACCORDINGLY, ROUTINE BLOOD TESTING CANNOT
BE RELIABLY USED TO REDUCE THE INCIDENCE OF APLASTIC ANEMIA, BUT, IT WILL, IN
SOME CASES, ALLOW THE DETECTION OF THE HEMATOLOGIC CHANGES BEFORE THE
SYNDROME DECLARES ITSELF CLINICALLY. FELBATOL® SHOULD BE DISCONTINUED IF
ANY EVIDENCE OF BONE MARROW DEPRESSION OCCURS.
2. HEPATIC FAILURE
EVALUATION OF POSTMARKETING EXPERIENCE SUGGESTS THAT ACUTE LIVER
FAILURE IS ASSOCIATED WITH THE USE OF FELBATOL®. THE REPORTED RATE IN THE
U.S. HAS BEEN ABOUT 6 CASES OF LIVER FAILURE LEADING TO DEATH OR TRANSPLANT
PER 75,000 PATIENT YEARS OF USE. THIS RATE IS AN UNDERESTIMATE BECAUSE OF
UNDER REPORTING, AND THE TRUE RATE COULD BE CONSIDERABLY GREATER THAN
THIS. FOR EXAMPLE, IF THE REPORTING RATE IS 10%, THE TRUE RATE WOULD BE ONE
CASE PER 1,250 PATIENT YEARS OF USE.
OF THE CASES REPORTED, ABOUT 67% RESULTED IN DEATH OR LIVER
TRANSPLANTATION, USUALLY WITHIN 5 WEEKS OF THE ONSET OF SIGNS AND
SYMPTOMS OF LIVER FAILURE. THE EARLIEST ONSET OF SEVERE HEPATIC
DYSFUNCTION FOLLOWED SUBSEQUENTLY BY LIVER FAILURE WAS 3 WEEKS AFTER
INITIATION OF FELBATOL®. ALTHOUGH SOME REPORTS DESCRIBED DARK URINE AND
NONSPECIFIC PRODROMAL SYMPTOMS (E.G., ANOREXIA, MALAISE, AND
GASTROINTESTINAL SYMPTOMS), IN OTHER REPORTS IT WAS NOT CLEAR IF ANY
PRODROMAL SYMPTOMS PRECEDED THE ONSET OF JAUNDICE.
IT IS NOT KNOWN WHETHER OR NOT THE RISK OF DEVELOPING HEPATIC FAILURE
CHANGES WITH DURATION OF EXPOSURE.
IT IS NOT KNOWN WHETHER OR NOT THE DOSAGE OF FELBATOL® AFFECTS THE
INCIDENCE OF HEPATIC FAILURE.
IT IS NOT KNOWN WHETHER CONCOMITANT USE OF OTHER ANTIEPILEPTIC DRUGS
AND/OR OTHER DRUGS AFFECT THE INCIDENCE OF HEPATIC FAILURE.
FELBATOL® SHOULD NOT BE PRESCRIBED FOR ANYONE WITH A HISTORY OF HEPATIC
DYSFUNCTION.
TREATMENT WITH FELBATOL® SHOULD BE INITIATED ONLY IN INDIVIDUALS WITHOUT
ACTIVE LIVER DISEASE AND WITH NORMAL BASELINE SERUM TRANSAMINASES. IT HAS
NOT BEEN PROVED THAT PERIODIC SERUM TRANSAMINASE TESTING WILL PREVENT
SERIOUS INJURY BUT IT IS GENERALLY BELIEVED THAT EARLY DETECTION OF DRUG
INDUCED HEPATIC INJURY ALONG WITH IMMEDIATE WITHDRAWAL OF THE SUSPECT
DRUG ENHANCES THE LIKELIHOOD FOR RECOVERY. THERE IS NO INFORMATION
AVAILABLE THAT DOCUMENTS HOW RAPIDLY PATIENTS CAN PROGRESS FROM
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Page 3
NORMAL LIVER FUNCTION TO LIVER FAILURE, BUT OTHER DRUGS KNOWN TO BE
HEPATOTOXINS CAN CAUSE LIVER FAILURE RAPIDLY (E.G., FROM NORMAL ENZYMES
TO LIVER FAILURE IN 2-4 WEEKS). ACCORDINGLY, MONITORING OF SERUM
TRANSAMINASE LEVELS (AST AND ALT) IS RECOMMENDED AT BASELINE AND
PERIODICALLY THEREAFTER. WHILE THE MORE FREQUENT THE MONITORING THE
GREATER THE CHANCES OF EARLY DETECTION, THE PRECISE SCHEDULE FOR
MONITORING IS A MATTER OF CLINICAL JUDGEMENT.
FELBATOL® SHOULD BE DISCONTINUED IF EITHER SERUM AST OR SERUM ALT LEVELS
BECOME INCREASED ≥ 2 TIMES THE UPPER LIMIT OF NORMAL, OR IF CLINICAL SIGNS
AND SYMPTOMS SUGGEST LIVER FAILURE (SEE PRECAUTIONS ). PATIENTS WHO
DEVELOP EVIDENCE OF HEPATOCELLULAR INJURY WHILE ON FELBATOL® AND ARE
WITHDRAWN FROM THE DRUG FOR ANY REASON SHOULD BE PRESUMED TO BE AT
INCREASED RISK FOR LIVER INJURY IF FELBATOL® IS REINTRODUCED. ACCORDINGLY,
SUCH PATIENTS SHOULD NOT BE CONSIDERED FOR RE-TREATMENT.
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DESCRIPTION
119
Felbatol® (felbamate) is an antiepileptic available as 400 mg and 600 mg tablets and as a 600 mg/5 mL
120
suspension for oral administration. Its chemical name is 2-phenyl-1,3-propanediol dicarbamate.
121
122
Felbamate is a white to off-white crystalline powder with a characteristic odor. It is very slightly soluble
123
in water, slightly soluble in ethanol, sparingly soluble in methanol, and freely soluble in dimethyl
124
sulfoxide. The molecular weight is 238.24; felbamate's molecular formula is C
H N O ; its
11
14
2
4
125
structural formula is:
126
structural formula
128
129
The inactive ingredients for Felbatol® (felbamate) Tablets 400 mg and 600 mg are starch,
130
microcrystalline cellulose, croscarmellose sodium, lactose, magnesium stearate, FD&C Yellow No. 6,
131
D&C Yellow No. 10, and FD&C Red No. 40 (600 mg tablets only). The inactive ingredients for
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Felbatol® (felbamate) Oral Suspension 600 mg/5 mL are sorbitol, glycerin, microcrystalline cellulose,
133
carboxymethylcellulose sodium, simethicone, polysorbate 80, methylparaben, saccharin sodium,
134
propylparaben, FD&C Yellow No. 6, FD&C Red No. 40, flavorings, and purified water.
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136
CLINICAL PHARMACOLOGY
137
Mechanism of Action:
138
The mechanism by which felbamate exerts its anticonvulsant activity is unknown, but in animal test
139
systems designed to detect anticonvulsant activity, felbamate has properties in common with other
140
marketed anticonvulsants. Felbamate is effective in mice and rats in the maximal electroshock test, the
141
subcutaneous pentylenetetrazol seizure test, and the subcutaneous picrotoxin seizure test. Felbamate also
142
exhibits anticonvulsant activity against seizures induced by intracerebroventricular administration of
143
glutamate in rats and N-methyl-D,L-aspartic acid in mice. Protection against maximal electroshock
144
induced seizures suggests that felbamate may reduce seizure spread, an effect possibly predictive of
145
efficacy in generalized tonic-clonic or partial seizures. Protection against pentylenetetrazol-induced
146
seizures suggests that felbamate may increase seizure threshold, an effect considered to be predictive of
147
potential efficacy in absence seizures.
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Receptor-binding studies in vitro indicate that felbamate has weak inhibitory effects on GABA-receptor
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binding, benzodiazepine receptor binding, and is devoid of activity at the MK-801 receptor binding site of
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the NMDA receptor-ionophore complex. However, felbamate does interact as an antagonist at the
152
strychnine-insensitive glycine recognition site of the NMDA receptor-ionophore complex. Felbamate is
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not effective in protecting chick embryo retina tissue against the neurotoxic effects of the excitatory
154
amino acid agonists NMDA, kainate, or quisqualate in vitro.
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The monocarbamate, p-hydroxy, and 2-hydroxy metabolites were inactive in the maximal electroshock
157
induced seizure test in mice. The monocarbamate and p-hydroxy metabolites had only weak (0.2 to 0.6)
158
activity compared with felbamate in the subcutaneous pentylenetetrazol seizure test. These metabolites
159
did not contribute significantly to the anticonvulsant action of felbamate.
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Pharmacokinetics:
162
The numbers in the pharmacokinetic section are mean ± standard deviation.
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Felbamate is well-absorbed after oral administration. Over 90% of the radioactivity after a dose of
165
1000 mg
14 C felbamate was found in the urine. Absolute bioavailability (oral vs. parenteral) has not been
166
measured. The tablet and suspension were each shown to be bioequivalent to the capsule used in clinical
167
trials, and pharmacokinetic parameters of the tablet and suspension are similar. There was no effect of
168
food on absorption of the tablet; the effect of food on absorption of the suspension has not been evaluated.
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Following oral administration, felbamate is the predominant plasma species (about 90% of plasma
171
radioactivity). About 40-50% of absorbed dose appears unchanged in urine, and an additional 40% is
172
present as unidentified metabolites and conjugates. About 15% is present as parahydroxyfelbamate, 2
173
hydroxyfelbamate, and felbamate monocarbamate, none of which have significant anticonvulsant activity.
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Binding of felbamate to human plasma protein was independent of felbamate concentrations between 10
176
and 310 micrograms/mL. Binding ranged from 22% to 25%, mostly to albumin, and was dependent on
177
the albumin concentration.
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Felbamate is excreted with a terminal half-life of 20-23 hours, which is unaltered after multiple doses.
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Clearance after a single 1200 mg dose is 26±3 mL/hr/kg, and after multiple daily doses of 3600 mg is
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30±8 mL/hr/kg. The apparent volume of distribution was 756±82 mL/kg after a 1200 mg dose. Felbamate
182
Cmax and AUC are proportionate to dose after single and multiple doses over a range of 100-800 mg
183
single doses and 1200-3600 mg daily doses. Cmin (trough) blood levels are also dose proportional.
184
Multiple daily doses of 1200, 2400, and 3600 mg gave Cmin values of 30±5, 55±8, and 83±21
185
micrograms/mL (N=10 patients). Linear and dose proportional pharmacokinetics were also observed at
186
doses above 3600 mg/day up to the maximum dose studied of 6000 mg/day. Felbamate gave dose
187
proportional steady-state peak plasma concentrations in children age 4-12 over a range of 15, 30, and 45
188
mg/kg/day with peak concentrations of 17, 32, and 49 micrograms/mL.
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The effects of race and gender on felbamate pharmacokinetics have not been systematically evaluated, but
191
plasma concentrations in males (N=5) and females (N=4) given felbamate have been similar. The effects
192
of felbamate kinetics on hepatic functional impairment have not been evaluated.
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Renal Impairment:
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Felbamate's single dose monotherapy pharmacokinetic parameters were evaluated in 12 otherwise healthy
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individuals with renal impairment. There was a 40-50% reduction in total body clearance and 9-15 hours
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prolongation of half-life in renally impaired subjects compared to that in subjects with normal renal
Reference ID: 3180666
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NDA 020189/S-027
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function. Reduced felbamate clearance and a longer half-life were associated with diminishing renal
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function.
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Pharmacodynamics:
202
Typical Physiologic Responses:
203
1.Cardiovascular:
204
In adults, there is no effect of felbamate on blood pressure. Small but statistically significant mean
205
increases in heart rate were seen during adjunctive therapy and monotherapy; however, these mean
206
increases of up to 5 bpm were not clinically significant. In children, no clinically relevant changes in
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blood pressure or heart rate were seen during adjunctive therapy or monotherapy with felbamate.
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2. Other Physiologic Effects:
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The only other change in vital signs was a mean decrease of approximately 1 respiration per minute in
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respiratory rate during adjunctive therapy in children. In adults, statistically significant mean reductions in
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body weight were observed during felbamate monotherapy and adjunctive therapy. In children, there were
213
mean decreases in body weight during adjunctive therapy and monotherapy; however, these mean
214
changes were not statistically significant. These mean reductions in adults and children were
215
approximately 5% of the mean weights at baseline.
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CLINICAL STUDIES
218
The results of controlled clinical trials established the efficacy of Felbatol® (felbamate) as monotherapy
219
and adjunctive therapy in adults with partial-onset seizures with or without secondary generalization and
220
in partial and generalized seizures associated with Lennox-Gastaut syndrome in children.
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Felbatol® Monotherapy Trials in Adults
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Felbatol® (3600 mg/day given QID) and low-dose valproate (15 mg/kg/day) were compared as
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monotherapy during a 112-day treatment period in a multicenter and a single-center double-blind efficacy
225
trial. Both trials were conducted according to an identical study design. During a 56-day baseline period,
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all patients had at least four partial-onset seizures per 28 days and were receiving one antiepileptic drug at
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a therapeutic level, the most common being carbamazepine. In the multicenter trial, baseline seizure
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frequencies were 12.4 per 28 days in the Felbatol® group and 21.3 per 28 days in the low-dose valproate
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group. In the single-center trial, baseline seizure frequencies were 18.1 per 28 days in the Felbatol®
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group and 15.9 per 28 days in the low-dose valproate group. Patients were converted to monotherapy with
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Felbatol® or low-dose valproic acid during the first 28 days of the 112-day treatment period. Study
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endpoints were completion of 112 study days or fulfilling an escape criterion. Criteria for escape relative
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to baseline were: (1) twofold increase in monthly seizure frequency, (2) twofold increase in highest 2-day
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seizure frequency, (3) single generalized tonic-clonic seizure (GTC) if none occurred during baseline, or
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(4) significant prolongation of GTCs. The primary efficacy variable was the number of patients in each
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treatment group who met escape criteria.
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In the multicenter trial, the percentage of patients who met escape criteria was 40% (18/45) in the
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Felbatol® group and 78% (39/50) in the low-dose valproate group. In the single-center trial, the
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percentage of patients who met escape criteria was 14% (3/21) in the Felbatol® group and 90% (19/21) in
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the low-dose valproate group. In both trials, the difference in the percentage of patients meeting escape
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criteria was statistically significant (P<.001) in favor of Felbatol®. These two studies by design were
243
intended to demonstrate the effectiveness of Felbatol® monotherapy. The studies were not designed or
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intended to demonstrate comparative efficacy of the two drugs. For example, valproate was not used at
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the maximally effective dose.
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Felbatol® Adjunctive Therapy Trials in Adults
Reference ID: 3180666
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A double-blind, placebo-controlled crossover trial consisted of two 10-week outpatient treatment periods.
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Patients with refractory partial-onset seizures who were receiving phenytoin and carbamazepine at
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therapeutic levels were administered Felbatol® (felbamate) as add-on therapy at a starting dosage of 1400
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mg/day in three divided doses, which was increased to 2600 mg/day in three divided doses. Among the 56
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patients who completed the study, the baseline seizure frequency was 20 per month. Patients treated with
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Felbatol® had fewer seizures than patients treated with placebo for each treatment sequence. There was a
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23% (P=.018) difference in percentage seizure frequency reduction in favor of Felbatol®.
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256
Felbatol® 3600 mg/day given QID and placebo were compared in a 28-day double-blind add-on trial in
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patients who had their standard antiepileptic drugs reduced while undergoing evaluations for surgery of
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intractable epilepsy. All patients had confirmed partial-onset seizures with or without generalization,
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seizure frequency during surgical evaluation not exceeding an average of four partial seizures per day or
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more than one generalized seizure per day, and a minimum average of one partial or generalized tonic
261
clonic seizure per day for the last 3 days of the surgical evaluation. The primary efficacy variable was
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time to fourth seizure after randomization to treatment with Felbatol® or placebo. Thirteen (46%) of 28
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patients in the Felbatol® group versus 29 (88%) of 33 patients in the placebo group experienced a fourth
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seizure. The median times to fourth seizure were greater than 28 days in the Felbatol® group and 5 days
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in the placebo group. The difference between Felbatol® and placebo in time to fourth seizure was
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statistically significant (P=.002) in favor of Felbatol®.
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Felbatol® Adjunctive Therapy Trial in Children with Lennox-Gastaut Syndrome
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In a 70-day double-blind, placebo-controlled add-on trial in the Lennox-Gastaut syndrome, Felbatol® 45
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mg/kg/day given QID was superior to placebo in controlling the multiple seizure types associated with
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this condition. Patients had at least 90 atonic and/or atypical absence seizures per month while receiving
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therapeutic dosages of one or two other antiepileptic drugs. Patients had a past history of using an average
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of eight antiepileptic drugs. The most commonly used antiepileptic drug during the baseline period was
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valproic acid. The frequency of all types of seizures during the baseline period was 1617 per month in the
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Felbatol® group and 716 per month in the placebo group. Statistically significant differences in the effect
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on seizure frequency favored Felbatol® over placebo for total seizures (26% reduction vs. 5% increase,
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P<.001), atonic seizures (44% reduction vs. 7% reduction, P=.002), and generalized tonic-clonic seizures
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(40% reduction vs. 12% increase, P=.017). Parent/guardian global evaluations based on impressions of
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quality of life with respect to alertness, verbal responsiveness, general well-being, and seizure control
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significantly (P<.001) favored Felbatol® over placebo.
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When efficacy was analyzed by gender in four well-controlled trials of felbamate as adjunctive and
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monotherapy for partial-onset seizures and Lennox-Gastaut syndrome, a similar response was seen in 122
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males and 142 females.
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INDICATIONS AND USAGE
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Felbatol® is not indicated as a first line antiepileptic treatment (see Warnings). Felbatol® is
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recommended for use only in those patients who respond inadequately to alternative treatments and
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whose epilepsy is so severe that a substantial risk of aplastic anemia and/or liver failure is deemed
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acceptable in light of the benefits conferred by its use.
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If these criteria are met and the patient has been fully advised of the risk, and has provided written
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acknowledgement, Felbatol® can be considered for either monotherapy or adjunctive therapy in the
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treatment of partial seizures, with and without generalization, in adults with epilepsy and as adjunctive
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therapy in the treatment of partial and generalized seizures associated with Lennox-Gastaut syndrome in
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children.
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Reference ID: 3180666
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NDA 020189/S-027
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CONTRAINDICATIONS
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Felbatol® is contraindicated in patients with known hypersensitivity to Felbatol®, its ingredients, or
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known sensitivity to other carbamates. It should not be used in patients with a history of any blood
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dyscrasia or hepatic dysfunction.
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WARNINGS
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See Boxed Warning regarding aplastic anemia and hepatic failure.
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Antiepileptic drugs should not be suddenly discontinued because of the possibility of increasing seizure
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frequency.
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Suicidal Behavior and Ideation
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Antiepileptic drugs (AEDs) including Felbatol ®, increase the risk of suicidal thoughts or behavior in
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patients taking these drugs for any indication. Patients treated with any AED for any indication should be
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monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any
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unusual changes in mood or behavior.
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Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different
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AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted
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Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to
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placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate
319
of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24%
320
among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal
321
thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in
322
the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about
323
drug effect on suicide.
324
325
The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after
326
starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most
327
trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior
328
beyond 24 weeks could not be assessed.
329
330
The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The
331
finding of increased risk with AEDs of varying mechanisms of action and across a range of indications
332
suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by
333
age (5-100 years) in the clinical trials analyzed.
334
335
Table 1 shows absolute and relative risk by indication for all evaluated AEDs.
Table 1 Risk by Indication for Antiepileptic Drugs in the Pooled Analysis
Indication
Placebo Patients
with Events
Per 1000 Patients
Drug Patients with
Events Per
1000 Patients
Relative Risk:
Incidence of
Events in Drug
Patients/Incidence
in Placebo Patients
Risk Difference:
Additional Drug
Patients with
Events Per 1000
Patients
Epilepsy
1.0
3.4
3.5
2.4
Psychiatric
5.7
8.5
1.5
2.9
Other
1.0
1.8
1.9
0.9
Total
2.4
4.3
1.8
1.9
336
337
The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical
338
trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and
339
psychiatric indications.
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340
341
Anyone considering prescribing Felbatol or any other AED must balance the risk of suicidal thoughts or
342
behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are
343
prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal
344
thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber
345
needs to consider whether the emergence of these symptoms in any given patient may be related to the
346
illness being treated.
347
348
Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal
349
thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the
350
signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of
351
suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported
352
immediately to healthcare providers.
353
354
PRECAUTIONS
355
Dosage Adjustment in the Renally Impaired: A study in otherwise healthy individuals with renal
356
dysfunction indicated that prolonged half-life and reduced clearance of felbamate are associated with
357
diminishing renal function. Felbamate should be used with caution in patients with renal dysfunction (see
358
DOSAGE AND ADMINISTRATION).
359
360
Information for Patients: Patients should be informed that the use of Felbatol® is associated with
361
aplastic anemia and hepatic failure, potentially fatal conditions acutely or over a long term.
362
363
The physician should obtain written acknowledgement prior to initiation of Felbatol® therapy (see
364
PATIENT/PHYSICIAN ACKNOWLEDGMENT FORM section).
365
366
Patients should be instructed to read the Medication Guide supplied as required by law when
367
Felbatol® is dispensed. The complete text of the Medication Guide is reprinted at the end of this
368
document.
369
370
Aplastic anemia in the general population is relatively rare. The absolute risk for the individual patient is
371
not known with any degree of reliability, but patients on Felbatol® may be at more than a 100 fold greater
372
risk for developing the syndrome than the general population.
373
374
The long term outlook for patients with aplastic anemia is variable. Although many patients are
375
apparently cured, others require repeated transfusions and other treatments for relapses, and some,
376
although surviving for years, ultimately develop serious complications that sometimes prove fatal (e.g.,
377
leukemia).
378
379
At present there is no way to predict who is likely to get aplastic anemia, nor is there a documented
380
effective means to monitor the patient so as to avoid and/or reduce the risk. Patients with a history of any
381
blood dyscrasia should not receive Felbatol®.
382
383
Patients should be advised to be alert for signs of infection, bleeding, easy bruising, or signs of anemia
384
(fatigue, weakness, lassitude, etc.) and should be advised to report to the physician immediately if any
385
such signs or symptoms appear.
386
387
Hepatic failure in the general population is relatively rare. The absolute risk for an individual patient is
388
not known with any degree of reliability but patients on Felbatol® are at a greater risk for developing
389
hepatic failure than the general population.
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390
391
At present, there is no way to predict who is likely to develop hepatic failure, however, patients with a
392
history of hepatic dysfunction should not be started on Felbatol®.
393
394
Patients should be advised to follow their physician's directives for liver function testing both before
395
starting Felbatol® (felbamate) and at frequent intervals while taking Felbatol®.
396
397
Patients should be advised to be alert for signs of liver dysfunction (jaundice, anorexia, gastrointestinal
398
complaints, malaise, etc.) and to report them to their doctor immediately if they should occur.
399
400
Laboratory Tests: Full hematologic evaluations should be performed before Felbatol® therapy,
401
frequently during therapy, and for a significant period of time after discontinuation of Felbatol® therapy.
402
While it might appear prudent to perform frequent CBCs in patients continuing on Felbatol®, there is no
403
evidence that such monitoring will allow early detection of marrow suppression before aplastic anemia
404
occurs. (see Boxed Warnings). Complete pretreatment blood counts, including platelets and reticulocytes
405
should be obtained as a baseline. If any hematologic abnormalities are detected during the course of
406
treatment, immediate consultation with a hematologist is advised. Felbatol® should be discontinued if
407
any evidence of bone marrow depression occurs.
408
409
See Box Warnings for recommended monitoring of serum transaminases. If significant, confirmed liver
410
abnormalities are detected during the course of Felbatol® treatment, Felbatol® should be discontinued
411
immediately with continued liver function monitoring until values return to normal. (see
412
PATIENT/PHYSICIAN ACKNOWLEDGMENT FORM ).
413
414
Suicidal Thinking and Behavior: Patients, their caregivers, and families should be counseled
415
that AEDs, including Felbatol®, may increase the risk of suicidal thoughts and behavior and
416
should be advised of the need to be alert for the emergence or worsening of symptoms of
417
depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts,
418
behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to
419
healthcare providers.
420
421
Pregnancy: Patients should be encouraged to enroll in the North American Antiepileptic Drug
422
(NAAED) Pregnancy Registry if they become pregnant. This registry is collecting information
423
about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll free
424
number 1-888-233-2334 (see Pregnancy section).
425
426
Drug Interactions:
427
The drug interaction data described in this section were obtained from controlled clinical trials and studies
428
involving otherwise healthy adults with epilepsy.
429
430
Use in Conjunction with Other Antiepileptic Drugs (see DOSAGE AND ADMINISTRATION):
431
432
The addition of Felbatol® to antiepileptic drugs (AEDs) affects the steady-state plasma
433
concentrations of AEDs. The net effect of these interactions is summarized in Table 2:
434
Table 2 Steady-State Plasma Concentrations of Felbatol When Coadministered With Other AEDs
AED
Coadministered
AED
Concentration
Felbatol®
Concentration
Phenytoin
↑
↓
Valproate
↑
↔**
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Page 10
Carbamazepine (CBZ)
*CBZ epoxide
↓
↑
↓
Phenobarbital
↑
↓
*Not administered but an active metabolite of carbamazepine.
**No significant effect.
435
436
Specific Effects of Felbatol® on Other Antiepileptic Drugs:
437
Phenytoin: Felbatol® causes an increase in steady-state phenytoin plasma concentrations. In 10
438
otherwise healthy subjects with epilepsy ingesting phenytoin, the steady-state trough (Cmin) phenytoin
439
plasma concentration was 17±5 micrograms/mL. The steady-state Cmin increased to 21±5
440
micrograms/mL when 1200 mg/day of felbamate was coadministered. Increasing the felbamate dose to
441
1800 mg/day in six of these subjects increased the steady-state phenytoin Cmin to 25±7 micrograms/mL.
442
In order to maintain phenytoin levels, limit adverse experiences, and achieve the felbamate dose of 3600
443
mg/day, a phenytoin dose reduction of approximately 40% was necessary for eight of these 10 subjects.
444
445
In a controlled clinical trial, a 20% reduction of the phenytoin dose at the initiation of Felbatol® therapy
446
resulted in phenytoin levels comparable to those prior to Felbatol® administration.
447
448
Carbamazepine: Felbatol® causes a decrease in the steady-state carbamazepine plasma concentrations
449
and an increase in the steady-state carbamazepine epoxide plasma concentration. In nine otherwise
450
healthy subjects with epilepsy ingesting carbamazepine, the steady-state trough (Cmin) carbamazepine
451
concentration was 8±2 micrograms/mL. The carbamazepine steady-state Cmin decreased 31% to 5±1
452
micrograms/mL when felbamate (3000 mg/day, divided into three doses) was coadministered.
453
Carbamazepine epoxide steady-state Cmin concentrations increased 57% from 1.0±0.3 to 1.6±0.4
454
micrograms/mL with the addition of felbamate.
455
456
In clinical trials, similar changes in carbamazepine and carbamazepine epoxide were seen.
457
458
Valproate: Felbatol® causes an increase in steady-state valproate concentrations. In four subjects with
459
epilepsy ingesting valproate, the steady-state trough (Cmin) valproate plasma concentration was 63±16
460
micrograms/mL. The steady-state Cmin increased to 78±14 micrograms/mL when 1200 mg/day of
461
felbamate was coadministered. Increasing the felbamate dose to 2400 mg/day increased the steady-state
462
valproate Cmin to 96±25 micrograms/mL. Corresponding values for free valproate Cmin concentrations
463
were 7±3, 9±4, and 11±6 micrograms/mL for 0, 1200, and 2400 mg/day Felbatol®, respectively. The
464
ratios of the AUCs of unbound valproate to the AUCs of the total valproate were 11.1%, 13.0%, and
465
11.5%, with coadministration of 0, 1200, and 2400 mg/day of Felbatol®, respectively. This indicates that
466
the protein binding of valproate did not change appreciably with increasing doses of Felbatol®.
467
468
Phenobarbital: Coadministration of felbamate with phenobarbital causes an increase in phenobarbital
469
plasma concentrations. In 12 otherwise healthy male volunteers ingesting phenobarbital, the steady-state
470
trough (Cmin) phenobarbital concentration was 14.2 micrograms/mL. The steady-state Cmin
471
concentration increased to 17.8 micrograms/mL when 2400 mg/day of felbamate was coadministered for
472
one week.
473
474
Effects of Other Antiepileptic Drugs on Felbatol®:
475
Phenytoin: Phenytoin causes an approximate doubling of the clearance of Felbatol® (felbamate) at
476
steady-state and, therefore, the addition of phenytoin causes an approximate 45% decrease in the steady
477
state trough concentrations of Felbatol® as compared to the same dose of Felbatol® given as
478
monotherapy.
479
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480
Carbamazepine: Carbamazepine causes an approximate 50% increase in the clearance of Felbatol® at
481
steady-state and, therefore, the addition of carbamazepine results in an approximate 40% decrease in the
482
steady-state trough concentrations of Felbatol® as compared to the same dose of Felbatol® given as
483
monotherapy.
484
485
Valproate: Available data suggest that there is no significant effect of valproate on the clearance of
486
Felbatol® at steady-state. Therefore, the addition of valproate is not expected to cause a clinically
487
important effect on Felbatol® (felbamate) plasma concentrations.
488
489
Phenobarbital: It appears that phenobarbital may reduce plasma felbamate concentrations. Steady-state
490
plasma felbamate concentrations were found to be 29% lower than the mean concentrations of a group of
491
newly diagnosed subjects with epilepsy also receiving 2400 mg of felbamate a day.
492
493
Effects of Antacids on Felbatol®:
494
The rate and extent of absorption of a 2400 mg dose of Felbatol® as monotherapy given as tablets was
495
not affected when coadministered with antacids.
496
497
Effects of Erythromycin on Felbatol®:
498
The coadministration of erythromycin (1000 mg/day) for 10 days did not alter the pharmacokinetic
499
parameters of Cmax, Cmin, AUC, Cl/kg or Tmax at felbamate daily doses of 3000 or 3600 mg/day in 10
500
otherwise healthy subjects with epilepsy.
501
502
Effects of Felbatol® on Low-Dose Combination Oral Contraceptives:
503
A group of 24 nonsmoking, healthy white female volunteers established on an oral contraceptive regimen
504
containing 30 μg ethinyl estradiol and 75 μg gestodene for at least 3 months received 2400 mg/day of
505
felbamate from midcycle (day 15) to midcycle (day 14) of two consecutive oral contraceptive cycles.
506
Felbamate treatment resulted in a 42% decrease in the gestodene AUC 0-24, but no clinically relevant
507
effect was observed on the pharmacokinetic parameters of ethinyl estradiol. No volunteer showed
508
hormonal evidence of ovulation, but one volunteer reported intermenstrual bleeding during felbamate
509
treatment.
510
511
Drug/Laboratory Test Interactions: There are no known interactions of Felbatol® with commonly used
512
laboratory tests.
513
514
Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity studies were conducted in mice
515
and rats. Mice received felbamate as a feed admixture for 92 weeks at doses of 300, 600, and 1200 mg/kg
516
and rats were also dosed by feed admixture for 104 weeks at doses of 30, 100, and 300 (males) or 10, 30,
517
and 100 (females) mg/kg. The maximum doses in these studies produced steady-state plasma
518
concentrations that were equal to or less than the steady-state plasma concentrations in epileptic patients
519
receiving 3600 mg/day. There was a statistically significant increase in hepatic cell adenomas in high
520
dose male and female mice and in high-dose female rats. Hepatic hypertrophy was significantly increased
521
in a dose-related manner in mice, primarily males, but also in females. Hepatic hypertrophy was not
522
found in female rats. The relationship between the occurrence of benign hepatocellular adenomas and the
523
finding of liver hypertrophy resulting from liver enzyme induction has not been examined. There was a
524
statistically significant increase in benign interstitial cell tumors of the testes in high-dose male rats
525
receiving felbamate. The relevance of these findings to humans is unknown.
526
527
As a result of the synthesis process, felbamate could contain small amounts of two known animal
528
carcinogens, the genotoxic compound ethyl carbamate (urethane) and the nongenotoxic compound methyl
529
carbamate. It is theoretically possible that a 50 kg patient receiving 3600 mg of felbamate could be
530
exposed to up to 0.72 micrograms of urethane and 1800 micrograms of methyl carbamate. These daily
Reference ID: 3180666
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531
doses are approximately 1/35,000 (urethane) and 1/5,500 (methyl carbamate) on a mg/kg basis, and
532
1/10,000 (urethane) and 1/1,600 (methyl carbamate) on a mg/m
2 basis, of the dose levels shown to be
533
carcinogenic in rodents. Any presence of these two compounds in felbamate used in the lifetime
534
carcinogenicity studies was inadequate to cause tumors.
535
536
Microbial and mammalian cell assays revealed no evidence of mutagenesis in the Ames Salmonella
537
/microsome plate test, CHO/HGPRT mammalian cell forward gene mutation assay, sister chromatid
538
exchange assay in CHO cells, and bone marrow cytogenetics assay.
539
540
Reproduction and fertility studies in rats showed no effects on male or female fertility at oral doses of up
541
to 13.9 times the human total daily dose of 3600 mg on a mg/kg basis, or up to 3 times the human total
542
daily dose on a mg/m
2 basis.
543
544
Pregnancy: Pregnancy Category C. The incidence of malformations was not increased compared to
545
control in offspring of rats or rabbits given doses up to 13.9 times (rat) and 4.2 times (rabbit) the human
546
daily dose on a mg/kg basis, or 3 times (rat) and less than 2 times (rabbit) the human daily dose on a
547
mg/m
2 basis. However, in rats, there was a decrease in pup weight and an increase in pup deaths during
548
lactation. The cause for these deaths is not known. The no effect dose for rat pup mortality was 6.9 times
549
the human dose on a mg/kg basis or 1.5 times the human dose on a mg/m
2 basis.
550
551
Placental transfer of felbamate occurs in rat pups. There are, however, no studies in pregnant women.
552
Because animal reproduction studies are not always predictive of human response, this drug should be
553
used during pregnancy only if clearly needed.
554
555
To provide information regarding the effects of in utero exposure to Felbatol®, physicians are advised to
556
recommend that pregnant patients taking Felbatol enroll in the NAAED Pregnancy Registry. This can be
557
done by calling the toll free number 1-888-233-2334, and must be done by patients themselves.
558
Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/.
559
560
Labor and Delivery: The effect of felbamate on labor and delivery in humans is unknown.
561
562
Nursing Mothers: Felbamate has been detected in human milk. The effect on the nursing infant is
563
unknown (see Pregnancy section).
564
565
Pediatric Use: The safety and effectiveness of Felbatol® in children other than those with Lennox
566
Gastaut syndrome has not been established.
567
568
Geriatric Use: No systematic studies in geriatric patients have been conducted. Clinical studies of
569
Felbatol® did not include sufficient numbers of patients aged 65 and over to determine whether they
570
respond differently from younger patients. Other reported clinical experience has not identified
571
differences in responses between the elderly and younger patients. In general, dosage selection for an
572
elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the
573
greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other
574
drug therapy.
575
576
ADVERSE REACTIONS
577
To report SUSPECTED ADVERSE REACTIONS, contact Meda Pharmaceuticals Inc. at
578
1-800-526-3840 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .
579
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Page 13
580
The most common adverse reactions seen in association with Felbatol® (felbamate) in adults during
581
monotherapy are anorexia, vomiting, insomnia, nausea, and headache. The most common adverse
582
reactions seen in association with Felbatol® in adults during adjunctive therapy are anorexia, vomiting,
583
insomnia, nausea, dizziness, somnolence, and headache.
584
585
The most common adverse reactions seen in association with Felbatol® in children during adjunctive
586
therapy are anorexia, vomiting, insomnia, headache, and somnolence.
587
588
The dropout rate because of adverse experiences or intercurrent illnesses among adult felbamate patients
589
was 12 percent (120/977). The dropout rate because of adverse experiences or intercurrent illnesses
590
among pediatric felbamate patients was six percent (22/357). In adults, the body systems associated with
591
causing these withdrawals in order of frequency were: digestive (4.3%), psychological (2.2%), whole
592
body (1.7%), neurological (1.5%), and dermatological (1.5%). In children, the body systems associated
593
with causing these withdrawals in order of frequency were: digestive (1.7%), neurological (1.4%),
594
dermatological (1.4%), psychological (1.1%), and whole body (1.0%). In adults, specific events with an
595
incidence of 1% or greater associated with causing these withdrawals, in order of frequency were:
596
anorexia (1.6%), nausea (1.4%), rash (1.2%), and weight decrease (1.1%). In children, specific events
597
with an incidence of 1% or greater associated with causing these withdrawals, in order of frequency was
598
rash (1.1%).
599
600
Incidence in Clinical Trials:
601
The prescriber should be aware that the figures cited in the following table cannot be used to predict the
602
incidence of side effects in the course of usual medical practice where patient characteristics and other
603
factors differ from those which prevailed in the clinical trials. Similarly, the cited frequencies cannot be
604
compared with figures obtained from other clinical investigations involving different investigators,
605
treatments, and uses including the use of Felbatol® (felbamate) as adjunctive therapy where the incidence
606
of adverse events may be higher due to drug interactions. The cited figures, however, do provide the
607
prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors
608
to the side effect incidence rate in the population studied.
609
610
Adults
611
Incidence in Controlled Clinical Trials--Monotherapy Studies in Adults:
612
The table that follows enumerates adverse events that occurred at an incidence of 2% or more among 58
613
adult patients who received Felbatol® monotherapy at dosages of 3600 mg/day in double-blind controlled
614
trials. Table 3 presents reported adverse events that were classified using standard WHO-based dictionary
615
terminology.
616
Table 3 Adults Treatment-Emergent Adverse Event Incidence in Controlled Monotherapy Trials
Felbatol®* (N=58)
Low Dose Valproate** (N=50)
Body System Event
%
%
Body as a Whole
Fatigue
Weight Decrease
Face Edema
6.9
3.4
3.4
4.0
0
0
Central Nervous System
Insomnia
Headache
Anxiety
8.6
6.9
5.2
4.0
18.0
2.0
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Page 14
Dermatological
Acne
Rash
3.4
3.4
0
0
Digestive
Dyspepsia
Vomiting
Constipation
Diarrhea
SGPT Increased
8.6
8.6
6.9
5.2
5.2
2.0
2.0
2.0
0
2.0
Metabolic/Nutritional
Hypophosphatemia
3.4
0
Respiratory
Upper Respiratory Tract Infection
Rhinitis
8.6
6.9
4.0
0
Special Senses
Diplopia
Otitis Media
3.4
3.4
4.0
0
Urogenital
Intramenstrual Bleeding
Urinary Tract Infection
3.4
3.4
0
2.0
*3600 mg/day;** 15 mg/kg/day
617
618
Incidence in Controlled Add-On Clinical Studies in Adults:
619
Table 4 enumerates adverse events that occurred at an incidence of 2% or more among 114 adult patients
620
who received Felbatol® adjunctive therapy in add-on controlled trials at dosages up to 3600 mg/day.
621
Reported adverse events were classified using standard WHO-based dictionary terminology.
622
623
Many adverse experiences that occurred during adjunctive therapy may be a result of drug interactions.
624
Adverse experiences during adjunctive therapy typically resolved with conversion to monotherapy, or
625
with adjustment of the dosage of other antiepileptic drugs.
Reference ID: 3180666
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020189/S-027
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Page 15
626
Table 4 Adults Treatment-Emergent Adverse Event Incidence in Controlled Add-On Trials
Felbatol®
Placebo
(N=114)
(N=43)
Body System/Event
%
%
Body as a Whole
Fatigue
16.8
7.0
Fever
2.6
4.7
Chest Pain
2.6
0
Central Nervous System
Headache
36.8
9.3
Somnolence
19.3
7.0
Dizziness
18.4
14.0
Insomnia
17.5
7.0
Nervousness
7.0
2.3
Tremor
6.1
2.3
Anxiety
5.3
4.7
Gait Abnormal
5.3
0
Depression
5.3
0
Paraesthesia
3.5
2.3
Ataxia
3.5
0
Mouth Dry
2.6
0
Stupor
2.6
0
Dermatological
Rash
3.5
4.7
Digestive
Nausea
34.2
2.3
Anorexia
19.3
2.3
Vomiting
16.7
4.7
Dyspepsia
12.3
7.0
Constipation
11.4
2.3
Diarrhea
5.3
2.3
Abdominal Pain
5.3
0
SGPT Increased
3.5
0
Musculoskeletal
Myalgia
2.6
0
Respiratory
Upper Respiratory Tract Infection
Sinusitis
Pharyngitis
5.3
3.5
2.6
7.0
0
0
Special Senses
Diplopia
6.1
0
Taste Perversion
6.1
0
Vision Abnormal
5.3
2.3
627
628
Reference ID: 3180666
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Page 16
629
Children
630
Incidence in a Controlled Add-On Trial in Children with Lennox-Gastaut Syndrome:
631
Table 5 enumerates adverse events that occurred more than once among 31 pediatric patients who
632
received Felbatol® up to 45 mg/kg/day or a maximum of 3600 mg/day. Reported adverse events were
633
classified using standard WHO-based dictionary terminology.
634
NDA 020189/S-027
FDA Approved Labeling Text dated 8/27/2012
Table 5 Children Treatment-Emergent Adverse Event Incidence in Controlled Add-On
Lennox-Gastaut Trials
Felbatol®
Placebo
(N=31)
(N=27)
Body System/Event
%
%
Body as a Whole
Fever
22.6
11.1
Fatigue
9.7
3.7
Weight Decrease
6.5
0
Pain
6.5
0
Central Nervous System
Somnolence
48.4
11.1
Insomnia
16.1
14.8
Nervousness
16.1
18.5
Gait Abnormal
9.7
0
Headache
6.5
18.5
Thinking Abnormal
6.5
3.7
Ataxia
6.5
3.7
Urinary Incontinence
6.5
7.4
Emotional Lability
6.5
0
Miosis
6.5
0
Dermatological
Rash
9.7
7.4
Digestive
Anorexia
54.8
14.8
Vomiting
38.7
14.8
Constipation
12.9
0
Hiccup
9.7
3.7
Nausea
6.5
0
Dyspepsia
6.5
3.7
Hematologic
Purpura
Leukopenia
12.9
6.5
7.4
0
Respiratory
Upper Respiratory Tract Infection
45.2
25.9
Pharyngitis
9.7
3.7
Coughing
6.5
0
Special Senses
Otitis Media
9.7
0
635
636
Other Events Observed in Association with the Administration of Felbatol® (felbamate):
637
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For current labeling information, please visit https://www.fda.gov/drugsatfda
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FDA Approved Labeling Text dated 8/27/2012
Page 17
638
In the paragraphs that follow, the adverse clinical events, other than those in the preceding tables, that
639
occurred in a total of 977 adults and 357 children exposed to Felbatol® (felbamate) and that are
640
reasonably associated with its use are presented. They are listed in order of decreasing frequency.
641
Because the reports cite events observed in open-label and uncontrolled studies, the role of Felbatol® in
642
their causation cannot be reliably determined.
643
644
Events are classified within body system categories and enumerated in order of decreasing frequency
645
using the following definitions: frequent adverse events are defined as those occurring on one or more
646
occasions in at least 1/100 patients; infrequent adverse events are those occurring in 1/100-1/1000
647
patients; and rare events are those occurring in fewer than 1/1000 patients.
648
649
Event frequencies are calculated as the number of patients reporting an event divided by the total number
650
of patients (N=1334) exposed to Felbatol®.
651
652
Body as a Whole: Frequent: Weight increase, asthenia, malaise, influenza-like symptoms; Rare:
653
anaphylactoid reaction, chest pain substernal.
654
Cardiovascular: Frequent: Palpitation, tachycardia; Rare: supraventricular tachycardia.
655
Central Nervous System: Frequent: Agitation, psychological disturbance, aggressive reaction:
656
Infrequent: hallucination, euphoria, suicide attempt, migraine.
657
Digestive: Frequent: SGOT increased; Infrequent: esophagitis, appetite increased; Rare: GGT elevated.
658
Hematologic: Infrequent: Lymphadenopathy, leukopenia, leukocytosis, thrombocytopenia,
659
granulocytopenia; Rare: antinuclear factor test positive, qualitative platelet disorder, agranulocytosis.
660
Metabolic/Nutritional: Infrequent: Hypokalemia, hyponatremia, LDH increased, alkaline phosphatase
661
increased, hypophosphatemia; Rare: creatinine phosphokinase increased.
662
Musculoskeletal: Infrequent: Dystonia.
663
Dermatological: Frequent: Pruritus; Infrequent: urticaria, bullous eruption; Rare: buccal mucous
664
membrane swelling, Stevens-Johnson Syndrome.
665
Special Senses: Rare: Photosensitivity allergic reaction.
666
667
Postmarketing Adverse Event Reports:
668
Voluntary reports of adverse events in patients taking Felbatol® (usually in conjunction with other drugs)
669
have been received since market introduction and may have no causal relationship with the drug(s). These
670
include the following by body system:
671
Body as a Whole: neoplasm, sepsis, L.E. syndrome, SIDS, sudden death, edema, hypothermia, rigors,
672
hyperpyrexia.
673
Cardiovascular: atrial fibrillation, atrial arrhythmia, cardiac arrest, torsade de pointes, cardiac failure,
674
hypotension, hypertension, flushing, thrombophlebitis, ischemic necrosis, gangrene, peripheral ischemia,
675
bradycardia, Henoch-Schönlein purpura (vasculitis).
676
Central & Peripheral Nervous System: delusion, paralysis, mononeuritis, cerebrovascular disorder,
677
cerebral edema, coma, manic reaction, encephalopathy, paranoid reaction, nystagmus, choreoathetosis,
678
extrapyramidal disorder, confusion, psychosis, status epilepticus, dyskinesia, dysarthria, respiratory
679
depression, apathy, concentration impaired.
680
Dermatological: abnormal body odor, sweating, lichen planus, livedo reticularis, alopecia, toxic
681
epidermal necrolysis.
682
Digestive: (Refer to WARNINGS ) hepatitis, hepatic failure, G.I. hemorrhage, hyperammonemia,
683
pancreatitis, hematemesis, gastritis, rectal hemorrhage, flatulence, gingival bleeding, acquired megacolon,
684
ileus, intestinal obstruction, enteritis, ulcerative stomatitis, glossitis, dysphagia, jaundice, gastric ulcer,
685
gastric dilatation, gastroesophageal reflux.
686
Fetal Disorders: fetal death, microcephaly, genital malformation, anencephaly, encephalocele.
687
Hematologic: (Refer to WARNINGS ) increased and decreased prothrombin time, anemia, hypochromic
688
anemia, aplastic anemia, pancytopenia, hemolytic uremic syndrome, increased mean corpuscular volume
Reference ID: 3180666
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020189/S-027
FDA Approved Labeling Text dated 8/27/2012
Page 18
689
(mcv) with and without anemia, coagulation disorder, embolism-limb, disseminated intravascular
690
coagulation, eosinophilia, hemolytic anemia, leukemia, including myelogenous leukemia, and lymphoma,
691
including T-cell and B-cell lymphoproliferative disorders.
692
Metabolic/Nutritional: hypernatremia, hypoglycemia, SIADH, hypomagnesemia, dehydration,
693
hyperglycemia, hypocalcemia.
694
Musculoskeletal: arthralgia, muscle weakness, involuntary muscle contraction, rhabdomyolysis.
695
Respiratory: dyspnea, pneumonia, pneumonitis, hypoxia, epistaxis, pleural effusion, respiratory
696
insufficiency, pulmonary hemorrhage, asthma.
697
Special Senses: hemianopsia, decreased hearing, conjunctivitis.
698
Urogenital: menstrual disorder, acute renal failure, hepatorenal syndrome, hematuria, urinary retention,
699
nephrosis, vaginal hemorrhage, abnormal renal function, dysuria, placental disorder.
700
701
DRUG ABUSE AND DEPENDENCE
702
Abuse: Abuse potential was not evaluated in human studies.
703
704
Dependence: Rats administered felbamate orally at doses 8.3 times the recommended human dose 6 days
705
each week for 5 consecutive weeks demonstrated no signs of physical dependence as measured by weight
706
loss following drug withdrawal on day 7 of each week.
707
708
OVERDOSAGE
709
Four subjects inadvertently received Felbatol® (felbamate) as adjunctive therapy in dosages ranging from
710
5400 to 7200 mg/day for durations between 6 and 51 days. One subject who received 5400 mg/day as
711
monotherapy for 1 week reported no adverse experiences. Another subject attempted suicide by ingesting
712
12,000 mg of Felbatol® in a 12-hour period. The only adverse experiences reported were mild gastric
713
distress and a resting heart rate of 100 bpm. No serious adverse reactions have been reported.
714
General supportive measures should be employed if overdosage occurs. It is not known if felbamate is
715
dialyzable.
716
717
DOSAGE AND ADMINISTRATION
718
Felbatol® (felbamate) has been studied as monotherapy and adjunctive therapy in adults and as
719
adjunctive therapy in children with seizures associated with Lennox-Gastaut syndrome. As Felbatol® is
720
added to or substituted for existing AEDs, it is strongly recommended to reduce the dosage of those
721
AEDs in the range of 20-33% to minimize side effects (see Drug Interactions subsection).
722
723
Dosage Adjustment in the Renally Impaired: Felbamate should be used with caution in patients with
724
renal dysfunction. In the renally impaired, starting and maintenance doses should be reduced by one-half
725
(see CLINICAL PHARMACOLOGY / Pharmacokinetics and PRECAUTIONS). Adjunctive therapy
726
with medications which affect felbamate plasma concentrations, especially AEDs, may warrant further
727
reductions in felbamate daily doses in patients with renal dysfunction.
728
729
Adults (14 years of age and over)
730
The majority of patients received 3600 mg/day in clinical trials evaluating its use as both monotherapy
731
and adjunctive therapy.
732
733
Monotherapy: (Initial therapy) Felbatol® (felbamate) has not been systematically evaluated as initial
734
monotherapy. Initiate Felbatol® at 1200 mg/day in divided doses three or four times daily. The prescriber
735
is advised to titrate previously untreated patients under close clinical supervision, increasing the dosage in
736
600-mg increments every 2 weeks to 2400 mg/day based on clinical response and thereafter to 3600
737
mg/day if clinically indicated.
738
Reference ID: 3180666
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020189/S-027
FDA Approved Labeling Text dated 8/27/2012
Page 19
739
Conversion to Monotherapy: Initiate Felbatol® at 1200 mg/day in divided doses three or four times
740
daily. Reduce the dosage of concomitant AEDs by one-third at initiation of Felbatol® therapy. At week 2,
741
increase the Felbatol® dosage to 2400 mg/day while reducing the dosage of other AEDs up to an
742
additional one-third of their original dosage. At week 3, increase the Felbatol® dosage up to 3600 mg/day
743
and continue to reduce the dosage of other AEDs as clinically indicated.
744
745
Adjunctive Therapy: Felbatol® should be added at 1200 mg/day in divided doses three or four times
746
daily while reducing present AEDs by 20% in order to control plasma concentrations of concurrent
747
phenytoin, valproic acid, phenobarbital, and carbamazepine and its metabolites. Further reductions of the
748
concomitant AEDs dosage may be necessary to minimize side effects due to drug interactions. Increase
749
the dosage of Felbatol® by 1200 mg/day increments at weekly intervals to 3600 mg/day. Most side
750
effects seen during Felbatol® adjunctive therapy resolve as the dosage of concomitant AEDs is
751
decreased.
752
Table 6 Dosage Table (adults)
Dosage reduction of
concomitant AEDs
WEEK 1
REDUCE original dose by
20–33%*
WEEK 2
REDUCE original dose by
up to an additional 1/3*
WEEK 3
REDUCE as
clinically
indicated
Felbatol®
Dosage
1200 mg/day Initial dose
2400 mg/day
Therapeutic dosage range
3600 mg/day
Therapeutic dosage range
*See Adjunctive and Conversion to Monotherapy sections.
753
754
While the above Felbatol® conversion guidelines may result in a Felbatol® 3600 mg/day dose within 3
755
weeks, in some patients titration to a 3600 mg/day Felbatol® dose has been achieved in as little as 3 days
756
with appropriate adjustment of other AEDs.
757
758
Children with Lennox-Gastaut Syndrome (Ages 2-14 years)
759
Adjunctive Therapy: Felbatol® should be added at 15 mg/kg/day in divided doses three or four times
760
daily while reducing present AEDs by 20% in order to control plasma levels of concurrent phenytoin,
761
valproic acid, phenobarbital, and carbamazepine and its metabolites. Further reductions of the
762
concomitant AEDs dosage may be necessary to minimize side effects due to drug interactions. Increase
763
the dosage of Felbatol® by 15 mg/kg/day increments at weekly intervals to 45 mg/kg/day. Most side
764
effects seen during Felbatol® adjunctive therapy resolve as the dosage of concomitant AEDs is
765
decreased.
766
767
HOW SUPPLIED
768
Felbatol® (felbamate) Tablets, 400 mg, are yellow, scored, capsule-shaped tablets, debossed 0430 on one
769
side and FELBATOL 400 on the other; available in bottles of 100 (NDC 0037-0430-01). Felbatol®
770
(felbamate) Tablets, 600 mg, are peach-colored, scored, capsule-shaped tablets, debossed 0431
771
on one side and FELBATOL 600 on the other; available in bottles of 100 (NDC 0037-0431-01).
772
Felbatol® (felbamate) Oral Suspension, 600 mg/5 mL, is peach-colored; available in 8 oz bottles (NDC
773
0037-0442-67) and 32 oz bottles (NDC 0037-0442-17).
774
775
Shake suspension well before using. Store at controlled room temperature 20°-25°C (68°-77°F). Dispense
776
in tight container.
777
778
To report SUSPECTED ADVERSE REACTIONS, contact Meda Pharmaceuticals Inc. at
779
1-800-526-3840 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
780
781
MEDA Pharmaceuticals®
Reference ID: 3180666
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020189/S-027
FDA Approved Labeling Text dated 8/27/2012
Page 20
782
MEDA Pharmaceuticals Inc.
783
Somerset, NJ 08873
784
IN-00431-18
Rev. 7/11
785
786
PATIENT/PHYSICIAN ACKNOWLEDGMENT FORM
787
788
FELBATOL® (felbamate) SHOULD NOT BE USED BY PATIENTS UNTIL THERE HAS BEEN A
789
COMPLETE DISCUSSION OF THE RISKS.
790
All patients treated with Felbatol should acknowledge that they understand the risks and other information
791
about Felbatol discussed below, and physicians should acknowledge this discussion.
792
793
IMPORTANT INFORMATION AND WARNING:
794
Felbatol®, taken by itself or with other prescription and/or non-prescription drugs, can result in a severe,
795
potentially fatal blood abnormality ("aplastic anemia") and/or severe, potentially fatal liver damage.
796
797
PATIENT ACKNOWLEDGMENT:
798
799
Do not sign this form if there is anything you do not understand about the information you
800
have received. Ask your doctor about anything you do not understand before you initial
801
any of the items below or sign this form.
802
803
My [My son, daughter, ward ___________________________________________________________'s]
804
treatment with Felbatol® has been personally explained to me by Dr._____________________________.
805
The following points of information, among others, have been specifically discussed and made clear and I
806
have had the opportunity to ask any questions concerning this information:
807
808
1. I, _______________________________________________________________ (Patient's Name),
809
understand that Felbatol® is used to treat certain types of seizures and my physician has told me that I
810
have this type(s) of seizures;
811
INITIALS: __________________________
812
813
2. I understand that Felbatol® is being used because my seizures have not been satisfactorily treated with
814
other antiepileptic drugs;
815
INITIALS: __________________________
816
817
3. I understand that there is a serious risk that I could develop aplastic anemia and/or liver failure, both of
818
which are potentially fatal, by using Felbatol®;
819
INITIALS: __________________________
820
821
4. I understand that there are no laboratory tests which will predict if I am at an increased risk for one of
822
the potentially fatal conditions;
823
INITIALS: __________________________
824
825
5. I understand that I should have the recommended blood work before my treatment with Felbatol® is
826
begun (baseline) and periodically thereafter as clinical judgement warrants. I understand that although this
827
blood work may help detect if I develop one of these conditions, it may do so only after significant,
828
irreversible and potentially fatal damage has already occurred;
829
INITIALS: __________________________
830
Reference ID: 3180666
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020189/S-027
FDA Approved Labeling Text dated 8/27/2012
Page 21
831
6. If I am currently taking other antiepileptic drugs, I understand that the manufacturer of Felbatol®
832
recommends that the dosage of these other drugs be decreased by a certain amount when Felbatol® is
833
started; if my physician determines that this should not be done in my case, he/she has explained the
834
reason(s) for this decision;
835
INITIALS: __________________________
836
837
7. I understand that I must immediately report any unusual symptoms to Dr. _______________________
838
and be especially aware of any rashes, easy bruising, bleeding, sore throats, fever, and/or dark urine;
839
INITIALS: __________________________
840
841
8. I understand that antiepileptic drugs such as Felbatol® may increase the risk of suicidal thoughts and
842
behavior. I understand that I must immediately report any unusual changes in mood or behavior,
843
symptoms of depression or thoughts about self-harm to Dr. ____________________.
844
INITIALS: __________________________
845
846
847
_______________________________________________
848
Patient, Parent, or Guardian
849
_______________________________________________
850
Address
851
________________________________________________
852
Telephone
853
854
PHYSICIAN STATEMENT:
855
I have fully explained to the patient, ___________________________________________, the nature and
856
purpose of the treatment with Felbatol
® (felbamate) and the potential risks associated with that treatment.
857
I have asked the patient if he/she has any questions regarding this treatment or the risks and have
858
answered those questions to the best of my ability. I also acknowledge that I have read and understand the
859
prescribing information.
860
_________________________________________________________________________
861
Physician
Date
862
863
Revised: 7/11
864
865
NOTE TO PHYSICIAN: It is strongly recommended that you retain a signed copy of the
866
Patient/Physician Acknowledgment Form with the patient's medical records.
867
868
SUPPLY OF PATIENT/PHYSICIAN ACKNOWLEDGMENT FORMS:
869
A supply of "Patient/Physician Acknowledgement" Forms as printed above is available, free of charge,
870
from your local MEDA Pharmaceuticals representative, or may be obtained by calling 1-800-526-3840.
871
Permission to use the above Patient/Physician Acknowledgment Form by photocopy reproduction is also
872
hereby granted by MEDA Pharmaceuticals Inc.
873
874 company logo
875
876
Reference ID: 3180666
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
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FELBATOL® (felbamate)
Tablets 400 mg and 600 mg, Oral Suspension 600 mg/5 mL
Before Prescribing Felbatol® (felbamate), the physician should be thoroughly familiar with the
details of this prescribing information.
FELBATOL® SHOULD NOT BE USED BY PATIENTS UNTIL THERE HAS BEEN A
COMPLETE DISCUSSION OF THE RISKS AND THE PATIENT, PARENT, OR GUARDIAN
HAS BEEN PROVIDED THE FELBATOL WRITTEN INFORMED CONSENT (SEE PATIENT
INFORMATION/CONSENT SECTION).
WARNING
1. APLASTIC ANEMIA
THE USE OF FELBATOL® (felbamate) IS ASSOCIATED WITH A MARKED INCREASE IN THE
INCIDENCE OF APLASTIC ANEMIA. ACCORDINGLY, FELBATOL® SHOULD ONLY BE USED
IN PATIENTS WHOSE EPILEPSY IS SO SEVERE THAT THE RISK OF APLASTIC ANEMIA IS
DEEMED ACCEPTABLE IN LIGHT OF THE BENEFITS CONFERRED BY ITS USE (SEE
INDICATIONS ). ORDINARILY, A PATIENT SHOULD NOT BE PLACED ON AND/OR
CONTINUED ON FELBATOL® WITHOUT CONSIDERATION OF APPROPRIATE EXPERT
HEMATOLOGIC CONSULTATION.
AMONG FELBATOL® TREATED PATIENTS, APLASTIC ANEMIA (PANCYTOPENIA IN THE
PRESENCE OF A BONE MARROW LARGELY DEPLETED OF HEMATOPOIETIC PRECURSORS)
OCCURS AT AN INCIDENCE THAT MAY BE MORE THAN A 100 FOLD GREATER THAN THAT
SEEN IN THE UNTREATED POPULATION (I.E., 2 TO 5 PER MILLION PERSONS PER YEAR).
THE RISK OF DEATH IN PATIENTS WITH APLASTIC ANEMIA GENERALLY VARIES AS A
FUNCTION OF ITS SEVERITY AND ETIOLOGY; CURRENT ESTIMATES OF THE OVERALL
CASE FATALITY RATE ARE IN THE RANGE OF 20 TO 30%, BUT RATES AS HIGH AS 70%
HAVE BEEN REPORTED IN THE PAST.
THERE ARE TOO FEW FELBATOL® ASSOCIATED CASES, AND TOO LITTLE KNOWN ABOUT
THEM TO PROVIDE A RELIABLE ESTIMATE OF THE SYNDROME'S INCIDENCE OR ITS CASE
FATALITY RATE OR TO IDENTIFY THE FACTORS, IF ANY, THAT MIGHT CONCEIVABLY BE
USED TO PREDICT WHO IS AT GREATER OR LESSER RISK.
IN MANAGING PATIENTS ON FELBATOL®, IT SHOULD BE BORNE IN MIND THAT THE
CLINICAL MANIFESTATION OF APLASTIC ANEMIA MAY NOT BE SEEN UNTIL AFTER A
PATIENT HAS BEEN ON FELBATOL® FOR SEVERAL MONTHS (E.G., ONSET OF APLASTIC
ANEMIA AMONG FELBATOL® EXPOSED PATIENTS FOR WHOM DATA ARE AVAILABLE
HAS RANGED FROM 5 TO 30 WEEKS). HOWEVER, THE INJURY TO BONE MARROW STEM
CELLS THAT IS HELD TO BE ULTIMATELY RESPONSIBLE FOR THE ANEMIA MAY OCCUR
WEEKS TO MONTHS EARLIER. ACCORDINGLY, PATIENTS WHO ARE DISCONTINUED
FROM FELBATOL® REMAIN AT RISK FOR DEVELOPING ANEMIA FOR A VARIABLE, AND
UNKNOWN, PERIOD AFTERWARDS.
IT IS NOT KNOWN WHETHER OR NOT THE RISK OF DEVELOPING APLASTIC ANEMIA
CHANGES WITH DURATION OF EXPOSURE. CONSEQUENTLY, IT IS NOT SAFE TO ASSUME
THAT A PATIENT WHO HAS BEEN ON FELBATOL® WITHOUT SIGNS OF HEMATOLOGIC
ABNORMALITY FOR LONG PERIODS OF TIME IS WITHOUT RISK.
IT IS NOT KNOWN WHETHER OR NOT THE DOSE OF FELBATOL® AFFECTS THE
INCIDENCE OF APLASTIC ANEMIA.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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IT IS NOT KNOWN WHETHER OR NOT CONCOMITANT USE OF ANTIEPILEPTIC DRUGS
AND/OR OTHER DRUGS AFFECTS THE INCIDENCE OF APLASTIC ANEMIA.
APLASTIC ANEMIA TYPICALLY DEVELOPS WITHOUT PREMONITORY CLINICAL OR
LABORATORY SIGNS, THE FULL BLOWN SYNDROME PRESENTING WITH SIGNS OF
INFECTION, BLEEDING, OR ANEMIA. ACCORDINGLY, ROUTINE BLOOD TESTING CANNOT
BE RELIABLY USED TO REDUCE THE INCIDENCE OF APLASTIC ANEMIA, BUT, IT WILL, IN
SOME CASES, ALLOW THE DETECTION OF THE HEMATOLOGIC CHANGES BEFORE THE
SYNDROME DECLARES ITSELF CLINICALLY. FELBATOL® SHOULD BE DISCONTINUED IF
ANY EVIDENCE OF BONE MARROW DEPRESSION OCCURS.
2. HEPATIC FAILURE
EVALUATION OF POSTMARKETING EXPERIENCE SUGGESTS THAT ACUTE LIVER
FAILURE IS ASSOCIATED WITH THE USE OF FELBATOL®. THE REPORTED RATE IN THE
U.S. HAS BEEN ABOUT 6 CASES OF LIVER FAILURE LEADING TO DEATH OR TRANSPLANT
PER 75,000 PATIENT YEARS OF USE. THIS RATE IS AN UNDERESTIMATE BECAUSE OF
UNDER REPORTING, AND THE TRUE RATE COULD BE CONSIDERABLY GREATER THAN
THIS. FOR EXAMPLE, IF THE REPORTING RATE IS 10%, THE TRUE RATE WOULD BE ONE
CASE PER 1,250 PATIENT YEARS OF USE.
OF THE CASES REPORTED, ABOUT 67% RESULTED IN DEATH OR LIVER
TRANSPLANTATION, USUALLY WITHIN 5 WEEKS OF THE ONSET OF SIGNS AND
SYMPTOMS OF LIVER FAILURE. THE EARLIEST ONSET OF SEVERE HEPATIC
DYSFUNCTION FOLLOWED SUBSEQUENTLY BY LIVER FAILURE WAS 3 WEEKS AFTER
INITIATION OF FELBATOL®. ALTHOUGH SOME REPORTS DESCRIBED DARK URINE AND
NONSPECIFIC PRODROMAL SYMPTOMS (E.G., ANOREXIA, MALAISE, AND
GASTROINTESTINAL SYMPTOMS), IN OTHER REPORTS IT WAS NOT CLEAR IF ANY
PRODROMAL SYMPTOMS PRECEDED THE ONSET OF JAUNDICE.
IT IS NOT KNOWN WHETHER OR NOT THE RISK OF DEVELOPING HEPATIC FAILURE
CHANGES WITH DURATION OF EXPOSURE.
IT IS NOT KNOWN WHETHER OR NOT THE DOSAGE OF FELBATOL® AFFECTS THE
INCIDENCE OF HEPATIC FAILURE.
IT IS NOT KNOWN WHETHER CONCOMITANT USE OF OTHER ANTIEPILEPTIC DRUGS
AND/OR OTHER DRUGS AFFECT THE INCIDENCE OF HEPATIC FAILURE.
FELBATOL® SHOULD NOT BE PRESCRIBED FOR ANYONE WITH A HISTORY OF HEPATIC
DYSFUNCTION.
TREATMENT WITH FELBATOL® SHOULD BE INITIATED ONLY IN INDIVIDUALS WITHOUT
ACTIVE LIVER DISEASE AND WITH NORMAL BASELINE SERUM TRANSAMINASES. IT HAS
NOT BEEN PROVED THAT PERIODIC SERUM TRANSAMINASE TESTING WILL PREVENT
SERIOUS INJURY BUT IT IS GENERALLY BELIEVED THAT EARLY DETECTION OF DRUG
INDUCED HEPATIC INJURY ALONG WITH IMMEDIATE WITHDRAWAL OF THE SUSPECT
DRUG ENHANCES THE LIKELIHOOD FOR RECOVERY. THERE IS NO INFORMATION
AVAILABLE THAT DOCUMENTS HOW RAPIDLY PATIENTS CAN PROGRESS FROM
NORMAL LIVER FUNCTION TO LIVER FAILURE, BUT OTHER DRUGS KNOWN TO BE
HEPATOTOXINS CAN CAUSE LIVER FAILURE RAPIDLY (E.G., FROM NORMAL ENZYMES
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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TO LIVER FAILURE IN 2-4 WEEKS). ACCORDINGLY, MONITORING OF SERUM
TRANSAMINASE LEVELS (AST AND ALT) IS RECOMMENDED AT BASELINE AND
PERIODICALLY THEREAFTER. WHILE THE MORE FREQUENT THE MONITORING THE
GREATER THE CHANCES OF EARLY DETECTION, THE PRECISE SCHEDULE FOR
MONITORING IS A MATTER OF CLINICAL JUDGEMENT.
FELBATOL® SHOULD BE DISCONTINUED IF EITHER SERUM AST OR SERUM ALT LEVELS
BECOME INCREASED ≥ 2 TIMES THE UPPER LIMIT OF NORMAL, OR IF CLINICAL SIGNS
AND SYMPTOMS SUGGEST LIVER FAILURE (SEE PRECAUTIONS ). PATIENTS WHO
DEVELOP EVIDENCE OF HEPATOCELLULAR INJURY WHILE ON FELBATOL® AND ARE
WITHDRAWN FROM THE DRUG FOR ANY REASON SHOULD BE PRESUMED TO BE AT
INCREASED RISK FOR LIVER INJURY IF FELBATOL® IS REINTRODUCED. ACCORDINGLY,
SUCH PATIENTS SHOULD NOT BE CONSIDERED FOR RE-TREATMENT.
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DESCRIPTION
Felbatol® (felbamate) is an antiepileptic available as 400 mg and 600 mg tablets and as a 600 mg/5 mL
suspension for oral administration. Its chemical name is 2-phenyl-1,3-propanediol dicarbamate.
Felbamate is a white to off-white crystalline powder with a characteristic odor. It is very slightly soluble
in water, slightly soluble in ethanol, sparingly soluble in methanol, and freely soluble in dimethyl
sulfoxide. The molecular weight is 238.24; felbamate's molecular formula is C
H N O ; its
11
14
2
4
structural formula is: Chemical Structure
The inactive ingredients for Felbatol® (felbamate) tablets 400 mg and 600 mg are starch, microcrystalline
cellulose, croscarmellose sodium, lactose, magnesium stearate, FD&C Yellow No. 6, D&C Yellow No.
10, and FD&C Red No. 40 (600 mg tablets only). The inactive ingredients for Felbatol® (felbamate)
suspension 600 mg/5 mL are sorbitol, glycerin, microcrystalline cellulose, carboxymethylcellulose
sodium, simethicone, polysorbate 80, methylparaben, saccharin sodium, propylparaben, FD&C Yellow
No. 6, FD&C Red No. 40, flavorings, and purified water.
CLINICAL PHARMACOLOGY
Mechanism of Action:
The mechanism by which felbamate exerts its anticonvulsant activity is unknown, but in animal test
systems designed to detect anticonvulsant activity, felbamate has properties in common with other
marketed anticonvulsants. Felbamate is effective in mice and rats in the maximal electroshock test, the
subcutaneous pentylenetetrazol seizure test, and the subcutaneous picrotoxin seizure test. Felbamate also
exhibits anticonvulsant activity against seizures induced by intracerebroventricular administration of
glutamate in rats and N-methyl-D,L-aspartic acid in mice. Protection against maximal electroshock-
induced seizures suggests that felbamate may reduce seizure spread, an effect possibly predictive of
efficacy in generalized tonic-clonic or partial seizures. Protection against pentylenetetrazol-induced
seizures suggests that felbamate may increase seizure threshold, an effect considered to be predictive of
potential efficacy in absence seizures.
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Receptor-binding studies in vitro indicate that felbamate has weak inhibitory effects on GABA-receptor
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binding, benzodiazepine receptor binding, and is devoid of activity at the MK-801 receptor binding site of
150
the NMDA receptor-ionophore complex. However, felbamate does interact as an antagonist at the
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strychnine-insensitive glycine recognition site of the NMDA receptor-ionophore complex. Felbamate is
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not effective in protecting chick embryo retina tissue against the neurotoxic effects of the excitatory
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amino acid agonists NMDA, kainate, or quisqualate in vitro.
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The monocarbamate, p-hydroxy, and 2-hydroxy metabolites were inactive in the maximal electroshock
156
induced seizure test in mice. The monocarbamate and p-hydroxy metabolites had only weak (0.2 to 0.6)
157
activity compared with felbamate in the subcutaneous pentylenetetrazol seizure test. These metabolites
158
did not contribute significantly to the anticonvulsant action of felbamate.
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Pharmacokinetics:
161
The numbers in the pharmacokinetic section are mean ± standard deviation.
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Felbamate is well-absorbed after oral administration. Over 90% of the radioactivity after a dose of 1000
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mg
14 C felbamate was found in the urine. Absolute bioavailability (oral vs. parenteral) has not been
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measured. The tablet and suspension were each shown to be bioequivalent to the capsule used in clinical
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trials, and pharmacokinetic parameters of the tablet and suspension are similar. There was no effect of
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food on absorption of the tablet; the effect of food on absorption of the suspension has not been evaluated.
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Following oral administration, felbamate is the predominant plasma species (about 90% of plasma
170
radioactivity). About 40-50% of absorbed dose appears unchanged in urine, and an additional 40% is
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present as unidentified metabolites and conjugates. About 15% is present as parahydroxyfelbamate, 2
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hydroxyfelbamate, and felbamate monocarbamate, none of which have significant anticonvulsant activity.
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Binding of felbamate to human plasma protein was independent of felbamate concentrations between 10
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and 310 micrograms/mL. Binding ranged from 22% to 25%, mostly to albumin, and was dependent on
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the albumin concentration.
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Felbamate is excreted with a terminal half-life of 20-23 hours, which is unaltered after multiple doses.
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Clearance after a single 1200 mg dose is 26±3 mL/hr/kg, and after multiple daily doses of 3600 mg is
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30±8 mL/hr/kg. The apparent volume of distribution was 756±82 mL/kg after a 1200 mg dose. Felbamate
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Cmax and AUC are proportionate to dose after single and multiple doses over a range of 100-800 mg
182
single doses and 1200-3600 mg daily doses. Cmin (trough) blood levels are also dose proportional.
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Multiple daily doses of 1200, 2400, and 3600 mg gave Cmin values of 30±5, 55±8, and 83±21
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micrograms/mL (N=10 patients). Linear and dose proportional pharmacokinetics were also observed at
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doses above 3600 mg/day up to the maximum dose studied of 6000 mg/day. Felbamate gave dose
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proportional steady-state peak plasma concentrations in children age 4-12 over a range of 15, 30, and 45
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mg/kg/day with peak concentrations of 17, 32, and 49 micrograms/mL.
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The effects of race and gender on felbamate pharmacokinetics have not been systematically evaluated, but
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plasma concentrations in males (N=5) and females (N=4) given felbamate have been similar. The effects
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of felbamate kinetics on hepatic functional impairment have not been evaluated.
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Renal Impairment: Felbamate's single dose monotherapy pharmacokinetic parameters were evaluated in
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12 otherwise healthy individuals with renal impairment. There was a 40-50% reduction in total body
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clearance and 9-15 hours prolongation of half-life in renally impaired subjects compared to that in
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subjects with normal renal function. Reduced felbamate clearance and a longer half-life were associated
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with diminishing renal function.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
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Pharmacodynamics:
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Typical Physiologic responses:
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1. Cardiovascular In adults, there is no effect of felbamate on blood pressure. Small but statistically
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significant mean increases in heart rate were seen during adjunctive therapy and monotherapy; however,
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these mean increases of up to 5 bpm were not clinically significant. In children, no clinically relevant
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changes in blood pressure or heart rate were seen during adjunctive therapy or monotherapy with
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felbamate.
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2. Other Physiologic Effects: The only other change in vital signs was a mean decrease of approximately
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1 respiration per minute in respiratory rate during adjunctive therapy in children. In adults, statistically
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significant mean reductions in body weight were observed during felbamate monotherapy and adjunctive
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therapy. In children, there were mean decreases in body weight during adjunctive therapy and
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monotherapy; however, these mean changes were not statistically significant. These mean reductions in
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adults and children were approximately 5% of the mean weights at baseline.
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CLINICAL STUDIES
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The results of controlled clinical trials established the efficacy of Felbatol® (felbamate) as monotherapy
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and adjunctive therapy in adults with partial-onset seizures with or without secondary generalization and
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in partial and generalized seizures associated with Lennox-Gastaut syndrome in children.
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Felbatol® Monotherapy Trials in Adults
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Felbatol® (3600 mg/day given QID) and low-dose valproate (15 mg/kg/day) were compared as
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monotherapy during a 112-day treatment period in a multicenter and a single-center double-blind efficacy
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trial. Both trials were conducted according to an identical study design. During a 56-day baseline period,
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all patients had at least four partial-onset seizures per 28 days and were receiving one antiepileptic drug at
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a therapeutic level, the most common being carbamazepine. In the multicenter trial, baseline seizure
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frequencies were 12.4 per 28 days in the Felbatol® group and 21.3 per 28 days in the low-dose valproate
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group. In the single-center trial, baseline seizure frequencies were 18.1 per 28 days in the Felbatol®
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group and 15.9 per 28 days in the low-dose valproate group. Patients were converted to monotherapy with
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Felbatol® or low-dose valproic acid during the first 28 days of the 112-day treatment period. Study
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endpoints were completion of 112 study days or fulfilling an escape criterion. Criteria for escape relative
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to baseline were: (1) twofold increase in monthly seizure frequency, (2) twofold increase in highest 2-day
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seizure frequency, (3) single generalized tonic-clonic seizure (GTC) if none occurred during baseline, or
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(4) significant prolongation of GTCs. The primary efficacy variable was the number of patients in each
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treatment group who met escape criteria.
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In the multicenter trial, the percentage of patients who met escape criteria was 40% (18/45) in the
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Felbatol® group and 78% (39/50) in the low-dose valproate group. In the single-center trial, the
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percentage of patients who met escape criteria was 14% (3/21) in the Felbatol® group and 90% (19/21) in
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the low-dose valproate group. In both trials, the difference in the percentage of patients meeting escape
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criteria was statistically significant (P<.001) in favor of Felbatol®. These two studies by design were
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intended to demonstrate the effectiveness of Felbatol® monotherapy. The studies were not designed or
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intended to demonstrate comparative efficacy of the two drugs. For example, valproate was not used at
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the maximally effective dose.
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Felbatol® Adjunctive Therapy Trials in Adults
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A double-blind, placebo-controlled crossover trial consisted of two 10-week outpatient treatment periods.
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Patients with refractory partial-onset seizures who were receiving phenytoin and carbamazepine at
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therapeutic levels were administered Felbatol® (felbamate) as add-on therapy at a starting dosage of 1400
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mg/day in three divided doses, which was increased to 2600 mg/day in three divided doses. Among the 56
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patients who completed the study, the baseline seizure frequency was 20 per month. Patients treated with
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Felbatol® had fewer seizures than patients treated with placebo for each treatment sequence. There was a
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23% (P=.018) difference in percentage seizure frequency reduction in favor of Felbatol®.
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Felbatol® 3600 mg/day given QID and placebo were compared in a 28-day double-blind add-on trial in
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patients who had their standard antiepileptic drugs reduced while undergoing evaluations for surgery of
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intractable epilepsy. All patients had confirmed partial-onset seizures with or without generalization,
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seizure frequency during surgical evaluation not exceeding an average of four partial seizures per day or
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more than one generalized seizure per day, and a minimum average of one partial or generalized tonic
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clonic seizure per day for the last 3 days of the surgical evaluation. The primary efficacy variable was
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time to fourth seizure after randomization to treatment with Felbatol® or placebo. Thirteen (46%) of 28
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patients in the Felbatol® group versus 29 (88%) of 33 patients in the placebo group experienced a fourth
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seizure. The median times to fourth seizure were greater than 28 days in the Felbatol® group and 5 days
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in the placebo group. The difference between Felbatol® and placebo in time to fourth seizure was
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statistically significant (P=.002) in favor of Felbatol®.
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Felbatol® Adjunctive Therapy Trial in Children with Lennox-Gastaut Syndrome
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In a 70-day double-blind, placebo-controlled add-on trial in the Lennox-Gastaut syndrome, Felbatol® 45
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mg/kg/day given QID was superior to placebo in controlling the multiple seizure types associated with
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this condition. Patients had at least 90 atonic and/or atypical absence seizures per month while receiving
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therapeutic dosages of one or two other antiepileptic drugs. Patients had a past history of using an average
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of eight antiepileptic drugs. The most commonly used antiepileptic drug during the baseline period was
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valproic acid. The frequency of all types of seizures during the baseline period was 1617 per month in the
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Felbatol® group and 716 per month in the placebo group. Statistically significant differences in the effect
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on seizure frequency favored Felbatol® over placebo for total seizures (26% reduction vs 5% increase,
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P<.001), atonic seizures (44% reduction vs 7% reduction, P=.002), and generalized tonic-clonic seizures
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(40% reduction vs 12% increase, P=.017). Parent/guardian global evaluations based on impressions of
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quality of life with respect to alertness, verbal responsiveness, general well-being, and seizure control
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significantly (P<.001) favored Felbatol® over placebo.
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When efficacy was analyzed by gender in four well-controlled trials of felbamate as adjunctive and
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monotherapy for partial-onset seizures and Lennox-Gastaut syndrome, a similar response was seen in 122
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males and 142 females.
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INDICATIONS AND USAGE
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Felbatol® is not indicated as a first line antiepileptic treatment (see Warnings). Felbatol® is
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recommended for use only in those patients who respond inadequately to alternative treatments and
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whose epilepsy is so severe that a substantial risk of aplastic anemia and/or liver failure is deemed
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acceptable in light of the benefits conferred by its use.
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If these criteria are met and the patient has been fully advised of the risk, and has provided written,
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informed consent, Felbatol® can be considered for either monotherapy or adjunctive therapy in the
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treatment of partial seizures, with and without generalization, in adults with epilepsy and as adjunctive
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therapy in the treatment of partial and generalized seizures associated with Lennox-Gastaut syndrome in
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children.
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CONTRAINDICATIONS
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Felbatol® is contraindicated in patients with known hypersensitivity to Felbatol®, its ingredients, or
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known sensitivity to other carbamates. It should not be used in patients with a history of any blood
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dyscrasia or hepatic dysfunction.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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WARNINGS
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See Boxed Warning regarding aplastic anemia and hepatic failure.
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Antiepileptic drugs should not be suddenly discontinued because of the possibility of increasing seizure
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frequency.
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Suicidal Behavior and Ideation
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Antiepileptic drugs (AEDs) including Felbatol ®, increase the risk of suicidal thoughts or behavior in
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patients taking these drugs for any indication. Patients treated with any AED for any indication should be
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monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any
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unusual changes in mood or behavior.
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Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11
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different AEDs showed that patients randomized to one of the AEDs had approximately twice
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the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared
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to patients randomized to placebo. In these trials, which had a median treatment duration of 12
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weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated
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patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an
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increase of approximately one case of suicidal thinking or behavior for every 530 patients
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treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated
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patients, but the number is too small to allow any conclusion about drug effect on suicide.
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The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one
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week after starting drug treatment with AEDs and persisted for the duration of treatment
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assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk
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of suicidal thoughts or behavior beyond 24 weeks could not be assessed.
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The risk of suicidal thoughts or behavior was generally consistent among drugs in the data
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analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across
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a range of indications suggests that the risk applies to all AEDs used for any indication. The risk
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did not vary substantially by age (5-100 years) in the clinical trials analyzed.
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Table 1 shows absolute and relative risk by indication for all evaluated AEDs.
Table 1 Risk by indication for antiepileptic drugs in the pooled analysis
Indication
Placebo Patients
with Events
Per 1000 Patients
Drug Patients with
Events Per
1000 Patients
Relative Risk:
Incidence of
Events in Drug
Patients/Incidence
in Placebo Patients
Risk Difference:
Additional Drug
Patients with
Events Per 1000
Patients
Epilepsy
1.0
3.4
3.5
2.4
Psychiatric
5.7
8.5
1.5
2.9
Other
1.0
1.8
1.9
0.9
Total
2.4
4.3
1.8
1.9
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The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in
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clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for
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the epilepsy and psychiatric indications.
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Anyone considering prescribing Felbatol or any other AED must balance the risk of suicidal thoughts or
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behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are
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prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal
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thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber
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needs to consider whether the emergence of these symptoms in any given patient may be related
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to the illness being treated.
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Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal
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thoughts and behavior and should be advised of the need to be alert for the emergence or
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worsening of the signs and symptoms of depression, any unusual changes in mood or behavior,
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or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of
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concern should be reported immediately to healthcare providers.
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PRECAUTIONS
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Dosage Adjustment in the Renally Impaired: A study in otherwise healthy individuals with renal
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dysfunction indicated that prolonged half-life and reduced clearance of felbamate are associated with
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diminishing renal function. Felbamate should be used with caution in patients with renal dysfunction (see
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DOSAGE AND ADMINISTRATION).
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Information for Patients: Patients should be informed that the use of Felbatol® is associated with
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aplastic anemia and hepatic failure, potentially fatal conditions acutely or over a long term.
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The physician should provide obtain written, informed consent prior to initiation of Felbatol® therapy
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(see PATIENT INFORMATION/CONSENT section).
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Aplastic anemia in the general population is relatively rare. The absolute risk for the individual patient is
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not known with any degree of reliability, but patients on Felbatol® may be at more than a 100 fold greater
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risk for developing the syndrome than the general population.
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The long term outlook for patients with aplastic anemia is variable. Although many patients are
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apparently cured, others require repeated transfusions and other treatments for relapses, and some,
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although surviving for years, ultimately develop serious complications that sometimes prove fatal (e.g.,
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leukemia).
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At present there is no way to predict who is likely to get aplastic anemia, nor is there a documented
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effective means to monitor the patient so as to avoid and/or reduce the risk. Patients with a history of any
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blood dyscrasia should not receive Felbatol®.
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Patients should be advised to be alert for signs of infection, bleeding, easy bruising, or signs of anemia
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(fatigue, weakness, lassitude, etc.) and should be advised to report to the physician immediately if any
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such signs or symptoms appear.
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Hepatic failure in the general population is relatively rare. The absolute risk for an individual patient is
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not known with any degree of reliability but patients on Felbatol® are at a greater risk for developing
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hepatic failure than the general population.
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At present, there is no way to predict who is likely to develop hepatic failure, however, patients with a
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history of hepatic dysfunction should not be started on Felbatol®.
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Patients should be advised to follow their physician's directives for liver function testing both before
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starting Felbatol® (felbamate) and at frequent intervals while taking Felbatol®.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
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Patients should be advised to be alert for signs of liver dysfunction (jaundice, anorexia, gastrointestinal
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complaints, malaise, etc.) and to report them to their doctor immediately if they should occur.
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Laboratory Tests: Full hematologic evaluations should be performed before Felbatol® therapy,
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frequently during therapy, and for a significant period of time after discontinuation of Felbatol® therapy.
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While it might appear prudent to perform frequent CBCs in patients continuing on Felbatol®, there is no
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evidence that such monitoring will allow early detection of marrow suppression before aplastic anemia
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occurs. (See Boxed Warnings ). Complete pretreatment blood counts, including platelets and
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reticulocytes should be obtained as a baseline. If any hematologic abnormalities are detected during the
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course of treatment, immediate consultation with a hematologist is advised. Felbatol® should be
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discontinued if any evidence of bone marrow depression occurs.
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See Box Warnings for recommended monitoring of serum transaminases. If significant, confirmed liver
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abnormalities are detected during the course of Felbatol® treatment, Felbatol® should be discontinued
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immediately with continued liver function monitoring until values return to normal. (see PATIENT
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INFORMATION/CONSENT ).
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Suicidal Thinking and Behavior - Patients, their caregivers, and families should be counseled
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that AEDs, including Felbatol®, may increase the risk of suicidal thoughts and behavior and
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should be advised of the need to be alert for the emergence or worsening of symptoms of
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depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts,
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behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to
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healthcare providers.
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Pregnancy: Patients should be encouraged to enroll in the North American Antiepileptic Drug
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(NAAED) Pregnancy Registry if they become pregnant. This registry is collecting information
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about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll free
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number 1-888-233-2334 (see Pregnancy section).
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Drug Interactions:
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The drug interaction data described in this section were obtained from controlled clinical trials and studies
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involving otherwise healthy adults with epilepsy.
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Use in Conjunction with Other Antiepileptic Drugs (See DOSAGE AND ADMINISTRATION):
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The addition of Felbatol® to antiepileptic drugs (AEDs) affects the steady-state plasma
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concentrations of AEDs. The net effect of these interactions is summarized in Table 2:
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Table 2 Steady-State Plasma Concentrations of Felbatol When Coadministered With Other AEDs
AED
Coadministered
AED
Concentration
Felbatol®
Concentration
Phenytoin
↑
↓
Valproate
↑
↔**
Carbamazepine (CBZ)
*CBZ epoxide
↓
↑
↓
Phenobarbital
↑
↓
*Not significant but an active metabolite of carbamazepine.
**No significant effect.
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Specific Effects of Felbatol® on Other Antiepileptic Drugs:
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Phenytoin : Felbatol® causes an increase in steady-state phenytoin plasma concentrations. In 10
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otherwise healthy subjects with epilepsy ingesting phenytoin, the steady-state trough (Cmin) phenytoin
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plasma concentration was 17±5 micrograms/mL. The steady-state Cmin increased to 21±5
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micrograms/mL when 1200 mg/day of felbamate was coadministered. Increasing the felbamate dose to
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1800 mg/day in six of these subjects increased the steady-state phenytoin Cmin to 25±7 micrograms/mL.
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In order to maintain phenytoin levels, limit adverse experiences, and achieve the felbamate dose of 3600
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mg/day, a phenytoin dose reduction of approximately 40% was necessary for eight of these 10 subjects.
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In a controlled clinical trial, a 20% reduction of the phenytoin dose at the initiation of Felbatol® therapy
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resulted in phenytoin levels comparable to those prior to Felbatol® administration.
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Carbamazepine : Felbatol® causes a decrease in the steady-state carbamazepine plasma concentrations
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and an increase in the steady-state carbamazepine epoxide plasma concentration. In nine otherwise
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healthy subjects with epilepsy ingesting carbamazepine, the steady-state trough (Cmin) carbamazepine
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concentration was 8±2 micrograms/mL. The carbamazepine steady-state Cmin decreased 31% to 5±1
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micrograms/mL when felbamate (3000 mg/day, divided into three doses) was coadministered.
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Carbamazepine epoxide steady-state Cmin concentrations increased 57% from 1.0±0.3 to 1.6±0.4
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micrograms/mL with the addition of felbamate.
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In clinical trials, similar changes in carbamazepine and carbamazepine epoxide were seen.
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Valproate : Felbatol® causes an increase in steady-state valproate concentrations. In four subjects with
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epilepsy ingesting valproate, the steady-state trough (Cmin) valproate plasma concentration was 63±16
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micrograms/mL. The steady-state Cmin increased to 78±14 micrograms/mL when 1200 mg/day of
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felbamate was coadministered. Increasing the felbamate dose to 2400 mg/day increased the steady-state
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valproate Cmin to 96±25 micrograms/mL. Corresponding values for free valproate Cmin concentrations
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were 7±3, 9±4, and 11±6 micrograms/mL for 0, 1200, and 2400 mg/day Felbatol®, respectively. The
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ratios of the AUCs of unbound valproate to the AUCs of the total valproate were 11.1%, 13.0%, and
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11.5%, with coadministration of 0, 1200, and 2400 mg/day of Felbatol®, respectively. This indicates that
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the protein binding of valproate did not change appreciably with increasing doses of Felbatol®.
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Phenobarbital : Coadministration of felbamate with phenobarbital causes an increase in phenobarbital
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plasma concentrations. In 12 otherwise healthy male volunteers ingesting phenobarbital, the steady-state
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trough (Cmin) phenobarbital concentration was 14.2 micrograms/mL. The steady-state Cmin
464
concentration increased to 17.8 micrograms/mL when 2400 mg/day of felbamate was coadministered for
465
one week.
466
467
Effects of Other Antiepileptic Drugs on Felbatol®:
468
Phenytoin : Phenytoin causes an approximate doubling of the clearance of Felbatol® (felbamate) at
469
steady state and, therefore, the addition of phenytoin causes an approximate 45% decrease in the steady
470
state trough concentrations of Felbatol® as compared to the same dose of Felbatol® given as
471
monotherapy.
472
473
Carbamazepine : Carbamazepine causes an approximate 50% increase in the clearance of Felbatol® at
474
steady state and, therefore, the addition of carbamazepine results in an approximate 40% decrease in the
475
steady-state trough concentrations of Felbatol® as compared to the same dose of Felbatol® given as
476
monotherapy.
477
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
478
Valproate : Available data suggest that there is no significant effect of valproate on the clearance of
479
Felbatol® at steady state. Therefore, the addition of valproate is not expected to cause a clinically
480
important effect on Felbatol® (felbamate) plasma concentrations.
481
482
Phenobarbital : It appears that phenobarbital may reduce plasma felbamate concentrations. Steady-state
483
plasma felbamate concentrations were found to be 29% lower than the mean concentrations of a group of
484
newly diagnosed subjects with epilepsy also receiving 2400 mg of felbamate a day.
485
486
Effects of Antacids on Felbatol®:
487
The rate and extent of absorption of a 2400 mg dose of Felbatol® as monotherapy given as tablets was
488
not affected when coadministered with antacids.
489
490
Effects of Erythromycin on Felbatol®:
491
The coadministration of erythromycin (1000 mg/day) for 10 days did not alter the pharmacokinetic
492
parameters of Cmax, Cmin, AUC, Cl/kg or tmax at felbamate daily doses of 3000 or 3600 mg/day in 10
493
otherwise healthy subjects with epilepsy.
494
495
Effects of Felbatol® on Low-Dose Combination Oral Contraceptives:
496
A group of 24 nonsmoking, healthy white female volunteers established on an oral contraceptive regimen
497
containing 30 μg ethinyl estradiol and 75 μg gestodene for at least 3 months received 2400 mg/day of
498
felbamate from midcycle (day 15) to midcycle (day 14) of two consecutive oral contraceptive cycles.
499
Felbamate treatment resulted in a 42% decrease in the gestodene AUC 0-24, but no clinically relevant
500
effect was observed on the pharmacokinetic parameters of ethinyl estradiol. No volunteer showed
501
hormonal evidence of ovulation, but one volunteer reported intermenstrual bleeding during felbamate
502
treatment.
503
504
Drug/Laboratory Test Interactions: There are no known interactions of Felbatol® with commonly used
505
laboratory tests.
506
507
Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity studies were conducted in mice
508
and rats. Mice received felbamate as a feed admixture for 92 weeks at doses of 300, 600, and 1200 mg/kg
509
and rats were also dosed by feed admixture for 104 weeks at doses of 30, 100, and 300 (males) or 10, 30,
510
and 100 (females) mg/kg. The maximum doses in these studies produced steady-state plasma
511
concentrations that were equal to or less than the steady-state plasma concentrations in epileptic patients
512
receiving 3600 mg/day. There was a statistically significant increase in hepatic cell adenomas in high
513
dose male and female mice and in high-dose female rats. Hepatic hypertrophy was significantly increased
514
in a dose-related manner in mice, primarily males, but also in females. Hepatic hypertrophy was not
515
found in female rats. The relationship between the occurrence of benign hepatocellular adenomas and the
516
finding of liver hypertrophy resulting from liver enzyme induction has not been examined. There was a
517
statistically significant increase in benign interstitial cell tumors of the testes in high-dose male rats
518
receiving felbamate. The relevance of these findings to humans is unknown.
519
520
As a result of the synthesis process, felbamate could contain small amounts of two known animal
521
carcinogens, the genotoxic compound ethyl carbamate (urethane) and the nongenotoxic compound methyl
522
carbamate. It is theoretically possible that a 50 kg patient receiving 3600 mg of felbamate could be
523
exposed to up to 0.72 micrograms of urethane and 1800 micrograms of methyl carbamate. These daily
524
doses are approximately 1/35,000 (urethane) and 1/5,500 (methyl carbamate) on a mg/kg basis, and
525
1/10,000 (urethane) and 1/1,600 (methyl carbamate) on a mg/m
2 basis, of the dose levels shown to be
526
carcinogenic in rodents. Any presence of these two compounds in felbamate used in the lifetime
527
carcinogenicity studies was inadequate to cause tumors.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
528
529
Microbial and mammalian cell assays revealed no evidence of mutagenesis in the Ames Salmonella
530
/microsome plate test, CHO/HGPRT mammalian cell forward gene mutation assay, sister chromatic
531
exchange assay in CHO cells, and bone marrow cytogenetics assay.
532
533
Reproduction and fertility studies in rats showed no effects on male or female fertility at oral doses of up
534
to 13.9 times the human total daily dose of 3600 mg on a mg/kg basis, or up to 3 times the human total
535
daily dose on a mg/m
2 basis.
536
537
Pregnancy: Pregnancy Category C. The incidence of malformations was not increased compared to
538
control in offspring of rats or rabbits given doses up to 13.9 times (rat) and 4.2 times (rabbit) the human
539
daily dose on a mg/kg basis, or 3 times (rat) and less than 2 times (rabbit) the human daily dose on a
540
mg/m
2 basis. However, in rats, there was a decrease in pup weight and an increase in pup deaths during
541
lactation. The cause for these deaths is not known. The no effect dose for rat pup mortality was 6.9 times
542
the human dose on a mg/kg basis or 1.5 times the human dose on a mg/m
2 basis.
543
544
Placental transfer of felbamate occurs in rat pups. There are, however, no studies in pregnant women.
545
Because animal reproduction studies are not always predictive of human response, this drug should be
546
used during pregnancy only if clearly needed.
547
548
To provide information regarding the effects of in utero exposure to Felbatol®, physicians are
549
advised to recommend that pregnant patients taking Felbatol enroll in the NAAED Pregnancy
550
Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by
551
patients themselves. Information on the registry can also be found at the website
552
http://www.aedpregnancyregistry.org/.
553
554
Labor and Delivery: The effect of felbamate on labor and delivery in humans is unknown.
555
556
Nursing Mothers: Felbamate has been detected in human milk. The effect on the nursing infant is
557
unknown (see Pregnancy section).
558
559
Pediatric Use: The safety and effectiveness of Felbatol® in children other than those with Lennox
560
Gastaut syndrome has not been established.
561
562
Geriatric Use: No systematic studies in geriatric patients have been conducted. Clinical studies of
563
Felbatol® did not include sufficient numbers of patients aged 65 and over to determine whether they
564
respond differently from younger patients. Other reported clinical experience has not identified
565
differences in responses between the elderly and younger patients. In general, dosage selection for an
566
elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the
567
greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other
568
drug therapy.
569
570
ADVERSE REACTIONS
571
To report SUSPECTED ADVERSE REACTIONS, contact Meda Pharmaceuticals at
572
1-800-526-3840 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
573
574
The most common adverse reactions seen in association with Felbatol® (felbamate) in adults during
575
monotherapy, are anorexia, vomiting, insomnia, nausea, and headache. The most common adverse
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
576
reactions seen in association with Felbatol® in adults during adjunctive therapy are anorexia, vomiting,
577
insomnia, nausea, dizziness, somnolence, and headache.
578
579
The most common adverse reactions seen in association with Felbatol® in children during adjunctive
580
therapy are anorexia, vomiting, insomnia, headache, and somnolence.
581
582
The dropout rate because of adverse experiences or intercurrent illnesses among adult felbamate patients
583
was 12 percent (120/977). The dropout rate because of adverse experiences or intercurrent illnesses
584
among pediatric felbamate patients was six percent (22/357). In adults, the body systems associated with
585
causing these withdrawals in order of frequency were: digestive (4.3%), psychological (2.2%), whole
586
body (1.7%), neurological (1.5%), and dermatological (1.5%). In children, the body systems associated
587
with causing these withdrawals in order of frequency were: digestive (1.7%), neurological (1.4%),
588
dermatological (1.4%), psychological (1.1%), and whole body (1.0%). In adults, specific events with an
589
incidence of 1% or greater associated with causing these withdrawals, in order of frequency were:
590
anorexia (1.6%), nausea (1.4%), rash (1.2%), and weight decrease (1.1%). In children, specific events
591
with an incidence of 1% or greater associated with causing these withdrawals, in order of frequency was
592
rash (1.1%).
593
594
Incidence in Clinical Trials:
595
The prescriber should be aware that the figures cited in the following table cannot be used to predict the
596
incidence of side effects in the course of usual medical practice where patient characteristics and other
597
factors differ from those which prevailed in the clinical trials. Similarly, the cited frequencies cannot be
598
compared with figures obtained from other clinical investigations involving different investigators,
599
treatments, and uses including the use of Felbatol® (felbamate) as adjunctive therapy where the incidence
600
of adverse events may be higher due to drug interactions. The cited figures, however, do provide the
601
prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors
602
to the side effect incidence rate in the population studied.
603
604
Adults
605
Incidence in Controlled Clinical Trials--Monotherapy Studies in Adults:
606
The table that follows enumerates adverse events that occurred at an incidence of 2% or more among 58
607
adult patients who received Felbatol® monotherapy at dosages of 3600 mg/day in double-blind controlled
608
trials. Table 3 presents reported adverse events that were classified using standard WHO-based dictionary
609
terminology.
610
Table 3 Adults Treatment-Emergent Adverse Event Incidence in Controlled Monotherapy Trials
Felbatol® (N=58)
Low Dose Valproate** (N=50)
Body System Event
%
%
Body as a Whole
Fatigue
Weight Decrease
Face Edema
6.9
3.4
3.4
4.0
0
0
Central Nervous System
Insomnia
Headache
Anxiety
8.6
6.9
5.2
4.0
18.0
2.0
Dermatological
Acne
Rash
3.4
3.4
0
0
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Digestive
Dyspepsia
Vomiting
Constipation
Diarrhea
SGPT Increased
8.6
8.6
6.9
5.2
5.2
2.0
2.0
2.0
0
2.0
Metabolic/Nutritional
Hypophosphatemia
3.4
0
Respiratory
Upper Respiratory Tract Infection
Rhinitis
8.6
6.9
4.0
0
Special Senses
Diplopia
Otitis Media
3.4
3.4
4.0
0
Urogenital
Intramenstrual Bleeding
Urinary Tract Infection
3.4
3.4
0
2.0
*3600 mg/day, ** 15 mg/kg/day
611
612
Incidence in Controlled Add-On Clinical Studies in Adults:
613
Table 4 enumerates adverse events that occurred at an incidence of 2% or more among 114 adult patients
614
who received Felbatol® adjunctive therapy in add-on controlled trials at dosages up to 3600 mg/day.
615
Reported adverse events were classified using standard WHO-based dictionary terminology.
616
617
Many adverse experiences that occurred during adjunctive therapy may be a result of drug interactions.
618
Adverse experiences during adjunctive therapy typically resolved with conversion to monotherapy, or
619
with adjustment of the dosage of other antiepileptic drugs.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
620
Table 4 Adults Treatment-Emergent Adverse Event Incidence in Controlled Add-On Trials
Felbatol®
Placebo
(N=114)
(N=43)
Body System/Event
%
%
Body as a Whole
Fatigue
16.8
7.0
Fever
2.6
4.7
Chest Pain
2.6
0
Central Nervous System
Headache
36.8
9.3
Somnolence
19.3
7.0
Dizziness
18.4
14.0
Insomnia
17.5
7.0
Nervousness
7.0
2.3
Tremor
6.1
2.3
Anxiety
5.3
4.7
Gait Abnormal
5.3
0
Depression
5.3
0
Paraesthesia
3.5
2.3
Ataxia
3.5
0
Mouth Dry
2.6
0
Stupor
2.6
0
Dermatological
Rash
3.5
4.7
Digestive
Nausea
34.2
2.3
Anorexia
19.3
2.3
Vomiting
16.7
4.7
Dyspepsia
12.3
7.0
Constipation
11.4
2.3
Diarrhea
5.3
2.3
Abdominal Pain
5.3
0
SGPT Increased
3.5
0
Musculoskeletal
Myalgia
2.6
0
Respiratory
Upper Respiratory Tract Infection
Sinusitis
Pharyngitis
5.3
3.5
2.6
7.0
0
0
Special Senses
Diplopia
6.1
0
Taste Perversion
6.1
0
Vision Abnormal
5.3
2.3
621
622
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
623
Children
624
Incidence in a Controlled Add-On Trial in Children with Lennox-Gastaut Syndrome:
625
Table 5 enumerates adverse events that occurred more than once among 31 pediatric patients who
626
received Felbatol® up to 45 mg/kg/day or a maximum of 3600 mg/day. Reported adverse events were
627
classified using standard WHO-based dictionary terminology.
628
Table 5 Children Treatment-Emergent Adverse Event Incidence in Controlled Add-On Lenox
Trials
Felbatol®
Placebo
(N=31)
(N=27)
Body System/Event
%
%
Body as a Whole
Fever
22.6
11.1
Fatigue
9.7
3.7
Weight Decrease
6.5
0
Pain
6.5
0
Central Nervous System
Somnolence
48.4
11.1
Insomnia
16.1
14.8
Nervousness
16.1
18.5
Gait Abnormal
9.7
0
Headache
6.5
18.5
Thinking Abnormal
6.5
3.7
Ataxia
6.5
3.7
Urinary Incontinence
6.5
7.4
Emotional Lability
6.5
0
Miosis
6.5
0
Dermatological
Rash
9.7
7.4
Digestive
Anorexia
54.8
14.8
Vomiting
38.7
14.8
Constipation
12.9
0
Hiccup
9.7
3.7
Nausea
6.5
0
Dyspepsia
6.5
3.7
Hematologic
Purpura
Leukopenia
12.9
6.5
7.4
0
Respiratory
Upper Respiratory Tract Infection
45.2
25.9
Pharyngitis
9.7
3.7
Coughing
6.5
0
Special Senses
Otitis Media
9.7
0
629
630
Other Events Observed in Association with the Administration of Felbatol® (felbamate):
631
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
632
In the paragraphs that follow, the adverse clinical events, other than those in the preceding tables, that
633
occurred in a total of 977 adults and 357 children exposed to Felbatol® (felbamate) and that are
634
reasonably associated with its use are presented. They are listed in order of decreasing frequency.
635
Because the reports cite events observed in open-label and uncontrolled studies, the role of Felbatol® in
636
their causation cannot be reliably determined.
637
638
Events are classified within body system categories and enumerated in order of decreasing frequency
639
using the following definitions: frequent adverse events are defined as those occurring on one or more
640
occasions in at least 1/100 patients; infrequent adverse events are those occurring in 1/100-1/1000
641
patients; and rare events are those occurring in fewer than 1/1000 patients.
642
643
Event frequencies are calculated as the number of patients reporting an event divided by the total number
644
of patients (N=1334) exposed to Felbatol®.
645
646
Body as a Whole: Frequent: Weight increase, asthenia, malaise, influenza-like symptoms; Rare:
647
anaphylactoid reaction, chest pain substernal.
648
Cardiovascular: Frequent: Palpitation, tachycardia; Rare: supraventricular tachycardia.
649
Central Nervous System: Frequent: Agitation, psychological disturbance, aggressive reaction:
650
Infrequent: hallucination, euphoria, suicide attempt, migraine.
651
Digestive: Frequent: SGOT increased; Infrequent: esophagitis, appetite increased; Rare: GGT elevated.
652
Hematologic: Infrequent: Lymphadenopathy, leukopenia, leukocytosis, thrombocytopenia,
653
granulocytopenia; Rare: antinuclear factor test positive, qualitative platelet disorder, agranulocytosis.
654
Metabolic/Nutritional: Infrequent: Hypokalemia, hyponatremia, LDH increased, alkaline phosphatase
655
increased, hypophosphatemia; Rare: creatinine phosphokinase increased.
656
Musculoskeletal: Infrequent: Dystonia.
657
Dermatological: Frequent: Pruritus; Infrequent: urticaria, bullous eruption; Rare: buccal mucous
658
membrane swelling, Stevens-Johnson Syndrome.
659
Special Senses: Rare: Photosensitivity allergic reaction.
660
661
Postmarketing Adverse Event Reports:
662
Voluntary reports of adverse events in patients taking Felbatol® (usually in conjunction with other drugs)
663
have been received since market introduction and may have no causal relationship with the drug(s). These
664
include the following by body system:
665
Body as a Whole: neoplasm, sepsis, L.E. syndrome, SIDS, sudden death, edema, hypothermia, rigors,
666
hyperpyrexia.
667
Cardiovascular: atrial fibrillation, atrial arrhythmia, cardiac arrest, torsade de pointes, cardiac failure,
668
hypotension, hypertension, flushing, thrombophlebitis, ischemic necrosis, gangrene, peripheral ischemia,
669
bradycardia, Henoch-Schönlein purpura (vasculitis).
670
Central & Peripheral Nervous System: delusion, paralysis, mononeuritis, cerebrovascular disorder,
671
cerebral edema, coma, manic reaction, encephalopathy, paranoid reaction, nystagmus, choreoathetosis,
672
extrapyramidal disorder, confusion, psychosis, status epilepticus, dyskinesia, dysarthria, respiratory
673
depression, apathy, concentration impaired.
674
Dermatological: abnormal body odor, sweating, lichen planus, livedo reticularis, alopecia, toxic
675
epidermal necrolysis.
676
Digestive: (Refer to WARNINGS ) hepatitis, hepatic failure, G.I. hemorrhage, hyperammonemia,
677
pancreatitis, hematemesis, gastritis, rectal hemorrhage, flatulence, gingival bleeding, acquired megacolon,
678
ileus, intestinal obstruction, enteritis, ulcerative stomatitis, glossitis, dysphagia, jaundice, gastric ulcer,
679
gastric dilatation, gastroesophageal reflux.
680
Fetal Disorders: fetal death, microcephaly, genital malformation, anencephaly, encephalocele.
681
Hematologic: (Refer to WARNINGS ) increased and decreased prothrombin time, anemia, hypochromic
682
anemia, aplastic anemia, pancytopenia, hemolytic uremic syndrome, increased mean corpuscular volume
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
683
(mcv) with and without anemia, coagulation disorder, embolism-limb, disseminated intravascular
684
coagulation, eosinophilia, hemolytic anemia, leukemia, including myelogenous leukemia, and lymphoma,
685
including T-cell and B-cell lymphoproliferative disorders.
686
Metabolic/Nutritional: hypernatremia, hypoglycemia, SIADH, hypomagnesemia, dehydration,
687
hyperglycemia, hypocalcemia.
688
Musculoskeletal: arthralgia, muscle weakness, involuntary muscle contraction, rhabdomyolysis.
689
Respiratory: dyspnea, pneumonia, pneumonitis, hypoxia, epistaxis, pleural effusion, respiratory
690
insufficiency, pulmonary hemorrhage, asthma.
691
Special Senses: hemianopsia, decreased hearing, conjunctivitis.
692
Urogenital menstrual disorder, acute renal failure, hepatorenal syndrome, hematuria, urinary retention,
693
nephrosis, vaginal hemorrhage, abnormal renal function, dysuria, placental disorder.
694
695
DRUG ABUSE AND DEPENDENCE
696
Abuse: Abuse potential was not evaluated in human studies.
697
698
Dependence: Rats administered felbamate orally at doses 8.3 times the recommended human dose 6 days
699
each week for 5 consecutive weeks demonstrated no signs of physical dependence as measured by weight
700
loss following drug withdrawal on day 7 of each week.
701
702
OVERDOSAGE
703
Four subjects inadvertently received Felbatol® (felbamate) as adjunctive therapy in dosages ranging from
704
5400 to 7200 mg/day for durations between 6 and 51 days. One subject who received 5400 mg/day as
705
monotherapy for 1 week reported no adverse experiences. Another subject attempted suicide by ingesting
706
12,000 mg of Felbatol® in a 12-hour period. The only adverse experiences reported were mild gastric
707
distress and a resting heart rate of 100 bpm. No serious adverse reactions have been reported.
708
General supportive measures should be employed if overdosage occurs. It is not known if felbamate is
709
dialyzable.
710
711
DOSAGE AND ADMINISTRATION
712
Felbatol® (felbamate) has been studied as monotherapy and adjunctive therapy in adults and as
713
adjunctive therapy in children with seizures associated with Lennox-Gastaut syndrome. As Felbatol® is
714
added to or substituted for existing AEDs, it is strongly recommended to reduce the dosage of those
715
AEDs in the range of 20-33% to minimize side effects (see Drug Interactions subsection).
716
717
Dosage Adjustment in the Renally Impaired: Felbamate should be used with caution in patients with
718
renal dysfunction. In the renally impaired, starting and maintenance doses should be reduced by one-half
719
(See CLINICAL PHARMACOLOGY / Pharmacokinetics and PRECAUTIONS ). Adjunctive therapy
720
with medications which affect felbamate plasma concentrations, especially AEDs, may warrant further
721
reductions in felbamate daily doses in patients with renal dysfunction.
722
723
Adults (14 years of age and over)
724
The majority of patients received 3600 mg/day in clinical trials evaluating its use as both monotherapy
725
and adjunctive therapy.
726
727
Monotherapy: (Initial therapy) Felbatol® (felbamate) has not been systematically evaluated as initial
728
monotherapy. Initiate Felbatol® at 1200 mg/day in divided doses three or four times daily. The prescriber
729
is advised to titrate previously untreated patients under close clinical supervision, increasing the dosage in
730
600-mg increments every 2 weeks to 2400 mg/day based on clinical response and thereafter to 3600
731
mg/day if clinically indicated.
732
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
733
Conversion to Monotherapy: Initiate Felbatol® at 1200 mg/day in divided doses three or four times
734
daily. Reduce the dosage of concomitant AEDs by one-third at initiation of Felbatol® therapy. At week 2,
735
increase the Felbatol® dosage to 2400 mg/day while reducing the dosage of other AEDs up to an
736
additional one-third of their original dosage. At week 3, increase the Felbatol® dosage up to 3600 mg/day
737
and continue to reduce the dosage of other AEDs as clinically indicated.
738
739
Adjunctive Therapy: Felbatol® should be added at 1200 mg/day in divided doses three or four times
740
daily while reducing present AEDs by 20% in order to control plasma concentrations of concurrent
741
phenytoin, valproic acid, phenobarbital, and carbamazepine and its metabolites. Further reductions of the
742
concomitant AEDs dosage may be necessary to minimize side effects due to drug interactions. Increase
743
the dosage of Felbatol® by 1200 mg/day increments at weekly intervals to 3600 mg/day. Most side
744
effects seen during Felbatol® adjunctive therapy resolve as the dosage of concomitant AEDs is
745
decreased.
746
Table 6 Dosage Table (adults)
Dosage reduction of
concomitant AEDs
WEEK 1
REDUCE original dose by
20–33%*
WEEK 2
REDUCE original dose by
up to an additional 1/3*
WEEK 3
REDUCE as
clinically
indicated
Felbatol®
Dosage
1200 mg/day Initial dose
2400 mg/day
Therapeutic dosage range
3600 mg/day
Therapeutic dosage range
*See Adjunctive and Conversion to Monotherapy sections.
747
748
While the above Felbatol® conversion guidelines may result in a Felbatol® 3600 mg/day dose within 3
749
weeks, in some patients titration to a 3600 mg/day Felbatol® dose has been achieved in as little as 3 days
750
with appropriate adjustment of other AEDs.
751
752
Children with Lennox-Gastaut Syndrome (Ages 2-14 years)
753
Adjunctive Therapy: Felbatol® should be added at 15 mg/kg/day in divided doses three or four times
754
daily while reducing present AEDs by 20% in order to control plasma levels of concurrent phenytoin,
755
valproic acid, phenobarbital, and carbamazepine and its metabolites. Further reductions of the
756
concomitant AEDs dosage may be necessary to minimize side effects due to drug interactions. Increase
757
the dosage of Felbatol® by 15 mg/kg/day increments at weekly intervals to 45 mg/kg/day. Most side
758
effects seen during Felbatol® adjunctive therapy resolve as the dosage of concomitant AEDs is
759
decreased.
760
761
HOW SUPPLIED
762
Felbatol® (felbamate) Tablets, 400 mg, are yellow, scored, capsule-shaped tablets, debossed 0430 on one
763
side and FELBATOL 400 on the other; available in bottles of 100 (NDC 0037-0430-01). Felbatol®
764
(felbamate) Tablets, 600 mg, are peach-colored, scored, capsule-shaped tablets, debossed 0431
765
on one side and FELBATOL 600 on the other; available in bottles of 100 (NDC 0037-0431-01).
766
Felbatol® (felbamate) Oral Suspension, 600 mg/5 mL, is peach-colored; available in 8 oz bottles (NDC
767
0037-0442-67) and 32 oz bottles (NDC 0037-0442-17).
768
769
Shake suspension well before using. Store at controlled room temperature 20°-25°C (68°-77°F). Dispense
770
in tight container.
771
772
To report SUSPECTED ADVERSE REACTIONS, contact Meda Pharmaceuticals at
773
1-800-526-3840 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
774
775
MEDA Pharmaceuticals
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
776
MEDA Pharmaceuticals Inc.
777
Somerset, NJ 08873
778
IN-00431-19 Rev. MM/YY
779
780
PATIENT INFORMATION/CONSENT
781
782
FELBATOL® (felbamate) SHOULD NOT BE USED BY PATIENTS UNTIL THERE HAS BEEN A
783
COMPLETE DISCUSSION OF THE RISKS AND WRITTEN INFORMED CONSENT HAS BEEN
784
OBTAINED.
785
786
IMPORTANT INFORMATION AND WARNING:
787
Felbatol®, taken by itself or with other prescription and/or non-prescription drugs, can result in severe,
788
potentially fatal blood abnormality ("aplastic anemia") and/or severe, potentially fatal liver damage.
789
PATIENT CONSENT:
790
791
My [My son, daughter, ward ___________________________________________________________'s]
792
treatment with Felbatol® has been personally explained to me by Dr._____________________________.
793
794
The following points of information, among others, have been specifically discussed and made clear and I
795
have had the opportunity to ask any questions concerning this information:
796
797
1. I, _______________________________________________________________ (Patient's Name),
798
understand that Felbatol® is used to treat certain types of seizures and my physician has told me that I
799
have this type(s) of seizures;
800
INITIALS: __________________________
801
802
803
2. I understand that Felbatol® is being used since my seizures have not been satisfactorily treated with
804
other antiepileptic drugs;
805
INITIALS: __________________________
806
807
3. I understand that there is a serious risk that I could develop aplastic anemia and/or liver failure, both of
808
which are potentially fatal, by using Felbatol®;
809
INITIALS: __________________________
810
811
4. I understand that there are no laboratory tests which will predict if I am at an increased risk for one of
812
the potentially fatal conditions;
813
INITIALS: __________________________
814
815
5. I understand that I should have the recommended blood work before my treatment with Felbatol® is
816
begun (baseline) and periodically thereafter as clinical judgement warrants. I understand that although this
817
blood work may help detect if I develop one of these conditions, it may do so only after significant,
818
irreversible and potentially fatal damage has already occurred;
819
INITIALS: __________________________
820
821
6. If I am currently taking another antiepileptic drug, I understand that the manufacturer of Felbatol®
822
recommends that the dosage of these other drugs be decreased by a certain amount when Felbatol® is
823
started; if my physician determines that this should not be done in my case, he/she has explained the
824
reason(s) for this decision;
825
INITIALS: __________________________
826
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
827
7. I understand that I must immediately report any unusual symptoms to Dr. _______________________
828
and be especially aware of any rashes, easy bruising, bleeding, sore throats, fever, and/or dark urine;
829
INITIALS: __________________________
830
831
8. I understand that antiepileptic drugs such as Felbatol® may increase the risk of suicidal thoughts and
832
behavior. I understand that I must immediately report any unusual changes in mood or behavior,
833
symptoms of depression or thoughts about self-harm to Dr. ____________________.
834
INITIALS: __________________________
835
836
837
I now authorize Dr. _____________________________________________ to begin my treatment
838
with Felbatol®; OR, if my treatment has already begun with Felbatol®, to continue such treatment.
839
840
_______________________________________________
841
Patient, Parent, or Guardian
842
_______________________________________________
843
Address
844
________________________________________________
845
Telephone
846
847
PHYSICIAN STATEMENT:
848
I have fully explained to the patient, ___________________________________________, the nature and
849
purpose of the treatment with Felbatol® (felbamate) and the potential risks associated with that treatment.
850
I have asked the patient if he/she has any questions regarding this treatment or the risks and have
851
answered those questions to the best of my ability. I also acknowledge that I have read and understand the
852
prescribing information listed above.
853
854
_________________________________________________________________________
855
Physician
856
Date
857
NOTE TO PHYSICIAN: It is strongly recommended that you retain a signed copy of the informed
858
consent with the patient's medical records.
859
860
SUPPLY OF PATIENT INFORMATION/CONSENT FORMS:
861
A supply of "Patient Information/Consent" forms as printed above is available, free of charge, from your
862
local MEDA Pharmaceuticals representative, or may be obtained by calling 1-800-526-3840. Permission
863
to use the above Patient Information/Consent by photocopy reproduction is also hereby granted by
864
MEDA Pharmaceuticals Inc.
865
866
MEDA Pharmaceuticals
867
MEDA Pharmaceuticals Inc.
868
Somerset, NJ 08873
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:47:01.155722
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020189s022lbl.pdf', 'application_number': 20189, 'submission_type': 'SUPPL ', 'submission_number': 22}
|
12,312
|
ELMIRON®-100 mg
(pentosan polysulfate sodium) Capsules
Prescribing Information
DESCRIPTION
Pentosan polysulfate sodium is a semi-synthetically produced heparin-like
macromolecular carbohydrate derivative, which chemically and structurally
resembles glycosaminoglycans. It is a white odorless powder, slightly hygroscopic
and soluble in water to 50% at pH 6. It has a molecular weight of 4000 to
6000 Dalton with the following structural formula:
Ch
emical
St
ru
ctur
e
ELMIRON® is supplied in white opaque hard gelatin capsules containing 100 mg
pentosan polysulfate sodium, microcrystalline cellulose, and magnesium stearate. It
also contains pharmaceutical glaze (modified) in SD-45, synthetic black iron oxide,
FD&C Blue No. 2 aluminum lake, FD&C Red No. 40 aluminum lake, FD&C Blue
No. 1 aluminum lake, D&C Yellow No. 10 aluminum lake, n-butyl alcohol,
propylene glycol, SDA-3A alcohol, and titanium dioxide. It is formulated for oral use.
CLINICAL PHARMACOLOGY
General:
Pentosan polysulfate sodium is a low molecular weight heparin-like compound. It has
anticoagulant and fibrinolytic effects. The mechanism of action of pentosan
polysulfate sodium in interstitial cystitis is not known.
Pharmacokinetics:
Absorption:
In a clinical pharmacology study in which healthy female volunteers received a single
oral 300 or 450 mg dose of pentosan polysulfate sodium containing radiolabeled drug
as a solution under fasted conditions, maximal levels of plasma radioactivity were
seen approximately at a median of 2 hours (range 0.6-120 hours) after dosing. Based
on urinary excretion of radioactivity, a mean of approximately 6% of a radiolabeled
1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
oral dose of pentosan polysulfate sodium is absorbed and reaches the systemic
circulation.
Food Effects: In clinical trials, ELMIRON® was administered with water 1 hour
before or 2 hours after meals; the effect of food on absorption of pentosan polysulfate
sodium is not known.
Distribution:
Preclinical studies with parenterally administered radiolabeled pentosan polysulfate
sodium showed distribution to the uroepithelium of the genitourinary tract with lesser
amounts found in the liver, spleen, lung, skin, periosteum, and bone marrow.
Erythrocyte penetration is low in animals.
Metabolism:
The fraction of pentosan polysulfate sodium that is absorbed is metabolized by partial
desulfation in the liver and spleen, and by partial depolymerization in the kidney to a
large number of metabolites. Both the desulfation and depolymerization can be
saturated with continued dosing.
Excretion:
Following administration of an oral solution of a 300 or 450 mg dose of pentosan
polysulfate sodium containing radiolabeled drug to groups of healthy subjects, plasma
radioactivity declined with mean half-lives of 27 and 20 hours, respectively. A large
proportion of the orally administered dose of pentosan polysulfate sodium (mean 84%
in the 300 mg group and 58% in the 450 mg group) is excreted in feces as unchanged
drug. A mean of 6% of an oral dose is excreted in the urine, mostly as desulfated and
depolymerized metabolites. Only a small fraction of the administered dose (mean
0.14%) is recovered as intact drug in urine.
Special Populations:
The pharmacokinetics of pentosan polysulfate sodium has not been studied in
geriatric patients or in patients with hepatic or renal impairment. See also
PRECAUTIONS-Hepatic Insufficiency.
Drug-Drug Interactions:
In a study in which healthy subjects received pentosan polysulfate sodium 100 mg
capsule or placebo every 8 hours for 7 days, and were titrated with warfarin to an INR
of 1.4 to 1.8, the pharmacokinetic parameters of R-warfarin and S-warfarin were
similar in the absence and presence of pentosan polysulfate sodium. INR for warfarin
+ placebo and warfarin + pentosan polysulfate sodium were comparable. See also
2
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PRECAUTIONS on the use of ELMIRON® in patients receiving other therapies
with anticoagulant effects.
Pharmacodynamics:
The mechanism by which pentosan polysulfate sodium achieves its effects in patients
is unknown. In preliminary clinical models, pentosan polysulfate sodium adhered to
the bladder wall mucosal membrane. The drug may act as a buffer to control cell
permeability preventing irritating solutes in the urine from reaching the cells.
CLINICAL TRIALS
ELMIRON® was evaluated in two clinical trials for the relief of pain in patients with
chronic interstitial cystitis (IC). All patients met the NIH definition of IC based upon
the results of cystoscopy, cytology, and biopsy. One blinded, randomized, placebo
controlled study evaluated 151 patients (145 women, 5 men, 1 unknown) with a mean
age of 44 years (range 18 to 81). Approximately equal numbers of patients received
either placebo or ELMIRON® 100 mg three times a day for 3 months. Clinical
improvement in bladder pain was based upon the patient’s own assessment. In this
study, 28/74 (38%) of patients who received ELMIRON® and 13/74 (18%) of patients
who received placebo, showed greater than 50% improvement in bladder pain
(p=0.005).
A second clinical trial, the physician’s usage study, was a prospectively designed
retrospective analysis of 2499 patients who received ELMIRON® 300 mg a day
without blinding. Of the 2499 patients, 2220 were women, 254 were men, and
25 were of unknown sex. The patients had a mean age of 47 years and 23% were over
60 years of age. By 3 months, 1307 (52%) of the patients had dropped out or were
ineligible for analysis, overall, 1192 (48%) received ELMIRON® for 3 months;
892 (36%) received ELMIRON® for 6 months; and 598 (24%) received ELMIRON®
for one year.
Patients had unblinded evaluations every 3 months for the patient’s rating of overall
change in pain in comparison to baseline and for the difference calculated in
“pain/discomfort” scores. At baseline, pain/discomfort scores for the original
2499 patients were severe or unbearable in 60%, moderate in 33% and mild or none
in 7% of patients. The extent of the patients’ pain improvement is shown in Table 1.
At 3 months, 722/2499 (29%) of the patients originally in the study had pain scores
that improved by one or two categories. By 6 months, in the 892 patients who
continued taking ELMIRON®, an additional 116/2499 (5%) of patients had improved
pain scores. After 6 months, the percent of patients who reported the first onset of
3
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
pain relief was less than 1.5% of patients who originally entered in the study
(see Table 2).
Table 1: Pain Scores in Reference to Baseline in Open Label Physician’s Usage Study (N=2499)1
Efficacy Parameter
3 months2
6 months2
Patient Rating of Overall Change in Pain
(Recollection of difference between
current pain and baseline pain)3
Change in Pain/Discomfort Score
(Calculated difference in scores at the
time point and baseline)4
N=1161
Median=3
Mean=3.44
CI: (3.37, 3.51)
N=1440
Median=1
Mean=0.51
CI: (0.45, 0.57)
N=724
Median=4
Mean=3.91
CI: (3.83, 3.99)
N=904
Median=1
Mean=0.66
CI: (0.61, 0.71)
1Trial not designed to detect onset of pain relief
2CI = 95% confidence interval
36-point scale: 1 = worse, 2 = no better, 3 = slightly improved, 4 = moderately improved, 5 = greatly
improved, 6 = symptom gone
43-point scale: 1 = none or mild, 2 = moderate, 3 = severe or unbearable
Table 2: Number (%) of Patients with New Relief of Pain/Discomfort1 in the Open-Label
Physician’s Usage Study (N=2499)
at 3 months2
(n=1192)
at 6 months3
(n=892)
Considering only the patients who
continued treatment
Considering all the patients originally
enrolled in the study
722/1192 (61%)
722/2499 (29%)
116/892 (13%)
116/2499 (5%)
1First-time Improvement in pain/discomfort score by 1 or 2 categories
2Number (%) of patients with improvement of pain/discomfort score at 3 months when compared to
baseline
3Number (%) of patients without pain/discomfort improvement at 3 months who had improvement at 6
months
INDICATIONS AND USAGE
ELMIRON® (pentosan polysulfate sodium) is indicated for the relief of bladder pain
or discomfort associated with interstitial cystitis.
CONTRAINDICATIONS
ELMIRON® is contraindicated in patients with known hypersensitivity to the drug,
structurally related compounds, or excipients.
WARNINGS
None.
4
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PRECAUTIONS
General:
ELMIRON® is a weak anticoagulant (1/15 the activity of heparin). At a daily dose of
300 mg (n = 128), rectal hemorrhage was reported as an adverse event in 6.3% of
patients. Bleeding complications of ecchymosis, epistaxis, and gum hemorrhage have
been reported (see ADVERSE REACTIONS). Patients undergoing invasive
procedures or having signs/symptoms of underlying coagulopathy or other increased
risk of bleeding (due to other therapies such as coumarin anticoagulants, heparin,
t-PA, streptokinase, high dose aspirin, or nonsteroidal anti-inflammatory drugs)
should be evaluated for hemorrhage. Patients with diseases such as aneurysms,
thrombocytopenia, hemophilia, gastrointestinal ulcerations, polyps, or diverticula
should be carefully evaluated before starting ELMIRON®.
A similar product that was given subcutaneously, sublingually, or intramuscularly
(and not initially metabolized by the liver) is associated with delayed immunoallergic
thrombocytopenia with symptoms of thrombosis and hemorrhage. Caution should be
exercised when using ELMIRON® in patients who have a history of heparin induced
thrombocytopenia.
Alopecia is associated with pentosan polysulfate and with heparin products. In
clinical trials of ELMIRON®, alopecia began within the first 4 weeks of treatment.
Ninety-seven percent (97%) of the cases of alopecia reported were alopecia areata,
limited to a single area on the scalp.
Hepatic Insufficiency:
ELMIRON® has not been studied in patients with hepatic insufficiency. Because
there is evidence of hepatic contribution to the elimination of ELMIRON®, hepatic
impairment may have an impact on the pharmacokinetics of ELMIRON®. Caution
should be exercised when using ELMIRON® in this patient population.
Mildly (<2.5 x normal) elevated transaminase, alkaline phosphatase, γ-glutamyl
transpeptidase, and lactic dehydrogenase occurred in 1.2% of patients. The increases
usually appeared 3 to 12 months after the start of ELMIRON® therapy, and were not
associated with jaundice or other clinical signs or symptoms. These abnormalities are
usually transient, may remain essentially unchanged, or may rarely progress with
continued use. Increases in PTT and PT (<1% for both) or thrombocytopenia
(0.2%) were noted.
5
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Information for Patients:
Patients should take the drug as prescribed, in the dosage prescribed, and no more
frequently than prescribed. Patients should be reminded that ELMIRON® has a weak
anticoagulant effect. This effect may increase bleeding times.
Laboratory Test Findings:
Pentosan polysulfate sodium did not affect prothrombin time (PT) or partial
thromboplastin time (PTT) up to 1200 mg per day in 24 healthy male subjects treated
for 8 days. Pentosan polysulfate sodium also inhibits the generation of factor Xa in
plasma and inhibits thrombin-induced platelet aggregation in human platelet rich
plasma ex vivo. (See PRECAUTIONS-Hepatic Insufficiency Section for additional
information.)
Carcinogenicity, Mutagenesis, Impairment of Fertility:
Long term carcinogenicity studies of ELMIRON® in F344/N rats and B6C3F1 mice
have been conducted. In these studies, ELMIRON® was orally administered once
daily via gavage, 5 days per week, for up to 2 years. The dosages administered to
mice were 56, 168 or 504 mg/kg. The dosages administered to rats were 14, 42, or
126 mg/kg for males, and 28, 84, or 252 mg/kg for females. The dosages tested were
up to 60 times the maximum recommended human dose (MRHD) in rats, and up to
117 times the MRHD in mice, on a mg/kg basis. The results of these studies in
rodents showed no clear evidence of drug-related tumorigenesis or carcinogenic risk.
Pentosan polysulfate sodium was not clastogenic or mutagenic when tested in the
mouse micronucleus test or the Ames test (S. typhimurium). The effect of pentosan
polysulfate sodium on spermatogenesis has not been investigated.
Pregnancy Category B:
Reproduction studies have been performed in mice and rats with intravenous daily
doses of 15 mg/kg, and in rabbits with 7.5 mg/kg. These doses are 0.42 and
0.14 times the daily oral human doses of ELMIRON® when normalized to body
surface area. These studies did not reveal evidence of impaired fertility or harm to the
fetus from ELMIRON®. Direct in vitro bathing of cultured mouse embryos with
pentosan polysulfate sodium (PPS) at a concentration of 1 mg/mL may cause
reversible limb bud abnormalities. Adequate and well-controlled studies have not
been performed in pregnant women. Because animal studies are not always predictive
of human response, this drug should be used in pregnancy only if clearly needed.
6
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Nursing Mothers:
It is not known whether this drug is excreted in human milk. Because many drugs are
excreted in human milk, caution should be exercised when ELMIRON® is
administered to a nursing woman.
Pediatric Use:
Safety and effectiveness in pediatric patients below the age of 16 years have not been
established.
ADVERSE REACTIONS
ELMIRON® was evaluated in clinical trials in a total of 2627 patients (2343 women,
262 men, 22 unknown) with a mean age of 47 [range 18 to 88 with 581 (22%) over
60 years of age]. Of the 2627 patients, 128 patients were in a 3 month trial and the
remaining 2499 patients were in a long term, unblinded trial.
Deaths occurred in 6/2627 (0.2%) patients who received the drug over a period of 3 to
75 months. The deaths appear to be related to other concurrent illnesses or
procedures, except in one patient for whom the cause was not known.
Serious adverse events occurred in 33/2627 (1.3%) patients. Two patients had severe
abdominal pain or diarrhea and dehydration that required hospitalization. Because
there was not a control group of patients with interstitial cystitis who were
concurrently evaluated, it is difficult to determine which events are associated with
ELMIRON® and which events are associated with concurrent illness, medicine, or
other factors.
7
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Adverse Experience In Placebo-Controlled Clinical Trials of ELMIRON® 100 mg Three Times a
Day for 3 Months
Body System/Adverse Experience
ELMIRON®
n=128
Placebo
n=130
CNS
Overall Number of Patients*
3
5
Insomnia
Headache
Severe Emotional Lability/Depression
Nystagmus/Dizziness
Hyperkinesia
1
1
2
1
1
0
3
1
1
1
GI
Overall Number of Patients*
7
7
Nausea
Diarrhea
Dyspepsia
Jaundice
Vomiting
3
3
1
0
0
3
6
0
1
2
Skin/Allergic
Overall Number of Patients*
2
4
Rash
Pruritus
Lacrimation
Rhinitis
Increased Sweating
0
0
1
1
1
2
2
1
1
0
Other Overall Number of Patients*
1
3
Amenorrhea
Arthralgia
Vaginitis
0
0
1
1
1
1
Total Events
17
27
Total Number of Patients Reporting Adverse Events
13
19
*Within a body system, the individual events do not sum to equal overall number of patients
because a patient may have more than one event.
The adverse events described below were reported in an unblinded clinical trial of
2499 interstitial cystitis patients treated with ELMIRON®. Of the original
2499 patients, 1192 (48%) received ELMIRON® for 3 months; 892 (36%) received
ELMIRON® for 6 months; and 598 (24%) received ELMIRON® for one year,
355 (14%) received ELMIRON® for 2 years, and 145 (6%) for 4 years.
Frequency (1 to 4%): Alopecia (4%), diarrhea (4%), nausea (4%), headache (3%),
rash (3%), dyspepsia (2%), abdominal pain (2%), liver function abnormalities (1%),
dizziness (1%).
Frequency (< 1%):
Digestive: Vomiting, mouth ulcer, colitis, esophagitis, gastritis, flatulence,
constipation, anorexia, gum hemorrhage.
Hematologic: Anemia, ecchymosis, increased prothrombin time, increased partial
thromboplastin time, leukopenia, thrombocytopenia.
8
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Hypersensitive Reactions: Allergic reaction, photosensitivity.
Respiratory System: Pharyngitis, rhinitis, epistaxis, dyspnea.
Skin and Appendages: Pruritus, urticaria.
Special Senses: Conjunctivitis, tinnitus, optic neuritis, amblyopia, retinal hemorrhage.
Post-Marketing Experience:
Rectal Hemorrhage:
ELMIRON® was evaluated in a randomized, double-blind, parallel group,
Phase 4 study conducted in 380 patients with interstitial cystitis dosed for 32 weeks.
At a daily dose of 300 mg (n = 128), rectal hemorrhage was reported as an adverse
event in 6.3% of patients. The severity of the events was described as “mild” in most
patients. Patients in that study who were administered ELMIRON® 900 mg daily, a
dose higher than the approved dose, experienced a higher incidence of rectal
hemorrhage, 15%.
Liver Function Abnormality:
A randomized, double-blind, parallel group, phase 2 study was conducted in 100 men
(51 ELMIRON® and 49 placebo) dosed for 16 weeks. At a daily dose of 900 mg, a
dose higher than the approved dose, elevated liver function tests were reported as an
adverse event in 11.8% (n = 6) of ELMIRON® treated patients and 2% (n = 1) of
placebo treated patients.
OVERDOSAGE
Overdose has not been reported. Based upon the pharmacodynamics of the drug,
toxicity is likely to be reflected as anticoagulation, bleeding, thrombocytopenia, liver
function abnormalities, and gastric distress. (See CLINICAL PHARMACOLOGY
and PRECAUTIONS sections.) At a daily dose of 900 mg for 32 weeks (n = 127) in
a clinical trial, rectal hemorrhage was reported as an adverse event in 15% of patients.
At a daily dose of ELMIRON® 900 mg for 16 weeks in a clinical trial that enrolled
51 patients in the ELMIRON® group and 49 in the placebo group, elevated liver
function tests were reported as an adverse event in 11.8% of patients in the
ELMIRON® group and 2% of patients in the placebo group. In the event of acute
overdosage, the patient should be given gastric lavage if possible, carefully observed
and given symptomatic and supportive treatment.
9
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
DOSAGE AND ADMINISTRATION
The recommended dose of ELMIRON® is 300 mg/day taken as one 100 mg capsule
orally three times daily. The capsules should be taken with water at least 1 hour
before meals or 2 hours after meals.
Patients receiving ELMIRON® should be reassessed after 3 months. If improvement
has not occurred and if limiting adverse events are not present, ELMIRON® may be
continued for another 3 months.
The clinical value and risks of continued treatment in patients whose pain has not
improved by 6 months is not known.
HOW SUPPLIED
ELMIRON® is supplied in white opaque hard gelatin capsules imprinted “BNP7600”
containing 100 mg pentosan polysulfate sodium. Supplied in bottles of 100 capsules.
NDC NUMBER 0062-9800-01
STORAGE
Store at controlled room temperature 15°-30°C (59°-86°F).
ELMIRON® is a Registered Trademark of IVAX Research, LLC under license to
Ortho−McNeil−Janssen Pharmaceuticals, Inc.
© OMJPI 2002,1998
Ortho
Women’s
Health
&
Urology,
Division
of
Ortho−McNeil−Janssen
Pharmaceuticals, Inc.
Raritan, New Jersey 08869
Manufactured by:
Janssen Ortho LLC
Gurabo, Puerto Rico 00778
Manufactured for:
Ortho
Women’s
Health
&
Urology,
Division
of
Ortho−McNeil−Janssen
Pharmaceuticals, Inc.
Raritan, New Jersey 08869
10
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Revised XXX
1011040X
U.S. Patent #5,180,715
11
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Please dispense one patient leaflet per perscription
Please dispense one patient leaflet per perscription
Questions and Answers About
ELMIRON®
(Generic name = pentosan polysulfate sodium)
Capsules
What is the most important information
I should know about ELMIRON®?
ELMIRON® (pronounced EL ma ron) is used to treat the pain or discomfort of
interstitial cystitis (IC).
You must take ELMIRON® as prescribed by your doctor in the dosage prescribed but
no more frequently than prescribed.
ELMIRON® is a weak anticoagulant (blood thinner) which may increase bleeding.
Call your doctor if you will be undergoing surgery or will begin taking anticoagulant
therapy such as warfarin sodium, heparin, high doses of aspirin, or anti-inflammatory
drugs such as ibuprofen.
What is ELMIRON®?
ELMIRON® is used to treat the pain or discomfort of interstitial cystitis (IC). It is not
known exactly how ELMIRON® works, but it is not a pain medication like aspirin or
acetaminophen and therefore must be taken continuously for relief as prescribed.
Who should not take ELMIRON®?
• Patients undergoing surgery should speak with their doctor about when to
discontinue ELMIRON® prior to surgery.
• ELMIRON® should be used during pregnancy only if clearly needed.
12
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
What does your doctor need to know?
• If you are taking anticoagulant therapy such as warfarin sodium, heparin, high
doses of aspirin, or anti-inflammatory drugs such as ibuprofen.
• If you are pregnant.
• If you have any liver problems.
How should I take ELMIRON®?
You should take 1 capsule of ELMIRON® by mouth three times a day, with water at
least 1 hour before meals or 2 hours after meals. Each capsule contains 100 mg of
ELMIRON®.
What should I avoid while taking ELMIRON®?
Anticoagulant therapy such as warfarin sodium, heparin, high doses of aspirin or anti
inflammatory drugs such as ibuprofen until you speak with your doctor.
What are the most common side effects of ELMIRON®?
The most common side effects are hair loss, diarrhea, nausea, blood in the stool,
headache, rash, upset stomach, abnormal liver function tests, dizziness and bruising.
Call your doctor if these side effects persist or are bothersome or if there is blood in
your stool.
If you suspect that someone may have taken more than the prescribed dose of this
medicine, contact your local poison control center or emergency room immediately.
This medication was prescribed for your particular condition. Do not use it for
another condition or give the drug to others.
This leaflet provides a summary of information about ELMIRON®. Medicines are
sometimes prescribed for uses other than those listed in a Patient Leaflet. If you have
any questions or concerns, or want more information about ELMIRON®, contact your
doctor or pharmacist. Your pharmacist also has a longer leaflet about ELMIRON®
that is written for health professionals that you can ask to read.
ELMIRON® is a Registered Trademark of IVAX Research, LLC under license to
Ortho−McNeil−Janssen Pharmaceuticals, Inc.
© OMJPI 2002,1998
13
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Ortho
Women’s
Health
&
Urology,
Division
of
Ortho−McNeil−Janssen
Pharmaceuticals, Inc.
Raritan, New Jersey 08869
Revised XXX
14
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:47:01.197923
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/020193s009lbl.pdf', 'application_number': 20193, 'submission_type': 'SUPPL ', 'submission_number': 9}
|
12,313
|
NDA 20-198/S-017
Page 2
ADALAT® CC
(nifedipine)
Extended Release Tablets
For Oral Use
08918360, R.0
10/04
DESCRIPTION
ADALAT® CC is an extended release tablet dosage form of the calcium channel blocker nifedipine. Nifedipine is 3,5-
pyridinedicarboxylic acid, 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-dimethyl ester, C17H18N2O6, and has the structural
formula:
Nifedipine is a yellow crystalline substance, practically insoluble in water but soluble in ethanol. It has a molecular
weight of 346.3. ADALAT CC tablets consist of an external coat and an internal core. Both contain nifedipine, the
coat as a slow release formulation and the core as a fast release formulation. ADALAT CC tablets contain either
30, 60, or 90 mg of nifedipine for once-a-day oral administration.
Inert ingredients in the formulation are: hydroxypropylcellulose, lactose, corn starch, crospovidone, microcrystalline
cellulose, silicon dioxide, and magnesium stearate. The inert ingredients in the film coating are: hypromellose,
polyethylene glycol, ferric oxide, and titanium dioxide.
CLINICAL PHARMACOLOGY
Nifedipine is a calcium ion influx inhibitor (slow-channel blocker or calcium ion antagonist) which inhibits the
transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. The contractile processes
of vascular smooth muscle and cardiac muscle are dependent upon the movement of extracellular calcium ions into
these cells through specific ion channels. Nifedipine selectively inhibits calcium ion influx across the cell
membrane of vascular smooth muscle and cardiac muscle without altering serum calcium concentrations.
Mechanism of Action: The mechanism by which nifedipine reduces arterial blood pressure involves peripheral
arterial vasodilatation and, consequently, a reduction in peripheral vascular resistance. The increased peripheral
vascular resistance that is an underlying cause of hypertension results from an increase in active tension in the
vascular smooth muscle. Studies have demonstrated that the increase in active tension reflects an increase in
cytosolic free calcium.
Nifedipine is a peripheral arterial vasodilator which acts directly on vascular smooth muscle. The binding of
nifedipine to voltage-dependent and possibly receptor-operated channels in vascular smooth muscle results in an
inhibition of calcium influx through these channels. Stores of intracellular calcium in vascular smooth muscle are
limited and thus dependent upon the influx of extracellular calcium for contraction to occur. The reduction in
calcium influx by nifedipine causes arterial vasodilation and decreased peripheral vascular resistance which results
in reduced arterial blood pressure.
Pharmacokinetics and Metabolism: Nifedipine is completely absorbed after oral administration. The
bioavailability of nifedipine as ADALAT CC relative to immediate release nifedipine is in the range of 84%-89%.
After ingestion of ADALAT CC tablets under fasting conditions, plasma concentrations peak at about 2.5-5 hours
with a second small peak or shoulder evident at approximately 6-12 hours post dose. The elimination half-life of
nifedipine administered as ADALAT CC is approximately 7 hours in contrast to the known 2 hour elimination
half-life of nifedipine administered as an immediate release capsule.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-198/S-017
Page 3
When ADALAT CC is administered as multiples of 30 mg tablets over a dose range of 30 mg to 90 mg, the area
under the curve (AUC) is dose proportional; however, the peak plasma concentration for the 90 mg dose given
as 3 × 30 mg is 29% greater than predicted from the 30 mg and 60 mg doses.
Two 30 mg ADALAT CC tablets may be interchanged with a 60 mg ADALAT CC tablet. Three 30 mg ADALAT
CC tablets, however, result in substantially higher Cmax values than those after a single 90 mg ADALAT CC tablet.
Three 30 mg tablets should, therefore, not be considered interchangeable with a 90 mg tablet.
Once daily dosing of ADALAT CC under fasting conditions results in decreased fluctuations in the plasma
concentration of nifedipine when compared to t.i.d. dosing with immediate release nifedipine capsules. The mean
peak plasma concentration of nifedipine following a 90 mg ADALAT CC tablet, administered under fasting
conditions, is approximately 115 ng/mL. When ADALAT CC is given immediately after a high fat meal in healthy
volunteers, there is an average increase of 60% in the peak plasma nifedipine concentration, a prolongation in the
time to peak concentration, but no significant change in the AUC. Plasma concentrations of nifedipine when
ADALAT CC is taken after a fatty meal result in slightly lower peaks compared to the same daily dose of the
immediate release formulation administered in three divided doses. This may be, in part, because ADALAT CC is
less bioavailable than the immediate release formulation.
Nifedipine is extensively metabolized to highly water soluble, inactive metabolites accounting for 60% to 80% of
the dose excreted in the urine. Only traces (less than 0.1% of the dose) of the unchanged form can be detected in the
urine. The remainder is excreted in the feces in metabolized form, most likely as a result of biliary excretion.
No studies have been performed with ADALAT CC in patients with renal failure; however, significant alterations
in the pharmacokinetics of nifedipine immediate release capsules have not been reported in patients undergoing
hemodialysis or chronic ambulatory peritoneal dialysis. Since the absorption of nifedipine from ADALAT CC
could be modified by renal disease, caution should be exercised in treating such patients.
Because hepatic biotransformation is the predominant route for the disposition of nifedipine, its pharmacokinetics
may be altered in patients with chronic liver disease. ADALAT CC has not been studied in patients with hepatic
disease; however, in patients with hepatic impairment (liver cirrhosis) nifedipine has a longer elimination half-life
and higher bioavailability than in healthy volunteers.
The degree of protein binding of nifedipine is high (92%-98%). Protein binding may be greatly reduced in patients
with renal or hepatic impairment.
After administration of ADALAT CC to healthy elderly men and women (age > 60 years), the mean Cmax is 36%
higher and the average plasma concentration is 70% greater than in younger patients.
In healthy subjects, the elimination half-life of a different sustained release nifedipine formulation was longer in
elderly subjects (6.7 h) compared to young subjects (3.8 h) following oral administration. A decreased clearance was
also observed in the elderly (348 mL/min) compared to young subjects (519 mL/min) following intravenous
administration.
Co-administration of nifedipine with grapefruit juice results in up to a 2-fold increase in AUC and Cmax, due to
inhibition of CYP3A4 related first-pass metabolism.
Clinical Studies: ADALAT CC produced dose-related decreases in systolic and diastolic blood pressure as
demonstrated in two double-blind, randomized, placebo-controlled trials in which over 350 patients were treated
with ADALAT CC 30, 60 or 90 mg once daily for 6 weeks. In the first study, ADALAT CC was given as
monotherapy and in the second study, ADALAT CC was added to a beta-blocker in patients not controlled on a
beta-blocker alone. The mean trough (24 hours post-dose) blood pressure results from these studies are shown
below:
MEAN REDUCTIONS IN TROUGH SUPINE BLOOD PRESSURE (mmHg)
SYSTOLIC/DIASTOLIC
STUDY 1
ADALAT CC
N
MEAN TROUGH
DOSE
REDUCTION*
30 MG
60
5.3/2.9
60 MG
57
8.0/4.1
90 MG
55
12.5/8.1
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-198/S-017
Page 4
STUDY 2
ADALAT CC
N
MEAN TROUGH
DOSE
REDUCTION*
30 MG
58
7.6/3.8
60 MG
63
10.1/5.3
90 MG
62
10.2/5.8
*Placebo response subtracted.
The trough/peak ratios estimated from 24 hour blood pressure monitoring ranged from 41%-78% for diastolic and
46%-91% for systolic blood pressure.
Hemodynamics: Like other slow-channel blockers, nifedipine exerts a negative inotropic effect on isolated
myocardial tissue. This is rarely, if ever, seen in intact animals or man, probably because of reflex responses to its
vasodilating effects. In man, nifedipine decreases peripheral vascular resistance which leads to a fall in systolic and
diastolic pressures, usually minimal in normotensive volunteers (less than 5-10 mm Hg systolic), but sometimes
larger. With ADALAT CC, these decreases in blood pressure are not accompanied by any significant change in
heart rate. Hemodynamic studies of the immediate release nifedipine formulation in patients with normal
ventricular function have generally found a small increase in cardiac index without major effects on ejection
fraction, left ventricular end-diastolic pressure (LVEDP) or volume (LVEDV). In patients with impaired
ventricular function, most acute studies have shown some increase in ejection fraction and reduction in left
ventricular filling pressure.
Electrophysiologic Effects: Although, like other members of its class, nifedipine causes a slight depression of
sinoatrial node function and atrioventricular conduction in isolated myocardial preparations, such effects have not
been seen in studies in intact animals or in man. In formal electrophysiologic studies, predominantly in patients
with normal conduction systems, nifedipine administered as the immediate release capsule has had no tendency to
prolong atrioventricular conduction or sinus node recovery time, or to slow sinus rate.
INDICATION AND USAGE
ADALAT CC is indicated for the treatment of hypertension. It may be used alone or in combination with other
antihypertensive agents.
CONTRAINDICATIONS
Known hypersensitivity to nifedipine.
WARNINGS
Excessive Hypotension: Although in most patients the hypotensive effect of nifedipine is modest and well
tolerated, occasional patients have had excessive and poorly tolerated hypotension. These responses have usually
occurred during initial titration or at the time of subsequent upward dosage adjustment, and may be more likely in
patients using concomitant beta-blockers.
Severe hypotension and/or increased fluid volume requirements have been reported in patients who received
immediate release capsules together with a beta-blocking agent and who underwent coronary artery bypass surgery
using high dose fentanyl anesthesia. The interaction with high dose fentanyl appears to be due to the combination
of nifedipine and a beta-blocker, but the possibility that it may occur with nifedipine alone, with low doses of
fentanyl, in other surgical procedures, or with other narcotic analgesics cannot be ruled out. In nifedipine-treated
patients where surgery using high dose fentanyl anesthesia is contemplated, the physician should be aware of these
potential problems and, if the patient’s condition permits, sufficient time (at least 36 hours) should be allowed for
nifedipine to be washed out of the body prior to surgery.
Increased Angina and/or Myocardial Infarction: Rarely, patients, particularly those who have severe
obstructive coronary artery disease, have developed well-documented increased frequency, duration and/or
severity of angina or acute myocardial infarction upon starting nifedipine or at the time of dosage increase. The
mechanism of this effect is not established.
Beta-Blocker Withdrawal: When discontinuing a beta-blocker it is important to taper its dose, if possible, rather
than stopping abruptly before beginning nifedipine. Patients recently withdrawn from beta blockers may develop a
withdrawal syndrome with increased angina, probably related to increased sensitivity to catecholamines. Initiation
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-198/S-017
Page 5
of nifedipine treatment will not prevent this occurrence and on occasion has been reported to increase it.
Congestive Heart Failure: Rarely, patients (usually while receiving a beta-blocker) have developed heart failure
after beginning nifedipine. Patients with tight aortic stenosis may be at greater risk for such an event, as the
unloading effect of nifedipine would be expected to be of less benefit to these patients, owing to their fixed
impedance to flow across the aortic valve.
PRECAUTIONS
General - Hypotension: Because nifedipine decreases peripheral vascular resistance, careful monitoring of blood
pressure during the initial administration and titration of ADALAT CC is suggested. Close observation is especially
recommended for patients already taking medications that are known to lower blood pressure (See WARNINGS).
Peripheral Edema: Mild to moderate peripheral edema occurs in a dose-dependent manner with ADALAT CC.
The placebo subtracted rate is approximately 8% at 30 mg, 12% at 60 mg and 19% at 90 mg daily. This edema is a
localized phenomenon, thought to be associated with vasodilation of dependent arterioles and small blood
vessels and not due to left ventricular dysfunction or generalized fluid retention. With patients whose
hypertension is complicated by congestive heart failure, care should be taken to differentiate this peripheral
edema from the effects of increasing left ventricular dysfunction.
Information for Patients: ADALAT CC is an extended release tablet and should be swallowed whole and taken
on an empty stomach. It should not be administered with food. Do not chew, divide or crush tablets.
Laboratory Tests: Rare, usually transient, but occasionally significant elevations of enzymes such as alkaline
phosphatase, CPK, LDH, SGOT, and SGPT have been noted. The relationship to nifedipine therapy is uncertain in
most cases, but probable in some. These laboratory abnormalities have rarely been associated with clinical
symptoms; however, cholestasis with or without jaundice has been reported. A small increase (<5%) in mean
alkaline phosphatase was noted in patients treated with ADALAT CC. This was an isolated finding and it rarely
resulted in values which fell outside the normal range. Rare instances of allergic hepatitis have been reported with
nifedipine treatment. In controlled studies, ADALAT CC did not adversely affect serum uric acid, glucose,
cholesterol or potassium.
Nifedipine, like other calcium channel blockers, decreases platelet aggregation in vitro. Limited clinical studies
have demonstrated a moderate but statistically significant decrease in platelet aggregation and increase in bleeding
time in some nifedipine patients. This is thought to be a function of inhibition of calcium transport across the
platelet membrane. No clinical significance for these findings has been demonstrated.
Positive direct Coombs’ test with or without hemolytic anemia has been reported but a causal relationship between
nifedipine administration and positivity of this laboratory test, including hemolysis, could not be determined.
Although nifedipine has been used safely in patients with renal dysfunction and has been reported to exert a
beneficial effect in certain cases, rare reversible elevations in BUN and serum creatinine have been reported in
patients with pre-existing chronic renal insufficiency. The relationship to nifedipine therapy is uncertain in most
cases but probable in some.
Drug Interactions:
Beta-adrenergic blocking agents (See WARNINGS.)
Nifedipine is mainly eliminated by metabolism and is a substrate of CYP3A. Inhibitors and inducers of
CYP3A4 can impact the exposure to nifedipine and consequently its desirable and undesirable effects. In vitro
and in vivo data indicate that nifedipine can inhibit the metabolism of drugs that are substrates of CYP3A,
thereby increasing the exposure to other drugs. Nifedipine is a vasodilator, and co-administration of other drugs
affecting blood pressure may result in pharmacodynamic interactions.
CardiovascularDrugs
Antiarrhythmics
Quinidine: Quinidine is a substrate of CYP3A and has been shown to inhibit CYP3A in vitro. Co-administration
of multiple doses of quinidine sulfate, 200 mg t.i.d., and nifedipine, 20 mg t.i.d., increased Cmax and AUC of
nifedipine in healthy volunteers by factors of 2.30 and 1.37, respectively. The heart rate in the initial interval after
drug administration was increased by up to 17.9 beats/minute. The exposure to quinidine was not importantly
changed in the presence of nifedipine. Monitoring of heart rate and adjustment of the nifedipine dose, if
necessary, are recommended when quinidine is added to a treatment with nifedipine.
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NDA 20-198/S-017
Page 6
Flecainide: There has been too little experience with the co-administration of TAMBOCOR with nifedipine
to recommend concomitant use.
Calcium Channel Blockers
Diltiazem: Pre-treatment of healthy volunteers with 30 mg or 90 mg t.i.d. diltiazem p.o. increased the AUC
of nifedipine after a single dose of 20 mg nifedipine by factors of 2.2 and 3.1, respectively. The
corresponding Cmax values of nifedipine increased by factors of 2.0 and 1.7, respectively. Caution should be
exercised when co-administering diltiazem and nifedipine and a reduction of the dose of nifedipine should
be considered.
Verapamil: Verapamil, a CYP3A inhibitor, can inhibit the metabolism of nifedipine and increase the
exposure to nifedipine during concomitant therapy. Blood pressure should be monitored and reduction of the
dose of nifedipine considered.
ACE Inhibitors
Benazepril: In healthy volunteers receiving single dose of 20 mg nifedipine ER and benazepril 20 mg, the
plasma concentrations of benazeprilat and nifedipine in the presence and absence of each other were not
statistically significantly different. A hypotensive effect was only seen after co-administration of the two
drugs. The tachycardic effect of nifedipine was attenuated in the presence of benazepril.
Angiotensin-II Blockers
Irbesartan: In vitro studies show significant inhibition of the formation of oxidized irbesartan metabolites
by nifedipine. However, in clinical studies, concomitant nifedipine had no effect on irbesartan
pharmacokinetics.
Candesartan: No significant drug interaction has been reported in studies with candesartan cilexitil given
together with nifedipine. Because candesartan is not significantly metabolized by the cytochrome P450
system and at therapeutic concentrations has no effect on cytochrome P450 enzymes, interactions with drugs
that inhibit or are metabolized by those enzymes would not be expected.
Beta-blockers
ADALAT CC was well tolerated when administered in combination with beta-blockers in 187 hypertensive
patients in a placebo-controlled clinical trial. However, there have been occasional literature reports
suggesting that the combination of nifedipine and beta-adrenergic blocking drugs may increase the
likelihood of congestive heart failure, severe hypotension or exacerbation of angina in patients with
cardiovascular disease. Clinical monitoring is recommended and a dose adjustment of nifedipine should be
considered.
Timolol: Hypotension is more likely to occur if dihydropryridine calcium antagonists such as nifedipine are
co-administered with timolol.
Central Alpha1-Blockers
Doxazosin: Healthy volunteers participating in a multiple dose doxazosin-nifedipine interaction study
received 2 mg doxazosin q.d. alone or combined with 20 mg nifedipine ER b.i.d. Co-administration of
nifedipine resulted in a decrease in AUC and Cmax of doxazosin to 83% and 86% of the values in the absence
of nifedipine, respectively. In the presence of doxazosin, AUC and Cmax of nifedipine were increased by
factors of 1.13 and 1.23, respectively. Compared to nifedipine monotherapy, blood pressure was lower in
the presence of doxazosin. Blood pressure should be monitored when doxazosin is co-administered with
nifedipine, and dose reduction of nifedipine considered.
Digitalis
Digoxin: Since there have been isolated reports of patients with elevated digoxin levels, and there is a
possible interaction between digoxin and ADALAT CC, it is recommended that digoxin levels be monitored
when initiating, adjusting and discontinuing ADALAT CC to avoid possible over- or under- digitalization.
Antithrombotics
Coumarins: There have been rare reports of increased prothrombin time in patients taking coumarin
anticoagulants to whom nifedipine was administered. However the relationship to nifedipine therapy is
uncertain.
Platelet Aggregation Inhibitors
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NDA 20-198/S-017
Page 7
Clopidogrel: No clinically significant pharmacodynamic interactions were observed when clopidrogrel was
co-administered with nifedipine.
Tirofiban: Co-administration of nifedipine did not alter the exposure to tirofiban importantly.
Non-Cardiovascular Drugs
Antifungal Drugs
Ketoconazole, itraconazole and fluconazole are CYP3A inhibitors and can inhibit the metabolism of
nifedipine and increase the exposure to nifedipine during concomitant therapy. Blood pressure should be
monitored and a dose reduction of nifedipine considered.
Antisecretory Drugs
Omeprazole: In healthy volunteers receiving a single dose of 10 mg nifedipine, AUC and Cmax of nifedipine
after pretreatment with omeprazole 20 mg q.d. for 8 days were 1.26 and 0.87 times those after pre-treatment
with placebo. Pretreatment with or co-administration of omeprazole did not impact the effect of nifedipine
on blood pressure or heart rate. The impact of omeprazole on nifedipine is not likely to be of clinical
relevance.
Pantoprazole: In healthy volunteers the exposure to neither drug was changed significantly in the presence
of the other drug.
Ranitidine: Five studies in healthy volunteers investigated the impact of multiple ranitidine doses on the
single or multiple dose pharmacokinetics of nifedipine. Two studies investigated the impact of co-
administered ranitidine on blood pressure in hypertensive subjects on nifedipine. Co-administration of
ranitidine did not have relevant effects on the exposure to nifedipine that affected the blood pressure or heart
rate in normotensive or hypertensive subjects.
Cimetidine: Five studies in healthy volunteers investigated the impact of multiple cimetidine doses on the
single or multiple dose pharmacokinetics of nifedipine. Two studies investigated the impact of co-
administered cimetidine on blood pressure in hypertensive subjects on nifedipine. In normotensive subjects
receiving single doses of 10 mg or multiple doses of up to 20 mg nifedipine t.i.d. alone or together with
cimetidine up to 1000 mg/day, the AUC values of nifedipine in the presence of cimetidine were between
1.52 and 2.01 times those in the absence of cimetidine. The Cmax values of nifedipine in the presence of
cimetidine were increased by factors ranging between 1.60 and 2.02. The increase in exposure to nifedipine
by cimetidine was accompanied by relevant changes in blood pressure or heart rate in normotensive
subjects. Hypertensive subjects receiving 10 mg q.d. nifedipine alone or in combination with cimetidine
1000 mg q.d. also experienced relevant changes in blood pressure when cimetidine was added to nifedipine.
The interaction between cimetidine and nifedipine is of clinical relevance and blood pressure should be
monitored and a reduction of the dose of nifedipine considered.
Antibacterial Drugs
Quinupristin/Dalfopristin: In vitro drug interaction studies have demonstrated that quinupristin/dalfopristin
significantly
inhibits
the
CYP3A
metabolism
of
nifedipine.
Concomitant
administration
of
quinupristin/dalfopristin and nifedipine (repeated oral dose) in healthy volunteers increased AUC and Cmax
for nifedipine by factors of 1.44 and 1.18, respectively, compared to nifedipine monotherapy. Upon co-
administration of quinupristin/dalfopristin with nifedipine, blood pressure should be monitored and a
reduction of the dose of nifedipine considered.
Erythromycin: Erythromycin, a CYP3A inhibitor, can inhibit the metabolism of nifedipine and increase the
exposure to nifedipine during concomitant therapy. Blood pressure should be monitored and reduction of the
dose of nifedipine considered.
Antitubercular Drugs
Rifampin: Pretreatment of healthy volunteers with 600 mg/day rifampin p.o. decreased the exposure to oral
nifedipine (20 µg/kg) to 13%. The exposure to intravenous nifedipine by the same rifampin treatment was
decreased to 70%. Dose adjustment of nifedipine may be necessary if nifedipine is co-administered with
rifampin.
Rifapentine: Rifapentine, as an inducer of CYP3A4, can decrease the exposure to nifedipine. A dose
adjustment of nifedipine when co-administered with rifapentine should be considered.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-198/S-017
Page 8
Antiviral Drugs
Amprenavir, atanazavir, delavirine, fosamprinavir, indinavir, nelfinavir and ritonavir, as CYP3A inhibitors,
can inhibit the metabolism of nifedipine and increase the exposure to nifedipine. Caution is warranted and
clinical monitoring of patients recommended.
CNS Drugs
Nefazodone, a CYP3A inhibitor, can inhibit the metabolism of nifedipine and increase the exposure to
nifedipine during concomitant therapy. Blood pressure should be monitored and a reduction of the dose of
nifedipine considered.
Valproic acid may increase the exposure to nifedipine during concomitant therapy. Blood pressure should
be monitored and a dose reduction of nifedipine considered.
Phenytoin: Nifedipine is metabolized by CYP3A4. Co-administration of nifedipine 10 mg capsule and 60
mg nifedipine coat-core tablet with phenytoin, an inducer of CYP3A4, lowered the AUC and Cmax of
nifedipine by approximately 70%. When using nifedipine with phenytoin, the clinical response to nifedipine
should be monitored and its dose adjusted if necessary.
Phenobarbitone and carbamazepine as inducers of CYP3A can decrease the exposure to nifedipine. Dose
adjustment of nifedipine may be necessary if phenobarbitone, carbamazepine or phenytoin is co-
administered.
Antiemetic Drugs
Dolasetron: In patients taking dolasetron by the oral or intravenous route and nifedipine, no effect was
shown on the clearance of hydrodolasetron.
Immunosuppressive Drugs
Tacrolimus: Nifedipine has been shown to inhibit the metabolism of tacrolimus in vitro. Transplant patients
on tacrolimus and nifedipine required from 26% to 38% smaller doses than patients not receiving nifedipine.
Nifedipine can increase the exposure to tacrolimus. When nifedipine is co-administered with tacrolimus the
blood concentrations of tacrolimus should be monitored and a reduction of the dose of tacrolimus
considered.
Sirolimus: A single 60 mg dose of nifedipine and a single 10 mg dose of sirolimus oral solution were
administered to 24 healthy volunteers. Clinically significant pharmacokinetic drug interactions were not
observed.
Glucose Lowering Drugs
Pioglitazone: Co-administration of pioglitazone for 7 days with 30 mg nifedipine ER administered orally
q.d. for 4 days to male and female volunteers resulted in least square mean (90% CI) values for unchanged
nifedipine of 0.83 (0.73-0.95) for Cmax and 0.88 (0.80-0.96) for AUC relative to nifedipine monotherapy. In
view of the high variability of nifedipine pharmacokinetics, the clinical significance of this finding is
unknown.
Rosiglitazone: Co-administration of rosiglitazone (4 mg b.i.d.) was shown to have no clinically relevant
effect on the pharmacokinetics of nifedipine.
Metformin: A single dose metformin-nifedipine interaction study in normal healthy volunteers demonstrated
that co-administration of nifedipine increased plasma metformin Cmax and AUC by 20% and 9%,
respectively, and increased the amount of metformin excreted in urine. Tmax and half-life were unaffected.
Nifedipine appears to enhance the absorption of metformin.
Miglitol: No effect of miglitol was observed on the pharmacokinetics and pharmacodynamics of nifedipine.
Repaglinide: Co-administration of 10 mg nifedipine with a single dose of 2 mg repaglinide (after 4 days
nifedipine 10 mg t.i.d. and repaglinide 2 mg t.i.d.) resulted in unchanged AUC and Cmax values for both
drugs.
Acarbose: Nifedipine tends to produce hyperglycemia and may lead to loss of glucose control. If nifedipine
is co-administered with acarbose, blood glucose levels should be monitored carefully and a dose adjustment
of nifedipine considered.
Drugs Interfering with Food Absorption
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-198/S-017
Page 9
Orlistat: In 17 normal-weight subjects receiving orlistat 120 mg t.i.d. for 6 days, orlistat did not alter the
bioavailability of 60 mg nifedipine (extended release tablets).
Dietary Supplements
Grapefruit Juice: In healthy volunteers, a single dose co-administration of 250 mL double strength
grapefruit juice with 10 mg nifedipine increased AUC and Cmax by factors of 1.35 and 1.13, respectively.
Ingestion of repeated doses of grapefruit juice (5 x 200 mL in 12 hours) after administration of 20 mg
nifedipine ER increased AUC and Cmax of nifedipine by a factor of 2.0. Grapefruit juice should be avoided
by patients on nifedipine. The intake of grapefruit juice should be stopped at least 3 days prior to initiating
patients on nifedipine.
Herbals
St. John’s Wort: Is an inducer of CYP3A4 and may decrease the exposure to nifedipine. Dose adjustment of
nifedipine may be necessary if St. John’s Wort is co-administered.
CYP2D6 Probe Drug
Debrisoquine: In healthy volunteers, pretreatment with nifedipine 20 mg t.i.d. for 5 days did not change the
metabolic ratio of hydroxydebrisoquine to debrisoquine measured in urine after a single dose of 10 mg
debrisoquine. Thus, it is improbable that nifedipine inhibits in vivo the metabolism of other drugs that are
substrates of CYP2D6.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Nifedipine was administered orally to rats for two years
and was not shown to be carcinogenic. When given to rats prior to mating, nifedipine caused reduced fertility at a
dose approximately 30 times the maximum recommended human dose. There is a literature report of reversible
reduction in the ability of human sperm obtained from a limited number of infertile men taking recommended
doses of nifedipine to bind to and fertilize an ovum in vitro. In vivo mutagenicity studies were negative.
Pregnancy: Pregnancy Category C. In rodents, rabbits and monkeys, nifedipine has been shown to have a variety
of embryotoxic, placentotoxic and fetotoxic effects, including stunted fetuses (rats, mice and rabbits), digital
anomalies (rats and rabbits), rib deformities (mice), cleft palate (mice), small placentas and underdeveloped
chorionic villi (monkeys), embryonic and fetal deaths (rats, mice and rabbits), prolonged pregnancy (rats; not
evaluated in other species), and decreased neonatal survival (rats; not evaluated in other species). On a mg/kg or
mg/m2 basis, some of the doses associated with these various effects are higher than the maximum recommended
human dose and some are lower, but all are within an order of magnitude of it.
The digital anomalies seen in nifedipine-exposed rabbit pups are strikingly similar to those seen in pups exposed to
phenytoin, and these are in turn similar to the phalangeal deformities that are the most common malformation seen
in human children with in utero exposure to phenytoin.
There are no adequate and well-controlled studies in pregnant women. ADALAT CC should generally be avoided
during pregnancy and used only if the potential benefit justifies the potential risk to the fetus.
Nursing Mothers: Nifedipine is excreted in human milk. Therefore, a decision should be made to discontinue
nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Geriatric Use: Although small pharmacokinetic studies have identified an increased half-life and increased Cmax
and AUC (See CLINICAL PHARMACOLOGY: Pharmacokinetics and Metabolism), clinical studies of
nifedipine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond
differently from younger subjects. Other reported clinical experience has not identified differences in responses
between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious,
usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or
cardiac function, and of concomitant disease or other drug therapy.
ADVERSE EXPERIENCES
The incidence of adverse events during treatment with ADALAT CC in doses up to 90 mg daily were derived from
multi-center placebo-controlled clinical trials in 370 hypertensive patients. Atenolol 50 mg once daily was used
concomitantly in 187 of the 370 patients on ADALAT CC and in 64 of the 126 patients on placebo. All adverse
events reported during ADALAT CC therapy were tabulated independently of their causal relationship to
medication.
The most common adverse event reported with ADALAT CC was peripheral edema. This was dose related and the
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-198/S-017
Page 10
frequency was 18% on ADALAT CC 30 mg daily, 22% on ADALAT CC 60 mg daily and 29% on ADALAT CC 90
mg daily versus 10% on placebo.
Other common adverse events reported in the above placebo-controlled trials include:
ADALAT CC (%)
(n=370)
PLACEBO (%)
(n=126)
Adverse Event
Headache
19
13
Flushing/heat sensation
4
0
Dizziness
4
2
Fatigue/asthenia
4
4
Nausea
2
1
Constipation
1
0
Where the frequency of adverse events with ADALAT CC and placebo is similar, causal relationship cannot be
established.
The following adverse events were reported with an incidence of 3% or less in daily doses up to 90 mg:
Body as a Whole/Systemic: chest pain, leg pain
Central Nervous System: paresthesia, vertigo
Dermatologic: rash
Gastrointestinal: constipation
Musculoskeletal: leg cramps
Respiratory: epistaxis, rhinitis
Urogenital: impotence, urinary frequency
Other adverse events reported with an incidence of less than 1.0% were:
Body as a Whole/Systemic: allergic reaction, asthenia, cellulitis, substernal chest pain, chills, facial edema, lab
test abnormal, malaise, neck pain, pelvic pain, pain, photosensitivity reaction
Cardiovascular: atrial fibrillation, bradycardia, cardiac arrest, extrasystole, hypotension, migraine, palpitations,
phlebitis, postural hypotension, tachycardia, cutaneous angiectases
Central Nervous System: anxiety, confusion, decreased libido, depression, hypertonia, hypesthesia, insomnia,
somnolence
Dermatologic: angioedema, petechial rash, pruritus, sweating
Gastrointestinal: abdominal pain, diarrhea, dry mouth, dysphagia, dyspepsia, eructation, esophagitis, flatulence,
gastrointestinal disorder, gastrointestinal hemorrhage, GGT increased, gum disorder, gum hemorrhage, vomiting
Hematologic: eosinophilia, lymphadenopathy
Metabolic: gout, weight loss
Musculoskeletal: arthralgia, arthritis, joint disorder, myalgia, myasthenia
Respiratory: dyspnea, increased cough, rales, pharyngitis, stridor
Special Senses: abnormal vision, amblyopia, conjunctivitis, diplopia, eye disorder, eye hemorrhage, tinnitus
Urogenital/Reproductive: dysuria, kidney calculus, nocturia, breast engorgement, polyuria, urogenital disorder
The following adverse events have been reported rarely in patients given nifedipine in coat core or other
formulations: allergenic hepatitis, alopecia, anaphylactic reaction, anemia, arthritis with ANA (+), depression,
erythromelalgia, exfoliative dermatitis, fever, gingival hyperplasia, gynecomastia, hyperglycemia, jaundice,
leukopenia, mood changes, muscle cramps, nervousness, paranoid syndrome, purpura, shakiness, sleep disturbances,
Stevens-Johnson syndrome, syncope, taste perversion, thrombocytopenia, toxic epidermal necrolysis, transient
blindness at the peak of plasma level, tremor and urticaria.
OVERDOSAGE
Experience with nifedipine overdosage is limited. Symptoms associated with severe nifedipine overdosage
include loss of consciousness, drop in blood pressure, heart rhythm disturbances, metabolic acidosis, hypoxia,
cardiogenic shock with pulmonary edema. Generally, overdosage with nifedipine leading to pronounced
hypotension calls for active cardiovascular support including monitoring of cardiovascular and respiratory
function, elevation of extremities, judicious use of calcium infusion, pressor agents and fluids. Clearance of
nifedipine would be expected to be prolonged in patients with impaired liver function. Since nifedipine is highly
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-198/S-017
Page 11
protein bound, dialysis is not likely to be of any benefit; however, plasmapheresis may be beneficial.
There has been one reported case of massive overdosage with tablets of another extended release formulation of
nifedipine. The main effects of ingestion of approximately 4800 mg of nifedipine in a young man attempting
suicide as a result of cocaine-induced depression was initial dizziness, palpitations, flushing, and nervousness.
Within several hours of ingestion, nausea, vomiting, and generalized edema developed. No significant
hypotension was apparent at presentation, 18 hours post ingestion. Blood chemistry abnormalities consisted of a
mild, transient elevation of serum creatinine, and modest elevations of LDH and CPK, but normal SGOT. Vital
signs remained stable, no electrocardiographic abnormalities were noted and renal function returned to normal
within 24 to 48 hours with routine supportive measures alone. No prolonged sequelae were observed.
The effect of a single 900 mg ingestion of nifedipine capsules in a depressed anginal patient on tricyclic
antidepressants was loss of consciousness within 30 minutes of ingestion, and profound hypotension, which
responded to calcium infusion, pressor agents, and fluid replacement. A variety of ECG abnormalities were seen in
this patient with a history of bundle branch block, including sinus bradycardia and varying degrees of AV block.
These dictated the prophylactic placement of a temporary ventricular pacemaker, but otherwise resolved
spontaneously. Significant hyperglycemia was seen initially in this patient, but plasma glucose levels rapidly
normalized without further treatment.
A young hypertensive patient with advanced renal failure ingested 280 mg of nifedipine capsules at one time, with
resulting marked hypotension responding to calcium infusion and fluids. No AV conduction abnormalities,
arrhythmias, or pronounced changes in heart rate were noted, nor was there any further deterioration in renal
function.
DOSAGE AND ADMINISTRATION
Dosage should be adjusted according to each patient’s needs. It is recommended that ADALAT CC be
administered orally once daily on an empty stomach. ADALAT CC is an extended release dosage form and tablets
should be swallowed whole, not bitten or divided. In general, titration should proceed over a 7-14 day period
starting with 30 mg once daily. Upward titration should be based on therapeutic efficacy and safety. The usual
maintenance dose is 30 mg to 60 mg once daily. Titration to doses above 90 mg daily is not recommended.
If discontinuation of ADALAT CC is necessary, sound clinical practice suggests that the dosage should be
decreased gradually with close physician supervision.
Co-administration of nifedipine with grapefruit juice is to be avoided (See CLINICAL PHARMACOLOGY and
PRECAUTIONS).
Care should be taken when dispensing ADALAT CC to assure that the extended release dosage form has been
prescribed.
HOW SUPPLIED
ADALAT
Color
Markings
30 mg
Pink
30 on one side and
ADALAT CC on the other side
60 mg
Salmon
60 on one side and
ADALAT CC on the other side
90 mg
Dark Red
90 on one side and
ADALAT CC on the other side
ADALAT® CC Tablets are supplied in:
Strength
NDC Code
Bottles of 100
30 mg
0085-1701-02
60 mg
0085-1716-02
90 mg
0085-1722-01
Unit Dose Packages of 100
30 mg
0085-1701-03
60 mg
0085-1716-03
90 mg
0085-1722-02
Bottles of 1000
30 mg
0085-1701-01
60 mg
0085-1716-01
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-198/S-017
Page 12
The tablets should be protected from light and moisture and stored below 86°F (30°C). Dispense in tight, light-
resistant containers.
Manufactured by:
Bayer Pharmaceuticals Corporation
400 Morgan Lane
West Haven, CT 06516
Made in Germany
Distributed by:
Schering Corporation
Kenilworth, NJ 07033
ADALAT is a registered trademark of Bayer Aktiengesellschaft and is used under license by Schering Corporation.
Rx Only
08918360, R.0
10/04
12559
©2004 Bayer Pharmaceuticals Corporation
Printed in U.S.A.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:47:01.341737
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/20198s017lbl.pdf', 'application_number': 20198, 'submission_type': 'SUPPL ', 'submission_number': 17}
|
12,314
|
HIVID® (zalcitabine) Tablets - PACKAGE INSERT
1
HIVID®
(zalcitabine)
TABLETS
WARNING:
THE USE OF HIVID HAS BEEN ASSOCIATED WITH SIGNIFICANT CLINICAL
ADVERSE REACTIONS, SOME OF WHICH ARE POTENTIALLY FATAL. HIVID CAN
CAUSE SEVERE PERIPHERAL NEUROPATHY AND BECAUSE OF THIS SHOULD BE
USED WITH EXTREME CAUTION IN PATIENTS WITH PREEXISTING
NEUROPATHY. HIVID MAY ALSO RARELY CAUSE PANCREATITIS AND
PATIENTS WHO DEVELOP ANY SYMPTOMS SUGGESTIVE OF PANCREATITIS
WHILE USING HIVID SHOULD HAVE THERAPY SUSPENDED IMMEDIATELY
UNTIL THIS DIAGNOSIS IS EXCLUDED.
LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS,
INCLUDING FATAL CASES, HAVE BEEN REPORTED WITH THE USE OF
ANTIRETROVIRAL NUCLEOSIDE ANALOGUES ALONE OR IN COMBINATION,
INCLUDING HIVID (SEE WARNINGS).
IN ADDITION, RARE CASES OF HEPATIC FAILURE AND DEATH CONSIDERED
POSSIBLY RELATED TO UNDERLYING HEPATITIS B AND HIVID HAVE BEEN
REPORTED (SEE WARNINGS AND PRECAUTIONS).
DESCRIPTION
HIVID is the Hoffmann-La Roche brand of zalcitabine [formerly called 2',3'-dideoxycytidine
(ddC)], a synthetic pyrimidine nucleoside analogue active against the human immunodeficiency
virus (HIV). HIVID is available as film-coated tablets for oral administration in strengths of 0.375
mg and 0.750 mg. Each tablet also contains the inactive ingredients lactose, microcrystalline
cellulose, croscarmellose sodium, magnesium stearate, hydroxypropyl methylcellulose, polyethylene
glycol, and polysorbate 80 along with the following colorant system: 0.375 mg tablet — synthetic
brown, black, red and yellow iron oxides, and titanium dioxide; 0.750 mg tablet — synthetic black
iron oxide and titanium dioxide. The chemical name for zalcitabine is 4-amino-1-beta-D-2', 3'-
dideoxyribofuranosyl-2-(1H)-pyrimidone or 2',3'-dideoxycytidine with the molecular formula
C9H13N3O3 and a molecular weight of 211.22. Zalcitabine has the following structural formula:
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
HIVID® (zalcitabine) Tablets - PACKAGE INSERT
2
Zalcitabine is a white to off-white crystalline powder with an aqueous solubility of 76.4 mg/mL at
25°C.
MICROBIOLOGY
Mechanism of Action: Zalcitabine is a synthetic nucleoside analogue of the naturally occurring
nucleoside deoxycytidine, in which the 3'-hydroxyl group is replaced by hydrogen. Within cells,
zalcitabine is converted to the active metabolite, dideoxycytidine 5'-triphosphate (ddCTP), by the
sequential action of cellular enzymes. Dideoxycytidine 5'-triphosphate inhibits the activity of the
HIV-reverse transcriptase both by competing for utilization of the natural substrate, deoxycytidine
5'-triphosphate (dCTP), and by its incorporation into viral DNA. The lack of a 3'-OH group in the
incorporated nucleoside analogue prevents the formation of the 5' to 3' phosphodiester linkage
essential for DNA chain elongation and, therefore, the viral DNA growth is terminated. The active
metabolite, ddCTP, is also an inhibitor of cellular DNA polymerase-beta and mitochondrial DNA
polymerase-gamma and has been reported to be incorporated into the DNA of cells in culture.
In Vitro HIV Susceptibility: The in vitro anti-HIV activity of zalcitabine was assessed by infecting
cell lines of lymphoblastic and monocytic origin and peripheral blood lymphocytes with laboratory
and clinical isolates of HIV. The IC50 and IC95 values (50% and 95% inhibitory concentration) were
in the range of 30 to 500 nM and 100 to 1000 nM, respectively (1 nM = 0.21 ng/mL). Zalcitabine
showed antiviral activity in all acute infections; however, activity was substantially less in
chronically infected cells. In drug combination studies with zidovudine (ZDV) or saquinavir,
zalcitabine showed additive to synergistic activity in cell culture. The relationship between the in
vitro susceptibility of HIV to reverse-transcriptase inhibitors and the inhibition of HIV replication in
humans has not been established.
Drug Resistance: HIV isolates with a reduction in sensitivity to zalcitabine (ddC) have been
isolated from a small number of patients treated with HIVID by 1 year of therapy. Genetic analysis
of these isolates showed point mutations (Lys 65 Arg or Asn, Thr 69 Asp, Leu 74 Val, Val 75 Thr or
Ala, Met 184 Val or Tyr 215 Cys) in the pol gene that encodes for the reverse transcriptase.
Combination therapy with HIVID and ZDV does not appear to prevent the emergence of
zidovudine-resistant isolates.
Cross-resistance: The potential for cross-resistance between HIV-reverse transcriptase inhibitors
and HIV-protease inhibitors is low because of the different enzyme targets involved. The point
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For current labeling information, please visit https://www.fda.gov/drugsatfda
HIVID® (zalcitabine) Tablets - PACKAGE INSERT
3
mutation at position 69 appears to be specific to ddC in its selection and effect. Additionally, the
point mutations at positions 65, 74, 75, and 184 are associated with resistance to didanosine (ddI),
that at position 75 with resistance to stavudine (d4T), and those at positions 65 (Lys to Arg), and
184 (Met to Val) with resistance to lamivudine (3TC). HIV isolates with multidrug resistance to
ZDV, ddI, ddC, d4T, and 3TC were recovered from a small number of patients treated for 1 year
with the combination of ZDV, ddI or ddC. The pattern of resistance mutations in the combination
therapy was different (Ala 62 Val, Val 75 Ile, Phe 77 Leu, Phe 116 Tyr and Gln 151 Met) from
monotherapy with mutation 151 being most significant for multidrug resistance.
CLINICAL PHARMACOLOGY
Pharmacokinetics: The pharmacokinetics of zalcitabine has been evaluated in studies in HIV-
infected patients following 0.01 mg/kg, 0.03 mg/kg, and 1.5 mg oral doses, and a 1.5 mg
intravenous dose administered as a 1-hour infusion.
Absorption and Bioavailability in Adults: Following oral administration to HIV-infected patients,
the mean absolute bioavailability of zalcitabine was >80% (30% CV, range 23% to 124%, n=19).
The absorption rate of a 1.5 mg oral dose of zalcitabine (n=20) was reduced when administered with
food. This resulted in a 39% decrease in mean maximum plasma concentrations (Cmax) from 25.2
ng/mL (35% CV, range 11.6 to 37.5 ng/mL) to 15.5 ng/mL (24% CV, range 9.1 to 23.7 ng/mL), and
a twofold increase in time to achieve maximum plasma concentrations from a mean of 0.8 hours
under fasting conditions to 1.6 hours when the drug was given with food. The extent of absorption
(as reflected by AUC) was decreased by 14%, from 72 ng·hr/mL (28% CV, range 43 to 119
ng·hr/mL) to 62 ng·hr/mL (23% CV, range 42 to 91 ng·hr/mL). The clinical relevance of these
decreases is unknown. Absorption of zalcitabine does not appear to be reduced in patients with
diarrhea not caused by an identified pathogen.
Distribution in Adults: The steady-state volume of distribution following intravenous administration
of a 1.5 mg dose of zalcitabine averaged 0.534 (± 0.127) L/kg (24% CV, range 0.304 to 0.734 L/kg,
n=20). Cerebrospinal fluid obtained from 9 patients at 2 to 3.5 hours following 0.06 mg/kg or 0.09
mg/kg intravenous infusion showed measurable concentrations of zalcitabine. The CSF:plasma
concentration ratio ranged from 9% to 37% (mean 20%), demonstrating penetration of the drug
through the blood-brain barrier. The clinical relevance of these ratios has not been evaluated.
Metabolism and Elimination in Adults: Zalcitabine is phosphorylated intracellularly to zalcitabine
triphosphate, the active substrate for HIV-reverse transcriptase. Concentrations of zalcitabine
triphosphate are too low for quantitation following administration of therapeutic doses to humans.
Zalcitabine does not undergo a significant degree of metabolism by the liver. The primary
metabolite of zalcitabine that has been identified is dideoxyuridine (ddU), which accounts for less
than 15% of an oral dose in both urine and feces (n=4). Approximately 10% of an orally
administered radiolabeled dose of zalcitabine appears in the feces (n=10), comprised primarily of
unchanged drug and ddU. Renal excretion of unchanged drug appears to be the primary route of
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For current labeling information, please visit https://www.fda.gov/drugsatfda
HIVID® (zalcitabine) Tablets - PACKAGE INSERT
4
elimination, accounting for approximately 80% of an intravenous dose and 60% of an orally
administered dose within 24 hours after dosing (n=19). The mean elimination half-life is 2 hours
and generally ranges from 1 to 3 hours in individual patients. Total clearance following an
intravenous dose averaged 285 mL/min (29% CV, range 165 to 447 mL/min, n=20). Renal
clearance averaged approximately 235 mL/min or about 80% of total clearance (30% CV, range 129
to 348 mL/min, n=20). Renal clearance exceeds glomerular filtration rate suggesting renal tubular
secretion contributes to the elimination of zalcitabine by the kidneys.
In patients with impaired kidney function, prolonged elimination of zalcitabine may be expected.
Preliminary results from 7 patients with renal impairment (estimated creatinine clearance <55
mL/min) indicate that the half-life was prolonged (up to 8.5 hours) in these patients compared to
those with normal renal function. Maximum plasma concentrations were higher in some patients
after a single dose (see PRECAUTIONS).
In patients with normal renal function, the pharmacokinetics of zalcitabine was not altered during 3
times daily multiple dosing (n=9). Accumulation of drug in plasma during this regimen was
negligible. The drug was <4% bound to plasma proteins, indicating that drug interactions involving
binding-site displacement are unlikely (see Drug Interactions).
Drug Interactions: Zidovudine: There was no significant pharmacokinetic interaction between
zidovudine and zalcitabine when single doses of zalcitabine (1.5 mg) and zidovudine (200 mg) were
coadministered to 12 HIV-positive patients.
Probenecid: Following administration of a single oral 1.5 mg dose of zalcitabine alone during
probenecid treatment (500 mg at 8 and 2 hours before and 4 hours after zalcitabine dosing) to 12
HIV-positive patients, mean renal clearance decreased from 310 mL/min (28% CV) to 180 mL/min
(22% CV) and AUC increased from 59 ng·hr/mL (27% CV) to 91 ng·hr/mL (22% CV), indicating
an increase in exposure of approximately 50% to zalcitabine. Mean half-life of zalcitabine increased
from 1.7 to 2.5 hours (see PRECAUTIONS).
Cimetidine: Administration of a single dose of 1.5 mg zalcitabine with a single dose of 800 mg
cimetidine to 12 HIV-positive patients resulted in a decrease in renal clearance from 224 mL/min
(27% CV) to 171 mL/min (39% CV) and an increase in AUC from 75 ng·hr/mL (29% CV) to 102
ng·hr/mL (35% CV) (see PRECAUTIONS) indicating an increase in exposure of approximately
36% to zalcitabine.
Maalox: Concomitant administration of Maalox® TC (30 mL) with single dose of 1.5 mg zalcitabine
to 12 HIV-positive patients resulted in a decrease in mean Cmax from 25.2 ng/mL (28% CV) to 18.4
ng/mL (34% CV) and AUC from 75 ng·hr/mL (29% CV, n=10) to 58 ng·hr/mL (36% CV, n=10)
indicating a decrease in bioavailability of approximately 25% to zalcitabine (see PRECAUTIONS).
Metoclopramide: Administration of a single dose of 1.5 mg zalcitabine with 20 mg metoclopramide
(10 mg 1 hour before and 10 mg 4 hours after zalcitabine dose) to 12 HIV-positive patients resulted
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
HIVID® (zalcitabine) Tablets - PACKAGE INSERT
5
in a decrease in AUC from 69 ng·hr/mL (16% CV) to 62 ng·hr/mL (21% CV) indicating a decrease
in bioavailability of approximately 10% (see PRECAUTIONS).
Loperamide: Administration of a single dose of 1.5 mg zalcitabine during loperamide treatment
(4 mg 16 hours before zalcitabine, 2 mg at 10 hours and 4 hours before zalcitabine, and 2 mg 2
hours after the zalcitabine dose) to 12 HIV-positive patients with diarrhea resulted in no significant
pharmacokinetic interaction between zalcitabine and loperamide.
Pharmacokinetics in Pediatric Patients: For pharmacokinetic properties in pediatric patients, see
PRECAUTIONS: Pediatric Use. Limited pharmacokinetic data have been reported for 5 HIV-
positive pediatric patients using doses of 0.03 and 0.04 mg/kg HIVID administered orally every 6
hours.1 The mean bioavailability of zalcitabine in these pediatric patients was 54% and mean
apparent systemic clearance was 150 mL/min/m2. Due to the small number of subjects and different
analytical techniques, it is difficult to make comparisons between pediatric and adult data.
INDICATIONS AND USAGE
HIVID is indicated in combination with antiretroviral agents for the treatment of HIV infection.
This indication is based on study results showing a reduction in the rate of disease progression
(AIDS-defining events or death) in patients with limited prior antiretroviral therapy who were
treated with the combination of HIVID and zidovudine (see Description of Clinical Studies). This
indication is also based on a study showing a reduction in both mortality and AIDS-defining clinical
events for patients who received INVIRASE® (saquinavir mesylate) in combination with HIVID
compared to patients who received either HIVID or INVIRASE alone.
Description of Clinical Studies: The use of HIVID in combination with zidovudine is based on the
clinical results from study ACTG 175. ACTG 175 was a randomized, double-blind, controlled trial
that compared zidovudine 200 mg three times daily; didanosine 200 mg twice daily;
zidovudine+didanosine; and zidovudine+HIVID 0.750 mg three times daily. A total of 2467 HIV-
infected adults (mean baseline CD4 count = 352 cells/mm3) with no prior AIDS-defining event
enrolled with the following demographics: male (82%), Caucasian (70%), mean age of 35 years,
asymptomatic HIV infection (81%) and prior antiretroviral use (57%, mean duration = 89.5 weeks).
The overall mean duration of study treatment was 99 weeks. The incidence of AIDS-defining events
or death is shown in Table 1:
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
HIVID® (zalcitabine) Tablets - PACKAGE INSERT
6
Table 1. First AIDS-defining Event or Death and Death Only
by Study Arm and Antiretroviral Experience in ACTG 175
Treatment
Antiretroviral
Experience
Event
zidovudine
zidovudine +
didanosine
zidovudine +
HIVID
didanosine
Overall
n
AIDS/Death
Death Only
619
96 (16%)
54 (9%)
613
65 (11%)
31 (5%)
615
76 (12%)
40 (7%)
620
71 (11%)
29 (5%)
Naive
n
AIDS/Death
Death Only
269
32 (12%)
18 (7%)
263
20 (8%)
11 (4%)
267
16 (6%)
9 (3%)
268
23 (9%)
11 (4%)
Experienced
n
AIDS/Death
Death Only
350
64 (18%)
36 (10%)
350
45 (13%)
20 (6%)
348
60 (17%)
31 (9%)
352
48 (14%)
18 (5%)
Although no antiretroviral agent should be used as monotherapy, a description of CPCRA 002 is
included here as it provides a comparison of the safety and efficacy of HIVID compared to ddI.
CPCRA 002 was a randomized, multicenter, open-label study in which HIVID was compared to ddI
as treatment for patients with advanced HIV infection (median CD4 cell count = 37 cells/mm3) who
were clinically intolerant to ZDV, or who had met criteria for having disease progression while
receiving ZDV.2 Patients in this study had a mean of 17.5 months of prior ZDV use. The median
duration of treatment for both HIVID and ddI was 34 weeks. The results demonstrate that HIVID
was at least as efficacious as ddI in terms of time to an AIDS-defining event or death, while for
survival alone the results favored HIVID. However, most of the patients (66%) in either group had
disease progression over the median 16 months of follow-up. Overall rates of study drug
intolerance, discontinuation and adverse events were similar for the two groups, although the types
of events were different.
A clinical study (N3300/ACTG 114) has demonstrated ZDV to be superior to HIVID as
monotherapy for advanced HIV disease (CD4 cell count ≤200 cells/mm3) in previously untreated
patients.3,4 The final analysis of this study indicated that 134 patients (42%) in the HIVID group
with a median follow-up of 85 weeks and 120 patients (38%) in the ZDV group with a median
follow-up of 96 weeks died with a relative risk for mortality of ZDV to HIVID of 0.54.
CONTRAINDICATIONS
HIVID is contraindicated in patients with clinically significant hypersensitivity to zalcitabine or to
any of the excipients contained in the tablets.
WARNINGS
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SIGNIFICANT CLINICAL ADVERSE REACTIONS, SOME OF WHICH ARE POTENTIALLY
FATAL, HAVE BEEN REPORTED WITH HIVID. PATIENTS WITH DECREASED CD4 CELL
COUNTS APPEAR TO HAVE AN INCREASED INCIDENCE OF ADVERSE EVENTS.
1. Peripheral Neuropathy:
THE MAJOR CLINICAL TOXICITY OF HIVID IS PERIPHERAL NEUROPATHY, WHICH
MAY OCCUR IN UP TO 1/3 OF PATIENTS WITH ADVANCED DISEASE TREATED WITH
HIVID. The incidence in patients with less-advanced disease is lower.
HIVID-related peripheral neuropathy is a sensorimotor neuropathy characterized initially by
numbness and burning dysesthesia involving the distal extremities. These symptoms may be
followed by sharp shooting pains or severe continuous burning pain if the drug is not withdrawn.
The neuropathy may progress to severe pain requiring narcotic analgesics and is potentially
irreversible. In some patients, symptoms of neuropathy may initially progress despite
discontinuation of HIVID. With prompt discontinuation of HIVID, the neuropathy is usually slowly
reversible.
There are no data regarding the use of HIVID in patients with preexisting peripheral neuropathy
since these patients were excluded from clinical trials; therefore, HIVID should be used with
extreme caution in these patients. Individuals with moderate or severe peripheral neuropathy, as
evidenced by symptoms accompanied by objective findings, are advised to avoid HIVID.
HIVID should be used with caution in patients with a risk of developing peripheral neuropathy:
patients with low CD4 cell counts (CD4 <50 cells/mm3), diabetes, weight loss and/or patients
receiving HIVID concomitantly with drugs that have the potential to cause peripheral neuropathy
(see PRECAUTIONS: Drug Interactions). Careful monitoring is strongly recommended for these
individuals.
HIVID should be stopped promptly if signs or symptoms of peripheral neuropathy occur, such as
when moderate discomfort from numbness, tingling, burning or pain of the extremities progresses,
or any related symptoms occur that are accompanied by an objective finding (see DOSAGE AND
ADMINISTRATION).
2. Pancreatitis:
PANCREATITIS, WHICH HAS BEEN FATAL IN SOME CASES, HAS BEEN OBSERVED
WITH THE ADMINISTRATION OF HIVID. Pancreatitis is an uncommon complication of HIVID
occurring in up to 1.1% of patients.
Patients with a history of pancreatitis or known risk factors for the development of pancreatitis
should be followed more closely while on HIVID therapy. Of 528 HIVID-treated patients enrolled
in an expanded-access safety study (N3544), who had a history of prior pancreatitis or increased
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amylase, 28 (5.3%) developed pancreatitis and an additional 23 (4.4%) developed asymptomatic
elevated serum amylase.
Treatment with HIVID should be stopped immediately if clinical signs or symptoms (nausea,
vomiting, abdominal pain) or if abnormalities in laboratory values (hyperamylasemia associated
with dysglycemia, rising triglyceride level, decreasing serum calcium) suggestive of pancreatitis
should occur. If clinical pancreatitis develops during HIVID administration, it is recommended that
HIVID be permanently discontinued. Treatment with HIVID should also be interrupted if treatment
with another drug known to cause pancreatitis (eg, intravenous pentamidine) is required (see Drug
Interactions).
3. Lactic Acidosis/Severe Hepatomegaly With Steatosis and Hepatic Toxicity:
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported
with the use of nucleoside analogues alone or in combination, including HIVID and other
antiretrovirals.5,6 A majority of these cases have been in women. Obesity and prolonged nucleoside
exposure may be risk factors. Particular caution should be exercised when administering HIVID to
any patient with known risk factors for liver disease; however, cases have also been reported in
patients with no known risk factors. Treatment with HIVID should be suspended in any patient who
develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity
(which may include hepatomegaly and steatosis even in the absence of marked transaminase
elevations).
IN ADDITION, RARE CASES OF HEPATIC FAILURE AND DEATH CONSIDERED
POSSIBLY RELATED TO UNDERLYING HEPATITIS B AND HIVID HAVE BEEN
REPORTED. Treatment with HIVID in patients with preexisting liver disease, liver enzyme
abnormalities, a history of ethanol abuse or hepatitis should be approached with caution. Treatment
with HIVID should be suspended in any patient who develops clinical or laboratory findings
suggestive of pronounced hepatotoxicity. In clinical trials, drug interruption was recommended if
liver function tests exceeded >5 times the upper limit of normal.
4. Other Serious Toxicities:
a) Oral Ulcers: Severe oral ulcers occurred in up to 3% of patients receiving HIVID in CPCRA
002 and ACTG 175; less severe oral ulcerations have occurred at higher frequencies in other
clinical trials.
b) Esophageal Ulcers: Infrequent cases of esophageal ulcers have also been attributed to HIVID
therapy. Interruption of HIVID should be considered in patients who develop esophageal ulcers
that do not respond to specific treatment for opportunistic pathogens in order to assess a possible
relationship to HIVID.
c) Cardiomyopathy/Congestive Heart Failure: Cardiomyopathy and congestive heart failure in
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patients with AIDS have been associated with the use of nucleoside analogues. Infrequent cases
have been reported in patients receiving HIVID. Treatment with HIVID in patients with baseline
cardiomyopathy or history of congestive heart failure should be approached with caution.
d) Anaphylactoid Reaction: An anaphylactoid reaction was reported in a patient receiving both
HIVID and zidovudine. In addition, there have been several reports of hypersensitivity reactions
(including anaphylactic reaction or urticaria without other signs of anaphylaxis).
PRECAUTIONS
General:
1. Renal Impairment: Patients with renal impairment (estimated creatinine clearance <55 mL/min)
may be at a greater risk of toxicity from HIVID due to decreased drug clearance. Dosage
adjustment is recommended in these patients (see DOSAGE AND ADMINISTRATION).
2. Lymphoma: High doses of zalcitabine, administered for 3 months to B6C3F1 mice (resulting in
plasma concentrations over 1000 times those seen in patients taking the recommended doses of
HIVID) induced an increased incidence of thymic lymphoma.7 Although the pathogenesis of the
effect is uncertain, a predisposition to chemically induced thymic lymphoma and high rates of
spontaneous lymphoreticular neoplasms have previously been noted in this strain of mice.8
The incidence of lymphomas was reviewed in 13 comparative studies conducted by Roche, the
NIAID and the NCI, as well as 7 Roche expanded-access studies that included HIVID. In one
study, ACTG 155, a statistically significant increased rate of lymphomas was seen in patients
receiving HIVID or combination HIVID and zidovudine compared to zidovudine alone (rates of
0, 1.3, and 2.3 per 100 person years for zidovudine, HIVID, and combination HIVID and
zidovudine, respectively; log rank p-value=0.01, pooling HIVID, and combination HIVID and
zidovudine vs zidovudine, p-value=0.003). Based on review of the literature, the incidence of
lymphomas in HIV-infected patients with advanced disease on zidovudine monotherapy would be
expected to be approximately 1 to 2 per 100 person years of follow-up.
None of the other comparative studies evaluated showed a statistically significant difference in
rates of lymphomas in patients receiving HIVID. In a large, controlled clinical trial (ACTG 175)
HIVID in combination with zidovudine was not associated with an increase in the incidence of
lymphoma over that seen with zidovudine monotherapy (6 of 615 and 9 of 619, respectively).
Lymphoma has been identified as a consequence of HIV infection. This most likely represents a
consequence of prolonged immunosuppression; however, an association between the occurrence
of lymphoma and antiviral therapy cannot be excluded.
Patients receiving HIVID or any other antiretroviral therapy may continue to develop opportunistic
infections and other complications of HIV infections, and therefore should remain under close
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clinical observation by physicians experienced in the treatment of patients with associated HIV
diseases.
The duration of clinical benefit from antiretroviral therapy may be limited. Alterations in
antiretroviral therapy should be considered in cases of disease progression, either clinical or as
demonstrated by viral rebound (increase in HIV RNA after initial decline).
Information for Patients: Patients should be informed that HIVID is not a cure for HIV infection
and that they may continue to acquire illnesses associated with advanced HIV infection, including
opportunistic infections.
Patients should be told that there is currently no data demonstrating that HIVID therapy can reduce
the risk of transmitting HIV to others through sexual contact or blood contamination.
Patients should be advised to take HIVID every day as prescribed. Patients should not alter the dose
or discontinue therapy without consulting with their physician. If a dose is missed, patients should
take the dose as soon as possible and then return to their normal schedule. However, if a dose is
skipped, the patient should not double the next dose.
Patients should be instructed that the major toxicity of HIVID is peripheral neuropathy. Pancreatitis
and hepatic toxicity are other serious potentially life-threatening toxicities that have been reported in
patients treated with HIVID. Patients should be advised of the early symptoms of these conditions
and instructed to promptly report them to their physician. Since the development of peripheral
neuropathy appears to be dose-related to HIVID, patients should be advised to follow their
physicians’ instructions regarding the prescribed dose.
Laboratory Tests: Complete blood counts and clinical chemistry tests should be performed prior to
initiating HIVID therapy and at appropriate intervals thereafter. Baseline testing of serum amylase
and triglyceride levels should be performed in individuals with a prior history of pancreatitis,
increased amylase, those on parenteral nutrition or with a history of ethanol abuse.
Drug Interactions: Zidovudine: There is no significant pharmacokinetic interaction between ZDV
and zalcitabine which has been confirmed clinically. Zalcitabine also has no significant effect on the
intracellular phosphorylation of ZDV, as shown in vitro in peripheral blood mononuclear cells or in
the lymphoblastoid cell line h1A2v2. No information is available on pharmacokinetic interactions of
zalcitabine with didanosine, lamivudine, and stavudine.
Saquinavir: The combination of HIVID, saquinavir, and ZDV has been studied (as triple
combination) in adults. Pharmacokinetic data suggest that absorption, metabolism, and elimination
of each of these drugs are unchanged when they are used together.
Drugs Associated With Peripheral Neuropathy: The concomitant use of HIVID with drugs that have
the potential to cause peripheral neuropathy should be avoided where possible. Drugs that have been
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associated with peripheral neuropathy include antiretroviral nucleoside analogues, chloramphenicol,
cisplatin, dapsone, disulfiram, ethionamide, glutethimide, gold, hydralazine, iodoquinol, isoniazid,
metronidazole, nitrofurantoin, phenytoin, ribavirin, and vincristine. Concomitant use of HIVID with
didanosine is not recommended.
Intravenous Pentamidine: Treatment with HIVID should be interrupted when the use of a drug that
has the potential to cause pancreatitis is required. Death due to fulminant pancreatitis possibly
related to intravenous pentamidine and HIVID has been reported. If intravenous pentamidine is
required to treat Pneumocystis carinii pneumonia, treatment with HIVID should be interrupted (see
WARNINGS).
Amphotericin, Foscarnet, and Aminoglycosides: Drugs such as amphotericin, foscarnet, and
aminoglycosides may increase the risk of developing peripheral neuropathy (see WARNINGS:
Peripheral Neuropathy) or other HIVID-associated adverse events by interfering with the renal
clearance of zalcitabine (thereby raising systemic exposure). Patients who require the use of one of
these drugs with HIVID should have frequent clinical and laboratory monitoring with dosage
adjustment for any significant change in renal function.
Probenecid or Cimetidine: Concomitant administration of probenecid or cimetidine decreases the
elimination of zalcitabine, most likely by inhibition of renal tubular secretion of zalcitabine. Patients
receiving these drugs in combination with zalcitabine should be monitored for signs of toxicity and
the dose of zalcitabine reduced if warranted.
Magnesium/Aluminum-containing Antacid Products: Absorption of zalcitabine is moderately
reduced (approximately 25%) when coadministered with magnesium/aluminum-containing antacid
products. The clinical significance of this reduction is not known, hence zalcitabine is not
recommended to be ingested simultaneously with magnesium/aluminum-containing antacids.
Metoclopramide: Bioavailability is mildly reduced (approximately 10%) when zalcitabine and
metoclopramide are coadministered (see CLINICAL PHARMACOLOGY: Drug Interactions).
Doxorubicin: Doxorubicin caused a decrease in zalcitabine phosphorylation (>50% inhibition of
total phosphate formation) in U937/Molt 4 cells. Although there may be decreased zalcitabine
activity because of lessened active metabolite formation, the clinical relevance of these in vitro
results are not known.
Carcinogenesis, Mutagenesis and Impairment of Fertility: Carcinogenesis: Zalcitabine was
administered orally by dietary admixture to CRL:CD-1® (ICR) Br mice at dosages of 3, 83, or 250
mg/kg/day for 2 years. Plasma exposures (as measured by AUC) at these doses were 6-fold to 704-
fold greater than the systemic exposure in humans with the therapeutic dose. Zalcitabine was
administered orally by dietary admixture to CDF® (F-344)/CrlBR/CdBR rats at dosages of 3, 28, 83,
or 250 mg/kg/day. At the highest dose tested, the systemic exposure to zalcitabine was 833 times the
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systemic exposure in humans with the therapeutic dose.
A significant increase in thymic lymphoma in all zalcitabine dose groups and Harderian gland (a
gland of the eye of rodents) adenoma in the two highest dose groups was observed in female CD-1
mice after 2 years of dosing. No increase in tumor incidence was observed in rats or male mice
treated with zalcitabine. In an independent study, administration of zalcitabine to B6C3F1 mice at a
dose of 1000 mg/kg/day for 3 months induced an increased incidence of thymic lymphoma. A high
rate of spontaneous lymphoreticular neoplasms have previously been noted in this strain of mice.
Mutagenesis: Zalcitabine was positive in a cell transformation assay and induced chromosomal
aberrations in vitro in human peripheral blood lymphocytes. Oral doses of zalcitabine at 2500 and
4500 mg/kg were clastogenic in the mouse micronucleus assay. Zalcitabine showed no evidence of
mutagenicity in Ames tests, Chinese hamster lung cell assays and the mouse lymphoma assay. An
unscheduled DNA synthesis assay in rat hepatocytes showed that zalcitabine had no effect on DNA
repair.
Impairment of Fertility: Fertility and reproductive performance were assessed in rats at plasma
concentrations up to 2142 times those achieved with the maximum recommended human dose
(MRHD) based on AUC measurements. No adverse effects on rate of conception or general
reproductive performance were observed. The highest dose was associated with embryolethality and
evidence of teratogenicity. The next lower dose studied (plasma concentrations equivalent to 485
times the MRHD) was associated with a lower frequency of embryotoxicity but no teratogenicity.
The fertility of F1 males was significantly reduced at a calculated dose of 2142 (but not 485) times
the MRHD (based on AUC measurements) in a teratology study in which rat mothers were dosed on
gestation days 7 to 15. No adverse effects were observed on the fertility of parents or F1 generation
in the study of fertility and general reproductive performance or in the perinatal and postnatal
reproduction study.
Pregnancy: Teratogenic Effects: Pregnancy Category C. Zalcitabine has been shown to be
teratogenic in mice at calculated exposure levels of 1365 and 2730 times that of the MRHD (based
on AUC measurements). In rats, zalcitabine was teratogenic at a calculated exposure level of 2142
times the MRHD but not at an exposure level of 485 times the MRHD. In a perinatal and postnatal
study in the rat, a high incidence of hydrocephalus was observed in the F1 offspring derived from
litters of dams treated with 1071 (but not 485) times the MRHD (based on AUC measurements).
There are no adequate and well-controlled studies of zalcitabine in pregnant women. HIVID should
be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Fertile
women should not receive HIVID unless they are using effective contraception during therapy. If
pregnancy occurs, physicians are encouraged to report such cases by calling (800) 526-6367.
Nonteratogenic Effects: Increased embryolethality was observed in pregnant mice at doses 2730
times the MRHD and in pregnant rats above 485 (but not 98) times the MRHD (based on AUC
measurements). Average fetal body weight was significantly decreased in mice at doses of 1365
times the MRHD and in rats at 2142 times the MRHD (based on AUC measurements). In a perinatal
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and postnatal study, the learning and memory of a significant number of F1 offspring were impaired,
and they tended to stay hyperactive for a longer period of time. These effects, observed at a
calculated exposure level of 1071 (but not 485) times the MRHD (based on AUC measurements),
were considered to result from extensive damage to or gross underdevelopment of the brain of these
F1 offspring consistent with the finding of hydrocephalus.
Antiretroviral Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant women
exposed to antiretroviral medications, including HIVID, an Antiretroviral Pregnancy Registry has
been established. Physicians are encouraged to register patients by calling 1-800-258-4263.
Nursing Mothers: The Centers for Disease Control and Prevention recommend HIV-infected
mothers not breast-feed their infants to avoid risking postnatal transmission of HIV. It is not
known whether zalcitabine is excreted in human milk. Because of both the potential for HIV
transmission and the potential for serious adverse reactions in nursing infants, mothers should be
instructed not to breast-feed if they are receiving antiretroviral medications, including
HIVID.
Pediatric Use: Pharmacokinetics in Pediatric Patients: Limited pharmacokinetic data have been
reported for 5 HIV-positive pediatric patients using doses of 0.03 and 0.04 mg/kg HIVID
administered orally every 6 hours.1 The mean bioavailability of zalcitabine in these pediatric
patients was 54% and mean apparent systemic clearance was 150 mL/min/m2. Due to the small
number of subjects and different analytical techniques, it is difficult to make comparisons between
pediatric and adult data.
Safety and effectiveness of HIVID in HIV-infected pediatric patients younger than 13 years of age
have not been established.
Geriatric Use: Clinical studies of HIVID did not include sufficient numbers of subjects aged 65 and
over to determine whether they respond differently from younger subjects. In general, dose selection
for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal,
or cardiac function, and of concomitant disease or other drug therapy. HIVID is known to be
substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in
patients with impaired renal function. Because elderly patients are more likely to have decreased
renal function, care should be taken in dose selection. In addition, renal function should be
monitored and dosage adjustments should be made accordingly (see PRECAUTIONS: General:
Renal Impairment and DOSAGE AND ADMINISTRATION).
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ADVERSE REACTIONS: (See WARNINGS.)
Tables 2 and 3 summarize the clinical adverse events and laboratory abnormalities, respectively,
that occurred in ≥1% of patients in the comparative monotherapy trial (CPCRA 002) of HIVID vs
didanosine (ddI), and the comparative combination trial (ACTG 175) of zidovudine (ZDV)
monotherapy vs HIVID and zidovudine combination therapy, respectively. Other studies have found
a higher or lower incidence of adverse experiences depending upon disease status, generally being
lower in patients with less advanced disease.
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Table 2. Percentage of Patients With Clinical Adverse Experience
≥≥≥≥ Grade 3*† in ≥≥≥≥1% of Patients Receiving HIVID
CPCRA 002*
ZDV Intolerant or Failure
ACTG 175‡
ZDV Naive/Experienced
HIVID
0.750 mg q8h
n=237
ddI
250 mg q12h
n=230
ZDV
200 mg q8h
n=619
HIVID+ZDV
0.750 mg q8h
+200 mg q8h
n=615
Body System/Adverse Event
Systemic
Fatigue
Headache
Fever
3.8
2.1
1.7
2.6
1.3
0.4
2.7
2.4
2.7
2.3
2.6
2.9
Gastrointestinal
Abdominal Pain
Oral Lesions/Stomatitis§
Vomiting/Nausea§
Diarrhea/Constipation§
3.0
3.0
3.4
2.5
7.0
0.0
7.0
17.4
2.3
0.6
4.9
2.9
1.8
1.5
2.1
1.0
Hepatic
Abnormal Hepatic Function
8.9
7.0
||
||
Neurological
Convulsions
Peripheral Neuropathy¶
1.3
28.3
2.2
13.0
3.1
3.3
Skin
Rash/Pruritus/Urticaria
3.4
3.9
1.8
1.6
Metabolic and Nutrition
Pancreatitis
0.0
1.7
0.2
0.5
Psychological
Depression
0.4
0.0
1.1
1.8
Musculoskeletal
Painful/Swollen Joints
0.4
0.0
0.3
1.0
* Grade 2 Adverse Events possibly or probably related to treatment or unassessable were included
if study drug dosage was changed or interrupted.
† Grade 3 severity: event causing marked limitation in activity, requiring medical care and possible
hospitalization.
Grade 4 severity: completely disabling, unable to care for self, requiring active medical
intervention, probable hospitalization or hospice care.
‡ All relationships.
§ Adverse experiences were combined to form this category.
|| See Table 3.
¶ CPCRA 002 included patients who were dose-adjusted for Grade 2 events; ACTG 175 required
dose adjustment for Grade 2 peripheral neuropathy but recorded only Grade 3 events.
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Table 3. Percentage of Patients With Laboratory Abnormalities
Protocol Grade 3/4
CPCRA 002*
ZDV Intolerant or Failure
ACTG 175
ZDV Naive/Experienced
HIVID
0.750 mg q8h
n=237
ddI
250 mg q12h
n=230
ZDV
200 mg q8h
n=619
HIVID+ZDV
0.750 mg q8h
+200 mg q8h
n=615
Laboratory Abnormality
Anemia (<7.5 gm/dL)
8.4
7.4
1.8
3.1
Leukopenia
(<1500 cells/mm3)
13.1
9.6
N/A
N/A
Eosinophilia
(>1000 cells/mm3 or 25%)
2.5
1.7
N/A
N/A
Neutropenia
(<750 cells/mm3)
16.9
11.7
1.9
4.2
Thrombocytopenia
(<50,000 cells/mm3)
1.3
4.8
1.1
1.8
CPK Elevation*
(>4 x ULN)
0.8
0.0
5.8
5.7
ALT (SGPT) (>5 x ULN)
N/A
N/A
3.6
5.0
AST (SGOT) (>5 x ULN)
7.6
5.7
2.9
4.1
Bilirubin (>2.5 x ULN)
0.8
0.9
0.5
1.0
GGT (>5 x ULN)
N/A
N/A
0.5
1.0
Amylase (>2 x ULN)
5.1
3.9
1.0
1.5
Hyperglycemia*
(>250 mg/dL)
0.0
1.7
0.8
2.0
* Grade 3 or higher reported for CPCRA 002.
N/A Not available.
Additional clinical adverse experiences associated with HIVID that occurred in <1% of patients in
CPCRA 002 (at least possibly related, Grade 3 or higher), ACTG 175 (any relationship, Grade 3/4)
or in other clinical studies are listed below by body system. Several of these events occurred in
slightly higher rates in other studies. The incidence of adverse experiences varied in different
studies, generally being lower in patients with less-advanced disease.
Body as a Whole: abnormal weight loss, asthenia, cachexia, chest tightness or pain, chills,
cutaneous/allergic reaction, debilitation, difficulty moving, dry eyes/mouth, edema, facial pain or
swelling, flank pain, flushing, increased sweating, lymphadenopathy, hypersensitivity reactions (see
WARNINGS), malaise, night sweats, pain, pelvic/groin pain, rigors.
Cardiovascular: abnormal cardiac movement, arrhythmia, atrial fibrillation, cardiac failure, cardiac
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dysrhythmias, cardiomyopathy, heart racing, hypertension, palpitation, subarachnoid hemorrhage,
syncope, tachycardia, ventricular ectopy.
Endocrine/Metabolic: abnormal triglycerides, abnormal lipase, altered serum glucose, decreased
bicarbonate, diabetes mellitus, glycosuria, gout, hot flushes, hypercalcemia, hyperkalemia,
hyperlipemia, hypernatremia, hyperuricemia, hypocalcemia, hypoglycemia, hypokalemia,
hypomagnesemia, hyponatremia, hypophosphatemia, increased nonprotein nitrogen, lactic acidosis.
Gastrointestinal: abdominal bloating or cramps, acute pancreatitis, anal/rectal pain, anorexia,
bleeding gums, bloody or black stools, colitis, dental abscess, dry mouth, dyspepsia, dysphagia,
enlarged abdomen, epigastric pain, eructation, esophageal pain, esophageal ulcers, esophagitis,
flatulence, gagging with pills, gastritis, gastrointestinal hemorrhage, gingivitis, glossitis, gum
disorder, heartburn, hemorrhagic pancreatitis, hemorrhoids, increased saliva, left quadrant pain,
melena, mouth lesion, odynophagia, painful sore gums, painful swallowing, pancreatitis, rectal
hemorrhage, rectal mass, rectal ulcers, salivary gland enlargement, sore tongue, sore throat, tongue
disorder, tongue ulcer, toothache, unformed/loose stools, vomiting.
Hematologic: absolute neutrophil count alteration, anemia, epistaxis, decreased hematocrit,
granulocytosis, hemoglobinemia, leukopenia, neutrophilia, platelet alteration, purpura, thrombus,
unspecified hematologic toxicity, white blood cell alteration.
Hepatic: abnormal lactate dehydrogenase, bilirubinemia, cholecystitis, decreased alkaline
phosphatase, hepatitis, hepatocellular damage, hepatomegaly, increased alkaline phosphatase,
jaundice.
Musculoskeletal: arthralgia, arthritis, arthropathy, arthrosis, back pain, backache, bone pains/aches,
bursitis, cold extremities, extremity pain, joint inflammation, leg cramps, muscle aches, muscle
weakness, muscle disorder, muscle stiffness, muscle cramps, myalgia, myopathy, myositis, neck
pain, rib pain, stiff neck.
Neurological: abnormal coordination, aphasia, ataxia, Bell’s palsy, confusion, decreased
concentration, decreased neurological function, disequilibrium, dizziness, dysphonia, facial nerve
palsy, focal motor seizures, grand mal seizure, hyperkinesia, hypertonia, hypokinesia, memory loss,
migraine, neuralgia, neuritis, paralysis, seizures, speech disorder, status epilepticus, stupor, tremor,
twitch, vertigo.
Psychological: acute psychotic disorder, acute stress reaction, agitation, amnesia, anxiety,
confusion, decreased motivation, decreased sexual desire, depersonalization, emotional lability,
euphoria, hallucination, impaired concentration, insomnia, manic reaction, mood swings,
nervousness, paranoid state, somnolence, suicide attempt, dementia.
Respiratory: acute nasopharyngitis, chest congestion, coughing, cyanosis, difficulty breathing, dry
nasal mucosa, dyspnea, flu-like symptoms, hemoptysis, nasal discharge, pharyngitis, rales/rhonchi,
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respiratory distress, sinus congestion, sinus pain, sinusitis, wheezing.
Skin: acne, alopecia, bullous eruptions, carbuncle/furuncle, cellulitis, cold sore, dermatitis, dry skin,
dry rash desquamation, erythematous rash, exfoliative dermatitis, finger inflammation, follicular
rash, impetigo, infection, itchy rash, lip blisters/lesions, macular/papular rash, maculopapular rash,
moniliasis, mucocutaneous/skin disorder, nail disorder, photosensitivity reaction, pruritic disorder,
pruritus, skin disorder, skin lesions, skin fissure, skin ulcer, urticaria.
Special Senses: abnormal vision, blurred vision, burning eyes, decreased taste, decreased vision, ear
pain/problem, ear blockage, eye abnormality, eye inflammation, eye itching, eye pain, eye irritation,
eye redness, eye hemorrhage, fluid in ears, hearing loss, increased tears, loss of taste, mucopurulent
conjunctivitis, parosmia, photophobia, smell dysfunction, taste perversion, tinnitus, unequal-sized
pupils, xerophthalmia, yellow sclera.
Urogenital: abnormal renal function, acute renal failure, albuminuria, bladder pain, dysuria,
frequent urination, genital lesion/ulcer, increased blood urea nitrogen, increased creatinine,
micturition frequency, nocturia, painful penis sore, pain on urination, penile edema, polyuria, renal
cyst, renal calculus, testicular swelling, toxic nephropathy, urinary retention, vaginal itch, vaginal
ulcer, vaginal pain, vaginal/cervix disorder, vaginal discharge.
OVERDOSAGE
Acute Overdosage: Inadvertent pediatric overdoses have occurred with doses up to 1.5 mg/kg
HIVID. Pediatric patients had prompt gastric lavage and treatment with activated charcoal and had
no sequelae. Mixed overdoses including HIVID and other drugs have led to drowsiness and
vomiting (with HIVID or placebo, zidovudine and trimethoprim/sulfamethoxazole [TMP/SMX]), or
increased GGT (with 18.75 mg HIVID with zidovudine and lormetazepam) or increased creatine
phosphokinase (with HIVID or placebo, zidovudine, fluconazole, dapsone and wine). There is no
experience with acute HIVID overdosage at higher doses and sequelae are unknown. There is no
known antidote for HIVID overdosage. It is not known whether zalcitabine is dialyzable by
peritoneal dialysis or hemodialysis.
Chronic Overdosage: In an initial dose-finding study in which zalcitabine was administered at doses
25 times (0.25 mg/kg every 8 hours) the currently recommended dose, one patient discontinued
HIVID after 1½ weeks of treatment subsequent to the development of a rash and fever. In the early
Phase 1 studies, all patients receiving zalcitabine at approximately 6 times the current total daily
recommended dose experienced peripheral neuropathy by week 10. Eighty percent of patients who
received approximately 2 times the current total daily recommended dose experienced peripheral
neuropathy by week 12.
DOSAGE AND ADMINISTRATION
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
HIVID® (zalcitabine) Tablets - PACKAGE INSERT
19
Patients should be advised that HIVID is recommended for use in combination with active
antiretroviral therapy. Greater activity has been observed when new antiretroviral therapies are
begun at the same time as HIVID. Concomitant therapy should be based on a patient’s prior drug
exposure. The recommended regimen is one 0.750 mg tablet of HIVID orally every 8 hours (2.25
mg HIVID total daily dose) in combination with other antiretroviral agents. Please refer to the
complete product information for each of the other antiretroviral agents for the recommended doses
of these agents. Based on preliminary data, the recommended HIVID dosage reduction for patients
with impaired renal function is: creatinine clearance 10 to 40 mL/min: 0.750 mg of HIVID every 12
hours; creatinine clearance <10 mL/min: 0.750 mg of HIVID every 24 hours.
Monitoring of Patients: Complete blood counts and clinical chemistry tests should be performed
prior to initiating HIVID therapy and at appropriate intervals thereafter. For comprehensive patient
monitoring recommendations for other antiretroviral therapies, physicians should refer to the
complete product information for these drugs. Serum amylase levels should be monitored in those
individuals who have a history of elevated amylase, pancreatitis, ethanol abuse, who are on
parenteral nutrition or who are otherwise at high risk of pancreatitis. Careful monitoring for signs or
symptoms suggestive of peripheral neuropathy is recommended, particularly in individuals with a
low CD4 cell count or who are at a greater risk of developing peripheral neuropathy while on
therapy (see WARNINGS).
Dose Adjustment for HIVID: For toxicities that are likely to be associated with HIVID (eg,
peripheral neuropathy, severe oral ulcers, pancreatitis, elevated liver function tests especially in
patients with chronic Hepatitis B), HIVID should be interrupted or dose reduced. FOR SEVERE
TOXICITIES OR THOSE PERSISTING AFTER DOSE REDUCTION, HIVID SHOULD BE
INTERRUPTED. For recipients of combination therapy with HIVID and other antiretroviral agents,
dose adjustments or interruption for each drug should be based on the known toxicity profile of the
individual drugs. SEE INFORMATION FOR EACH DRUG USED IN COMBINATION FOR A
DESCRIPTION OF KNOWN DRUG-ASSOCIATED ADVERSE REACTIONS.
Patients developing moderate discomfort with signs or symptoms of peripheral neuropathy should
stop HIVID. HIVID-associated peripheral neuropathy may continue to worsen despite interruption
of HIVID. HIVID should be reintroduced at 50% dose — 0.375 mg every 8 hours only if all
findings related to peripheral neuropathy have improved to mild symptoms. HIVID should be
permanently discontinued if patients experience severe discomfort related to peripheral neuropathy
or moderate discomfort that progresses. If other moderate to severe clinical adverse reactions or
laboratory abnormalities (such as increased liver function tests) occur, then HIVID and/or the other
potential causative agent(s) should be interrupted until the adverse reaction abates. HIVID and/or
the other potential causative agent(s) should then be carefully reintroduced at lower doses if
appropriate. If adverse reactions recur at the reduced dose, therapy should be discontinued. The
minimum effective dose of HIVID in combination with zidovudine for the treatment of adult
patients with advanced HIV infection has not been established.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
HIVID® (zalcitabine) Tablets - PACKAGE INSERT
20
In patients with poor bone marrow reserve, particularly those patients with advanced symptomatic
HIV disease, frequent monitoring of hematologic indices is recommended to detect serious anemia
or granulocytopenia. Significant toxicities, such as anemia (hemoglobin of <7.5 gm/dL or reduction
of >25% of baseline) and/or granulocytopenia (granulocyte count of <750 cells/mm3 or reduction of
>50% from baseline), may require a treatment interruption of HIVID and zidovudine until evidence
of marrow recovery is observed. For less severe anemia or granulocytopenia, a reduction in daily
dose of zidovudine in those patients receiving combination therapy may be adequate. In patients
who experience hematologic toxicity, reduction in hemoglobin may occur as early as 2 to 4 weeks
after initiation of therapy, and granulocytopenia usually occurs after 6 to 8 weeks of therapy. In
patients who develop significant anemia, dose modification does not necessarily eliminate the need
for transfusion. If marrow recovery occurs following dose modification, gradual increases in dose
may be appropriate depending on hematologic indices and patient tolerance. For more details, refer
to the complete product information for zidovudine.
HOW SUPPLIED
HIVID 0.375 mg tablets are oval, beige, film-coated tablets with “HIVID 0.375” imprinted on one
side and “ROCHE” on the other side — bottles of 100 (NDC 0004-0220-01). HIVID 0.750 mg
tablets are oval, gray, film-coated tablets with “HIVID 0.750” imprinted on one side and “ROCHE”
on the other side — bottles of 100 (NDC 0004-0221-01).
The tablets should be stored in tightly closed bottles at 59° to 86°F (15° to 30°C).
REFERENCES:
1. Pizzo PA, Butler K, Balis F, et al. Dideoxycytidine alone and in an alternating schedule with
zidovudine in children with symptomatic human immunodeficiency virus infection. J Pediatr.
1990;117(5): 799-808.
2. Abrams DI, Goldman AI, Launer C, et al. A comparative trial of didanosine or zalcitabine after
treatment with zidovudine in patients with human immunodeficiency virus infection. N Engl J
Med. 1994;330(10): 657-662.
3. Follansbee S, Drew L, Olson R, et al. The efficacy of zalcitabine (ddC, HIVID) versus
zidovudine (ZDV) as monotherapy in ZDV-naive patients with advanced HIV disease; a
randomized, double-blind, comparative trial (ACTG 114; N3300). IXth International
Conference on AIDS/IV STD World Congress, Berlin, Germany, June 7-11, 1993. Poster PO-
B26-2113.
4. Remick S, Follansbee S, Olson R, et al. Safety and tolerance of zalcitabine (ddC, HIVID) in a
double-blind comparative trial (ACTG 114; N3300). IXth International Conference on AIDS/IV
STD World Congress, Berlin, Germany, June 7-11, 1993. Poster PO-B26-2115.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
HIVID® (zalcitabine) Tablets - PACKAGE INSERT
21
5. “Dear Doctor” letter, Burroughs Wellcome Co., June 1, 1993.
6. Food and Drug Administration Antiviral Drugs Advisory Committee Meeting, “Mitochondrial
Damage Associated with Nucleoside Analogues,” Rockville, MD, September 21, 1993.
7. Sanders VM, Elwell MR, Heath JE, et al. Induction of Thymic Lymphoma in Mice
Administered the Dideoxynucleoside ddC. Fundamental and Applied Toxicology. 1995;27: 263-
269.
8. Irons RD, Le AT, Som DB, et al. 2'3'-Dideoxycytidine-induced Thymic Lymphoma Correlates
with Species-specific Suppression of a Subpopulation of Primitive Hematopoietic Progenitor
Cells in Mouse but Not Rat or Human Bone Marrow. J Clin Invest. 1995;95: 2777-2782.
Maalox is a registered trademark of Novartis.
INVIRASE is a registered trademark of Hoffmann-La Roche Inc.
Rx only
27897976-0701
Revised: July 2000
Printed in USA
Copyright © 1998-2001 by Roche Laboratories Inc. All rights reserved.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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This is a representation of an electronic record that was signed electronically and
this page is the manifestation of the electronic signature.
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/s/
---------------------
Debra Birnkrant
7/3/02 03:53:24 PM
NDA 20-199, SLR 014
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2002/20199s014lbl.pdf', 'application_number': 20199, 'submission_type': 'SUPPL ', 'submission_number': 14}
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DOBUTamine
in 5% Dextrose Injection, USP
Flexible Plastic Container Rx only
DESCRIPTION
Dobutamine in 5% Dextrose Injection, USP is a sterile, nonpyrogenic, prediluted solution of
dobutamine hydrochloride and dextrose in water for injection. It is administered by intravenous
infusion.
Each 100 mL contains dobutamine hydrochloride equivalent to 100 mg, 200 mg, or 400 mg of
dobutamine; dextrose (derived from corn), hydrous 5 g in water for injection, with sodium
metabisulfite 25 mg and edetate disodium, dihydrate 10 mg added as stabilizers; osmolar
concentration, respectively, 263, 270, or 284 mOsmol/liter (calc.). The pH is 3.0 (2.5 to 5.5). May
contain hydrochloric acid and/or sodium hydroxide for pH adjustment. Dobutamine in 5%
Dextrose Injection, USP is oxygen sensitive.
Dobutamine Hydrochloride, USP is chemically designated (±)-4-[2-[[3-(p-hydroxyphenyl)-1-
methylpropyl]amino]ethyl]-pyrocatechol hydrochloride. It is a synthetic catecholamine.
Dextrose, USP is chemically designated D-glucose monohydrate (C6H12O6 · H2O), a hexose
sugar freely soluble in water. It has the following structural formula:
Water for Injection, USP is chemically designated H2O.
The flexible plastic container is fabricated from a specially formulated CR3 plastic material.
Water can permeate from inside the container into the overwrap but not in amounts sufficient to
affect the solution significantly. Solutions in contact with the plastic container may leach out
certain chemical components from the plastic in very small amounts; however, biological testing
was supportive of the safety of the plastic container materials. Exposure to temperatures above
25°C/77°F during transport and storage will lead to minor losses in moisture content. Higher
temperatures lead to greater losses. It is unlikely that these minor losses will lead to clinically
significant changes within the expiration period.
Reference ID: 3938718
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For current labeling information, please visit https://www.fda.gov/drugsatfda
EN-1227xxxx
Page 2 of 7
CLINICAL PHARMACOLOGY
Dobutamine is a direct-acting inotropic agent whose primary activity results from stimulation of
the β-receptors of the heart while producing comparatively mild chronotropic, hypertensive,
arrhythmogenic, and vasodilative effects. It does not cause the release of endogenous
norepinephrine, as does dopamine. In animal studies, dobutamine produces less increase in heart
rate and less decrease in peripheral vascular resistance for a given inotropic effect than does
isoproterenol.
In patients with depressed cardiac function, both dobutamine and isoproterenol increase the
cardiac output to a similar degree. In the case of dobutamine, this increase is usually not
accompanied by marked increases in heart rate (although tachycardia is occasionally observed), and
the cardiac stroke volume is usually increased. In contrast, isoproterenol increases the cardiac index
primarily by increasing the heart rate while stroke volume changes little or declines.
Facilitation of atrioventricular conduction has been observed in human electrophysiologic
studies and in patients with atrial fibrillation.
Systemic vascular resistance is usually decreased with administration of dobutamine.
Occasionally, minimum vasoconstriction has been observed.
Most clinical experience with dobutamine is short-term, not more than several hours in
duration. In the limited number of patients who were studied for 24, 48, and 72 hours, a persistent
increase in cardiac output occurred in some, whereas output returned toward baseline values in
others.
The onset of action of Dobutamine in 5% Dextrose Injection, USP is within 1 to 2 minutes;
however, as much as 10 minutes may be required to obtain the peak effect of a particular infusion
rate.
The plasma half-life of dobutamine in humans is 2 minutes. The principal routes of metabolism
are methylation of the catechol and conjugation. In human urine, the major excretion products are
the conjugates of dobutamine and 3-O-methyl dobutamine. The 3-O-methyl derivative of
dobutamine is inactive.
Alteration of synaptic concentrations of catecholamines with either reserpine or tricyclic
antidepressants does not alter the actions of dobutamine in animals, which indicates that the actions
of dobutamine are not dependent on presynaptic mechanisms.
The effective infusion rate of dobutamine varies widely from patient to patient, and titration is
always necessary (see DOSAGE AND ADMINISTRATION). At least in pediatric patients,
dobutamine-induced increases in cardiac output and systemic pressure are generally seen, in any
given patient, at lower infusion rates than those that cause substantial tachycardia (See Pediatric
Use under PRECAUTIONS).
INDICATIONS AND USAGE
Dobutamine in 5% Dextrose Injection, USP is indicated when parenteral therapy is necessary for
inotropic support in the short-term treatment of patients with cardiac decompensation due to
depressed contractility resulting either from organic heart disease or from cardiac surgical
procedures. Experience with intravenous dobutamine in controlled trials does not extend beyond 48
hours of repeated boluses and/or continuous infusions.
Whether given orally, continuously intravenously, or intermittently intravenously, neither
dobutamine nor any other cyclic-AMP-dependent inotrope has been shown in controlled trials to be
safe or effective in the long-term treatment of congestive heart failure. In controlled trials of
chronic oral therapy with various such agents, symptoms were not consistently alleviated, and the
Reference ID: 3938718
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For current labeling information, please visit https://www.fda.gov/drugsatfda
EN-1227xxxx
Page 3 of 7
cyclic-AMP-dependent inotropes were consistently associated with increased risks of
hospitalization and death. Patients with NYHA Class IV symptoms appeared to be at particular
risk.
CONTRAINDICATIONS
Dobutamine in 5% Dextrose Injection, USP is contraindicated in patients with idiopathic
hypertrophic subaortic stenosis and in patients who have shown previous manifestations of
hypersensitivity to dobutamine or any of its components.
WARNINGS
Increase in Heart Rate or Blood Pressure
Dobutamine hydrochloride may cause a marked increase in heart rate or blood pressure,
especially systolic pressure. Approximately 10% of adult patients in clinical studies have had
rate increases of 30 beats/minute or more, and about 7.5% have had a 50-mm Hg or greater
increase in systolic pressure. Usually, reduction of dosage reverses these effects.
Because dobutamine facilitates atrioventricular conduction, patients with atrial fibrillation are
at risk of developing rapid ventricular response. In patients who have atrial fibrillation with
rapid ventricular response, a digitalis preparation should be used prior to institution of therapy
with dobutamine. Patients with pre-existing hypertension appear to face an increased risk of
developing an exaggerated pressure response.
Ectopic Activity
Dobutamine may precipitate or exacerbate ventricular ectopic activity, but it rarely has caused
ventricular tachycardia.
Hypersensitivity
Reactions suggestive of hypersensitivity associated with administration of Dobutamine in 5%
Dextrose Injection, USP, including skin rash, fever, eosinophilia, and bronchospasm, have been
reported occasionally.
Dobutamine in 5% Dextrose Injection, USP contains sodium bisulfite, a sulfite that may cause
allergic-type reactions, including anaphylactic symptoms and life-threatening or less severe
asthmatic episodes, in certain susceptible people. The overall prevalence of sulfite sensitivity in
the general population is unknown and probably low. Sulfite sensitivity is seen more frequently
in asthmatic than in nonasthmatic people.
PRECAUTIONS
General
During the administration of dobutamine, as with any adrenergic agent, ECG and blood
pressure should be continuously monitored. In addition, pulmonary wedge pressure and
cardiac output should be monitored whenever possible to aid in the safe and effective
infusion of Dobutamine in 5% Dextrose Injection, USP.
Hypovolemia should be corrected with suitable volume expanders before treatment with
Dobutamine in 5% Dextrose Injection, USP is instituted.
Animal studies indicate that dobutamine may be ineffective if the patient has recently received a β-
blocking drug. In such a case, the peripheral vascular resistance may increase.
No improvement may be observed in the presence of marked mechanical obstruction, such as
severe valvular aortic stenosis.
Reference ID: 3938718
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For current labeling information, please visit https://www.fda.gov/drugsatfda
EN-1227xxxx
Page 4 of 7
Do not administer unless solution is clear and container is undamaged. Discard unused portion.
Usage Following Acute Myocardial Infarction: Clinical experience with dobutamine following
myocardial infarction has been insufficient to establish the safety of the drug for this use. There is
concern that any agent that increases contractile force and heart rate may increase the size of an
infarction by intensifying ischemia, but it is not known whether dobutamine does so.
Drug Interactions: There was no evidence of drug interactions in clinical studies in which
dobutamine hydrochloride was administered concurrently with other drugs, including digitalis
preparations, furosemide, spironolactone, lidocaine, glyceryl trinitrate, isosorbide dinitrate,
morphine, atropine, heparin, protamine, potassium chloride, folic acid, and acetaminophen.
Preliminary studies indicate that the concomitant use of dobutamine and nitroprusside results in a
higher cardiac output and, usually, a lower pulmonary wedge pressure than when either drug is
used alone.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Studies to evaluate the carcinogenic or
mutagenic potential of dobutamine or the potential of the drug to affect fertility adversely have not
been performed.
Pregnancy
Pregnancy Category B: Reproduction studies performed in rats and rabbits have revealed no
evidence of harm to the fetus due to dobutamine. The drug, however, has not been administered to
pregnant women and should be used only when the expected benefits clearly outweigh the potential
risks to the fetus.
Pediatric Use: Dobutamine has been shown to increase cardiac output and systemic pressure in
pediatric patients of every age group. In premature neonates, however, dobutamine is less effective
than dopamine in raising systemic blood pressure without causing undue tachycardia, and
dobutamine has not been shown to provide any added benefit when given to such infants already
receiving optimal infusions of dopamine.
Geriatric Use: Clinical studies of dobutamine did not include sufficient numbers of subjects aged
65 and over to determine whether they respond differently from younger subjects. Other reported
clinical experience has not identified differences in responses between the elderly and younger
patients. In general, dose selection for an elderly patient should be cautious, usually starting at the
low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac
function, and of concomitant disease or drug therapy.
ADVERSE REACTIONS
Increased Heart Rate, Blood Pressure, and Ventricular Ectopic Activity: A 10- to 20-mm Hg
increase in systolic blood pressure and an increase in heart rate of 5 to 15 beats/minute have been
noted in most patients (see WARNINGS regarding exaggerated chronotropic and pressor effects).
Approximately 5% of adult patients have had increased premature ventricular beats during
infusions. These effects are dose related.
Hypotension: Precipitous decreases in blood pressure have occasionally been described in
association with dobutamine therapy. Decreasing the dose or discontinuing the infusion typically
results in rapid return of blood pressure to baseline values. In rare cases, however, intervention may
be required and reversibility may not be immediate.
Reactions at Sites of Intravenous Infusion: Phlebitis has occasionally been reported. Local
inflammatory changes have been described following inadvertent infiltration.
Reference ID: 3938718
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For current labeling information, please visit https://www.fda.gov/drugsatfda
EN-1227xxxx
Page 5 of 7
Miscellaneous Uncommon Effects: The following adverse effects have been reported in 1% to
3% of adult patients: nausea, headache, anginal pain, nonspecific chest pain, palpitations, and
shortness of breath.
Administration of dobutamine, like other catecholamines, has been associated with decreases in
serum potassium concentrations, rarely to hypokalemic values (See PRECAUTIONS).
OVERDOSAGE
Overdoses of dobutamine have been reported rarely. The following is provided to serve as a guide
if such an overdose is encountered.
Signs and Symptoms: Toxicity from dobutamine hydrochloride is usually due to excessive cardiac
β-receptor stimulation. The duration of action of dobutamine hydrochloride is generally short
(T½ = 2 minutes) because it is rapidly metabolized by catechol-O-methyltransferase. The symptoms
of toxicity may include anorexia, nausea, vomiting, tremor, anxiety, palpitations, headache,
shortness of breath, and anginal and nonspecific chest pain. The positive inotropic and chronotropic
effects of dobutamine on the myocardium may cause hypertension, tachyarrhythmias, myocardial
ischemia, and ventricular fibrillation. Hypotension may result from vasodilation.
If the product is ingested, unpredictable absorption may occur from the mouth and the
gastrointestinal tract.
Treatment: To obtain up-to-date information about the treatment of overdose, a good resource is
your certified Regional Poison Control Center. Telephone numbers of certified poison control
centers are listed in the Physicians’ Desk Reference (PDR). In managing overdosage, consider the
possibility of multiple drug overdoses, interaction among drugs, and unusual drug kinetics in your
patient.
The initial actions to be taken in a dobutamine hydrochloride overdose are discontinuing
administration, establishing an airway, and ensuring oxygenation and ventilation. Resuscitative
measures should be initiated promptly. Severe ventricular tachyarrhythmias may be successfully
treated with propranolol or lidocaine. Hypertension usually responds to a reduction in dose or
discontinuation of therapy.
Protect the patient's airway and support ventilation and perfusion. If needed, meticulously
monitor and maintain, within acceptable limits, the patient's vital signs, blood gases, serum
electrolytes, etc. Absorption of drugs from the gastrointestinal tract may be decreased by giving
activated charcoal, which, in many cases, is more effective than emesis or lavage; consider charcoal
instead of or in addition to gastric emptying. Repeated doses of charcoal over time may hasten
elimination of some drugs that have been absorbed. Safeguard the patient's airway when employing
gastric emptying or charcoal.
Forced diuresis, peritoneal dialysis, hemodialysis, or charcoal hemoperfusion have not been
established as beneficial for an overdose of dobutamine hydrochloride.
DOSAGE AND ADMINISTRATION
Recommended Dosage
Dobutamine in 5% Dextrose Injection, USP is administered intravenously through a suitable
intravenous catheter or needle. A calibrated electronic infusion device is recommended for
controlling the rate of flow in mL/hour or drops/minute.
Infusion of dobutamine should be started at a low rate (0.5-1.0 µg/kg/min) and titrated at intervals
of a few minutes, guided by the patient’s response, including systemic blood pressure, urine flow,
Reference ID: 3938718
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EN-1227xxxx
Page 6 of 7
frequency of ectopic activity, heart rate, and (whenever possible) measurements of cardiac output,
central venous pressure, and/or pulmonary capillary wedge pressure. In reported trials, the optimal
infusion rates have varied from patient to patient, usually 2-20 µg/kg/min but sometimes slightly
outside of this range. On rare occasions, infusion rates up to 40 µg/kg/min have been required to
obtain the desired effect.
Rates of infusion in mL/hour for dobutamine hydrochloride concentrations of 500, 1,000, 2,000
and 4,000 mg/L may be calculated using the following formula:
Infusion Rate (mL/h) = [Dose (µg/kg/min) x Weight (kg) x 60 min/h]
Final Concentration (µg/mL)
Example calculations for infusion rates are as follows:
Example 1: for a 60 kg person at an initial dose of 0.5 µg/kg/min using a 500 µg/mL
concentration, the infusion rate would be as follows:
Infusion Rate (mL/h) = [0.5 (µg/kg/min) x 60 (kg) x 60 (min/h)] = 3.6 (mL/h)
500 (µg/mL)
Example 2: for a 80 kg person at a dose of 10 µg/kg/min using a 2,000 µg/mL
concentration, the infusion rate would be as follows:
Infusion Rate (mL/h) = [10 (µg/kg/min) x 80 (kg) x 60 (min/h)] = 24 (mL/h)
2,000 (µg/mL)
This container system may be inappropriate for the dosage requirements of pediatric patients under
30 kg.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior
to administration whenever solution and container permit.
Dobutamine in 5% Dextrose Injection, USP solutions may exhibit a pink color that, if present, will
increase with time. This color change is due to slight oxidation of the drug, but there is no
significant loss of potency.
Solutions containing dextrose should not be administered through the same administration set as
blood, as this may result in pseudoagglutination or hemolysis.
Do not add supplementary medications to Dobutamine in 5% Dextrose Injection, USP. Do
not administer Dobutamine in 5% Dextrose Injection, USP simultaneously with solutions
containing sodium bicarbonate or strong alkaline solutions.
Reference ID: 3938718
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For current labeling information, please visit https://www.fda.gov/drugsatfda
EN-1227xxxx
Page 7 of 7
INSTRUCTIONS FOR USE
To Open
Tear outer wrap at notch and remove solution container. Some opacity of the plastic due to
moisture absorption during the sterilization process may be observed. This is normal and does not
affect the solution quality or safety. The opacity will diminish gradually.
Preparation for Administration
(Use aseptic technique)
1. Close flow control clamp of administration set.
2. Remove cover from outlet port at bottom of container.
3. Insert piercing pin of administration set into port with a twisting motion until the set is firmly
seated. NOTE: See full directions on administration set carton.
4. Suspend container from hanger.
5. Squeeze and release drip chamber to establish proper fluid level in chamber.
6. Open flow control clamp and clear air from set. Close clamp.
7. Attach set to venipuncture device. If device is not indwelling, prime and make venipuncture.
8. Regulate rate of administration with flow control clamp.
WARNING: Do not use flexible container in series connections.
HOW SUPPLIED
DOBUTamine in 5% Dextrose Injection, USP is supplied in 250 and 500 mL LifeCare® flexible
containers as follows:
List No. 2346 – 250 mg DOBUTamine in 5% Dextrose Injection, USP 250 mL
List No. 2346 – 500 mg DOBUTamine in 5% Dextrose Injection, USP 500 mL
List No. 2347 – 500 mg DOBUTamine in 5% Dextrose Injection, USP 250 mL
List No. 3724 –1000 mg DOBUTamine in 5% Dextrose Injection, USP 250 mL
Do not freeze. Store at 20 to 25ºC (68 to 77ºF). [See USP Controlled Room Temperature.]
Revised: May, 2016
EN-xxxx
Hospira, Inc., Lake Forest, IL 60045 USA
Reference ID: 3938718
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/020201s036lbl.pdf', 'application_number': 20201, 'submission_type': 'SUPPL ', 'submission_number': 36}
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/020204s021lbl.pdf', 'application_number': 20204, 'submission_type': 'SUPPL ', 'submission_number': 21}
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For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic
signature.
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/s/
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KAREN M MAHONEY
02/25/2016
Reference ID: 3892622
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:47:01.664567
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/020204Orig1s048Lbl.pdf', 'application_number': 20204, 'submission_type': 'SUPPL ', 'submission_number': 48}
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12,319
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ZINECARD (dexrazoxane for injection)
US Package Insert
FDA Approved Labeling for S-006
1(10)
1
Zinecard®
2
dexrazoxane for injection
3
4
5
DESCRIPTION
6
7
ZINECARD® (dexrazoxane for injection) is a sterile, pyrogen-free lyophilizate intended for
8
intravenous administration. It is a cardioprotective agent for use in conjunction with doxorubicin.
9
10
Chemically, dexrazoxane is (S)-4,4'-(1-methyl-1,2-ethanediyl)bis-2,6-piperazinedione. The structural
11
formula is as follows:
12
13
C11H16N4O4
M.W. 268.28
14
15
Dexrazoxane, a potent intracellular chelating agent is a derivative of EDTA. Dexrazoxane is a whitish
16
crystalline powder which melts at 191° to 197°C. It is sparingly soluble in water and 0.1 N HCl,
17
slightly soluble in ethanol and methanol and practically insoluble in nonpolar organic solvents. The
18
pKa is 2.1. Dexrazoxane has an octanol/water partition coefficient of 0.025 and degrades rapidly
19
above a pH of 7.0.
20
21
ZINECARD is available in 250 mg and 500 mg single use only vials.
22
Each 250 mg vial contains dexrazoxane hydrochloride equivalent to 250 mg dexrazoxane.
23
Hydrochloric Acid, NF is added for pH adjustment. When reconstituted as directed with the 25
24
mL vial of 0.167 Molar (M/6) Sodium Lactate Injection, USP diluent provided, each mL
25
contains: 10 mg dexrazoxane. The pH of the resultant solution is 3.5 to 5.5.
26
Each 500 mg vial contains dexrazoxane hydrochloride equivalent to 500 mg dexrazoxane.
27
Hydrochloric Acid, NF is added for pH adjustment. When reconstituted as directed with the 50
28
mL vial of 0.167 Molar (M/6) Sodium Lactate Injection, USP diluent provided, each mL
29
contains: 10 mg dexrazoxane. The pH of the resultant solution is 3.5 to 5.5.
30
31
CLINICAL PHARMACOLOGY
32
33
Mechanism of Action: The mechanism by which ZINECARD exerts its cardioprotective activity is
34
not fully understood. Dexrazoxane is a cyclic derivative of EDTA that readily penetrates cell
35
membranes. Results of laboratory studies suggest that dexrazoxane is converted intracellularly to a
36
ring-opened chelating agent that interferes with iron-mediated free radical generation thought to be
37
responsible, in part, for anthracycline-induced cardiomyopathy.
38
39
Pharmacokinetics: The pharmacokinetics of dexrazoxane have been studied in advanced cancer
40
patients with normal renal and hepatic function. Generally, the pharmacokinetics of dexrazoxane can
41
be adequately described by a two-compartment open model with first-order elimination. Dexrazoxane
42
has been administered as a 15 minute infusion over a dose-range of 60 to 900 mg/m2 with 60 mg/m2
43
of doxorubicin, and at a fixed dose of 500 mg/m2 with 50 mg/m2 doxorubicin. The disposition
44
kinetics of dexrazoxane are dose-independent, as shown by linear relationship between the area under
45
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
ZINECARD (dexrazoxane for injection)
US Package Insert
FDA Approved Labeling for S-006
2(10)
plasma concentration-time curves and administered doses ranging from 60 to 900 mg/m2. The mean
46
peak plasma concentration of dexrazoxane was 36.5 µg/mL at the end of the 15 minute infusion of a
47
500 mg/m2 dose of ZINECARD administered 15 to 30 minutes prior to the 50 mg/m2 doxorubicin
48
dose. The important pharmacokinetic parameters of dexrazoxane are summarized in the following
49
table.
50
SUMMARY OF MEAN (%CVa) DEXRAZOXANE
51
PHARMACOKINETIC PARAMETERS AT A DOSAGE RATIO OF
52
10:1 OF ZINECARD: DOXORUBICIN
53
54
Dose
Doxorubicin
(mg/m2)
Dose
Zinecard
(mg/m2)
Number of
Subjects
Elimination
Half-Life
(h)
Plasma
Clearance
(L/h/m2)
Renal
Clearance
(L/h/m2)
bVolume of
Distribution
(L/m2)
50
500
10
2.5 (16)
7.88 (18)
3.35 (36)
22.4 (22)
60
600
5
2.1 (29)
6.25 (31)
22.0 (55)
a Coefficient of variation
55
b Steady-state volume of distribution
56
57
Following a rapid distributive phase (~0.2 to 0.3 hours), dexrazoxane reaches postdistributive
58
equilibrium within two to four hours. The estimated steady-state volume of distribution of
59
dexrazoxane suggests its distribution primarily in the total body water (25 L/m2). The mean systemic
60
clearance and steady-state volume of distribution of dexrazoxane in two Asian female patients at 500
61
mg/m2 dexrazoxane along with 50mg/m2 doxorubicin were 15.15 L/h/m2 and 36.27 L/m2,
62
respectively, but their elimination half-life and renal clearance of dexrazoxane were similar to those
63
of the ten Caucasian patients from the same study. Qualitative metabolism studies with ZINECARD
64
have confirmed the presence of unchanged drug, a diacid-diamide cleavage product, and two
65
monoacid-monoamide ring products in the urine of animals and man. The metabolite levels were not
66
measured in the pharmacokinetic studies.
67
68
Urinary excretion plays an important role in the elimination of dexrazoxane. Forty-two percent of the
69
500 mg/m2 dose of ZINECARD was excreted in the urine.
70
71
Protein Binding: In vitro studies have shown that ZINECARD is not bound to plasma proteins.
72
73
Special Populations:
74
Pediatric: The pharmacokinetics of ZINECARD have not been evaluated in pediatric patients.
75
Gender: Analysis of pooled data from two pharmacokinetic studies indicate that male patients have a
76
lower mean clearance value than female patients (110 ml/min/m2 versus 133 ml/min/m2). This gender
77
effect is not clinically relevant.
78
Renal insufficiency: The pharmacokinetics of ZINECARD have not been evaluated in patients with
79
renal impairment.
80
Hepatic insufficiency: The pharmacokinetics of ZINECARD have not been evaluated in patients with
81
hepatic impairment. The ZINECARD dose is dependent upon the dose of doxorubicin (see Dosage
82
and Administration). Since a doxorubicin dose reduction is recommended in the presence of
83
hyperbilirubinemia, the ZINECARD dosage is proportionately reduced in patients with hepatic
84
impairment.
85
Drug Interactions: There was no significant change in the pharmacokinetics of doxorubicin (50
86
mg/m2) and its predominant metabolite, doxorubicinol, in the presence of dexrazoxane (500 mg/m2)
87
in a crossover study in cancer patients.
88
89
90
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
ZINECARD (dexrazoxane for injection)
US Package Insert
FDA Approved Labeling for S-006
3(10)
CLINICAL STUDIES
91
92
The ability of ZINECARD to prevent/reduce the incidence and severity of doxorubicin-induced
93
cardiomyopathy was demonstrated in three prospectively randomized placebo-controlled studies. In
94
these studies, patients were treated with a doxorubicin-containing regimen and either ZINECARD or
95
placebo starting with the first course of chemotherapy. There was no restriction on the cumulative
96
dose of doxorubicin. Cardiac function was assessed by measurement of the left ventricular ejection
97
fraction (LVEF), utilizing resting multigated nuclear medicine (MUGA) scans, and by clinical
98
evaluations. Patients receiving ZINECARD had significantly smaller mean decreases from baseline in
99
LVEF and lower incidences of congestive heart failure than the control group. The difference in
100
decline from baseline in LVEF was evident beginning with a cumulative doxorubicin dose of 150
101
mg/m2 and reached statistical significance in patients who received ≥400 mg/m2 of doxorubicin. In
102
addition to evaluating the effect of ZINECARD on cardiac function, the studies also assessed the
103
effect of the addition of ZINECARD on the anti-tumor efficacy of the chemotherapy regimens. In one
104
study (the largest of three breast cancer studies) patients with advanced breast cancer receiving
105
fluorouracil, doxorubicin and cyclophosphamide (FAC) with ZINECARD had a lower response rate
106
(48% vs 63%; p=0.007) and a shorter time to progression than patients who received FAC + placebo,
107
although the survival of patients who did or did not receive ZINECARD with FAC was similar.
108
109
Two of the randomized breast cancer studies evaluating the efficacy and safety of FAC with either
110
ZINECARD or placebo were amended to allow patients on the placebo arm who had attained a
111
cumulative dose of doxorubicin of 300 mg/m2 (six courses of FAC) to receive FAC with open-label
112
ZINECARD for each subsequent course. This change in design allowed examination of whether there
113
was a cardioprotective effect of ZINECARD even when it was started after substantial exposure to
114
doxorubicin.
115
116
Retrospective historical analyses were then performed to compare the likelihood of heart failure in
117
patients to whom ZINECARD was added to the FAC regimen after they had received six (6) courses
118
of FAC (and who then continued treatment with FAC therapy) with the heart failure rate in patients
119
who had received six (6) courses of FAC and continued to receive this regimen without added
120
ZINECARD. These analyses showed that the risk of experiencing a cardiac event (see Table 1 for
121
definition) at a given cumulative dose of doxorubicin above 300 mg/m2 was substantially greater in
122
the 99 patients who did not receive ZINECARD beginning with their seventh course of FAC than in
123
the 102 patients who did receive ZINECARD (See Figure 1).
124
125
Table 1
126
The development of cardiac events is shown by:
127
1. Development of congestive heart failure, defined as having two or more of the following:
128
a. Cardiomegaly by X-ray
129
b. Basilar Rales
130
c. S3 Gallop
131
d. Paroxysmal nocturnal dyspnea and/or orthopnea and/or significant dyspnea on exertion.
132
2. Decline from baseline in LVEF by ≥10% and to below the lower limit of normal for the
133
institution.
134
3. Decline in LVEF by ≥20% from baseline value.
135
4. Decline in LVEF to ≥5% below lower limit of normal for the institution.
136
137
Figure 1 displays the risk of developing congestive heart failure by cumulative dose of doxorubicin in
138
patients who received ZINECARD starting with their seventh course of FAC compared to patients
139
who did not. Patients unprotected by ZINECARD had a 13 times greater risk of developing
140
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
ZINECARD (dexrazoxane for injection)
US Package Insert
FDA Approved Labeling for S-006
4(10)
congestive heart failure. Overall, 3% of patients treated with ZINECARD developed CHF compared
141
with 22% of patients not receiving ZINECARD.
142
143
Figure 1
144
Doxorubicin Dose at Congestive Heart Failure (CHF)
145
FAC vs. FAC/ZINECARD Patients
146
Patients Receiving At Least Seven Courses of Treatment
147
148
149
Because of its cardioprotective effect, ZINECARD permitted a greater percentage of patients to be
150
treated with extended doxorubicin therapy. Figure 2 shows the number of patients still on treatment at
151
increasing cumulative doses.
152
153
Figure 2
154
Cumulative Number of Patients On Treatment
155
FAC vs. FAC/ZINECARD Patients
156
Patients Receiving at Least Seven Courses of Treatment
157
158
159
In addition to evaluating the cardioprotective efficacy of ZINECARD in this setting, the time to
160
tumor progression and survival of these two groups of patients were also compared. There was a
161
similar time to progression in the two groups and survival was at least as long for the group of
162
patients that received ZINECARD starting with their seventh course, i.e., starting after a cumulative
163
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
ZINECARD (dexrazoxane for injection)
US Package Insert
FDA Approved Labeling for S-006
5(10)
dose of doxorubicin of 300 mg/m2. These time to progression and survival data should be interpreted
164
with caution, however, because they are based on comparisons of groups entered sequentially in the
165
studies and are not comparisons of prospectively randomized patients.
166
167
168
INDICATIONS AND USAGE
169
170
ZINECARD is indicated for reducing the incidence and severity of cardiomyopathy associated with
171
doxorubicin administration in women with metastatic breast cancer who have received a cumulative
172
doxorubicin dose of 300 mg/m2 and who will continue to receive doxorubicin therapy to maintain
173
tumor control. It is not recommended for use with the initiation of doxorubicin therapy (see
174
WARNINGS).
175
176
CONTRAINDICATIONS
177
178
ZINECARD should not be used with chemotherapy regimens that do not contain an anthracycline.
179
180
181
WARNINGS
182
183
ZINECARD may add to the myelosuppression caused by chemotherapeutic agents.
184
185
There is some evidence that the use of dexrazoxane concurrently with the initiation of fluorouracil,
186
doxorubicin and cyclophosphamide (FAC) therapy interferes with the antitumor efficacy of the
187
regimen, and this use is not recommended. In the largest of three breast cancer trials, patients who
188
received dexrazoxane starting with their first cycle of FAC therapy had a lower response rate (48% vs
189
63%; p=0.007) and shorter time to progression than patients who did not receive dexrazoxane (see
190
Clinical Studies section of CLINICAL PHARMACOLOGY). Therefore, ZINECARD should only
191
be used in those patients who have received a cumulative doxorubicin dose of 300 mg/m2 and are
192
continuing with doxorubicin therapy.
193
194
Although clinical studies have shown that patients receiving FAC with ZINECARD may receive a
195
higher cumulative dose of doxorubicin before experiencing cardiac toxicity than patients receiving
196
FAC without ZINECARD, the use of ZINECARD in patients who have already received a
197
cumulative dose of doxorubicin of 300 mg/m2 without ZINECARD, does not eliminate the potential
198
for anthracycline induced cardiac toxicity. Therefore, cardiac function should be carefully monitored.
199
200
Secondary malignancies (primarily acute myeloid leukemia) have been reported in patients treated
201
chronically with oral razoxane. Razoxane is the racemic mixture, of which dexrazoxane is the S(+)-
202
enantiomer. In these patients, the total cumulative dose of razoxane ranged from 26 to 480 grams and
203
the duration of treatment was from 42 to 319 weeks. One case of T-cell lymphoma, a case of B-cell
204
lymphoma and six to eight cases of cutaneous basal cell or squamous cell carcinoma have also been
205
reported in patients treated with razoxane.
206
207
208
PRECAUTIONS
209
210
General
211
212
Doxorubicin should not be given prior to the intravenous injection of ZINECARD. ZINECARD
213
should be given by slow I.V. push or rapid drip intravenous infusion from a bag. Doxorubicin should
214
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
ZINECARD (dexrazoxane for injection)
US Package Insert
FDA Approved Labeling for S-006
6(10)
be given within 30 minutes after beginning the infusion with ZINECARD. (See DOSAGE AND
215
ADMINISTRATION).
216
217
As ZINECARD will always be used with cytotoxic drugs, patients should be monitored closely.
218
While the myelosuppressive effects of ZINECARD at the recommended dose are mild, additive
219
effects upon the myelosuppressive activity of chemotherapeutic agents may occur.
220
221
Laboratory tests
222
223
As ZINECARD may add to the myelosuppressive effects of cytotoxic drugs, frequent complete blood
224
counts are recommended. (See ADVERSE REACTIONS).
225
226
Drug Interactions
227
228
ZINECARD does not influence the pharmacokinetics of doxorubicin.
229
230
Carcinogenesis, Mutagenesis, Impairment of Fertility (see WARNINGS section for information
231
on human carcinogenicity)
232
233
No long-term carcinogenicity studies have been carried out with dexrazoxane in animals.
234
Dexrazoxane was not mutagenic in the Ames test but was found to be clastogenic to human
235
lymphocytes in vitro and to mouse bone marrow erythrocytes in vivo(micronucleus test).
236
237
The possible adverse effects of ZINECARD on the fertility of humans and experimental animals,
238
male or female, have not been adequately studied. Testicular atrophy was seen with dexrazoxane
239
administration at doses as low as 30 mg/kg weekly for 6 weeks in rats (1/3 the human dose on a
240
mg/m2 basis) and as low as 20 mg/kg weekly for 13 weeks in dogs (approximately equal to the human
241
dose on a mg/m2 basis).
242
243
Pregnancy - Pregnancy Category C
244
245
Dexrazoxane was maternotoxic at doses of 2 mg/kg (1/40 the human dose on a mg/m2 basis) and
246
embryotoxic and teratogenic at 8 mg/kg (approximately 1/10 the human dose on a mg/m2 basis) when
247
given daily to pregnant rats during the period of organogenesis. Teratogenic effects in the rat included
248
imperforate anus, microphthalmia, and anophthalmia. In offspring allowed to develop to maturity,
249
fertility was impaired in the male and female rats treated in utero during organogenesis at 8 mg/kg. In
250
rabbits, doses of 5 mg/kg (approximately 1/10 the human dose on a mg/m2 basis) daily during the
251
period of organogenesis were maternotoxic and dosages of 20 mg/kg (1/2 the human dose on a mg/m2
252
basis) were embryotoxic and teratogenic. Teratogenic effects in the rabbit included several skeletal
253
malformations such as short tail, rib and thoracic malformations, and soft tissue variations including
254
subcutaneous, eye and cardiac hemorrhagic areas, as well as agenesis of the gallbladder and of the
255
intermediate lobe of the lung. There are no adequate and well-controlled studies in pregnant women.
256
ZINECARD should be used during pregnancy only if the potential benefit justifies the potential risk
257
to the fetus.
258
259
Nursing Mothers
260
261
It is not known whether dexrazoxane is excreted in human milk. Because many drugs are excreted in
262
human milk and because of the potential for serious adverse reactions in nursing infants exposed to
263
dexrazoxane, mothers should be advised to discontinue nursing during dexrazoxane therapy.
264
265
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
ZINECARD (dexrazoxane for injection)
US Package Insert
FDA Approved Labeling for S-006
7(10)
Pediatric Use
266
267
Safety and effectiveness of dexrazoxane in pediatric patients have not been established.
268
269
Geriatric Use
270
271
Clinical studies of ZINECARD did not include sufficient numbers of subjects aged 65 and over to
272
determine whether they respond differently from younger subjects. Other reported clinical experience
273
has not identified differences in responses between the elderly and younger patients. In general,
274
elderly patients should be treated with caution due to the greater frequency of decreased hepatic,
275
renal, or cardiac function, and concomitant disease or other drug therapy.
276
277
ADVERSE REACTIONS
278
279
ZINECARD at a dose of 500 mg/m2 has been administered in combination with FAC in randomized,
280
placebo-controlled, double-blind studies to patients with metastatic breast cancer. The dose of
281
doxorubicin was 50 mg/m2 in each of the trials. Courses were repeated every three weeks, provided
282
recovery from toxicity had occurred. Table 2 below lists the incidence of adverse experiences for
283
patients receiving FAC with either ZINECARD or placebo in the breast cancer studies. Adverse
284
experiences occurring during courses 1 through 6 are displayed for patients receiving ZINECARD or
285
placebo with FAC beginning with their first course of therapy (column 1 & 3, respectively). Adverse
286
experiences occurring at course 7 and beyond for patients who received placebo with FAC during the
287
first six courses and who then received either ZINECARD or placebo with FAC are also displayed
288
(column 2 & 4, respectively).
289
290
Table 2
291
PERCENTAGE (%) OF BREAST CANCER
PATIENTS WITH
ADVERSE EXPERIENCE
FAC + ZINECARD
FAC + PLACEBO
ADVERSE
EXPERIENCE
Courses 1-6
N = 413
Courses ≥ 7
N = 102
Courses 1-6
N = 458
Course ≥ 7
N = 99
Alopecia
94
100
97
98
Nausea
77
51
84
60
Vomiting
59
42
72
49
Fatigue/Malaise
61
48
58
55
Anorexia
42
27
47
38
Stomatitis
34
26
41
28
Fever
34
22
29
18
Infection
23
19
18
21
Diarrhea
21
14
24
7
Pain on Injection
12
13
3
0
Sepsis
17
12
14
9
Neurotoxicity
17
10
13
5
Streaking/Erythema
5
4
4
2
Phlebitis
6
3
3
5
Esophagitis
6
3
7
4
Dysphagia
8
0
10
5
Hemorrhage
2
3
2
1
Extravasation
1
3
1
2
Urticaria
2
2
2
0
Recall Skin Reaction
1
1
2
0
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
ZINECARD (dexrazoxane for injection)
US Package Insert
FDA Approved Labeling for S-006
8(10)
292
The adverse experiences listed above are likely attributable to the FAC regimen with the exception of
293
pain on injection that was observed mainly on the ZINECARD arm.
294
295
Myelosuppression
296
Patients receiving FAC with ZINECARD experienced more severe leucopenia, granulocytopenia and
297
thrombocytopenia at nadir than patients receiving FAC without ZINECARD, but recovery counts
298
were similar for the two groups of patients.
299
300
Hepatic and Renal
301
Some patients receiving FAC + ZINECARD or FAC + placebo experienced marked abnormalities in
302
hepatic or renal function tests, but the frequency and severity of abnormalities in bilirubin, alkaline
303
phosphatase, BUN, and creatinine were similar for patients receiving FAC with or without
304
ZINECARD.
305
306
307
OVERDOSAGE
308
309
There have been no instances of drug overdose in the clinical studies sponsored by either Pharmacia
310
& Upjohn Company or the National Cancer Institute. The maximum dose administered during the
311
cardioprotective trials was 1000 mg/m2 every three weeks.
312
313
Disposition studies with ZINECARD have not been conducted in cancer patients undergoing dialysis,
314
but retention of a significant dose fraction (>0.4) of the unchanged drug in the plasma pool, minimal
315
tissue partitioning or binding, and availability of greater than 90% of the systemic drug levels in the
316
unbound form suggest that it could be removed using conventional peritoneal or hemodialysis.
317
318
There is no known antidote for dexrazoxane. Instances of suspected overdose should be managed
319
with good supportive care until resolution of myelosuppression and related conditions is complete.
320
Management of overdose should include treatment of infections, fluid regulation, and maintenance of
321
nutritional requirements.
322
323
324
DOSAGE AND ADMINISTRATION
325
326
The recommended dosage ratio of ZINECARD:doxorubicin is 10:1 (eg, 500 mg/m2 ZINECARD:50
327
mg/m2 doxorubicin). Since a doxorubicin dose reduction is recommended in the presence of
328
hyperbilirubinemia, the ZINECARD dosage should be proportionately reduced (maintaining the 10:1
329
ratio) in patients with hepatic impairment. ZINECARD must be reconstituted with 0.167 Molar (M/6)
330
Sodium Lactate Injection, USP, to give a concentration of 10 mg ZINECARD for each mL of sodium
331
lactate. The reconstituted solution should be given by slow I.V. push or rapid drip intravenous
332
infusion from a bag. After completing the infusion of ZINECARD, and prior to a total elapsed time of
333
30 minutes (from the beginning of the ZINECARD infusion), the intravenous injection of
334
doxorubicin should be given.
335
336
Reconstituted ZINECARD, when transferred to an empty infusion bag, is stable for 6 hours from the
337
time of reconstitution when stored at controlled room temperature, 15° to 30°C (59° to 86°F) or under
338
refrigeration, 2° to 8°C (36° to 46°F). DISCARD UNUSED SOLUTIONS.
339
340
The reconstituted ZINECARD solution may be diluted with either 0.9% Sodium Chloride Injection,
341
USP or 5.0% Dextrose Injection, USP to a concentration range of 1.3 to 5.0 mg/mL in intravenous
342
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
ZINECARD (dexrazoxane for injection)
US Package Insert
FDA Approved Labeling for S-006
9(10)
infusion bags. The resultant solutions are stable for 6 hours when stored at controlled room
343
temperature, 15° to 30°C (59° to 86°F) or under refrigeration, 2° to 8°C (36° to 46°F). DISCARD
344
UNUSED SOLUTIONS.
345
346
Incompatibility
347
348
ZINECARD should not be mixed with other drugs.
349
350
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
351
administration, whenever solution and container permit.
352
353
Handling and Disposal: Caution in the handling and preparation of the reconstituted solution must
354
be exercised and the use of gloves is recommended. If ZINECARD powder or solutions contact the
355
skin or mucosae, immediately wash thoroughly with soap and water.
356
357
Procedures normally used for proper handling and disposal of anti-cancer drugs should be considered
358
for use with ZINECARD. Several guidelines on this subject have been published.1-7 There is no
359
general agreement that all of the procedures recommended in the guidelines are necessary or
360
appropriate.
361
362
363
HOW SUPPLIED
364
365
ZINECARD® (dexrazoxane for injection) is available in the following strengths as sterile, pyrogen-
366
free lyophilizates.
367
368
NDC 0013-8715-62
250 mg single dose vial with a red
369
flip-top seal, packaged in single vial packs.
370
(This package also contains a 25 mL vial of 0.167 Molar (M/6) Sodium Lactate Injection, USP.)
371
372
NDC 0013-8725-89
500 mg single dose vial with a blue
373
flip-top seal, packaged in single vial packs.
374
(This package also contains a 50 mL vial of 0.167 Molar (M/6) Sodium Lactate Injection, USP.)
375
376
Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room
377
Temperature]. Reconstituted solutions of ZINECARD are stable for 6 hours at controlled room
378
temperature or under refrigeration, 2° to 8°C (36° to 46°F). DISCARD UNUSED SOLUTIONS.
379
380
Rx only
381
382
383
REFERENCES:
384
385
1. ONS Clinical Practice Committee. Cancer Chemotherapy Guidelines and Recommendations for
386
Practice. Pittsburgh, Pa: Oncology Nursing Society; 1999:32-41.
387
388
2. Recommendations for the Safe Handling of Parenteral Antineoplastic Drugs. Washington, DC:
389
Division of Safety, Clinical Center Pharmacy Department and Cancer Nursing Services, National
390
Institutes of Health; 1992. US Dept of Health and Human Services, Public Health Service
391
Publication NIH 92-2621.
392
393
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
ZINECARD (dexrazoxane for injection)
US Package Insert
FDA Approved Labeling for S-006
10(10)
3. AMA Council on Scientific Affairs. Guidelines for Handling Parenteral Antineoplastics. JAMA.
394
1985;253:1590-1591.
395
396
4. National Study Commission on Cytotoxic Exposure – Recommendations for Handling Cytotoxic
397
Agents. 1987. Available from Louis P. Jeffrey, Sc.D., Chairman, National Study Commission on
398
Cytotoxic Exposure. Massachusetts College of Pharmacy and Allied Health Sciences, 179
399
Longwood Avenue, Boston, MA 02115.
400
401
5. Clinical Oncological Society of Australia. Guidelines and Recommendations for Safe Handling of
402
Antineoplastic Agents. Med J Australia. 1983;1:426-428.
403
404
6. Jones RB, Frank R, Mass T. Safe Handling of Chemotherapeutic Agents: A Report from the
405
Mount Sinai Medical Center. CA-A Cancer J for Clin. 1983;33:258-263.
406
407
7. American Society of Hospital Pharmacists. ASHP Technical Assistance Bulletin on Handling
408
Cytotoxic and Hazardous Drugs. Am J Hosp Pharm. 1990;47:1033-1049.
409
410
8. Controlling Occupational Exposure to Hazardous Drugs. (OSHA Work-Practice Guidelines). Am
411
J Health-Syst Pharm. 1996;53-1669-1685.
412
413
414
Manufactured for: Pharmacia & Upjohn Company
415
Kalamazoo, MI 49001, USA
416
By:
SP Pharmaceuticals LLC
417
Albuquerque, NM 87109, USA
418
419
August 1998
817 546 000
420
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
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2025-02-12T13:47:01.804113
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2002/20212se7-004,005,006lbl.pdf', 'application_number': 20212, 'submission_type': 'SUPPL ', 'submission_number': 5}
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12,318
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PRESCRIBING INFORMATION
1
ALKERAN®
2
(melphalan hydrochloride)
3
for Injection
4
5
WARNING
6
Melphalan should be administered under the supervision of a qualified physician experienced in
7
the use of cancer chemotherapeutic agents. Severe bone marrow suppression with resulting
8
infection or bleeding may occur. Controlled trials comparing intravenous (IV) to oral melphalan
9
have shown more myelosuppression with the IV formulation. Hypersensitivity reactions, including
10
anaphylaxis, have occurred in approximately 2% of patients who received the IV formulation.
11
Melphalan is leukemogenic in humans. Melphalan produces chromosomal aberrations in vitro and
12
in vivo and, therefore, should be considered potentially mutagenic in humans.
13
14
DESCRIPTION
15
Melphalan, also known as L-phenylalanine mustard, phenylalanine mustard, L-PAM, or
16
L-sarcolysin, is a phenylalanine derivative of nitrogen mustard. Melphalan is a bifunctional
17
alkylating agent that is active against selected human neoplastic diseases. It is known chemically as
18
4-[bis(2-chloroethyl)amino]-L-phenylalanine. The molecular formula is C13H18Cl2N2O2 and the
19
molecular weight is 305.20. The structural formula is:
20
21
22
23
Melphalan is the active L-isomer of the compound and was first synthesized in 1953 by Bergel
24
and Stock; the D-isomer, known as medphalan, is less active against certain animal tumors, and the
25
dose needed to produce effects on chromosomes is larger than that required with the L-isomer. The
26
racemic (DL-) form is known as merphalan or sarcolysin.
27
Melphalan is practically insoluble in water and has a pKa1 of ∼2.5.
28
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2
ALKERAN for Injection is supplied as a sterile, nonpyrogenic, freeze-dried powder. Each
29
single-use vial contains melphalan hydrochloride equivalent to 50 mg melphalan and 20 mg
30
povidone. ALKERAN for Injection is reconstituted using the sterile diluent provided. Each vial of
31
sterile diluent contains sodium citrate 0.2 g, propylene glycol 6.0 mL, ethanol (96%) 0.52 mL, and
32
Water for Injection to a total of 10 mL. ALKERAN for Injection is administered intravenously.
33
34
CLINICAL PHARMACOLOGY
35
Melphalan is an alkylating agent of the bischloroethylamine type. As a result, its cytotoxicity
36
appears to be related to the extent of its interstrand cross-linking with DNA, probably by binding at
37
the N7 position of guanine. Like other bifunctional alkylating agents, it is active against both resting
38
and rapidly dividing tumor cells.
39
Pharmacokinetics: The pharmacokinetics of melphalan after IV administration has been
40
extensively studied in adult patients. Following injection, drug plasma concentrations declined
41
rapidly in a biexponential manner with distribution phase and terminal elimination phase half-lives
42
of approximately 10 and 75 minutes, respectively. Estimates of average total body clearance varied
43
among studies, but typical values of approximately 7 to 9 mL/min/kg (250 to 325 mL/min/m2) were
44
observed. One study has reported that on repeat dosing of 0.5 mg/kg every 6 weeks, the clearance of
45
melphalan decreased from 8.1 mL/min/kg after the first course, to 5.5 mL/min/kg after the third
46
course, but did not decrease appreciably after the third course. Mean (±SD) peak melphalan plasma
47
concentrations in myeloma patients given IV melphalan at doses of 10 or 20 mg/m2 were 1.2 ± 0.4
48
and 2.8 ± 1.9 mcg/mL, respectively.
49
The steady-state volume of distribution of melphalan is 0.5 L/kg. Penetration into cerebrospinal
50
fluid (CSF) is low. The extent of melphalan binding to plasma proteins ranges from 60% to 90%.
51
Serum albumin is the major binding protein, while α1-acid glycoprotein appears to account for
52
about 20% of the plasma protein binding. Approximately 30% of the drug is (covalently)
53
irreversibly bound to plasma proteins. Interactions with immunoglobulins have been found to be
54
negligible.
55
Melphalan is eliminated from plasma primarily by chemical hydrolysis to
56
monohydroxymelphalan and dihydroxymelphalan. Aside from these hydrolysis products, no other
57
melphalan metabolites have been observed in humans. Although the contribution of renal
58
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
3
elimination to melphalan clearance appears to be low, one study noted an increase in the occurrence
59
of severe leukopenia in patients with elevated BUN after 10 weeks of therapy.
60
Clinical Trial: A randomized trial compared prednisone plus IV melphalan to prednisone plus oral
61
melphalan in the treatment of myeloma. As discussed below, overall response rates at week 22 were
62
comparable; however, because of changes in trial design, conclusions as to the relative activity of
63
the 2 formulations after week 22 are impossible to make.
64
Both arms received oral prednisone starting at 0.8 mg/kg/day with doses tapered over 6 weeks.
65
Melphalan doses in each arm were:
66
Arm 1 Oral melphalan 0.15 mg/kg/day x 7 followed by 0.05 mg/kg/day when WBC began to rise.
67
Arm 2 IV melphalan 16 mg/m2 q 2 weeks x 4 (over 6 weeks) followed by the same dose every
68
4 weeks.
69
Doses of melphalan were adjusted according to the following criteria:
70
71
Table 1. Criteria for Dosage Adjustment in a Randomized Clinical Trial
72
WBC/mm3
Platelets
Percent of Full Dose
≥4,000
≥100,000
100
≥3,000
≥75,000
75
≥2,000
≥50,000
50
≥2,000
<50,000
0
73
One hundred seven patients were randomized to the oral melphalan arm and 203 patients to the
74
IV melphalan arm. More patients had a poor-risk classification (58% versus 44%) and high tumor
75
load (51% versus 34%) on the oral compared to the IV arm (P<0.04). Response rates at week 22 are
76
shown in the following table:
77
78
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
4
Table 2. Response Rates at Week 22
79
Initial Arm
Evaluable
Patients
Responders
n (%)
P
Oral melphalan
100
44 (44%)
IV melphalan
195
74 (38%)
P>0.2
80
Because of changes in protocol design after week 22, other efficacy parameters such as response
81
duration and survival cannot be compared.
82
Severe myelotoxicity (WBC ≤1,000 and/or platelets ≤25,000) was more common in the IV
83
melphalan arm (28%) than in the oral melphalan arm (11%).
84
An association was noted between poor renal function and myelosuppression; consequently, an
85
amendment to the protocol required a 50% reduction in IV melphalan dose if the BUN was
86
≥30 mg/dL. The rate of severe leukopenia in the IV arm in the patients with BUN over 30 mg/dL
87
decreased from 50% (8/16) before protocol amendment to 11% (3/28) (P = 0.01) after the
88
amendment.
89
Before the dosing amendment, there was a 10% (8/77) incidence of drug-related death in the IV
90
arm. After the dosing amendment, this incidence was 3% (3/108). This compares to an overall 1%
91
(1/100) incidence of drug-related death in the oral arm.
92
93
INDICATIONS AND USAGE
94
ALKERAN for Injection is indicated for the palliative treatment of patients with multiple
95
myeloma for whom oral therapy is not appropriate.
96
97
CONTRAINDICATIONS
98
Melphalan should not be used in patients whose disease has demonstrated prior resistance to this
99
agent. Patients who have demonstrated hypersensitivity to melphalan should not be given the drug.
100
101
WARNINGS
102
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5
Melphalan should be administered in carefully adjusted dosage by or under the supervision
103
of experienced physicians who are familiar with the drug's actions and the possible
104
complications of its use.
105
As with other nitrogen mustard drugs, excessive dosage will produce marked bone marrow
106
suppression. Bone marrow suppression is the most significant toxicity associated with ALKERAN
107
for Injection in most patients. Therefore, the following tests should be performed at the start of
108
therapy and prior to each subsequent dose of ALKERAN: platelet count, hemoglobin, white blood
109
cell count, and differential. Thrombocytopenia and/or leukopenia are indications to withhold further
110
therapy until the blood counts have sufficiently recovered. Frequent blood counts are essential to
111
determine optimal dosage and to avoid toxicity. Dose adjustment on the basis of blood counts at the
112
nadir and day of treatment should be considered.
113
Hypersensitivity reactions including anaphylaxis have occurred in approximately 2% of patients
114
who received the IV formulation (see ADVERSE REACTIONS). These reactions usually occur
115
after multiple courses of treatment. Treatment is symptomatic. The infusion should be terminated
116
immediately, followed by the administration of volume expanders, pressor agents, corticosteroids,
117
or antihistamines at the discretion of the physician. If a hypersensitivity reaction occurs, IV or oral
118
melphalan should not be readministered since hypersensitivity reactions have also been reported
119
with oral melphalan.
120
Carcinogenesis: Secondary malignancies, including acute nonlymphocytic leukemia,
121
myeloproliferative syndrome, and carcinoma, have been reported in patients with cancer treated
122
with alkylating agents (including melphalan). Some patients also received other chemotherapeutic
123
agents or radiation therapy. Precise quantitation of the risk of acute leukemia, myeloproliferative
124
syndrome, or carcinoma is not possible. Published reports of leukemia in patients who have
125
received melphalan (and other alkylating agents) suggest that the risk of leukemogenesis increases
126
with chronicity of treatment and with cumulative dose. In one study, the 10-year cumulative risk of
127
developing acute leukemia or myeloproliferative syndrome after oral melphalan therapy was 19.5%
128
for cumulative doses ranging from 730 to 9,652 mg. In this same study, as well as in an additional
129
study, the 10-year cumulative risk of developing acute leukemia or myeloproliferative syndrome
130
after oral melphalan therapy was less than 2% for cumulative doses under 600 mg. This does not
131
mean that there is a cumulative dose below which there is no risk of the induction of secondary
132
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
6
malignancy. The potential benefits from melphalan therapy must be weighed on an individual basis
133
against the possible risk of the induction of a second malignancy.
134
Adequate and well-controlled carcinogenicity studies have not been conducted in animals.
135
However, intraperitoneal (IP) administration of melphalan in rats (5.4 to 10.8 mg/m2) and in mice
136
(2.25 to 4.5 mg/m2) 3 times per week for 6 months followed by 12 months post-dose observation
137
produced peritoneal sarcoma and lung tumors, respectively.
138
Mutagenesis: Melphalan has been shown to cause chromatid or chromosome damage in humans.
139
Intramuscular administration of melphalan at 6 and 60 mg/m2 produced structural aberrations of the
140
chromatid and chromosomes in bone marrow cells of Wistar rats.
141
Impairment of Fertility: Melphalan causes suppression of ovarian function in premenopausal
142
women, resulting in amenorrhea in a significant number of patients. Reversible and irreversible
143
testicular suppression have also been reported.
144
Pregnancy: Pregnancy Category D. Melphalan may cause fetal harm when administered to a
145
pregnant woman. While adequate animal studies have not been conducted with IV melphalan, oral
146
(6 to 18 mg/m2/day for 10 days) and IP (18 mg/m2) administration in rats was embryolethal and
147
teratogenic. Malformations resulting from melphalan included alterations of the brain
148
(underdevelopment, deformation, meningocele, and encephalocele) and eye (anophthalmia and
149
microphthalmos), reduction of the mandible and tail, as well as hepatocele (exomphaly). There are
150
no adequate and well-controlled studies in pregnant women. If this drug is used during pregnancy,
151
or if the patient becomes pregnant while taking this drug, the patient should be apprised of the
152
potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming
153
pregnant.
154
155
PRECAUTIONS
156
General: In all instances where the use of ALKERAN for Injection is considered for
157
chemotherapy, the physician must evaluate the need and usefulness of the drug against the risk of
158
adverse events. Melphalan should be used with extreme caution in patients whose bone marrow
159
reserve may have been compromised by prior irradiation or chemotherapy or whose marrow
160
function is recovering from previous cytotoxic therapy.
161
Dose reduction should be considered in patients with renal insufficiency receiving IV melphalan.
162
In one trial, increased bone marrow suppression was observed in patients with BUN levels
163
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
7
≥30 mg/dL. A 50% reduction in the IV melphalan dose decreased the incidence of severe bone
164
marrow suppression in the latter portion of this study.
165
Information for Patients: Patients should be informed that the major acute toxicities of
166
melphalan are related to bone marrow suppression, hypersensitivity reactions, gastrointestinal
167
toxicity, and pulmonary toxicity. The major long-term toxicities are related to infertility and
168
secondary malignancies. Patients should never be allowed to take the drug without close medical
169
supervision and should be advised to consult their physicians if they experience skin rash, signs or
170
symptoms of vasculitis, bleeding, fever, persistent cough, nausea, vomiting, amenorrhea, weight
171
loss, or unusual lumps/masses. Women of childbearing potential should be advised to avoid
172
becoming pregnant.
173
Laboratory Tests: Periodic complete blood counts with differentials should be performed during
174
the course of treatment with melphalan. At least 1 determination should be obtained prior to each
175
dose. Patients should be observed closely for consequences of bone marrow suppression, which
176
include severe infections, bleeding, and symptomatic anemia (see WARNINGS).
177
Drug Interactions: The development of severe renal failure has been reported in patients treated
178
with a single dose of IV melphalan followed by standard oral doses of cyclosporine. Cisplatin may
179
affect melphalan kinetics by inducing renal dysfunction and subsequently altering melphalan
180
clearance. IV melphalan may also reduce the threshold for BCNU lung toxicity. When nalidixic
181
acid and IV melphalan are given simultaneously, the incidence of severe hemorrhagic necrotic
182
enterocolitis has been reported to increase in pediatric patients.
183
Carcinogenesis, Mutagenesis, Impairment of Fertility: See WARNINGS section.
184
Pregnancy: Teratogenic Effects: Pregnancy Category D: See WARNINGS section.
185
Nursing Mothers: It is not known whether this drug is excreted in human milk. IV melphalan
186
should not be given to nursing mothers.
187
Pediatric Use: The safety and effectiveness in pediatric patients have not been established.
188
Geriatric Use: Clinical studies of ALKERAN for Injection did not include sufficient numbers of
189
subjects aged 65 and over to determine whether they respond differently from younger subjects.
190
Other reported clinical experience has not identified differences in responses between the elderly
191
and younger patients. In general, dose selection for an elderly patient should be cautious, usually
192
starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic,
193
renal, or cardiac function, and of concomitant disease or other drug therapy.
194
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
8
195
ADVERSE REACTIONS (see OVERDOSAGE)
196
The following information on adverse reactions is based on data from both oral and IV
197
administration of melphalan as a single agent, using several different dose schedules for treatment
198
of a wide variety of malignancies.
199
Hematologic: The most common side effect is bone marrow suppression. White blood cell count
200
and platelet count nadirs usually occur 2 to 3 weeks after treatment, with recovery in 4 to 5 weeks
201
after treatment. Irreversible bone marrow failure has been reported.
202
Gastrointestinal: Gastrointestinal disturbances such as nausea and vomiting, diarrhea, and oral
203
ulceration occur infrequently. Hepatic disorders ranging from abnormal liver function tests to
204
clinical manifestations such as hepatitis and jaundice have been reported. Hepatic veno-occlusive
205
disease has been reported.
206
Hypersensitivity: Acute hypersensitivity reactions including anaphylaxis were reported in 2.4%
207
of 425 patients receiving ALKERAN for Injection for myeloma (see WARNINGS). These reactions
208
were characterized by urticaria, pruritus, edema, and in some patients, tachycardia, bronchospasm,
209
dyspnea, and hypotension. These patients appeared to respond to antihistamine and corticosteroid
210
therapy. If a hypersensitivity reaction occurs, IV or oral melphalan should not be readministered
211
since hypersensitivity reactions have also been reported with oral melphalan.
212
Miscellaneous: Other reported adverse reactions include skin hypersensitivity, skin ulceration at
213
injection site, skin necrosis rarely requiring skin grafting, vasculitis, alopecia, hemolytic anemia,
214
allergic reaction, pulmonary fibrosis, and interstitial pneumonitis.
215
216
OVERDOSAGE
217
Overdoses resulting in death have been reported. Overdoses, including doses up to 290 mg/m2,
218
have produced the following symptoms: severe nausea and vomiting, decreased consciousness,
219
convulsions, muscular paralysis, and cholinomimetic effects. Severe mucositis, stomatitis, colitis,
220
diarrhea, and hemorrhage of the gastrointestinal tract occur at high doses (>100 mg/m2). Elevations
221
in liver enzymes and veno-occlusive disease occur infrequently. Significant hyponatremia caused
222
by an associated inappropriate secretion of ADH syndrome has been observed. Nephrotoxicity and
223
adult respiratory distress syndrome have been reported rarely. The principal toxic effect is bone
224
marrow suppression. Hematologic parameters should be closely followed for 3 to 6 weeks. An
225
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
9
uncontrolled study suggests that administration of autologous bone marrow or hematopoietic
226
growth factors (i.e., sargramostim, filgrastim) may shorten the period of pancytopenia. General
227
supportive measures together with appropriate blood transfusions and antibiotics should be
228
instituted as deemed necessary by the physician. This drug is not removed from plasma to any
229
significant degree by hemodialysis or hemoperfusion. A pediatric patient survived a 254-mg/m2
230
overdose treated with standard supportive care.
231
232
DOSAGE AND ADMINISTRATION
233
The usual IV dose is 16 mg/m2. Dosage reduction of up to 50% should be considered in patients
234
with renal insufficiency (BUN ≥30 mg/dL) (see PRECAUTIONS: General). The drug is
235
administered as a single infusion over 15 to 20 minutes. Melphalan is administered at 2-week
236
intervals for 4 doses, then, after adequate recovery from toxicity, at 4-week intervals. Available
237
evidence suggests about one third to one half of the patients with multiple myeloma show a
238
favorable response to the drug. Experience with oral melphalan suggests that repeated courses
239
should be given since improvement may continue slowly over many months, and the maximum
240
benefit may be missed if treatment is abandoned prematurely. Dose adjustment on the basis of
241
blood cell counts at the nadir and day of treatment should be considered.
242
Administration Precautions: As with other toxic compounds, caution should be exercised in
243
handling and preparing the solution of ALKERAN. Skin reactions associated with accidental
244
exposure may occur. The use of gloves is recommended. If the solution of ALKERAN contacts the
245
skin or mucosa, immediately wash the skin or mucosa thoroughly with soap and water.
246
Procedures for proper handling and disposal of anticancer drugs should be considered. Several
247
guidelines on this subject have been published.1-7 There is no general agreement that all of the
248
procedures recommended in the guidelines are necessary or appropriate.
249
Parenteral drug products should be visually inspected for particulate matter and discoloration
250
prior to administration whenever solution and container permit. If either occurs, do not use this
251
product.
252
Preparation for Administration/Stability
253
1. ALKERAN for Injection must be reconstituted by rapidly injecting 10 mL of the supplied
254
diluent directly into the vial of lyophilized powder using a sterile needle (20-gauge or larger
255
needle diameter) and syringe. Immediately shake vial vigorously until a clear solution is
256
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
10
obtained. This provides a 5-mg/mL solution of melphalan. Rapid addition of the diluent
257
followed by immediate vigorous shaking is important for proper dissolution.
258
2. Immediately dilute the dose to be administered in 0.9% Sodium Chloride Injection, USP, to a
259
concentration not greater than 0.45 mg/mL.
260
3. Administer the diluted product over a minimum of 15 minutes.
261
4. Complete administration within 60 minutes of reconstitution.
262
The time between reconstitution/dilution and administration of ALKERAN should be kept
263
to a minimum because reconstituted and diluted solutions of ALKERAN are unstable. Over as
264
short a time as 30 minutes, a citrate derivative of melphalan has been detected in reconstituted
265
material from the reaction of ALKERAN with Sterile Diluent for ALKERAN. Upon further dilution
266
with saline, nearly 1% label strength of melphalan hydrolyzes every 10 minutes.
267
A precipitate forms if the reconstituted solution is stored at 5°C. DO NOT REFRIGERATE THE
268
RECONSTITUTED PRODUCT.
269
270
HOW SUPPLIED
271
ALKERAN for Injection is supplied in a carton containing one single-use clear glass vial of
272
freeze-dried melphalan hydrochloride equivalent to 50 mg melphalan and one 10-mL clear glass
273
vial of sterile diluent (NDC 0173-0130-93).
274
Store at controlled room temperature 15° to 30°C (59° to 86°F) and protect from light.
275
276
REFERENCES
277
1. ONS Clinical Practice Committee. Cancer Chemotherapy Guidelines and Recommendations for
278
Practice. Pittsburgh, PA: Oncology Nursing Society;1999:32-41.
279
2. Recommendations for the safe handling of parenteral antineoplastic drugs. Washington, DC:
280
Division of Safety, Clinical Center Pharmacy Department and Cancer Nursing Services, National
281
Institutes of Health; 1992. US Dept of Health and Human Services. Public Health Service
282
publication NIH 92-2621.
283
3. AMA Council on Scientific Affairs. Guidelines for handling parenteral antineoplastics. JAMA.
284
1985;253:1590-1591.
285
4. National Study Commission on Cytotoxic Exposure. Recommendations for handling cytotoxic
286
agents. 1987. Available from Louis P. Jeffrey, Chairman, National Study Commission on
287
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
11
Cytotoxic Exposure. Massachusetts College of Pharmacy and Allied Health Sciences,
288
179 Longwood Avenue, Boston, MA 02115.
289
5. Clinical Oncological Society of Australia. Guidelines and recommendations for safe handling of
290
antineoplastic agents. Med J Australia. 1983;1:426-428.
291
6. Jones RB, Frank R, Mass T. Safe handling of chemotherapeutic agents: a report from the Mount
292
Sinai Medical Center. CA-A Cancer J for Clin. 1983;33: 258-263.
293
7. American Society of Hospital Pharmacists. ASHP technical assistance bulletin on handling
294
cytotoxic and hazardous drugs. Am J Hosp Pharm. 1990;47:1033-1049.
295
8. Controlling Occupational Exposure to Hazardous Drugs. (OSHA Work-Practice Guidelines.) Am
296
J Health-Syst Pharm. 1996;53:1669-1685.
297
298
299
GlaxoSmithKline
300
Research Triangle Park, NC 27709
301
302
2002, GlaxoSmithKline
303
All rights reserved.
304
305
Date of Issue
RL-
306
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:47:01.893953
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/20207slr007_alkeran_lbl.pdf', 'application_number': 20207, 'submission_type': 'SUPPL ', 'submission_number': 7}
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12,320
|
1
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
ZINECARD safely and effectively. See full prescribing information for
ZINECARD.
ZINECARD® (dexrazoxane) for injection
Initial U.S. Approval: 1995
---------------------------INDICATIONS AND USAGE-----------------------
ZINECARD is a cytoprotective agent indicated for reducing the incidence and
severity of cardiomyopathy associated with doxorubicin administration in
women with metastatic breast cancer who have received a cumulative
doxorubicin dose of 300 mg/m2 and who will continue to receive doxorubicin
therapy to maintain tumor control. Do not use ZINECARD with doxorubicin
initiation. (1)
-----------------------DOSAGE AND ADMINISTRATION----------------------
Reconstitute vial contents and dilute before use. (2.3)
Administer ZINECARD by intravenous infusion over 15 minutes.
DO NOT ADMINISTER VIA AN INTRAVENOUS PUSH. (2.1, 2.3)
The recommended dosage ratio of ZINECARD to doxorubicin is 10:1
(e.g., 500 mg/m2 ZINECARD to 50 mg/m2 doxorubicin). Do not
administer doxorubicin before ZINECARD. (2.1)
Reduce dose by 50% for patients with creatinine clearance <40 mL/min.
(2.2, 8.7)
----------------------DOSAGE FORMS AND STRENGTHS-------------
250 mg or 500 mg single dose vials as sterile, pyrogen-free lyophilizates. (3)
-------------------------------CONTRAINDICATIONS------------------------------
ZINECARD should not be used with non-anthracycline chemotherapy
regimens. (4)
-----------------------WARNINGS AND PRECAUTIONS------------------------
Myelosuppression: ZINECARD may increase the myelosuppresive
effects of chemotherapeutic agents. Perform hematological monitoring.
(5.1)
Embryo-Fetal Toxicity: Can cause fetal harm. Advise female patients of
reproductive potential of the potential hazard to the fetus. (5.5, 8.1)
------------------------------ADVERSE REACTIONS-------------------------------
In clinical studies, ZINECARD was administered to patients also receiving
chemotherapeutic agents for cancer. Pain on injection was observed more
frequently in patients receiving ZINECARD versus placebo. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Pfizer, Inc. at
1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
---------------------------USE IN SPECIFIC POPULATIONS----------------
Nursing Mothers: Discontinue drug or nursing. (8.3)
See 17 for PATIENT COUNSELING INFORMATION
Revised: 04/2014
_______________________________________________________________________________________________________________________________________
FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
2
DOSAGE AND ADMINISTRATION
2.1 Recommended Dose
2.2 Dose Modifications
2.3 Preparation and Administration
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1 Myelosuppression
5.2 Concomitant Chemotherapy
5.3 Cardiac Toxicity
5.4 Secondary Malignancies
5.5 Embryo-Fetal Toxicity
6
ADVERSE REACTIONS
6.1 Clinical Trials Experience
7
DRUG INTERACTIONS
8
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Females of Reproductive Potential
8.7 Renal Impairment
10
OVERDOSAGE
11
DESCRIPTION
12
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.3 Pharmacokinetics
13
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14
CLINICAL STUDIES
15
REFERENCES
16
HOW SUPPLIED/STORAGE AND HANDLING
17
PATIENT COUNSELING INFORMATION
17.1 Myelosuppression
17.2 Embryo-Fetal Toxicity
* Sections or subsections omitted from the full prescribing information are not
listed.
_____________________________________________________________________________________________________________________
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2
FULL PRESCRIBING INFORMATION
1
INDICATIONS AND USAGE
ZINECARD is indicated for reducing the incidence and severity of cardiomyopathy associated
with doxorubicin administration in women with metastatic breast cancer who have received a
cumulative doxorubicin dose of 300 mg/m2 and who will continue to receive doxorubicin
therapy to maintain tumor control. Do not use with the initiation of doxorubicin therapy [see
Warnings and Precautions (5.2)].
2
DOSAGE AND ADMINISTRATION
2.1
Recommended Dose
Administer ZINECARD Injection via intravenous infusion over 15 minutes. DO NOT
ADMINISTER VIA AN INTRAVENOUS PUSH.
The recommended dosage ratio of ZINECARD to doxorubicin is 10:1 (e.g., 500 mg/m2
ZINECARD to 50 mg/m2 doxorubicin). Do not administer doxorubicin before ZINECARD.
Administer doxorubicin within 30 minutes after the completion of ZINECARD infusion.
2.2
Dose Modifications
Dosing in Patients with Renal Impairment
Reduce ZINECARD dosage in patients with moderate to severe renal impairment (creatinine
clearance values less than 40 mL/min) by 50% (ZINECARD to doxorubicin ratio reduced to 5:1;
such as 250 mg/m2 ZINECARD to 50 mg/m2 doxorubicin) [see Use in Specific Populations (8.6)
and Clinical Pharmacology (12.3)].
Dosing in Patients with Hepatic Impairment
Since a doxorubicin dose reduction is recommended in the presence of hyperbilirubinemia,
reduce the ZINECARD dosage proportionately (maintaining the 10:1 ratio) in patients with
hepatic impairment.
2.3
Preparation and Administration
Preparation and Handling of Infusion Solution
Reconstitute ZINECARD with Sterile Water for Injection, USP. Reconstitute with
25 mL for a ZINECARD 250 mg vial and 50 mL for a ZINECARD 500 mg vial to give a
concentration of 10 mg/mL. Dilute the reconstituted solution further with Lactated Ringer’s
Injection, USP to a concentration of 1.3 to 3.0 mg/mL in intravenous infusion bags for
intravenous infusion.
Following reconstitution with Sterile Water for Injection, USP, ZINECARD is stable for
30 minutes at room temperature or if storage is necessary, up to 3 hours from the time of
reconstitution when stored under refrigeration, 2° to 8°C (36° to 46°F). The pH of the resultant
solution is 1.0 to 3.0. DISCARD UNUSED SOLUTIONS. The diluted infusion solutions are
Reference ID: 3460142
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3
stable for one hour at room temperature or if storage is necessary, up to 4 hours when stored
under refrigeration, 2° to 8°C (36° to 46°F). The infusion solutions have a pH of 3.5 to 5.5.
DISCARD UNUSED SOLUTIONS.
Parenteral drug products should be inspected visually for particulate matter and discoloration
prior to administration, whenever solution and container permit. Solutions containing a
precipitate should be discarded.
Use caution when handling and preparing the reconstituted solution. The use of gloves is
recommended. If ZINECARD powder or solutions contact the skin or mucosae, wash exposed
area immediately and thoroughly with soap and water. Follow special handling and disposal
procedures.1
Administration
Do not mix ZINECARD with other drugs.
Administer the final diluted solution of ZINECARD by intravenous infusion over 15 minutes
before the administration of doxorubicin. DO NOT ADMINISTER VIA AN INTRAVENOUS
PUSH. Administer doxorubicin within 30 minutes after the completion of ZINECARD infusion.
3
DOSAGE FORMS AND STRENGTHS
ZINECARD (dexrazoxane for injection) is available in 250 mg or 500 mg single dose vials as
sterile, pyrogen-free lyophilizates.
4
CONTRAINDICATIONS
Do not use ZINECARD with non-anthracycline chemotherapy regimens.
5
WARNINGS AND PRECAUTIONS
5.1
Myelosuppression
ZINECARD may add to the myelosuppression caused by chemotherapeutic agents. Obtain a
complete blood count prior to and during each course of therapy, and administer ZINECARD
and chemotherapy only when adequate hematologic parameters are met.
5.2
Concomitant Chemotherapy
Only use ZINECARD in those patients who have received a cumulative doxorubicin dose of
300 mg/m2 and are continuing with doxorubicin therapy. Do not use with chemotherapy
initiation as ZINECARD may interfere with the antitumor activity of the chemotherapy regimen.
In a trial conducted in patients with metastatic breast cancer who were treated with fluorouracil,
doxorubicin, and cyclophosphamide (FAC) with or without ZINECARD starting with their first
cycle of FAC therapy, patients who were randomized to receive ZINECARD had a lower
response rate (48% vs. 63%) and shorter time to progression than patients who were randomized
to receive placebo.
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4
5.3
Cardiac Toxicity
Treatment with ZINECARD does not completely eliminate the risk of anthracycline-induced
cardiac toxicity. Monitor cardiac function before and periodically during therapy to assess left
ventricular ejection fraction (LVEF). In general, if test results indicate deterioration in cardiac
function associated with doxorubicin, the benefit of continued therapy should be carefully
evaluated against the risk of producing irreversible cardiac damage.
5.4
Secondary Malignancies
Secondary malignancies such as acute myeloid leukemia (AML) and myelodysplastic syndrome
(MDS) have been reported in studies of pediatric patients who have received ZINECARD in
combination with chemotherapy. ZINECARD is not indicated for use in pediatric patients.
Some adult patients who received ZINECARD in combination with anti-cancer agents known to
be carcinogenic have also developed secondary malignancies, including AML and MDS.
Razoxane is the racemic mixture, of which dexrazoxane is the S(+)-enantiomer. Secondary
malignancies (primarily acute myeloid leukemia) have been reported in patients treated
chronically with oral razoxane. In these patients, the total cumulative dose of razoxane ranged
from 26 to 480 grams and the duration of treatment was from 42 to 319 weeks. One case of T-
cell lymphoma, one case of B-cell lymphoma, and six to eight cases of cutaneous basal cell or
squamous cell carcinoma have also been reported in patients treated with razoxane. Long-term
administration of razoxane to rodents was associated with the development of malignancies [see
Nonclinical Toxicology (13.1)].
5.5
Embryo-Fetal Toxicity
ZINECARD can cause fetal harm when administered to pregnant women. Dexrazoxane
administration during the period of organogenesis resulted in maternal toxicity, embryotoxicity
and teratogenicity in rats and rabbits at doses significantly lower than the clinically
recommended dose [see Use in Specific Populations (8.1)]. If this drug is used during
pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be
apprised of the potential hazard to a fetus.
Advise female patients of reproductive potential to avoid becoming pregnant and to use highly
effective contraception during treatment [see Use in Specific Populations (8.6)].
6
ADVERSE REACTIONS
6.1
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, the adverse reaction rates
observed cannot be directly compared to rates in other trials and may not reflect the rates
observed in clinical practice.
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5
The adverse reaction profile described in this section was identified from randomized, placebo-
controlled, double-blind studies in patients with metastatic breast cancer who received the
combination of the FAC chemotherapy regimen with or without ZINECARD. The dose of
doxorubicin was 50 mg/m2 in each of these trials. Treatment was administered every three
weeks until disease progression or cardiac toxicity..
Patients in clinical trials who received FAC with ZINECARD experienced more severe
leukopenia, granulocytopenia, and thrombocytopenia than patients receiving FAC without
ZINECARD [see Warnings and Precautions (5.1)].
Table 1 below lists the incidence of adverse reactions for patients receiving FAC with either
ZINECARD or placebo in the breast cancer studies. Adverse experiences occurring during
courses 1 through 6 are displayed for patients receiving ZINECARD or placebo with FAC
beginning with their first course of therapy (columns 1 and 3, respectively). Adverse
experiences occurring at course 7 and beyond for patients who received placebo with FAC
during the first six courses and who then received either ZINECARD or placebo with FAC are
also displayed (columns 2 and 4, respectively).
The adverse reactions listed below in Table 1 demonstrate that the frequency of adverse
reaction “Pain on Injection” has been greater for ZINECARD arm, as compared to placebo.
Table 1
Adverse Reaction
Percentage (%) of Breast Cancer Patients With Adverse Reaction
FAC + ZINECARD
FAC + Placebo
Courses 1-6
N = 413
Courses ≥ 7
N = 102
Courses 1-6
N = 458
Courses ≥ 7
N = 99
Alopecia
94
100
97
98
Nausea
77
51
84
60
Vomiting
59
42
72
49
Fatigue/Malaise
61
48
58
55
Anorexia
42
27
47
38
Stomatitis
34
26
41
28
Fever
34
22
29
18
Infection
23
19
18
21
Diarrhea
21
14
24
7
Pain on Injection
12
13
3
0
Sepsis
17
12
14
9
Neurotoxicity
17
10
13
5
Streaking/Erythema
5
4
4
2
Phlebitis
6
3
3
5
Esophagitis
6
3
7
4
Dysphagia
8
0
10
5
Hemorrhage
2
3
2
1
Extravasation
1
3
1
2
Urticaria
2
2
2
0
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6
Adverse Reaction
Percentage (%) of Breast Cancer Patients With Adverse Reaction
FAC + ZINECARD
FAC + Placebo
Courses 1-6
N = 413
Courses ≥ 7
N = 102
Courses 1-6
N = 458
Courses ≥ 7
N = 99
Recall Skin
Reaction
1
1
2
0
7
DRUG INTERACTIONS
No drug interactions have been identified [see Clinical Pharmacology (12.3)].
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Pregnancy Category D
Risk Summary
ZINECARD can cause fetal harm when administered to pregnant women. Dexrazoxane
administration resulted in maternal toxicity, embryotoxicity and teratogenicity in rats and rabbits
at doses significantly lower than the clinically recommended dose. If this drug is used during
pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be
apprised of the potential hazard to a fetus [see Warnings and Precautions (5.5)].
Animal Data
Dexrazoxane resulted in maternal toxicity in rats at doses of ≥2 mg/kg (1/40 the human dose on a
mg/m2 basis) and embryotoxicity and teratogenicity at 8 mg/kg (approximately 1/10 the human
dose on a mg/m2 basis) when given daily to pregnant rats during the period of organogenesis.
Teratogenic effects in the rat included imperforate anus, microphthalmia, and anophthalmia. In
offspring allowed to develop to maturity, fertility was impaired in the male and female rats
treated in utero during organogenesis at 8 mg/kg. In rabbits, doses of ≥5 mg/kg (approximately
1/10 the human dose on a mg/m2 basis) daily during the period of organogenesis caused maternal
toxicity and doses of 20 mg/kg (1/2 the human dose on a mg/m2 basis) were embryotoxic and
teratogenic. Teratogenic effects in the rabbit included several skeletal malformations such as
short tail, rib and thoracic malformations, and soft tissue variations including subcutaneous, eye
and cardiac hemorrhagic areas, as well as agenesis of the gallbladder and of the intermediate lobe
of the lung.
8.3
Nursing Mothers
It is not known whether dexrazoxane or its metabolites are excreted in human milk. Because
many drugs are excreted in human milk and because of the potential for serious adverse reactions
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7
in nursing infants from dexrazoxane, a decision should be made whether to discontinue nursing
or discontinue the drug, taking into account the importance of the drug to the mother.
8.4
Pediatric Use
The safety and effectiveness of dexrazoxane in pediatric patients have not been established [see
Warnings and Precautions (5.4)].
8.5
Geriatric Use
Clinical studies of ZINECARD did not include sufficient numbers of subjects aged 65 and over
to determine whether they respond differently than younger subjects. Other reported clinical
experience has not identified differences in responses between the elderly and younger patients.
In general, dose selection for an elderly patient should be cautious, usually starting at the low end
of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac
function, and of concomitant disease or other drug therapy.
8.6
Females of Reproductive Potential
Contraception
ZINECARD can cause fetal harm when administered during pregnancy. Advise female patients of
reproductive potential to use highly effective contraception during treatment [see Use in Specific
Populations (8.1)].
8.7
Renal Impairment
Greater exposure to dexrazoxane may occur in patients with compromised renal function.
Reduce the ZINECARD dose by 50% in patients with creatinine clearance values <40 mL/min
[see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].
10
OVERDOSAGE
There are no data on overdosage in the cardioprotective trials; the maximum dose administered
during the cardioprotective trials was 1000 mg/m2 every three weeks.
Disposition studies with ZINECARD have not been conducted in cancer patients undergoing
dialysis, but retention of a significant dose fraction (>0.4) of the unchanged drug in the plasma
pool, minimal tissue partitioning or binding, and availability of greater than 90% of the systemic
drug levels in the unbound form suggest that it could be removed using conventional peritoneal
or hemodialysis.
There is no known antidote for dexrazoxane. Instances of suspected overdose should be
managed with good supportive care until resolution of myelosuppression and related conditions
is complete. Management of overdose should include treatment of infections, fluid regulation,
and maintenance of nutritional requirements.
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8
11
DESCRIPTION
ZINECARD (dexrazoxane for injection), a cardioprotective agent for use in conjunction with
doxorubicin, is a sterile, pyrogen-free lyophilizate intended for intravenous administration.
Chemically, dexrazoxane is (S)-4,4'-(1-methyl-1,2-ethanediyl)bis-2,6-piperazinedione. The
structural formula is as follows:
C11H16N4O4 M.W. 268.28
Dexrazoxane, an intracellular chelating agent, is a derivative of EDTA. Dexrazoxane is a
whitish crystalline powder that melts at 191° to 197°C. It is sparingly soluble in water and
0.1 N HCl, slightly soluble in ethanol and methanol, and practically insoluble in nonpolar
organic solvents. The pKa is 2.1. Dexrazoxane has an octanol/water partition coefficient of
0.025 and degrades rapidly above a pH of 7.0.
Each 250 mg vial contains dexrazoxane hydrochloride equivalent to 250 mg dexrazoxane.
Hydrochloric Acid, NF is added for pH adjustment. When reconstituted as directed with 25 mL
of Sterile Water for Injection, USP, each mL contains: 10 mg dexrazoxane. The pH of the
resultant solution is 1.0 to 3.0.
Each 500 mg vial contains dexrazoxane hydrochloride equivalent to 500 mg dexrazoxane.
Hydrochloric Acid, NF is added for pH adjustment. When reconstituted as directed with 50 mL
of Sterile Water for Injection, USP, each mL contains: 10 mg dexrazoxane. The pH of the
resultant solution is 1.0 to 3.0.
The reconstituted ZINECARD solutions prepared from Sterile Water for Injection, USP, are
intended for further dilution with Lactated Ringer’s Injection, USP, for rapid intravenous drip
infusion. DO NOT ADMINISTER VIA AN INTRAVENOUS PUSH [see Dosage and
Administration (2.1, 2.3)].
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
The mechanism by which ZINECARD exerts its cytoprotective activity is not fully understood.
Dexrazoxane is a cyclic derivative of EDTA that penetrates cell membranes. Results of
laboratory studies suggest that dexrazoxane is converted intracellularly to a ring-opened
chelating agent that interferes with iron-mediated free radical generation thought to be
responsible, in part, for anthracycline-induced cardiomyopathy.
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9
12.3
Pharmacokinetics
The pharmacokinetics of dexrazoxane have been studied in advanced cancer patients with
normal renal and hepatic function. The pharmacokinetics of dexrazoxane can be adequately
described by a two-compartment open model with first-order elimination. Dexrazoxane has been
administered as a 15 minute infusion over a dose range of 60 to 900 mg/m2 with 60 mg/m2 of
doxorubicin, and at a fixed dose of 500 mg/m2 with 50 mg/m2 doxorubicin. The disposition
kinetics of dexrazoxane are dose-independent, as shown by linear relationship between the area
under plasma concentration-time curves and administered doses ranging from 60 to 900 mg/m2.
The mean peak plasma concentration of dexrazoxane was 36.5 µg/mL at 15- minute after
intravenous administration of 500 mg/m2 dose of ZINECARD over 15 to 30 minutes prior to the
50 mg/m2 doxorubicin dose.
The important pharmacokinetic parameters of dexrazoxane are summarized in Table 2:
Table 2: SUMMARY OF MEAN (%CVa) DEXRAZOXANE
PHARMACOKINETIC PARAMETERS AT A DOSAGE RATIO OF
10:1 OF ZINECARD:DOXORUBICIN
Dose
Doxorubicin
(mg/m2)
Dose
ZINECARD
(mg/m2)
Number of
Subjects
Elimination
Half-Life (h)
Plasma
Clearance
(L/h/m2)
Renal
Clearance
(L/h/m2)
bVolume of
Distribution
(L/m2)
50
500
10
2.5 (16)
7.88 (18)
3.35 (36)
22.4 (22)
60
600
5
2.1 (29)
6.25 (31)
—
22.0 (55)
a Coefficient of variation
b Steady-state volume of distribution
Distribution
Following a rapid distributive phase (0.2 to 0.3 hours), dexrazoxane reaches post-distributive
equilibrium within two to four hours. The estimated mean steady-state volume of distribution of
dexrazoxane is 22.4 L/m2 after 500 mg/m2 of ZINECARD dose followed by 50 mg/m2 of
doxorubicin, suggesting distribution throughout total body water (25 L/m2).
In vitro studies have shown that dexrazoxane is not bound to plasma proteins.
Metabolism
Qualitative metabolism studies with dexrazoxane have confirmed the presence of unchanged
drug, a diacid-diamide cleavage product, and two monoacid-monoamide ring products in the
urine of animals and man. The metabolite levels were not measured in the pharmacokinetic
studies.
Excretion
Urinary excretion plays an important role in the elimination of dexrazoxane. Forty-two percent
of a 500 mg/m2 dose of ZINECARD was excreted in the urine. Renal clearance averages
3.35 L/h/m2 after the 500 mg/m2 ZINECARD dose followed by 50 mg/m2 of doxorubicin.
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10
Specific Populations
Pediatric
Pharmacokinetics following ZINECARD administration have not been evaluated in pediatric
patients.
Effect of Renal Impairment
The pharmacokinetics of dexrazoxane were assessed following a single 15-minute IV infusion of
150 mg/m2 of ZINECARD. Dexrazoxane clearance was reduced in subjects with renal
dysfunction. Compared with controls, the mean AUC0-inf value was two-fold greater in subjects
with moderate (CLCR 30-50 mL/min) to severe (CLCR <30 mL/min) renal dysfunction.
Modeling demonstrated that equivalent exposure (AUC-inf) could be achieved if dosing were
reduced by 50% in subjects with creatinine clearance values <40 mL/min compared with
control subjects (CLCR >80 mL/min) [see Use in Specific Populations (8.7) and Dosage and
Administration (2.2)].
Effect of Hepatic Impairment
Pharmacokinetics following ZINECARD administration have not been evaluated in patients
with hepatic impairment. The ZINECARD dose is dependent upon the dose of doxorubicin [see
Dosage and Administration (2.2)].
Drug Interactions
There was no significant change in the pharmacokinetics of doxorubicin (50 mg/m2) and its
predominant metabolite, doxorubicinol, in the presence of dexrazoxane (500 mg/m2) in a
crossover study in cancer patients.
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
No long-term carcinogenicity studies have been carried out with dexrazoxane in animals.
Nevertheless, a study by the National Cancer Institute has reported that long-term dosing with
razoxane (the racemic mixture of dexrazoxane, ICRF-187, and its enantiomer ICRF-186) is
associated with the development of malignancies in rats and possibly in mice [see Warnings and
Precautions (5.4)].
Dexrazoxane was not mutagenic in the bacterial reverse mutation (Ames) test, but was found to
be clastogenic to human lymphocytes in vitro and to mouse bone marrow erythrocytes in vivo
(micronucleus test).
ZINECARD has the potential to impair fertility in male patients based on effects in repeat-dose
toxicology studies. Testicular atrophy was seen with dexrazoxane administration at doses as low
as 30 mg/kg weekly for 6 weeks in rats (1/3 the human dose on a mg/m2 basis) and as low as
20 mg/kg weekly for 13 weeks in dogs (approximately equal to the human dose on a mg/m2
basis).
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11
14
CLINICAL STUDIES
The ability of ZINECARD to prevent/reduce the incidence and severity of doxorubicin-induced
cardiomyopathy was evaluated in three prospectively randomized placebo-controlled studies. In
these studies, patients were treated with a doxorubicin-containing regimen and either
ZINECARD or placebo starting with the first course of chemotherapy. There was no restriction
on the cumulative dose of doxorubicin. Cardiac function was assessed by measurement of the
LVEF, utilizing resting multigated nuclear medicine (MUGA) scans, and by clinical evaluations.
Patients receiving ZINECARD had significantly smaller mean decreases from baseline in LVEF
and lower incidences of congestive heart failure than the control group; however, in the largest
study, patients with advanced breast cancer receiving FAC with ZINECARD had a lower
response rate (48% vs. 63%) and a shorter time to progression than patients who received FAC
versus placebo.
In the clinical trials, patients who were initially randomized to receive placebo were allowed to
receive ZINECARD after a cumulative dose of doxorubicin above 300 mg/m2. Retrospective
historical analyses showed that the risk of experiencing a cardiac event (see Table 3 for
definition) at a cumulative dose of doxorubicin above 300 mg/m2 was greater in the patients who
did not receive ZINECARD beginning with their seventh course of FAC than in the patients who
did receive ZINECARD (HR=13.08; 95% CI: 3.72, 46.03; p<0.001). Overall, 3% of patients
treated with ZINECARD developed CHF compared with 22% of patients not receiving
ZINECARD.
Table 3: Definition of Cardiac Events:
1.
Development of congestive heart failure, defined as having two or more of the
following:
a.
Cardiomegaly by X-ray
b.
Basilar Rales
c.
S3 Gallop
d.
Paroxysmal nocturnal dyspnea and/or orthopnea and/or significant dyspnea
on exertion.
2.
Decline from baseline in LVEF by ≥10% and to below the lower limit of normal
for the institution.
3.
Decline in LVEF by ≥20% from baseline value.
4.
Decline in LVEF to ≥5% below lower limit of normal for the institution.
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12
Figure 1 shows the number of patients still on treatment at increasing cumulative doses.
Figure 1
Cumulative Number of Patients On Treatment
FAC vs. FAC/ZINECARD Patients
Patients Receiving at Least Seven Courses of Treatment
15
REFERENCES
1. “OSHA Hazardous Drugs.” OSHA http://www.osha.gov/SLTC/hazardousdrugs/index.html.
16
HOW SUPPLIED/STORAGE AND HANDLING
ZINECARD (dexrazoxane for injection) is available in the following strengths as sterile,
pyrogen-free lyophilizates.
NDC 0013-8717-62
250 mg single dose vial with a red flip-top seal, packaged in single vial packs.
NDC 0013-8727-89
500 mg single dose vial with a blue flip-top seal, packaged in single vial packs.
Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled
Room Temperature].
Follow special handling and disposal procedures.1
Reference ID: 3460142
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13
17
PATIENT COUNSELING INFORMATION
17.1
Myelosuppression
Treatment with ZINECARD is associated with leukopenia, neutropenia, and thrombocytopenia.
Perform hematological monitoring [see Warnings and Precautions (5.1), (5.6)].
17.2
Embryo-Fetal Toxicity
Counsel patients on pregnancy planning and prevention. Advise female patients of reproductive
potential that ZINECARD can cause fetal harm and to use highly effective contraception during
treatment [see Warnings and Precautions (5.5) and Use in Specific Populations (8.1, 8.6)].
This product’s label may have been updated. For current full prescribing information, please visit
www.pfizer.com.
LAB-0060-8.3
Reference ID: 3460142
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|
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2025-02-12T13:47:01.953410
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HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
ZEMURON safely and effectively. See full prescribing information for
ZEMURON.
ZEMURON (rocuronium bromide) injection solution for intravenous use
Initial U.S. Approval: 1994
-------------------------------RECENT MAJOR CHANGES--------------------------
Dosage and Administration, Dosage in Specific Populations (2.5) 8/2008
Warnings and Precautions,
Residual Paralysis (5.4)
8/2008
Long-term Use in an Intensive Care Unit (5.5)
8/2008
QT Interval Prolongation (5.8)
8/2008
------------------------------INDICATIONS AND USAGE----------------------------
ZEMURON is a nondepolarizing neuromuscular blocking agent indicated as an
adjunct to general anesthesia to facilitate both rapid sequence and routine
tracheal intubation, and to provide skeletal muscle relaxation during surgery or
mechanical ventilation. (1)
-------------------------DOSAGE AND ADMINISTRATION------------------------
To be administered only by experienced clinicians or adequately trained
individuals supervised by an experienced clinician familiar with the use actions,
characteristics, and complications of neuromuscular blocking agents. (2)
• Individualize the dose for each patient. (2)
• Peripheral nerve stimulator recommended for determination of drug response
and need for additional doses, and to evaluate recovery. (2)
• Tracheal intubation: Recommended initial dose is 0.6 mg/kg (2.1)
• Rapid sequence intubation: 0.6 to 1.2 mg/kg (2.2)
• Maintenance doses: Guided by response to prior dose, not administered until
recovery is evident. (2.3)
• Continuous infusion: Initial rate of 10 to 12 mcg/kg/min. Start only after
early evidence of spontaneous recovery from an intubating dose. (2.4)
--------------------------DOSAGE FORMS AND STRENGTHS--------------------
• 5 mL multiple dose vials containing 50 mg rocuronium bromide injection (10
mg/mL) (3)
• 10 mL multiple dose vials containing 100 mg rocuronium bromide injection
(10 mg/mL) (3)
-----------------------------------CONTRAINDICATIONS--------------------------
• Hypersensitivity (e.g., anaphylaxis) to rocuronium bromide or other
neuromuscular blocking agents (4)
------------------------------WARNINGS AND PRECAUTIONS--------------------
• Appropriate Administration and Monitoring: Use only if facilities for
intubation, mechanical ventilation, oxygen therapy, and an antagonist are
immediately available. (5.1)
• Anaphylaxis: Severe anaphylaxis has been reported. Consider cross-
reactivity among neuromuscular blocking agents. (5.2)
• Need for Adequate Anesthesia: Must be accompanied by adequate anesthesia
or sedation. (5.3)
• Residual Paralysis: Consider using a reversal agent in cases where residual
paralysis is more likely to occur. (5.4)
-----------------------------------ADVERSE REACTIONS-----------------------------
Most common adverse reactions (2%) are transient hypotension and
hypertension. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Schering-
Plough at 1-800-526-4099 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
-----------------------------------DRUG INTERACTIONS-----------------------------
• Succinylcholine: Use before succinylcholine has not been studied. (7.11)
• Nondepolarizing muscle relaxants: Interactions have been observed. (7.7)
• Enhanced ZEMURON activity possible: Inhalation anesthetics (7.3), certain
antibiotics (7.1), quinidine (7.10), magnesium (7.6), lithium (7.4), local
anesthetics (7.5), procainamide (7.8)
• Reduced ZEMURON activity possible: Anticonvulsants (7.2)
------------------------------USE IN SPECIFIC POPULATIONS--------------------
• Labor and Delivery: Not recommended for rapid sequence induction in
patients undergoing Cesarean section. (8.2)
• Pediatric Use: Onset time and duration will vary with dose, age, and
anesthetic technique. Not recommended for rapid sequence intubation in
pediatric patients. (8.4)
See 17 for PATIENT COUNSELING INFORMATION.
Revised: 8/2008
1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
2
DOSAGE AND ADMINISTRATION
2.1
Dose for Tracheal Intubation
2.2
Rapid Sequence Intubation
2.3
Maintenance Dosing
2.4
Use by Continuous Infusion
2.5
Dosage in Specific Populations
2.6
Preparation for Administration of ZEMURON
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1
Appropriate Administration and Monitoring
5.2
Anaphylaxis
5.3
Need for Adequate Anesthesia
5.4
Residual Paralysis
5.5
Long-term Use in an Intensive Care Unit
5.6
Malignant Hyperthermia (MH)
5.7
Prolonged Circulation Time
5.8
QT Interval Prolongation
5.9
Conditions/Drugs Causing Potentiation of, or Resistance to,
Neuromuscular Block
5.10 Incompatibility with Alkaline Solutions
5.11 Increase in Pulmonary Vascular Resistance
5.12 Use in Patients with Myasthenia
5.13 Extravasation
6
ADVERSE REACTIONS
6.1
Clinical Trials Experience
6.2
Post-Marketing Experience
7
DRUG INTERACTIONS
7.1
Antibiotics
7.2
Anticonvulsants
7.3
Inhalation Anesthetics
7.4
Lithium Carbonate
7.5
Local Anesthetics
7.6
Magnesium
7.7
Nondepolarizing Muscle Relaxants
7.8
Procainamide
7.9
Propofol
7.10 Quinidine
7.11 Succinylcholine
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
8.2
Labor and Delivery
8.4. Pediatric Use
8.5. Geriatric Use
8.6. Patients with Hepatic Impairment
8.7. Patients with Renal Impairment
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
14.1 Adult Patients
14.2 Geriatric Patients
14.3 Pediatric Patients
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information are not
listed.
2
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
FULL PRESCRIBING INFORMATION
1
INDICATIONS AND USAGE
ZEMURON® (rocuronium bromide) Injection is indicated for inpatients and outpatients as an adjunct
to general anesthesia to facilitate both rapid sequence and routine tracheal intubation, and to provide
skeletal muscle relaxation during surgery or mechanical ventilation.
2
DOSAGE AND ADMINISTRATION
ZEMURON is for intravenous use only. This drug should only be administered by experienced
clinicians or trained individuals supervised by an experienced clinician familiar with the use, actions,
characteristics and complications of neuromuscular blocking agents. Doses of ZEMURON injection
should be individualized and a peripheral nerve stimulator should be used to monitor drug effect,
need for additional doses, adequacy of spontaneous recovery or antagonism, and to decrease the
complications of overdosage if additional doses are administered.
The dosage information which follows is derived from studies based upon units of drug per unit of
body weight. It is intended to serve as an initial guide to clinicians familiar with other neuromuscular
blocking agents to acquire experience with ZEMURON.
In patients in whom potentiation of, or resistance to, neuromuscular block is anticipated, a dose
adjustment should be considered [see Dosage and Administration (2.5), Warnings and Precautions (5.9,
5.12), Drug Interactions (7.2, 7.3, 7.4, 7.5 7.6, 7.8, 7.10), and Use in Specific Populations (8.6 ].
2.1 Dose for Tracheal Intubation
The recommended initial dose of ZEMURON, regardless of anesthetic technique, is 0.6 mg/kg.
Neuromuscular block sufficient for intubation (80% block or greater) is attained in a median (range) time
of 1 (0.4–6) minute(s) and most patients have intubation completed within 2 minutes. Maximum blockade
is achieved in most patients in less than 3 minutes. This dose may be expected to provide 31 (15–85)
minutes of clinical relaxation under opioid/nitrous oxide/oxygen anesthesia. Under halothane, isoflurane,
and enflurane anesthesia, some extension of the period of clinical relaxation should be expected [see Drug
Interactions (7.3)].
A lower dose of ZEMURON (0.45 mg/kg) may be used. Neuromuscular block sufficient for intubation
(80% block or greater) is attained in a median (range) time of 1.3 (0.8–6.2) minute(s) and most patients
have intubation completed within 2 minutes. Maximum blockade is achieved in most patients in less than 4
minutes. This dose may be expected to provide 22 (12–31) minutes of clinical relaxation under
opioid/nitrous oxide/oxygen anesthesia. Patients receiving this low dose of 0.45 mg/kg who achieve less
than 90% block (about 16% of these patients) may have a more rapid time to 25% recovery, 12 to 15
minutes.
A large bolus dose of 0.9 or 1.2 mg/kg can be administered under opioid/nitrous oxide/oxygen
anesthesia without adverse effects to the cardiovascular system [see Clinical Pharmacology (12.2)].
2.2 Rapid Sequence Intubation
In appropriately premedicated and adequately anesthetized patients, ZEMURON 0.6 to 1.2 mg/kg will
provide excellent or good intubating conditions in most patients in less than 2 minutes [see Clinical Studies
(14.1)].
2.3 Maintenance Dosing
Maintenance doses of 0.1, 0.15, and 0.2 mg/kg ZEMURON, administered at 25% recovery of control
T1 (defined as 3 twitches of train-of-four), provide a median (range) of 12 (2–31), 17 (6–50) and 24 (7–69)
minutes of clinical duration under opioid/nitrous oxide/oxygen anesthesia [see Clinical Pharmacology
(12.2)]. In all cases, dosing should be guided based on the clinical duration following initial dose or prior
maintenance dose and not administered until recovery of neuromuscular function is evident. A clinically
insignificant cumulation of effect with repetitive maintenance dosing has been observed [see Clinical
Pharmacology (12.2)].
3
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2.4 Use by Continuous Infusion
Infusion at an initial rate of 10 to 12 mcg/kg/min of ZEMURON should be initiated only after early
evidence of spontaneous recovery from an intubating dose. Due to rapid redistribution [see Clinical
Pharmacology (12.3)] and the associated rapid spontaneous recovery, initiation of the infusion after
substantial return of neuromuscular function (more than 10% of control T1), may necessitate additional
bolus doses to maintain adequate block for surgery.
Upon reaching the desired level of neuromuscular block, the infusion of ZEMURON must be
individualized for each patient. The rate of administration should be adjusted according to the patient’s
twitch response as monitored with the use of a peripheral nerve stimulator. In clinical trials, infusion rates
have ranged from 4 to 16 mcg/kg/min.
Inhalation anesthetics, particularly enflurane and isoflurane, may enhance the neuromuscular blocking
action of nondepolarizing muscle relaxants. In the presence of steady-state concentrations of enflurane or
isoflurane, it may be necessary to reduce the rate of infusion by 30 to 50%, at 45 to 60 minutes after the
intubating dose.
Spontaneous recovery and reversal of neuromuscular blockade following discontinuation of
ZEMURON infusion may be expected to proceed at rates comparable to that following comparable total
doses administered by repetitive bolus injections [see Clinical Pharmacology (12.2)].
Infusion solutions of ZEMURON can be prepared by mixing ZEMURON with an appropriate infusion
solution such as 5% glucose in water or lactated Ringers [see Dosage and Administration (2.6)]. These
infusion solutions should be used within 24 hours of mixing. Unused portions of infusion solutions should
be discarded.
Infusion rates of ZEMURON can be individualized for each patient using the following tables for three
different concentrations of ZEMURON solution as guidelines:
TABLE 1: Infusion Rates Using ZEMURON® Injection (0.5 mg/mL)*
Patient
Weight
Drug Delivery Rate (mcg/kg/min)
4
5
6
7
8
9
10
12
14
16
(kg)
(lbs)
Infusion Delivery Rate (mL/hr)
10
22
4. 8
6
7. 2
8. 4
9. 6
10. 8
12
14. 4
16. 8
19. 2
15
33
7. 2
9
10. 8
12. 6
14. 4
16. 2
18
21. 6
25. 2
28. 8
20
44
9. 6
12
14. 4
16. 8
19. 2
21. 6
24
28. 8
33. 6
38. 4
25
55
12
15
18
21
24
27
30
36
42
48
35
77
16. 8
21
25. 2
29. 4
33. 6
37. 8
42
50. 4
58. 8
67. 2
50
110
24
30
36
42
48
54
60
72
84
96
60
132
28. 8
36
43. 2
50. 4
57. 6
64. 8
72
86. 4
100. 8
115. 2
70
154
33. 6
42
50. 4
58. 8
67. 2
75. 6
84
100. 8
117. 6
134. 4
80
176
38. 4
48
57. 6
67. 2
76. 8
86. 4
96
115. 2
134. 4
153. 6
90
198
43. 2
54
64. 8
75. 6
86. 4
97. 2
108
129. 6
151. 2
172. 8
100
220
48
60
72
84
96
108
120
144
168
192
4
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
TABLE 2: Infusion Rates Using ZEMURON® Injection (1 mg/mL)**
Patient
Weight
Drug Delivery Rate (mcg/kg/min)
4
5
6
7
8
9
10
12
14
16
(kg)
(lbs)
Infusion Delivery Rate (mL/hr)
10
22
2. 4
3
3. 6
4. 2
4. 8
5. 4
6
7. 2
8. 4
9. 6
15
33
3. 6
4. 5
5. 4
6. 3
7. 2
8. 1
9
10. 8
12. 6
14. 4
20
44
4. 8
6
7. 2
8. 4
9. 6
10. 8
12
14. 4
16. 8
19. 2
25
55
6
7. 5
9
10. 5
12
13. 5
15
18
21
24
35
77
8..4
10. 5
12. 6
14. 7
16. 8
18. 9
21
25. 2
29. 4
33. 6
50
110
12
15
18
21
24
27
30
36
42
48
60
132
14.4
18
21. 6
25. 2
28. 8
32. 4
36
43. 2
50. 4
57. 6
70
154
16. 8
21
25. 2
29. 4
33. 6
37. 8
42
50. 4
58. 8
67. 2
80
176
19. 2
24
28. 8
33. 6
38. 4
43. 2
48
57. 6
67. 2
76. 8
90
198
21. 6
27
32. 4
37. 8
43. 2
48. 6
54
64. 8
75. 6
86. 4
100
220
24
30
36
42
48
54
60
72
84
96
TABLE 3: Infusion Rates Using ZEMURON® Injection (5 mg/mL)***
Patient
Weight
Drug Delivery Rate (mcg/kg/min)
4
5
6
7
8
9
10
12
14
16
(kg)
(lbs)
Infusion Delivery Rate (mL/hr)
10
22
0. 5
0. 6
0. 7
0. 8
1
1. 1
1. 2
1. 4
1. 7
1. 9
15
33
0. 7
0. 9
1. 1
1. 3
1. 4
1. 6
1. 8
2. 2
2. 5
2. 9
20
44
1
1. 2
1. 4
1. 7
1. 9
2. 2
2. 4
2. 9
3. 4
3. 8
25
55
1. 2
1. 5
1. 8
2. 1
2. 4
2. 7
3
3. 6
4. 2
4. 8
35
77
1. 7
2. 1
2. 5
2. 9
3. 4
3. 8
4. 2
5
5. 9
6. 7
50
110
2. 4
3
3. 6
4. 2
4. 8
5. 4
6
7. 2
8. 4
9. 6
60
132
2. 9
3. 6
4. 3
5
5. 8
6. 5
7. 2
8. 6
10. 1
11. 5
70
154
3. 4
4. 2
5
5. 9
6. 7
7. 6
8. 4
10. 1
11. 8
13. 4
80
176
3. 8
4. 8
5. 8
6. 7
7. 7
8. 6
9. 6
11. 5
13. 4
15. 4
90
198
4. 3
5. 4
6. 5
7. 6
8. 6
9. 7
10. 8
13
15. 1
17. 3
100
220
4. 8
6
7. 2
8. 4
9. 6
10. 8
12
14. 4
16. 8
19. 2
* 50 mg ZEMURON in 100 mL solution
** 100 mg ZEMURON® in 100 mL solution
***500 mg ZEMURON in 100 mL solution
2.5 Dosage in Specific Populations
Pediatric Patients
The recommended initial intubation dose of ZEMURON is 0.6 mg/kg, however, a lower dose of 0.45
mg/kg may be used depending on anesthetic technique and the age of the patient.
For sevoflurane (induction) ZEMURON doses of 0.45 mg/kg and 0.6 mg/kg in general produce
excellent to good intubating conditions within 75 seconds. When halothane is used, a 0.6 mg/kg dose of
ZEMURON resulted in excellent to good intubating conditions within 60 seconds.
The time to maximum block for an intubating dose was shortest in infants (28 days up to 3 months)
and longest in neonates (birth to less than 28 days). The duration of clinical relaxation following an
intubating dose is shortest in children (greater than 2 years up to 11 years) and longest in infants.
When sevoflurane is used for induction and isoflurane/nitrous oxide for maintenance of general
anesthesia, maintenance dosing of ZEMURON can be administered as bolus doses of 0.15 mg/kg at
reappearance of T3 in all pediatric age groups. Maintenance dosing can also be administered at the
reappearance of T2 at a rate of 7-10 mcg/kg/min with the lowest dose requirement for neonates (birth to
less than 28 days) and the highest dose requirement for children (greater than 2 years up to 11 years).
When halothane is used for general anesthesia, patients ranging from 3 months old through
adolescence can be administered ZEMURON maintenance doses of 0.075 to 0.125 mg/kg upon return of
T1 to 0.25% to provide clinical relaxation for 7 to 10 minutes. Alternatively, a continuous infusion of
5
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
ZEMURON initiated at a rate of 12 mcg/kg/min upon return of T1 to 10% (one twitch present in train-of
four), may also be used to maintain neuromuscular blockade in pediatric patients.
Additional information for administration to pediatric patients of all age groups is presented elsewhere
in the label [see Clinical Pharmacology (12.2)].
The infusion of ZEMURON must be individualized for each patient. The rate of administration should
be adjusted according to the patient’s twitch response as monitored with the use of a peripheral nerve
stimulator. Spontaneous recovery and reversal of neuromuscular blockade following discontinuation of
ZEMURON infusion may be expected to proceed at rates comparable to that following similar total
exposure to single bolus doses [see Clinical Pharmacology (12.2)].
ZEMURON is not recommended for rapid sequence intubation in pediatric patients.
Geriatric Patients
Geriatric patients (65 years or older) exhibited a slightly prolonged median (range) clinical duration of
46 (22–73), 62 (49–75), and 94 (64–138) minutes under opioid/nitrous oxide/oxygen anesthesia following
doses of 0.6, 0.9, and 1.2 mg/kg, respectively. No differences in duration of neuromuscular blockade
following maintenance doses of ZEMURON were observed between these subjects and younger subjects,
and other reported clinical experience has not identified differences in response between elderly and
younger patients, but greater sensitivity of some older individuals cannot be ruled out. [see Clinical
Pharmacology (12.2, 12.3)]
Patients with Renal or Hepatic Impairment
No differences from patients with normal hepatic and kidney function were observed for onset time at
a dose of 0.6 mg/kg ZEMURON. When compared to patients with normal renal and hepatic function, the
mean clinical duration is similar in patients with end-stage renal disease undergoing renal transplant, and is
about 1.5 times longer in patients with hepatic disease. Patients with renal failure may have a greater
variation in duration of effect [see Use in Specific Populations (8.6, 8.7) and Clinical Pharmacology
(12.3)].
Obese Patients
In obese patients, the initial dose of ZEMURON 0.6 mg/kg should be based upon the patient’s actual
body weight [see Clinical Studies (14.1)].
An analysis across all US controlled clinical studies indicates that the pharmacodynamics of
ZEMURON are not different between obese and non-obese patients when dosed based upon their actual
body weight.
Patients with Reduced Plasma Cholinesterase Activity
Rocuronium metabolism does not depend on plasma cholinesterase so dosing adjustments are not needed in
patients with reduced plasma cholinesterase activity.
Patients withProlonged Circulation Time
Because higher doses of ZEMURON produce a longer duration of action, the initial dosage should
usually not be increased in these patients to reduce onset time; instead, in these situations, when feasible,
more time should be allowed for the drug to achieve onset of effect [see Warnings and Precautions (5.7)].
Patients with Drugs or Conditions Causing Potentiation of Neuromuscular Block
The neuromuscular blocking action of ZEMURON is potentiated by isoflurane and enflurane
anesthesia. Potentiation is minimal when administration of the recommended dose of ZEMURON occurs
prior to the administration of these potent inhalation agents. The median clinical duration of a dose of 0.57
to 0.85 mg/kg was 34, 38, and 42 minutes under opioid/nitrous oxide/oxygen, enflurane and isoflurane
maintenance anesthesia, respectively. During 1 to 2 hours of infusion, the infusion rate of ZEMURON
required to maintain about 95% block was decreased by as much as 40% under enflurane and isoflurane
anesthesia [see Drug Interactions (7.3)].
6
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2.6 Preparation for Administration of ZEMURON
Diluent Compatibility
ZEMURON is compatible in solution with:
0.9% NaCl solution
sterile water for injection
5% glucose in water
lactated Ringers
5% glucose in saline
ZEMURON is compatible in the above solutions at concentrations up to 5 mg/mL for 24 hours at room
temperature in plastic bags, glass bottles, and plastic syringe pumps.
Drug Admixture Incompatibility
ZEMURON is physically incompatible when mixed with the following drugs:
amphotericin
hydrocortisone sodium succinate
amoxicillin
insulin
azathioprine
intralipid
cefazolin
ketorolac
cloxacillin
lorazepam
dexamethasone
methohexital
diazepam
methylprednisolone
erythromycin
thiopental
famotidine
trimethoprim
furosemide
vancomycin
If ZEMURON is administered via the same infusion line that is also used for other drugs, it is
important that this infusion line is adequately flushed between administration of ZEMURON and drugs for
which incompatibility with ZEMURON has been demonstrated or for which compatibility with
ZEMURON has not been established.
Infusion solutions should be used within 24 hours of mixing. Unused portions of infusion solutions
should be discarded.
ZEMURON should not be mixed with alkaline solutions [see Warnings and Precautions (5.10)].
Visual Inspection
Parenteral drug products should be inspected visually for particulate matter and clarity prior to
administration whenever solution and container permit. Do not use solution if particulate matter is present.
3
DOSAGE FORMS AND STRENGTHS
ZEMURON (rocuronium bromide) injection is available as
•
5 mL multiple dose vials containing 50 mg rocuronium bromide injection (10 mg/mL)
•
10 mL multiple dose vials containing 100 mg rocuronium bromide injection (10 mg/mL)
4
CONTRAINDICATIONS
ZEMURON is contraindicated in patients known to have hypersensitivity (e.g., anaphylaxis) to
rocuronium bromide or other neuromuscular blocking agents [see Warnings and Precautions (5.2)].
5
WARNINGS AND PRECAUTIONS
5.1 Appropriate Administration and Monitoring
ZEMURON should be administered in carefully adjusted dosages by or under the supervision of
experienced clinicians who are familiar with the drug’s actions and the possible complications of its use.
The drug should not be administered unless facilities for intubation, mechanical ventilation, oxygen
therapy, and an antagonist are immediately available. It is recommended that clinicians administering
neuromuscular blocking agents such as ZEMURON employ a peripheral nerve stimulator to monitor drug
effect, need for additional doses, adequacy of spontaneous recovery or antagonism, and to decrease the
complications of overdosage if additional doses are administered.
7
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5.2 Anaphylaxis
Severe anaphylactic reactions to neuromuscular blocking agents, including ZEMURON, have been
reported. These reactions have, in some cases (including cases with ZEMURON) been life threatening. Due
to the potential severity of these reactions, the necessary precautions, such as the immediate availability of
appropriate emergency treatment, should be taken.
5.3 Need for Adequate Anesthesia
ZEMURON has no known effect on consciousness, pain threshold, or cerebration. Therefore, its
administration must be accompanied by adequate anesthesia or sedation.
5.4 Residual Paralysis
In order to prevent complications resulting from residual paralysis, it is recommended to extubate only
after the patient has recovered sufficiently from neuromuscular block. Other factors which could cause
residual paralysis after extubation in the post-operative phase (such as drug interactions or patient
condition) should also be considered. If not used as part of standard clinical practice the use of a reversal
agent should be considered, especially in those cases where residual paralysis is more likely to occur.
5.5 Long-term Use in an Intensive Care Unit
ZEMURON has not been studied for long-term use in the intensive care unit (ICU). As with other
nondepolarizing neuromuscular blocking drugs, apparent tolerance to ZEMURON may develop during
chronic administration in the ICU. While the mechanism for development of this resistance is not known,
receptor up-regulation may be a contributing factor. It is strongly recommended that neuromuscular
transmission be monitored continuously during administration and recovery with the help of a nerve
stimulator. Additional doses of ZEMURON or any other neuromuscular blocking agent should not
be given until there is a definite response (one twitch of the train-of-four) to nerve stimulation.
Prolonged paralysis and/or skeletal muscle weakness may be noted during initial attempts to wean from the
ventilator patients who have chronically received neuromuscular blocking drugs in the ICU.
Myopathy after long term administration of other non-depolarizing neuromuscular blocking agents in
the ICU alone or in combination with corticosteroid therapy has been reported. Therefore, for patients
receiving both neuromuscular blocking agents and corticosteroids, the period of use of the neuromuscular
blocking agent should be limited as much as possible and only used in the setting where in the opinion of
the prescribing physician, the specific advantages of the drug outweigh the risk.
5.6 Malignant Hyperthermia (MH)
ZEMURON has not been studied in MH-susceptible patients. Because ZEMURON is always used
with other agents, and the occurrence of malignant hyperthermia during anesthesia is possible even in the
absence of known triggering agents, clinicians should be familiar with early signs, confirmatory diagnosis
and treatment of malignant hyperthermia prior to the start of any anesthetic.
In an animal study in MH-susceptible swine, the administration of ZEMURON Injection did not
appear to trigger malignant hyperthermia.
5.7 Prolonged Circulation Time
Conditions associated with an increased circulatory delayed time, e.g., cardiovascular disease or
advanced age, may be associated with a delay in onset time [see Dosage and Administration (2.5)].
5.8 QT Interval Prolongation
The overall analysis of ECG data in pediatric patients indicates that the concomitant use of
ZEMURON with general anesthetic agents can prolong the QTc interval [see Clinical Studies (14.3)].
5.9 Conditions/Drugs Causing Potentiation of, or Resistance to, Neuromuscular Block
Potentiation
Nondepolarizing neuromuscular blocking agents have been found to exhibit profound neuromuscular
blocking effects in cachectic or debilitated patients, patients with neuromuscular diseases, and patients with
carcinomatosis.
8
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Certain inhalation anesthetics, particularly enflurane and isoflurane, antibiotics, magnesium salts,
lithium, local anesthetics, procainamide, and quinidine have been shown to increase the duration of
neuromuscular block and decrease infusion requirements of neuromuscular blocking agents [see Drug
Interactions (7.3)].
In these or other patients in whom potentiation of neuromuscular block or difficulty with reversal may
be anticipated, a decrease from the recommended initial dose of ZEMURON should be considered [see
Dosage and Administration (2.5)].
Resistance
Resistance to nondepolarizing agents, consistent with up-regulation of skeletal muscle acetylcholine
receptors, is associated with burns, disuse atrophy, denervation, and direct muscle trauma. Receptor up-
regulation may also contribute to the resistance to nondepolarizing muscle relaxants which sometimes
develops in patients with cerebral palsy, patients chronically receiving anticonvulsant agents such as
carbamazepine or phenytoin or with chronic exposure to nondepolarizing agents. When ZEMURON is
administered to these patients, shorter durations of neuromuscular block may occur and infusion rates may
be higher due to the development of resistance to nondepolarizing muscle relaxants.
Potentiation or Resistance
Severe acid-base and/or electrolyte abnormalities may potentiate or cause resistance to the
neuromuscular blocking action of ZEMURON. No data are available in such patients and no dosing
recommendations can be made.
ZEMURON-induced neuromuscular blockade was modified by alkalosis and acidosis in experimental
pigs. Both respiratory and metabolic acidosis prolonged the recovery time. The potency of ZEMURON was
significantly enhanced in metabolic acidosis and alkalosis, but was reduced in respiratory alkalosis. In
addition, experience with other drugs has suggested that acute (e.g., diarrhea) or chronic (e.g.,
adrenocortical insufficiency) electrolyte imbalance may alter neuromuscular blockade. Since electrolyte
imbalance and acid-base imbalance are usually mixed, either enhancement or inhibition may occur.
5.10 Incompatibility with Alkaline Solutions
ZEMURON, which has an acid pH, should not be mixed with alkaline solutions (e.g., barbiturate
solutions) in the same syringe or administered simultaneously during intravenous infusion through the same
needle.
5.11 Increase in Pulmonary Vascular Resistance
ZEMURON may be associated with increased pulmonary vascular resistance, so caution is appropriate
in patients with pulmonary hypertension or valvular heart disease [see Clinical Studies (14.1)].
5.12 Use In Patients with Myasthenia
In patients with myasthenia gravis or myasthenic (Eaton-Lambert) syndrome, small doses of
nondepolarizing neuromuscular blocking agents may have profound effects. In such patients, a peripheral
nerve stimulator and use of a small test dose may be of value in monitoring the response to administration
of muscle relaxants.
5.13 Extravasation
If extravasation occurs, it may be associated with signs or symptoms of local irritation. The injection
or infusion should be terminated immediately and restarted in another vein.
ADVERSE REACTIONS
In clinical trials, the most common adverse reactions (2%) are transient hypotension and hypertension.
The following adverse reactions are described, or described in greater detail, in other sections:
•
Anaphylaxis [see Warnings and Precautions (5.2)]
•
Residual paralysis [see Warnings and Precautions (5.4)]
9
6
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For current labeling information, please visit https://www.fda.gov/drugsatfda
•
Myopathy [see Warnings and Precautions (5.5)]
•
Increased pulmonary vascular resistance [see Warnings and Precautions (5.11)]
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed
in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and
may not reflect the rates observed in practice.
Clinical studies in the U.S. (n=1137) and Europe (n=1394) totaled 2531 patients. The patients exposed
in the U.S. clinical studies provide the basis for calculation of adverse reaction rates. The following adverse
reactions were reported in patients administered ZEMURON (all events judged by investigators during the
clinical trials to have a possible causal relationship):
Adverse reactions in greater than 1% of patients: None
Adverse reactions in less than 1% of patients (probably related or relationship unknown):
Cardiovascular: arrhythmia, abnormal electrocardiogram, tachycardia
Digestive: nausea, vomiting
Respiratory: asthma (bronchospasm, wheezing, or rhonchi), hiccup
Skin and Appendages: rash, injection site edema, pruritus
In the European studies, the most commonly reported reactions were transient hypotension (2%) and
hypertension (2%); these are in greater frequency than the U.S. studies (0.1% and 0.1%). Changes in heart
rate and blood pressure were defined differently from in the U.S. studies in which changes in
cardiovascular parameters were not considered as adverse events unless judged by the investigator as
unexpected, clinically significant, or thought to be histamine related.
In a clinical study in patients with clinically significant cardiovascular disease undergoing coronary
artery bypass graft, hypertension and tachycardia were reported in some patients but these occurrences
were less frequent in patients receiving beta or calcium channel-blocking drugs. In some patients,
ZEMURON was associated with transient increases (30% or greater) in pulmonary vascular resistance. In
another clinical study of patients undergoing abdominal aortic surgery, transient increases (30% or greater)
in pulmonary vascular resistance were observed in about 24% of patients receiving ZEMURON 0.6 or 0.9
mg/kg.
In pediatric patient studies worldwide (n=704), tachycardia occurred at an incidence of 5.3% (n=37)
and it was judged by the investigator as related in 10 cases (1.4%).
6.2 Post-Marketing Experience
In clinical practice, there have been reports, of severe allergic reactions (anaphylactic and
anaphylactoid reactions and shock) with ZEMURON, including some that have been life-threatening and
fatal [see Warnings and Precautions (5.2)].
Because these reactions were reported voluntarily from a population of uncertain size, it is not possible
to reliably estimate their frequency.
DRUG INTERACTIONS
7.1 Antibiotics
Drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as
ZEMURON include certain antibiotics (e.g., aminoglycosides; vancomycin; tetracyclines; bacitracin;
polymyxins; colistin; and sodium colistimethate). If these antibiotics are used in conjunction with
ZEMURON, prolongation of neuromuscular block may occur.
7.2 Anticonvulsants
In 2 of 4 patients receiving chronic anticonvulsant therapy, apparent resistance to the effects of
ZEMURON was observed in the form of diminished magnitude of neuromuscular block, or shortened
10
7
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For current labeling information, please visit https://www.fda.gov/drugsatfda
clinical duration. As with other nondepolarizing neuromuscular blocking drugs, if ZEMURON is
administered to patients chronically receiving anticonvulsant agents such as carbamazepine or phenytoin,
shorter durations of neuromuscular block may occur and infusion rates may be higher due to the
development of resistance to nondepolarizing muscle relaxants. While the mechanism for development of
this resistance is not known, receptor up-regulation may be a contributing factor. [See Warnings and
Precautions (5.9)].
7.3 Inhalation Anesthetics
Use of inhalation anesthetics has been shown to enhance the activity of other neuromuscular blocking
agents (enflurane > isoflurane > halothane).
Isoflurane and enflurane may also prolong the duration of action of initial and maintenance doses of
ZEMURON and decrease the average infusion requirement of ZEMURON by 40% compared to
opioid/nitrous oxide/oxygen anesthesia. No definite interaction between ZEMURON and halothane has
been demonstrated. In one study, use of enflurane in 10 patients resulted in a 20% increase in mean clinical
duration of the initial intubating dose, and a 37% increase in the duration of subsequent maintenance doses,
when compared in the same study to 10 patients under opioid/nitrous oxide/oxygen anesthesia. The clinical
duration of initial doses of ZEMURON of 0.57 to 0.85 mg/kg under enflurane or isoflurane anesthesia, as
used clinically, was increased by 11% and 23%, respectively. The duration of maintenance doses was
affected to a greater extent, increasing by 30 to 50% under either enflurane or isoflurane anesthesia.
Potentiation by these agents is also observed with respect to the infusion rates of ZEMURON required
to maintain approximately 95% neuromuscular block. Under isoflurane and enflurane anesthesia, the
infusion rates are decreased by approximately 40% compared to opioid/nitrous oxide/oxygen anesthesia.
The median spontaneous recovery time (from 25 to 75% of control T1) is not affected by halothane, but is
prolonged by enflurane (15% longer) and isoflurane (62% longer). Reversal-induced recovery of
ZEMURON neuromuscular block is minimally affected by anesthetic technique. [See Dosage and
Administration (2.5) and Warnings and Precautions (5.9)].
7.4 Lithium Carbonate
Lithium has been shown to increase the duration of neuromuscular block and decrease infusion
requirements of neuromuscular blocking agents [see Warnings and Precautions (5.9)].
7.5 Local Anesthetics
Local anesthetics have been shown to increase the duration of neuromuscular block and decrease
infusion requirements of neuromuscular blocking agents [see Warnings and Precautions (5.9)].
7.6 Magnesium
Magnesium salts administered for the management of toxemia of pregnancy may enhance
neuromuscular blockade [see Warnings and Precautions (5.9)].
7.7 Nondepolarizing Muscle Relaxants
There are no controlled studies documenting the use of ZEMURON before or after other
nondepolarizing muscle relaxants. Interactions have been observed when other nondepolarizing muscle
relaxants have been administered in succession.
7.8 Procainamide
Procainamide has been shown to increase the duration of neuromuscular block and decrease infusion
requirements of neuromuscular blocking agents [see Warnings and Precautions (5.9)].
7.9 Propofol
The use of propofol for induction and maintenance of anesthesia does not alter the clinical duration or
recovery characteristics following recommended doses of ZEMURON.
11
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For current labeling information, please visit https://www.fda.gov/drugsatfda
8
7.10 Quinidine
Injection of quinidine during recovery from use of muscle relaxants is associated with recurrent
paralysis. This possibility must also be considered for ZEMURON [See Warnings and Precautions (5.9)]
7.11 Succinylcholine
The use of ZEMURON before succinylcholine, for the purpose of attenuating some of the side effects
of succinylcholine, has not been studied.
If ZEMURON is administered following administration of succinylcholine, it should not be given until
recovery from succinylcholine has been observed. The median duration of action of ZEMURON 0.6 mg/kg
administered after a 1 mg/kg dose of succinylcholine when T1 returned to 75% of control was 36 minutes
(range 14–57, n=12) vs. 28 minutes (17–51, n=12) without succinylcholine.
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category C
Developmental toxicology studies have been performed with rocuronium bromide in pregnant,
conscious, nonventilated rabbits and rats. Inhibition of neuromuscular function was the endpoint for high-
dose selection. The maximum tolerated dose served as the high-dose and was administered intravenously
three times a day to rats (0.3 mg/kg, 15 to 30% of human intubation dose of 0.6 to 1.2 mg/kg based on the
body surface unit of mg/m2) from day 6 to 17 and to rabbits (0.02 mg/kg, 25% human dose) from day 6 to
18 of pregnancy. High-dose treatment caused acute symptoms of respiratory dysfunction due to the
pharmacological activity of the drug. Teratogenicity was not observed in these animal species. The
incidence of late embryonic death was increased at the high-dose in rats most likely due to oxygen
deficiency. Therefore, this finding probably has no relevance for humans because immediate mechanical
ventilation of the intubated patient will effectively prevent embryo-fetal hypoxia. However, there are no
adequate and well-controlled studies in pregnant women. ZEMURON should be used during pregnancy
only if the potential benefit justifies the potential risk to the fetus.
8.2 Labor and Delivery
The use of ZEMURON in Cesarean section has been studied in a limited number of patients [see
Clinical Studies (14.5)]. ZEMURON is not recommended for rapid sequence induction in Cesarean section
patients.
8.4 Pediatric Use
The use of ZEMURON has been studied in pediatric patients 3 months to 14 years of age under
halothane anesthesia. Of the pediatric patients anesthetized with halothane who did not receive atropine for
induction, about 80% experienced a transient increase (30% or greater) in heart rate after intubation. One of
the 19 infants anesthetized with halothane and fentanyl who received atropine for induction experienced
this magnitude of change. [See Dosage and Administration (2.5) and Clinical Studies (14.3)]
ZEMURON was also studied in pediatric patients up to 17 years of age, including neonates, under
sevoflurane (induction) and isoflurane/nitrous oxide (maintenance) anesthesia. Onset time and clinical
duration varied with dose, the age of the patient, and anesthetic technique. The overall analysis of ECG
data in pediatric patients indicates that the concomitant use of ZEMURON with general anesthetic agents
can prolong the QTc interval. The data also suggest that ZEMURON may increase heart rate. However, it
was not possible to conclusively identify an effect of ZEMURON independent of that of anesthesia and
other factors. Additionally, when examining plasma levels of ZEMURON in correlation to QTc interval
prolongation, no relationship was observed [See Dosage and Administration (2.5), Warnings and
Precautions (5.8) and Clinical Studies (14.3)]
.
12
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For current labeling information, please visit https://www.fda.gov/drugsatfda
ZEMURON is not recommended for rapid sequence intubation in pediatric patients. Recommendations for
use in pediatric patients are discussed in other sections [see Dosage and Administration (2.5) and Clinical
Pharmaocology (12.2)].
8.5 Geriatric Use
ZEMURON was administered to 140 geriatric patients (65 years or greater) in U.S. clinical trials and
128 geriatric patients in European clinical trials. The observed pharmacokinetic profile for geriatric patients
(n=20) was similar to that for other adult surgical patients [see Clinical Pharmacology (12.3)]. Onset time
and duration of action were slightly longer for geriatric patients (n=43) in clinical trials. Clinical
experiences and recommendations for use in geriatric patients are discussed in other sections [see Dosage
and Administration (2.5), Clinical Pharmacology (12.2), and Clinical Studies (14.2)].
8.6 Patients with Hepatic Impairment
Since ZEMURON is primarily excreted by the liver, it should be used with caution in patients with
clinically significant hepatic impairment. ZEMURON 0.6 mg/kg has been studied in a limited number of
patients (n=9) with clinically significant hepatic impairment under steady-state isoflurane anesthesia. After
ZEMURON 0.6 mg/kg, the median (range) clinical duration of 60 (35–166) minutes was moderately
prolonged compared to 42 minutes in patients with normal hepatic function. The median recovery time of
53 minutes was also prolonged in patients with cirrhosis compared to 20 minutes in patients with normal
hepatic function. Four of eight patients with cirrhosis, who received ZEMURON 0.6 mg/kg under
opioid/nitrous oxide/oxygen anesthesia, did not achieve complete block. These findings are consistent with
the increase in volume of distribution at steady state observed in patients with significant hepatic
impairment [see Clinical Pharmacology (12.3)]. If used for rapid sequence induction in patients with
ascites, an increased initial dosage may be necessary to assure complete block. Duration will be prolonged
in these cases. The use of doses higher than 0.6 mg/kg has not been studied [see Dosage and
Administration (2.5)].
8.7 Patients with Renal Impairment
Due to the limited role of the kidney in the excretion of ZEMURON, usual dosing guidelines should be
followed. In patients with renal dysfunction, the duration of neuromuscular blockade was not prolonged;
however, there was substantial individual variability (range, 22–90 minutes). [see Clinical Pharmacology
(12.3)].
10 OVERDOSAGE
Overdosage with neuromuscular blocking agents may result in neuromuscular block beyond the time
needed for surgery and anesthesia. The primary treatment is maintenance of a patent airway, controlled
ventilation and adequate sedation until recovery of normal neuromuscular function is assured. Once
evidence of recovery from neuromuscular block is observed, further recovery may be facilitated by
administration of an anticholinesterase agent in conjunction with an appropriate anticholinergic agent.
Reversal of Neuromuscular Blockade
Anticholinesterase agents should not be administered prior to the demonstration of some
spontaneous recovery from neuromuscular blockade. The use of a nerve stimulator to document
recovery is recommended.
Patients should be evaluated for adequate clinical evidence of neuromuscular recovery, e.g., 5 second
head lift, adequate phonation, ventilation, and upper airway patency. Ventilation must be supported while
patients exhibit any signs of muscle weakness.
Recovery may be delayed in the presence of debilitation, carcinomatosis, and concomitant use of
certain drugs which enhance neuromuscular blockade or separately cause respiratory depression. Under
such circumstances the management is the same as that of prolonged neuromuscular blockade.
11 DESCRIPTION
ZEMURON (rocuronium bromide) injection is a nondepolarizing neuromuscular blocking agent with a
rapid to intermediate onset depending on dose and intermediate duration. Rocuronium bromide is
chemically designated as 1-[17β-(acetyloxy)-3α-hydroxy-2β-(4-morpholinyl)-5α-androstan-16β-yl]-1-(2
propenyl)pyrrolidinium bromide.
13
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For current labeling information, please visit https://www.fda.gov/drugsatfda
The structural formula is: Chemical Structure
The chemical formula is C32H53BrN2O4 with a molecular weight of 609.70. The partition coefficient of
rocuronium bromide in n-octanol/water is 0.5 at 20°C.
ZEMURON is supplied as a sterile, nonpyrogenic, isotonic solution that is clear, colorless to
yellow/orange, for intravenous injection only. Each mL contains 10 mg rocuronium bromide and 2 mg
sodium acetate. The aqueous solution is adjusted to isotonicity with sodium chloride and to a pH of 4 with
acetic acid and/or sodium hydroxide.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
ZEMURON is a nondepolarizing neuromuscular blocking agent with a rapid to intermediate onset
depending on dose and intermediate duration. It acts by competing for cholinergic receptors at the motor
end-plate. This action is antagonized by acetylcholinesterase inhibitors, such as neostigmine and
edrophonium.
12.2 Pharmacodynamics
The ED95 (dose required to produce 95% suppression of the first [T1] mechanomyographic [MMG]
response of the adductor pollicis muscle [thumb] to indirect supramaximal train-of-four stimulation of the
ulnar nerve) during opioid/nitrous oxide/oxygen anesthesia is approximately 0.3 mg/kg. Patient variability
around the ED95 dose suggests that 50% of patients will exhibit T1 depression of 91 to 97%.
Table 4 presents intubating conditions in patients with intubation initiated at 60 to 70 seconds.
Table 4: Percent of Excellent or Good Intubating Conditions and Median (Range) Time to Completion of Intubation in
Patients with Intubation Initiated at 60 to 70 Seconds
ZEMURON Dose
(mg/kg)
Administered over 5 sec
Percent of Patients With
Excellent or Good
Intubating Conditions
Time to Completion
of Intubation
(min)
Adults* 18 to 64 yrs
0.45 (n=43)
0.6 (n=51)
86%
96%
1.6 (1.0–7.0)
1.6 (1.0–3.2)
Infants** 3 mo to 1 yr
0.6 (n=18)
Pediatric** 1 to 12 yrs
0.6 (n=12)
100%
100%
1.0 (1.0–1.5)
1.0 (0.5–2.3)
* Excludes patients undergoing Cesarean section
**Pediatric patients were under halothane anesthesia
Excellent intubating conditions = jaw relaxed, vocal cords apart and immobile, no diaphragmatic movement
Good intubating conditions = same as excellent but with some diaphragmatic movement
Table 5 presents the time to onset and clinical duration for the initial dose of ZEMURON (rocuronium
bromide) injection under opioid/nitrous oxide/oxygen anesthesia in adults and geriatric patients, and under
halothane anesthesia in pediatric patients.
14
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For current labeling information, please visit https://www.fda.gov/drugsatfda
TABLE 5: Median (Range) Time to Onset and Clinical Duration Following Initial (Intubating) Dose
During Opioid/Nitrous Oxide/Oxygen Anesthesia (Adults) and Halothane Anesthesia (Pediatric
Patients)
ZEMURON Dose
(mg/kg)
Administered over 5 sec
Time to
≥80% Block
(min)
Time to
Maximum Block
(min)
Clinical
Duration
(min)
Adults 18 to 64 yrs
0.45 (n=50)
1.3 (0.8–6.2)
3.0 (1.3–8.2)
22 (12–31)
0.6 (n=142)
1.0 (0.4–6.0)
1.8 (0.6–13.0)
31 (15–85)
0.9 (n=20)
1.1 (0.3–3.8)
1.4 (0.8–6.2)
58 (27–111)
1.2 (n=18)
0.7 (0.4–1.7)
1.0 (0.6–4.7)
67 (38–160)
Geriatric ≥65 yrs
0.6 (n=31)
2.3 (1.0–8.3)
3.7 (1.3–11.3)
46 (22–73)
0.9 (n=5)
2.0 (1.0–3.0)
2.5 (1.2–5.0)
62 (49–75)
1.2 (n=7)
1.0 (0.8–3.5)
1.3 (1.2–4.7)
94 (64–138)
Infants 3 mo to 1 yr
0.6 (n=17)
—
0.8 (0.3–3.0)
41 (24–68)
0.8 (n=9)
—
0.7 (0.5–0.8)
40 (27–70)
Pediatric 1 to 12 yrs
0.6 (n=27)
0.8 (0.4–2.0)
1.0 (0.5–3.3)
26 (17–39)
0.8 (n=18)
—
0.5 (0.3–1.0)
30 (17–56)
n = the number of patients who had time to maximum block recorded
Clinical duration = time until return to 25% of control T1. Patients receiving doses of 0.45 mg/kg who achieved less than 90% block
(16% of these patients) had about 12 to 15 minutes to 25% recovery.
Table 6 presents the time to onset and clinical duration for the initial dose of ZEMURON (rocuronium
bromide) Injection under sevoflurane (induction) and isoflurane/nitrous oxide (maintenance) anesthesia in
pediatric patients.
TABLE 6: Median (Range) Time to Onset and Clinical Duration Following Initial (Intubating) Dose
During Sevoflurane (induction) and Isoflurane/Nitrous Oxide (maintenance) Anesthesia (Pediatric
Patients)
ZEMURON Dose
(mg/kg)
Administered over 5 sec
Time to
Maximum Block
(min)
Time to
Reappearance T3
(min)
Neonates birth to <28 days
0.45 (n=5)
1.1 (0.6-2.2)
40.3 (32.5-62.6)
0.6 (n=10)
1.0 (0.2-2.1)
49.7 (16.6-119.0)
1 (n=6)
0.6 (0.3-1.8)
114.4 (92.6-136.3)
Infants 28 days to ≤3 mo
0.45 (n=9)
0.5 (0.4-1.3)
49.1 (13.5-79.9)
0.6 (n=11)
0.4 (0.2-0.8)
59.8 (32.3-87.8)
1 (n=5)
0.3 (0.2-0.7)
103.3 (90.8-155.4)
Toddlers >3 mo to ≤2 yrs
0.45 (n=17)
0.8 (0.3-1.9)
39.2 (16.9-59.4)
0.6 (n=29)
0.6 (0.2-1.6)
44.2 (18.9-68.8)
1 (n=15)
0.5 (0.2-1.5)
72.0 (36.2-128.2)
Children >2 yrs to ≤11 yrs
0.45 (n=14)
0.9 (0.4-1.9)
21.5 (17.5-38.0)
0.6 (n=37)
0.8 (0.3-1.7)
36.7 (20.1-65.9)
1 (n=16)
0.7 (0.4-1.2)
53.1 (31.2-89.9)
Adolescents >11 to ≤17 yrs
0.45 (n=18)
1.0 (0.5-1.7)
37.5 (18.3-65.7)
0.6 (n=31)
0.9 (0.2-2.1)
41.4 (16.3-91.2)
1 (n=14)
0.7 (0.5-1.2)
67.1 (25.6-93.8)
n = the number of patients with the highest number of observations for time to maximum block or reappearance T3
The time to 80% or greater block and clinical duration as a function of dose are presented in Figures 1 and
2.
15
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Graph
FIGURE 1: Time to 80% or greater Block vs. Initial Dose of ZEMURON by Age Group (Median, 25th and 75th percentile,
and individual values) Graph
FIGURE 2: Duration of Clinical Effect vs. Initial Dose of ZEMURON by Age Group (Median, 25th and 75th percentile, and
individual values)
The clinical durations for the first five maintenance doses, in patients receiving five or more
maintenance doses are represented in Figure 3 [see Dosage and Administration (2.3)].
16
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Graph
FIGURE 3: Duration of Clinical Effect vs. Number of ZEMURON® Maintenance Doses, by Dose
Once spontaneous recovery has reached 25% of control T1, the neuromuscular block produced by
ZEMURON is readily reversed with anticholinesterase agents, e.g., edrophonium or neostigmine.
The median spontaneous recovery from 25 to 75% T1 was 13 minutes in adult patients. When
neuromuscular block was reversed in 36 adults at a T1 of 22 to 27%, recovery to a T1 of 89 (50–132)% and
T4/T1 of 69 (38–92)% was achieved within 5 minutes. Only five of 320 adults reversed received an
additional dose of reversal agent. The median (range) dose of neostigmine was 0.04 (0.01–0.09) mg/kg and
the median (range) dose of edrophonium was 0.5 (0.3–1.0) mg/kg.
In geriatric patients (n=51) reversed with neostigmine, the median T4/T1 increased from 40 to 88% in 5
minutes.
In clinical trials with halothane, pediatric patients (n=27) who received 0.5 mg/kg edrophonium had
increases in the median T4/T1 from 37% at reversal to 93% after 2 minutes. Pediatric patients (n=58) who
received 1 mg/kg edrophonium had increases in the median T4/T1 from 72% at reversal to 100% after 2
minutes. Infants (n=10) who were reversed with 0.03 mg/kg neostigmine recovered from 25 to 75% T1
within 4 minutes.
There were no reports of less than satisfactory clinical recovery of neuromuscular function.
The neuromuscular blocking action of ZEMURON may be enhanced in the presence of potent
inhalation anesthetics [see Drug Interactions (7.3)].
Hemodynamics
There were no dose-related effects on the incidence of changes from baseline (30% or greater) in mean
arterial blood pressure (MAP) or heart rate associated with ZEMURON administration over the dose range
of 0.12 to 1.2 mg/kg (4 x ED95) within 5 minutes after ZEMURON administration and prior to intubation.
Increases or decreases in MAP were observed in 2 to 5% of geriatric and other adult patients, and in about
1% of pediatric patients. Heart rate changes (30% or greater) occurred in 0 to 2% of geriatric and other
adult patients. Tachycardia (30% or greater) occurred in 12 of 127 pediatric patients. Most of the pediatric
patients developing tachycardia were from a single study where the patients were anesthetized with
halothane and who did not receive atropine for induction [see Clinical Studies (14.3)]. In U.S. studies,
laryngoscopy and tracheal intubation following ZEMURON administration were accompanied by transient
tachycardia (30% or greater increases) in about one-third of adult patients under opioid/nitrous
17
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oxide/oxygen anesthesia. Animal studies have indicated that the ratio of vagal:neuromuscular block
following ZEMURON administration is less than vecuronium but greater than pancuronium. The
tachycardia observed in some patients may result from this vagal blocking activity.
Histamine Release
In studies of histamine release, clinically significant concentrations of plasma histamine occurred in 1
of 88 patients. Clinical signs of histamine release (flushing, rash, or bronchospasm) associated with the
administration of ZEMURON were assessed in clinical trials and reported in 9 of 1137 (0.8%) patients.
12.3 Pharmacokinetics
Adult and Geriatric Patients
In an effort to maximize the information gathered in the in vivo pharmacokinetic studies, the data from
the studies was used to develop population estimates of the parameters for the subpopulations represented
(e.g., geriatric, pediatric, renal and hepatic impairment). These population based estimates and a measure of
the estimate variability are contained in the following section.
Following intravenous administration of ZEMURON, plasma levels of rocuronium follow a three
compartment open model. The rapid distribution half-life is 1 to 2 minutes and the slower distribution half-
life is 14 to 18 minutes. Rocuronium is approximately 30% bound to human plasma proteins. In geriatric
and other adult surgical patients undergoing either opioid/nitrous oxide/oxygen or inhalational anesthesia,
the observed pharmacokinetic profile was essentially unchanged.
TABLE 7: Mean (SD) Pharmacokinetic Parameters in Adults (n=22; ages 27 to 58 yrs) and Geriatric (n=20; 65 yrs or greater)
During Opioid/Nitrous Oxide/Oxygen Anesthesia
PK Parameters
Adults
(Ages 27 to 58 yrs)
Geriatrics
(≥65 yrs)
Clearance (L/kg/hr)
0.25 (0.08)
0.21 (0.06)
Volume of Distribution
at Steady State (L/kg)
0.25 (0.04)
0.22 (0.03)
t1/2 β Elimination (hr)
1.4 (0.4)
1.5 (0.4)
In general, studies with normal adult subjects did not reveal any differences in the pharmacokinetics of
rocuronium due to gender.
Studies of distribution, metabolism, and excretion in cats and dogs indicate that rocuronium is
eliminated primarily by the liver. The rocuronium analog 17-desacetyl-rocuronium, a metabolite, has been
rarely observed in the plasma or urine of humans administered single doses of 0.5 to 1 mg/kg with or
without a subsequent infusion (for up to 12 hr) of rocuronium. In the cat, 17-desacetyl-rocuronium has
approximately one-twentieth the neuromuscular blocking potency of rocuronium. The effects of renal
failure and hepatic disease on the pharmacokinetics and pharmacodynamics of rocuronium in humans are
consistent with these findings.
In general, patients undergoing cadaver kidney transplant have a small reduction in clearance which is
offset pharmacokinetically by a corresponding increase in volume, such that the net effect is an unchanged
plasma half-life. Patients with demonstrated liver cirrhosis have a marked increase in their volume of
distribution resulting in a plasma half-life approximately twice that of patients with normal hepatic
function. Table 8 shows the pharmacokinetic parameters in subjects with either impaired renal or hepatic
function.
18
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TABLE 8: Mean (SD) Pharmacokinetic Parameters in Adults with Normal Renal and Hepatic Function (n=10, ages 23 to 65),
Renal Transplant Patients (n=10, ages 21 to 45) and Hepatic Dysfunction Patients (n=9, ages 31 to 67) During Isoflurane
Anesthesia
PK Parameters
Normal Renal and
Hepatic Function
Renal Transplant
Patients
Hepatic Dysfunction
Patients
Clearance (L/kg/hr)
0.16 (0.05)*
0.13 (0.04)
0.13 (0.06)
Volume of Distribution
at Steady State (L/kg)
0.26 (0.03)
0.34 (0.11)
0.53 (0.14)
t1/2 β Elimination (hr)
2.4 (0.8)*
2.4 (1.1)
4.3 (2.6)
* Differences in the calculated t1/2 β and Cl between this study and the study in young adults vs. geriatrics (≥65 years) is related to the
different sample populations and anesthetic techniques
The net result of these findings is that subjects with renal failure have clinical durations that are similar
to but somewhat more variable than the duration that one would expect in subjects with normal renal
function. Hepatically impaired patients, due to the large increase in volume, may demonstrate clinical
durations approaching 1.5 times that of subjects with normal hepatic function. In both populations the
clinician should individualize the dose to the needs of the patient [see Dosage and Administration (2.5)].
Tissue redistribution accounts for most (about 80%) of the initial amount of rocuronium administered.
As tissue compartments fill with continued dosing (4 to 8 hours), less drug is redistributed away from the
site of action and, for an infusion-only dose, the rate to maintain neuromuscular blockade falls to about
20% of the initial infusion rate. The use of a loading dose and a smaller infusion rate reduces the need for
adjustment of dose.
Pediatric Patients
Under halothane anesthesia, the clinical duration of effects of ZEMURON did not vary with age in
patients 4 months to 8 years of age. The terminal half-life and other pharmacokinetic parameters of
rocuronium in these pediatric patients are presented in Table 9.
TABLE 9: Mean (SD) Pharmacokinetic Parameters of Rocuronium in Pediatric Patients (ages 3 to less than 12 mos, n=6; 1 to
less than 3 yrs, n=5; 3 to less than 8 yrs, n=7) During Halothane Anesthesia
PK Parameters
Patient Age Range
3 to <12 mos
1 to <3 yrs
3 to <8 yrs
Clearance (L/kg/hr)
0.35 (0.08)
0.32 (0.07)
0.44 (0.16)
Volume of Distribution
at Steady State (L/kg)
0.30 (0.04)
0.26 (0.06)
0.21 (0.03)
t1/2 β Elimination (hr)
1.3 (0.5)
1.1 (0.7)
0.8 (0.3)
Pharmacokinetics of ZEMURON were evaluated using a population analysis of the pooled
pharmacokinetic datasets from two trials under sevoflurane (induction) and isoflurane/nitrous oxide
(maintenance) anesthesia. All pharmacokinetic parameters were found to be linearly proportional to body
weight. In patients under the age of 18 years clearance (CL) and volume of distribution (Vss) increase with
bodyweight (kg) and age (years). As a result the terminal half-life of ZEMURON decreases with increasing
age from 1.1 hour to 0.7-0.8 hour. Table 10 presents the pharmacokinetic parameters in the different age
groups in the studies with sevoflurane (induction) and isoflurane/nitrous oxide (maintenance) anesthesia.
TABLE 10: Mean (SD) Pharmacokinetic Parameters of Rocuronium in Pediatric Patients During Sevoflurane (induction) and
Isoflurane/Nitrous Oxide (maintenance) Anesthesia
PK Parameters
Patient Age Range
Birth to < 28
days
28 days to ≤ 3
mos
3 mos to ≤ 2 yrs
2 to ≤ 11 yrs
11 to ≤ 17 yrs
CL (L/kg/hr)
0.31 (0.07)
0.30 (0.08)
0.33 (0.10)
0.35 (0.09)
0.29 (0.14)
Volume of Distribution (L/kg)
0.42 (0.06)
0.31 (0.03)
0.23 (0.03)
0.18 (0.02)
0.18 (0.01)
t1/2 β (hr)
1.1 (0.2)
0.9 (0.3)
0.8 (0.2)
0.7 (0.2)
0.8 (0.3)
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Studies in animals have not been performed with rocuronium bromide to evaluate carcinogenic
potential or impairment of fertility. Mutagenicity studies (Ames test, analysis of chromosomal aberrations
19
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in mammalian cells, and micronucleus test) conducted with rocuronium bromide did not suggest mutagenic
potential.
14 CLINICAL STUDIES
In U.S. clinical studies, a total of 1137 patients received ZEMURON, including 176 pediatric, 140
geriatric, 55 obstetric, and 766 other adults. Most patients (90%) were ASA physical status I or II, about
9% were ASA III, and 10 patients (undergoing coronary artery bypass grafting or valvular surgery) were
ASA IV. In European clinical studies, a total of 1394 patients received ZEMURON, including 52 pediatric,
128 geriatric (65 years or greater) and 1214 other adults.
14.1 Adult Patients
Intubation using doses of ZEMURON 0.6 to 0.85 mg/kg was evaluated in 203 adults in 11 clinical
studies. Excellent to good intubating conditions were generally achieved within 2 minutes and maximum
block occurred within 3 minutes in most patients. Doses within this range provide clinical relaxation for a
median (range) time of 33 (14–85) minutes under opioid/nitrous oxide/oxygen anesthesia. Larger doses (0.9
and 1.2 mg/kg) were evaluated in two studies with 19 and 16 patients under opioid/nitrous oxide/oxygen
anesthesia and provided 58 (27–111) and 67 (38–160) minutes of clinical relaxation, respectively.
Cardiovascular Disease
In one clinical study, 10 patients with clinically significant cardiovascular disease undergoing coronary
artery bypass graft received an initial dose of 0.6 mg/kg ZEMURON. Neuromuscular block was maintained
during surgery with bolus maintenance doses of 0.3 mg/kg. Following induction, continuous 8 mcg/kg/min
infusion of ZEMURON produced relaxation sufficient to support mechanical ventilation for 6 to 12 hours
in the surgical intensive care unit (SICU) while the patients were recovering from surgery.
Rapid Sequence Intubation
Intubating conditions were assessed in 230 patients in six clinical studies where anesthesia was
induced with either thiopental (3 to 6 mg/kg) or propofol (1.5 to 2.5 mg/kg) in combination with either
fentanyl (2 to 5 mcg/kg) or alfentanil (1 mg). Most of the patients also received a premedication such as
midazolam or temazepam. Most patients had intubation attempted within 60 to 90 seconds of
administration of ZEMURON 0.6 mg/kg or succinylcholine 1 to 1.5 mg/kg. Excellent or good intubating
conditions were achieved in 119/120 (99% [95% confidence interval 95–99.9%]) patients receiving
ZEMURON and in 108/110 (98% [94–99.8%]) patients receiving succinylcholine. The duration of action
of ZEMURON 0.6 mg/kg is longer than succinylcholine and at this dose is approximately equivalent to the
duration of other intermediate acting neuromuscular blocking drugs.
Obese Patients
ZEMURON was dosed according to actual body weight (ABW) in most clinical studies. The
administration of ZEMURON in the 47 of 330 (14%) patients who were at least 30% or more above their
ideal body weight (IBW) was not associated with clinically significant differences in the onset, duration,
recovery, or reversal of ZEMURON-induced neuromuscular block.
In one clinical study in obese patients, ZEMURON 0.6 mg/kg was dosed according to ABW (n=12) or
IBW (n=11). Obese patients dosed according to IBW had a longer time to maximum block, a shorter
median (range) clinical duration of 25 (14–29) minutes, and did not achieve intubating conditions
comparable to those dosed based on ABW. These results support the recommendation that obese patients
be dosed based on actual body weight. [See Dosage and Administration (2.5)]
Obstetric Patients
ZEMURON 0.6 mg/kg was administered with thiopental, 3 to 4 mg/kg (n=13) or 4 to 6 mg/kg (n=42),
for rapid sequence induction of anesthesia for Cesarean section. No neonate had APGAR scores greater
than 7 at 5 minutes. The umbilical venous plasma concentrations were 18% of maternal concentrations at
delivery. Intubating conditions were poor or inadequate in 5 of 13 women receiving 3 to 4 mg/kg thiopental
when intubation was attempted 60 seconds after drug injection. Therefore, ZEMURON is not
recommended for rapid sequence induction in Cesarean section patients.
20
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
14.2 Geriatric Patients
ZEMURON was evaluated in 55 geriatric patients (ages 65 to 80 years) in six clinical studies. Doses of
0.6 mg/kg provided excellent to good intubating conditions in a median (range) time of 2.3 (1–8) minutes.
Recovery times from 25 to 75% after these doses were not prolonged in geriatric patients compared to other
adult patients. [see Dosage and Administration (2.5) and Use in Specific Populations (8.5)]
14.3 Pediatric Patients
ZEMURON 0.45, 0.6 or 1 mg/kg was evaluated under sevoflurane (induction) and isoflurane/nitrous
oxide (maintenance) anesthesia for intubation in 326 patients in two studies. In one of these studies
maintenance bolus and infusion requirements were evaluated in 137 patients. In all age groups, doses of 0.6
mg/kg provided time to maximum block in about 1 minute. Across all age groups, median (range) time to
reappearance of T3 for doses of 0.6 mg/kg was shortest in the children [36.7 (20.1-65.9) minutes] and
longest in infants [59.8 (32.3-87.8) minutes]. For pediatric patients older than 3 months, the time to
recovery was shorter after stopping infusion maintenance when compared with bolus maintenance. [See
Dosage and Administration (2.5), and Use in Specific Populations(8.4) ].
ZEMURON 0.6 or 0.8 mg/kg was evaluated for intubation in 75 pediatric patients (n=28; age 3 to 12
months, n=47; age 1 to 12 years) in three studies using halothane (1 to 5%) and nitrous oxide (60 to 70%)
in oxygen. Doses of 0.6 mg/kg provided a median (range) time to maximum block of 1 (0.5–3.3) minute(s).
This dose provided a median (range) time of clinical relaxation of 41 (24–68) minutes in 3 month to 1 year-
old infants and 26 (17–39) minutes in 1 to 12 year-old pediatric patients. [See Dosage and Administration
(2.5) and Use in Specific Populations (8.4)]
16 HOW SUPPLIED/STORAGE AND HANDLING
ZEMURON (rocuronium bromide) injection is available in the following:
•
ZEMURON 5 mL multiple dose vials containing 50 mg rocuronium bromide injection (10
mg/mL)
Box of 10
NDC 0052-0450-15
•
ZEMURON 10 mL multiple dose vials containing 100 mg rocuronium bromide injection (10
mg/mL)
Box of 10
NDC 0052-0450-16
The packaging of this product contains no natural rubber (latex).
ZEMURON should be stored in a refrigerator, 2–8°C (36–46°F). DO NOT FREEZE. Upon removal
from refrigeration to room temperature storage conditions (25°C/77°F), use ZEMURON within 60 days.
Use opened vials of ZEMURON within 30 days.
Safety and Handling
There is no specific work exposure limit for ZEMURON. In case of eye contact, flush with water for at
least 10 minutes.
17 PATIENT COUNSELING INFORMATION
Obtain information about your patient’s medical history, current medications, any history of
hypersensitivity to rocuronium bromide or other neuromuscular blocking agents. If applicable, inform your
patients that certain medical conditions and medications might influence how ZEMURON works.
In addition, inform your patient that severe anaphylactic reactions to neuromuscular blocking agents,
including ZEMURON, have been reported. Since allergic cross-reactivity has been reported in this class,
request information from your patients about previous anaphylactic reactions to other neuromuscular
blocking agents.
21
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Manufactured for Organon USA Inc.
Roseland, NJ 07068
by Baxter Pharmaceutical Solutions LLC
Bloomington, IN 47403
or Organon (Ireland) Ltd., Swords, Co. Dublin, Ireland
8/18/08 version
22
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For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:47:02.179601
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/020214s030lbl.pdf', 'application_number': 20214, 'submission_type': 'SUPPL ', 'submission_number': 30}
|
12,322
|
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NOTE: PATIENT INFORMATION LEAFLET ATTACHED.
Premarin(conjugated estrogens)
Vaginal Cream in a nonliquefying base
℞ only
ESTROGENS INCREASE THE RISK OF ENDOMETRIAL CANCER
Close clinical surveillance of all women taking estrogens is important. Adequate diagnostic
measures, including endometrial sampling when indicated, should be undertaken to rule out
malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal bleeding. There
is no evidence that the use of “natural” estrogens results in a different endometrial risk profile
than synthetic estrogens of equivalent estrogen dose. (See WARNINGS, Malignant neoplasms,
Endometrial cancer.)
CARDIOVASCULAR AND OTHER RISKS
Estrogens with or without progestins should not be used for the prevention of cardiovascular
disease or dementia. (See WARNINGS, Cardiovascular disorders and Dementia.)
The Women’s Health Initiative (WHI) study reported increased risks of stroke and deep vein
thrombosis in postmenopausal women (50 to 79 years of age) during 6.8 years of treatment with
conjugated estrogens (0.625 mg) relative to placebo. (See CLINICAL PHARMACOLOGY,
Clinical Studies and WARNINGS, Cardiovascular disorders.)
The WHI study reported increased risks of myocardial infarction, stroke, invasive breast cancer,
pulmonary emboli, and deep vein thrombosis in postmenopausal women (50 to 79 years of age)
during 5 years of treatment with oral conjugated estrogens (0.625 mg) combined with
medroxyprogesterone acetate (2.5 mg) relative to placebo. (See CLINICAL
PHARMACOLOGY, Clinical Studies and WARNINGS, Cardiovascular disorders and
Malignant neoplasms, Breast cancer.)
The Women’s Health Initiative Memory Study (WHIMS), a substudy of WHI, reported
increased risk of developing probable dementia in postmenopausal women 65 years of age or
older during 5.2 years of treatment with oral conjugated estrogens alone and during 4 years of
treatment with conjugated estrogens combined with medroxyprogesterone acetate, relative to
placebo. It is unknown whether this finding applies to younger postmenopausal women. (See
CLINICAL PHARMACOLOGY, Clinical Studies, WARNINGS, Dementia and
PRECAUTIONS, Geriatric Use.)
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-216/S-054
NDA 10-402/S-048
Page 4
Other doses of conjugated estrogens and medroxyprogesterone acetate, and other combinations
and dosage forms of estrogens and progestins were not studied in the WHI clinical trials and, in
the absence of comparable data, these risks should be assumed to be similar. Because of these
risks, estrogens with or without progestins should be prescribed at the lowest effective doses and
for the shortest duration consistent with treatment goals and risks for the individual woman.
DESCRIPTION
Each gram of Premarin (conjugated estrogens) Vaginal Cream contains 0.625 mg conjugated
estrogens, USP in a nonliquefying base containing cetyl esters wax, cetyl alcohol, white wax,
glyceryl monostearate, propylene glycol monostearate, methyl stearate, benzyl alcohol, sodium
lauryl sulfate, glycerin, and mineral oil. Premarin Vaginal Cream is applied intravaginally.
Premarin (conjugated estrogens) Vaginal Cream contains a mixture of conjugated estrogens
obtained exclusively from natural sources, occurring as the sodium salts of water-soluble
estrogen sulfates blended to represent the average composition of material derived from pregnant
mares’ urine. It is a mixture of sodium estrone sulfate and sodium equilin sulfate. It contains as
concomitant components, as sodium sulfate conjugates, 17 α-dihydroequilin, 17 α-estradiol, and
17 β-dihydroequilin.
CLINICAL PHARMACOLOGY
Endogenous estrogens are largely responsible for the development and maintenance of the
female reproductive system and secondary sexual characteristics. Although circulating estrogens
exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal
intracellular human estrogen and is substantially more potent than its metabolites, estrone and
estriol, at the receptor level.
The primary source of estrogen in normally cycling adult women is the ovarian follicle, which
secretes 70 to 500 mcg of estradiol daily, depending on the phase of the menstrual cycle. After
menopause, most endogenous estrogen is produced by conversion of androstenedione, secreted
by the adrenal cortex, to estrone by peripheral tissues. Thus, estrone and the sulfate-conjugated
form, estrone sulfate, are the most abundant circulating estrogen in postmenopausal women.
Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, two
estrogen receptors have been identified. These vary in proportion from tissue to tissue.
Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone
(LH) and follicle stimulating hormone (FSH) through a negative feedback mechanism. Estrogens
act to reduce the elevated levels of these gonadotropins seen in postmenopausal women.
Pharmacokinetics
Absorption
Conjugated estrogens are soluble in water and are well absorbed through the skin, mucous
membranes, and the gastrointestinal tract after release from the drug formulation.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-216/S-054
NDA 10-402/S-048
Page 5
Distribution
The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are
widely distributed in the body and are generally found in higher concentration in the sex
hormone target organs. Estrogens circulate in the blood largely bound to sex hormone-binding
globulin (SHBG) and albumin.
Metabolism
Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating
estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations
take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be
converted to estriol, which is the major urinary metabolite. Estrogens also undergo enterohepatic
recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates
into the intestine, and hydrolysis in the gut followed by reabsorption. In postmenopausal women
a significant proportion of the circulating estrogens exists as sulfate conjugates, especially
estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens.
Excretion
Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate
conjugates.
Special Populations
No pharmacokinetic studies were conducted in special populations, including patients with renal
or hepatic impairment.
Drug Interactions
Data from a single-dose drug-drug interaction study involving oral conjugated estrogens and
medroxyprogesterone acetate indicate that the pharmacokinetic dispositions of both drugs are not
altered when the drugs are coadministered. No other clinical drug-drug interaction studies have
been conducted with conjugated estrogens.
In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome
P450 3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen drug
metabolism. Inducers of CYP3A4 such as St. John’s Wort preparations (Hypericum perforatum),
phenobarbital, carbamazepine, and rifampin may reduce plasma concentrations of estrogens,
possibly resulting in a decrease in therapeutic effects and/or changes in the uterine bleeding
profile. Inhibitors of CYP3A4 such as erythromycin, clarithromycin, ketoconazole, itraconazole,
ritonavir and grapefruit juice may increase plasma concentrations of estrogens and may result in
side effects.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-216/S-054
NDA 10-402/S-048
Page 6
Clinical Studies
Women’s Health Initiative Studies.
The Women’s Health Initiative (WHI) enrolled a total of 27,000 predominantly healthy
postmenopausal women to assess the risks and benefits of either the use of Premarin tablets
(0.625 mg conjugated estrogens per day) alone or the use of PREMPRO tablets (0.625 mg
conjugated estrogens plus 2.5 mg medroxyprogesterone acetate per day) compared to placebo in
the prevention of certain chronic diseases. The primary endpoint was the incidence of coronary
heart disease (CHD) (nonfatal myocardial infarction and CHD death), with invasive breast
cancer as the primary adverse outcome studied. A “global index” included the earliest occurrence
of CHD, invasive breast cancer, stroke, pulmonary embolism (PE), endometrial cancer,
colorectal cancer, hip fracture, or death due to other cause. The study did not evaluate the effects
of Premarin tablets or PREMPRO on menopausal symptoms.
The estrogen alone substudy was stopped early because an increased risk of stroke was observed
and it was deemed that no further information would be obtained regarding the risks and benefits
of estrogen alone in predetermined primary endpoints. Results of the estrogen alone substudy,
which included 10,739 women (average age of 63 years, range 50 to 79; 75.3% White,
15% Black, 6.1% Hispanic), after an average follow-up of 6.8 years are presented in Table 1
below.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-216/S-054
NDA 10-402/S-048
Page 7
TABLE 1. RELATIVE AND ABSOLUTE RISK SEEN IN THE ESTROGEN ALONE
SUBSTUDY OF WHIa
Placebo
n = 5429
Premarin
n = 5310
Eventc
Relative Risk*
Premarin vs Placebo
at 6.8 Years
(95% CI)
Absolute Risk per 10,000
Women-years
CHD events
0.91 (0.75-1.12)
54
49
Non-fatal MI
0.89 (0.70-1.12)
41
37
CHD death
0.94 (0.65-1.36)
16
15
Invasive breast cancer
0.77 (0.59-1.01)
33
26
Stroke
1.39 (1.10-1.77)
32
44
Pulmonary embolism
1.34 (0.87-2.06)
10
13
Colorectal cancer
1.08 (0.75-1.55)
16
17
Hip fracture
0.61 (0.41-0.91)
17
11
Death due to other causes than
the events above
1.08 (0.88-1.32)
50
53
Global Indexb
1.01 (0.91-1.12)
190
192
Deep vein thrombosisc
1.47 (1.04-2.08)
15
21
Vertebral fracturesc
0.62 (0.42-0.93)
17
11
Total fracturesc
0.70 (0.63-0.79)
195
139
a: adapted from JAMA, 2004; 291:1701-1712
b: a subset of the events was combined in a “global index,” defined as the earliest occurrence of
CHD events, invasive breast cancer, stroke, pulmonary embolism, endometrial cancer,
colorectal cancer, hip fracture, or death due to other causes
c: not included in Global Index
* nominal confidence intervals unadjusted for multiple looks and multiple comparisons.
For those outcomes included in the WHI “global index” that reached statistical significance, the
absolute excess risk per 10,000 women-years in the group treated with Premarin alone were
12 more strokes while the absolute risk reduction per 10,000 women-years was 6 fewer hip
fractures. The absolute excess risk of events included in the “global index” was a nonsignificant
2 events per 10,000 women-years. There was no difference between the groups in terms of
all-cause mortality. (See BOXED WARNINGS, WARNINGS, and PRECAUTIONS.)
The estrogen plus progestin substudy was also stopped early because, according to the
predefined stopping rule, the increased risk of breast cancer and cardiovascular events exceeded
the specified benefits included in the “global index.” Results of the estrogen plus progestin
substudy, which included 16,608 women (average age of 63 years, range 50 to 79; 83.9% White,
6.5% Black, 5.5% Hispanic), after an average follow-up of 5.2 years are presented in Table 2
below.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-216/S-054
NDA 10-402/S-048
Page 8
Table 2. RELATIVE AND ABSOLUTE RISK SEEN IN THE ESTROGEN PLUS
PROGESTIN SUBSTUDY OF WHIa
Placebo
Prempro
n = 8102
n = 8506
Event c
Relative Risk
Prempro vs Placebo
at 5.2 Years
(95% CI*)
Absolute Risk per 10,000
Women-years
CHD events
1.29 (1.02-1.63)
30
37
Non-fatal MI
1.32 (1.02-1.72)
23
30
CHD death
1.18 (0.70-1.97)
6
7
Invasive breast cancer b
1.26 (1.00-1.59)
30
38
Stroke
1.41 (1.07-1.85)
21
29
Pulmonary embolism
2.13 (1.39-3.25)
8
16
Colorectal cancer
0.63 (0.43-0.92)
16
10
Endometrial cancer
0.83 (0.47-1.47)
6
5
Hip fracture
0.66 (0.45-0.98)
15
10
Death due to causes other
than the events above
0.92 (0.74-1.14)
40
37
Global Index c
1.15 (1.03-1.28)
151
170
Deep vein thrombosis d
2.07 (1.49-2.87)
13
26
Vertebral fractures d
0.66 (0.44-0.98)
15
9
Other osteoporotic
fractures d
0.77 (0.69-0.86)
170
131
a
adapted from JAMA, 2002; 288:321-333
b
includes metastatic and non-metastatic breast cancer with the exception of in situ breast
cancer
c
a subset of the events was combined in a “global index”, defined as the earliest occurrence
of CHD events, invasive breast cancer, stroke, pulmonary embolism, endometrial cancer,
colorectal cancer, hip fracture, or death due to other causes
d
not included in Global Index
* nominal confidence intervals unadjusted for multiple looks and multiple comparisons
For those outcomes included in the WHI “global index,” the absolute excess risks per
10,000 women-years in the group treated with PREMPRO were 7 more CHD events, 8 more
strokes, 8 more PEs, and 8 more invasive breast cancers, while the absolute risk reductions per
10,000 women-years were 6 fewer colorectal cancers and 5 fewer hip fractures. The absolute
excess risk of events included in the “global index” was 19 per 10,000 women-years. There was
no difference between the groups in terms of all-cause mortality. (See BOXED WARNINGS,
WARNINGS, and PRECAUTIONS.)
Women’s Health Initiative Memory Study.
The estrogen alone Women’s Health Initiative Memory Study (WHIMS), a substudy of WHI,
enrolled 2,947 predominantly healthy postmenopausal women 65 years of age and older (45%
were age 65 to 69 years, 36% were 70 to 74 years, and 19% were 75 years of age and older) to
evaluate the effects of Premarin (0.625 mg conjugated estrogens) on the incidence of probable
dementia (primary outcome) compared with placebo.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-216/S-054
NDA 10-402/S-048
Page 9
After an average follow-up of 5.2 years, 28 women in the estrogen alone group (37 per
10,000 women-years) and 19 in the placebo group (25 per 10,000 women-years) were diagnosed
with probable dementia. The relative risk of probable dementia in the estrogen alone group was
1.49 (95% CI, 0.83 to 2.66) compared to placebo. It is unknown whether these findings apply to
younger postmenopausal women. (See BOXED WARNINGS, WARNINGS, Dementia and
PRECAUTIONS, Geriatric Use.)
The estrogen plus progestin WHIMS substudy enrolled 4,532 predominantly healthy
postmenopausal women 65 years of age and older (47% were age 65 to 69 years, 35% were
70 to 74 years, and 18% were 75 years of age and older) to evaluate the effects of PREMPRO
(0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate) on the incidence of
probable dementia (primary outcome) compared with placebo.
After an average follow-up of 4 years, 40 women in the estrogen/progestin group (45 per
10,000 women-years) and 21 in the placebo group (22 per 10,000 women-years) were diagnosed
with probable dementia. The relative risk of probable dementia in the hormone therapy group
was 2.05 (95% CI, 1.21 to 3.48) compared to placebo. Differences between groups became
apparent in the first year of treatment. It is unknown whether these findings apply to younger
postmenopausal women. (See BOXED WARNINGS, WARNINGS, Dementia and
PRECAUTIONS, Geriatric Use.)
INDICATIONS AND USAGE
Premarin (conjugated estrogens) Vaginal Cream is indicated in the treatment of atrophic vaginitis
and kraurosis vulvae.
CONTRAINDICATIONS
Premarin Vaginal Cream should not be used in women with any of the following conditions:
1. Undiagnosed abnormal genital bleeding.
2. Known, suspected, or history of cancer of the breast.
3. Known or suspected estrogen-dependent neoplasia.
4. Active deep vein thrombosis, pulmonary embolism or a history of these conditions.
5. Active or recent (e.g., within past year) arterial thromboembolic disease (e.g., stroke,
myocardial infarction).
6. Liver dysfunction or disease.
7. Premarin Vaginal Cream should not be used in patients with known hypersensitivity to its
ingredients.
8. Known or suspected pregnancy. There is no indication for Premarin Vaginal Cream in
pregnancy. There appears to be little or no increased risk of birth defects in children born to
women who have used estrogen and progestins from oral contraceptives inadvertently during
pregnancy. (See PRECAUTIONS.)
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-216/S-054
NDA 10-402/S-048
Page 10
WARNINGS
See BOXED WARNINGS.
Systemic absorption may occur with the use of Premarin Vaginal Cream. The warnings,
precautions, and adverse reactions associated with oral Premarin treatment should be taken into
account.
1. Cardiovascular disorders.
Estrogen and estrogen/progestin therapy have been associated with an increased risk of
cardiovascular events such as myocardial infarction and stroke, as well as venous thrombosis and
pulmonary embolism (venous thromboembolism or VTE). Should any of these occur or be
suspected, estrogens should be discontinued immediately.
Risk factors for arterial vascular disease (e.g., hypertension, diabetes mellitus, tobacco use,
hypercholesterolemia, and obesity) and/or venous thromboembolism (e.g., personal history or
family history of VTE, obesity, and systemic lupus erythematosus) should be managed
appropriately.
a. Coronary heart disease and stroke. In the estrogen alone substudy of the Women’s Health
Initiative (WHI) study, an increased risk of stroke was observed in women receiving Premarin
compared to women receiving placebo (44 vs 32 per 10,000 women-years). The increase in risk
was observed in year one and persisted. (See CLINICAL PHARMACOLOGY, Clinical
Studies.)
In the estrogen plus progestin substudy of WHI, an increased risk of coronary heart disease
(CHD) events (defined as nonfatal myocardial infarction and CHD death) was observed in
women receiving PREMPRO (0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone
acetate) per day compared to women receiving placebo (37 vs 30 per 10,000 women-years). The
increase in risk was observed in year one and persisted.
In the same estrogen plus progestin substudy of the WHI, an increased risk of stroke was
observed in women receiving PREMPRO compared to women receiving placebo (29 vs 21 per
10,000 women-years). The increase in risk was observed after the first year and persisted.
In postmenopausal women with documented heart disease (n = 2,763, average age 66.7 years) a
controlled clinical trial of secondary prevention of cardiovascular disease (Heart and
Estrogen/progestin Replacement Study; HERS) treatment with PREMPRO (0.625 mg conjugated
estrogen plus 2.5 mg medroxyprogesterone acetate per day) demonstrated no cardiovascular
benefit. During an average follow-up of 4.1 years, treatment with PREMPRO did not reduce the
overall rate of CHD events in postmenopausal women with established coronary heart disease.
There were more CHD events in the PREMPRO-treated group than in the placebo group in year
1, but not during the subsequent years. Two thousand three hundred and twenty one women from
the original HERS trial agreed to participate in an open label extension of HERS, HERS II.
Average follow-up in HERS II was an additional 2.7 years, for a total of 6.8 years overall. Rates
of CHD events were comparable among women in the PREMPRO group and the placebo group
in HERS, HERS II, and overall.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-216/S-054
NDA 10-402/S-048
Page 11
Large doses of estrogen (5 mg conjugated estrogens per day), comparable to those used to treat
cancer of the prostate and breast, have been shown in a large prospective clinical trial in men to
increase the risks of nonfatal myocardial infarction, pulmonary embolism, and thrombophlebitis.
b. Venous thromboembolism (VTE). In the estrogen alone substudy of the Women’s Health
Initiative (WHI) study, an increased risk of deep vein thrombosis was observed in women
receiving Premarin compared to placebo (21 vs 15 per 10,000 women-years). The increase in
VTE risk was observed during the first year. (See CLINICAL PHARMACOLOGY, Clinical
Studies.)
In the estrogen plus progestin substudy of WHI, a 2-fold greater rate of VTE, including deep
venous thrombosis and pulmonary embolism, was observed in women receiving PREMPRO
compared to women receiving placebo. The rate of VTE was 34 per 10,000 women-years in the
Prempro group compared to 16 per 10,000 women-years in the placebo group. The increase in
VTE risk was observed during the first year and persisted.
If feasible, estrogens should be discontinued at least 4 to 6 weeks before surgery of the type
associated with an increased risk of thromboembolism, or during periods of prolonged
immobilization.
2. Malignant neoplasms.
a. Endometrial cancer. The use of unopposed estrogens in women with intact uteri has been
associated with an increased risk of endometrial cancer. The reported endometrial cancer risk
among unopposed estrogen users is about 2- to 12-fold greater than in non-users, and appears
dependent on duration of treatment and on estrogen dose. Most studies show no significant
increased risk associated with use of estrogens for less than one year. The greatest risk appears
associated with prolonged use, with increased risks of 15- to 24-fold for five to ten years or more
and this risk has been shown to persist for at least 8 to 15 years after estrogen therapy is
discontinued.
Clinical surveillance of all women taking estrogen/progestin combinations is important.
Adequate diagnostic measures, including endometrial sampling when indicated, should be
undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal
vaginal bleeding. There is no evidence that the use of natural estrogens results in a different
endometrial risk profile than synthetic estrogens of equivalent estrogen dose. Adding a progestin
to postmenopausal estrogen therapy has been shown to reduce the risk of endometrial
hyperplasia, which may be a precursor to endometrial cancer.
b. Breast cancer. In some studies, the use of estrogens and progestins by postmenopausal
women has been reported to increase the risk of breast cancer. The most important randomized
clinical trial providing information about this issue is the Women’s Health Initiative (WHI) trial
of estrogen plus progestin (see CLINICAL PHARMACOLOGY, Clinical Studies). The
results from observational studies are generally consistent with those of the WHI clinical trial.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-216/S-054
NDA 10-402/S-048
Page 12
After a mean follow-up of 5.6 years, the WHI trial reported an increased risk of breast cancer in
women who took estrogen plus progestin. Observational studies have also reported an increased
risk for estrogen/progestin combination therapy, and a smaller increased risk for estrogen alone
therapy, after several years of use. For both findings, the excess risk increased with duration of
use, and appeared to return to baseline over about five years after stopping treatment (only the
observational studies have substantial data on risk after stopping). In these studies, the risk of
breast cancer was greater, and became apparent earlier, with estrogen/progestin combination
therapy as compared to estrogen alone therapy. However, these studies have not found
significant variation in the risk of breast cancer among different estrogens or among different
estrogen/progestin combinations, doses, or routes of administration.
In the WHI trial of estrogen plus progestin, 26% of the women reported prior use of estrogen
alone and/or estrogen/progestin combination hormone therapy. After a mean follow-up of
5.6 years during the clinical trial, the overall relative risk of invasive breast cancer was
1.24 (95% confidence interval 1.01-1.54), and the overall absolute risk was 41 vs. 33 cases per
10,000 women-years, for estrogen plus progestin compared with placebo. Among women who
reported prior use of hormone therapy, the relative risk of invasive breast cancer was 1.86, and
the absolute risk was 46 vs. 25 cases per 10,000 women-years, for estrogen plus progestin
compared with placebo. Among women who reported no prior use of hormone therapy, the
relative risk of invasive breast cancer was 1.09, and the absolute risk was 40 vs. 36 cases per
10,000 women-years for estrogen plus progestin compared with placebo. In the WHI trial,
invasive breast cancers were larger and diagnosed at a more advanced stage in the estrogen plus
progestin group compared with the placebo group. Metastatic disease was rare with no apparent
difference between the two groups. Other prognostic factors such as histologic subtype, grade
and hormone receptor status did not differ between the groups.
The observational Million Women Study in Europe reported an increased risk of mortality due to
breast cancer among current users of estrogens alone or estrogens plus progestins compared to
never users, while the estrogen plus progestin sub-study of WHI showed no effect on breast
cancer mortality with a mean follow-up of 5.6 years.
The use of estrogen plus progestin has been reported to result in an increase in abnormal
mammograms requiring further evaluation. All women should receive yearly breast
examinations by a healthcare provider and perform monthly breast self-examinations. In
addition, mammography examinations should be scheduled based on patient age, risk factors,
and prior mammogram results.
3. Dementia.
In the estrogen alone Women’s Health Initiative Memory Study (WHIMS), a substudy of WHI, a
population of 2,947 hysterectomized women aged 65 to 79 years was randomized to Premarin
(0.625 mg) or placebo. In the estrogen plus progestin WHIMS substudy, a population of 4,532
postmenopausal women aged 65 to 79 years was randomized to PREMPRO (0.625 mg/2.5 mg)
or placebo.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-216/S-054
NDA 10-402/S-048
Page 13
In the estrogen alone substudy, after an average follow-up of 5.2 years, 28 women in the
estrogen alone group and 19 women in the placebo group were diagnosed with probable
dementia. The relative risk of probable dementia for Premarin alone versus placebo was
1.49 (95% CI 0.83-2.66). The absolute risk of probable dementia for Premarin alone versus
placebo was 37 versus 25 cases per 10,000 women-years.
In the estrogen plus progestin substudy, after an average follow-up of 4 years, 40 women in the
estrogen plus progestin group and 21 women in the placebo group were diagnosed with probable
dementia. The relative risk of probable dementia for estrogen plus progestin versus placebo was
2.05 (95% CI 1.21-3.48). The absolute risk of probable dementia for PREMPRO versus placebo
was 45 versus 22 cases per 10,000 women-years.
Since both substudies were conducted in women aged 65 to 79 years, it is unknown whether
these findings apply to younger postmenopausal women. (See BOXED WARNINGS and
PRECAUTIONS, Geriatric Use.)
4. Gallbladder disease.
A 2- to 4-fold increase in the risk of gallbladder disease requiring surgery in postmenopausal
women receiving postmenopausal estrogens has been reported.
5. Hypercalcemia.
Estrogen administration may lead to severe hypercalcemia in patients with breast cancer and
bone metastases. If hypercalcemia occurs, use of the drug should be stopped and appropriate
measures taken to reduce the serum calcium level.
6. Visual abnormalities.
Retinal vascular thrombosis has been reported in patients receiving estrogens. Discontinue
medication pending examination if there is sudden partial or complete loss of vision, or a sudden
onset of proptosis, diplopia, or migraine. If examination reveals papilledema or retinal vascular
lesions, estrogens should be discontinued.
PRECAUTIONS
A. General
1. Addition of a progestin when a woman has not had a hysterectomy.
Studies of the addition of a progestin for 10 or more days of a cycle of estrogen administration or
daily with estrogen in a continuous regimen have reported a lowered incidence of endometrial
hyperplasia than would be induced by estrogen treatment alone. Endometrial hyperplasia may be
a precursor to endometrial cancer.
There are, however, possible risks that may be associated with the use of progestins with
estrogens compared to estrogen-alone regimens. These include a possible increased risk of breast
cancer, adverse effects on lipoprotein metabolism (e.g., lowering HDL, raising LDL) and
impairment of glucose tolerance.
2. Elevated blood pressure.
In a small number of case reports, substantial increases in blood pressure have been attributed to
idiosyncratic reactions to estrogens. In a large, randomized, placebo-controlled clinical trial, a
generalized effect of estrogen therapy on blood pressure was not seen. Blood pressure should be
monitored at regular intervals with estrogen use.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-216/S-054
NDA 10-402/S-048
Page 14
3. Hypertriglyceridemia.
In patients with pre-existing hypertriglyceridemia, estrogen therapy may be associated with
elevations of plasma triglycerides leading to pancreatitis and other complications.
4. Impaired liver function and past history of cholestatic jaundice.
Estrogens may be poorly metabolized in patients with impaired liver function. For patients with a
history of cholestatic jaundice associated with past estrogen use or with pregnancy, caution
should be exercised and in the case of recurrence, medication should be discontinued.
5. Hypothyroidism.
Estrogen administration leads to increased thyroid-binding globulin (TBG) levels. Patients with
normal thyroid function can compensate for the increased TBG by making more thyroid
hormone, thus maintaining free T4 and T3 serum concentrations in the normal range. Patients
dependent on thyroid hormone replacement therapy who are also receiving estrogens may
require increased doses of their thyroid replacement therapy. These patients should have their
thyroid function monitored in order to maintain their free thyroid hormone levels in an
acceptable range.
6. Fluid retention.
Because estrogens may cause some degree of fluid retention, patients with conditions that might
be influenced by this factor, such as cardiac or renal dysfunction, warrant careful observation
when estrogens are prescribed.
7. Hypocalcemia.
Estrogens should be used with caution in individuals with severe hypocalcemia.
8. Ovarian cancer.
The estrogen plus progestin substudy of WHI reported that after an average follow-up of
5.6 years, the relative risk for ovarian cancer for estrogen plus progestin versus placebo was
1.58 (95% confidence interval 0.77 – 3.24) but was not statistically significant. The absolute risk
for estrogen plus progestin versus placebo was 4.2 versus 2.7 cases per 10,000 women-years. In
some epidemiologic studies, the use of estrogen-only products, in particular for ten or more
years, has been associated with an increased risk of ovarian cancer. Other epidemiologic studies
have not found these associations.
9. Exacerbation of endometriosis.
Endometriosis may be exacerbated with administration of estrogen therapy.
A few cases of malignant transformation of residual endometrial implants have been reported in
women treated post-hysterectomy with estrogen alone therapy. For patients known to have
residual endometriosis post-hysterectomy, the addition of progestin should be considered.
10. Exacerbation of other conditions.
Estrogen therapy may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine,
porphyria, systemic lupus erythematosus, and hepatic hemangiomas and should be used with
caution in women with these conditions.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-216/S-054
NDA 10-402/S-048
Page 15
11. Barrier contraceptives.
Premarin Vaginal Cream exposure has been reported to weaken latex condoms. The potential for
Premarin Vaginal Cream to weaken and contribute to the failure of condoms, diaphragms, or
cervical caps made of latex or rubber should be considered.
B. Patient Information
Physicians are advised to discuss the contents of the PATIENT INFORMATION leaflet with
patients for whom they prescribe Premarin Vaginal Cream.
C. Laboratory Tests
Estrogen administration should be guided by clinical response at the lowest dose for the
treatment of postmenopausal vulvar and vaginal atrophy.
D. Drug/Laboratory Test Interactions
1. Accelerated prothrombin time, partial thromboplastin time, and platelet aggregation time;
increased platelet count; increased factors II, VII antigen, VIII antigen, VIII coagulant
activity, IX, X, XII, VII-X complex, II-VII-X complex, and beta-thromboglobulin; decreased
levels of antifactor Xa and antithrombin III, decreased antithrombin III activity; increased
levels of fibrinogen and fibrinogen activity; increased plasminogen antigen and activity.
2. Increased thyroid-binding globulin (TBG) leading to increased circulating total thyroid
hormone, as measured by protein-bound iodine (PBI), T4 levels (by column or by
radioimmunoassay) or T3 levels by radioimmunoassay. T3 resin uptake is decreased,
reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered. Patients on
thyroid replacement therapy may require higher doses of thyroid hormone.
3. Other binding proteins may be elevated in serum, i.e., corticosteroid binding globulin (CBG),
sex hormone-binding globulin (SHBG), leading to increased total circulating corticosteroids
and sex steroids, respectively. Free hormone concentrations may be decreased. Other plasma
proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin,
ceruloplasmin).
4. Increased plasma HDL and HDL2 cholesterol subfraction concentrations, reduced LDL
cholesterol concentration, increased triglyceride levels.
5. Impaired glucose tolerance.
6. Reduced response to metyrapone test.
E. Carcinogenesis, Mutagenesis, Impairment of Fertility
(See BOXED WARNINGS, WARNINGS, and PRECAUTIONS.)
Long-term continuous administration of natural and synthetic estrogens in certain animal species
increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis, and liver.
F. Pregnancy
Premarin Vaginal Cream should not be used during pregnancy. (See
CONTRAINDICATIONS.)
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-216/S-054
NDA 10-402/S-048
Page 16
G. Nursing Mothers
Estrogen administration to nursing mothers has been shown to decrease the quantity and quality
of breast milk. Detectable amounts of estrogens have been identified in the milk of mothers
receiving the drug. Caution should be exercised when Premarin Vaginal Cream is administered
to a nursing woman.
H. Pediatric Use
Estrogen therapy has been used for the induction of puberty in adolescents with some forms of
pubertal delay. Safety and effectiveness in pediatric patients have not otherwise been established.
Large and repeated doses of estrogen over an extended time period have been shown to
accelerate epiphyseal closure, which could result in short adult stature if treatment is initiated
before the completion of physiologic puberty in normally developing children. If estrogen is
administered to patients whose bone growth is not complete, periodic monitoring of bone
maturation and effects on epiphyseal centers is recommended during estrogen administration.
Estrogen treatment of prepubertal girls also induces premature breast development and vaginal
cornification, and may induce vaginal bleeding. In boys, estrogen treatment may modify the
normal pubertal process and induce gynecomastia. See INDICATIONS and DOSAGE AND
ADMINISTRATION sections.
I. Geriatric Use
Of the total number of subjects in the estrogen alone substudy of the Women’s Health Initiative
(WHI) study, 46% (n=4,943) were 65 years and over, while 7.1% (n=767) were 75 years and
over. There was a higher relative risk (Premarin vs. placebo) of stroke in women less than 75
years of age compared to women 75 years and over.
In the estrogen alone substudy of the Women’s Health Initiative Memory Study (WHIMS), a
substudy of WHI, a population of 2,947 hysterectomized women, aged 65 to 79 years, was
randomized to Premarin (0.625 mg) or placebo. In the estrogen alone group, after an average
follow-up of 5.2 years, the relative risk (Premarin versus placebo) of probable dementia was
1.49 (95% CI 0.83-2.66).
Of the total number of subjects in the estrogen plus progestin substudy of the Women’s Health
Initiative study, 44% (n = 7,320) were 65 years and over, while 6.6% (n = 1,095) were 75 years
and over. There was a higher relative risk (PREMPRO vs placebo) of stroke and invasive breast
cancer in women 75 and over compared to women less than 75 years of age.
In the estrogen plus progestin substudy of WHIMS, a population of 4,532 postmenopausal
women, aged 65 to 79 years, was randomized to PREMPRO (0.625 mg/2.5 mg) or placebo. In
the estrogen plus progestin group, after an average follow-up of 4 years, the relative risk
(PREMPRO versus placebo) of probable dementia was 2.05 (95% CI 1.21-3.48).
Pooling the events in women receiving Premarin or PREMPRO in comparison to those in
women on placebo, the overall relative risk for probable dementia was 1.76 (95% CI 1.19-2.60).
Since both substudies were conducted in women aged 65 to 79 years, it is unknown whether
these findings apply to younger postmenopausal women. (See BOXED WARNINGS and
WARNINGS, Dementia.)
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-216/S-054
NDA 10-402/S-048
Page 17
There have not been sufficient numbers of geriatric patients involved in studies utilizing
Premarin Vaginal Cream to determine whether those over 65 years of age differ from younger
subjects in their response to Premarin Vaginal Cream.
ADVERSE REACTIONS
See BOXED WARNINGS, WARNINGS, and PRECAUTIONS.
Systemic absorption may occur with the use of Premarin Vaginal Cream. Warnings, precautions,
and adverse reactions associated with oral Premarin treatment should be taken into account.
The following additional adverse reactions have been reported with estrogen and/or progestin
therapy:
1. Genitourinary system: Breakthrough bleeding, spotting, changes in vaginal bleeding pattern
and abnormal withdrawal bleeding or flow; dysmenorrhea; increase in size of uterine
leiomyomata; vaginitis, including vaginal candidiasis; change in cervical erosion and in
degree of cervical secretion; cystitis-like syndrome; application site reactions of vulvovaginal
discomfort including burning and irritation; genital pruritus; ovarian cancer; endometrial
hyperplasia; endometrial cancer; precocious puberty.
2. Breasts: Tenderness, pain, enlargement, secretion; breast cancer; fibrocystic breast changes.
3. Cardiovascular: Deep and superficial venous thrombosis, pulmonary embolism,
thrombophlebitis, myocardial infarction, stroke; increase in blood pressure.
4. Gastrointestinal: Nausea, vomiting, abdominal cramps, bloating; cholestatic jaundice;
pancreatitis; increased incidence of gallbladder disease; enlargement of hepatic
hemangiomas.
5. Skin: Chloasma or melasma which may persist when drug is discontinued; erythema
multiforme; erythema nodosum; hemorrhagic eruption; loss of scalp hair; hirsutism; pruritis;
rash.
6. Eyes: Retinal vascular thrombosis; intolerance to contact lenses.
7. Central Nervous System: Headache; migraine; dizziness; nervousness; mood disturbances;
irritability; mental depression; chorea; exacerbation of epilepsy; dementia.
8. Miscellaneous: Increase or decrease in weight; reduced carbohydrate tolerance; glucose
intolerance; aggravation of porphyria; edema; changes in libido; urticaria, angioedema,
anaphylactoid/anaphylactic reactions; hypocalcemia; exacerbation of asthma; increased
triglycerides; arthralgias; leg cramps.
OVERDOSAGE
Serious ill effects have not been reported following acute ingestion of large doses of
estrogen/progestin containing drug products by young children. Overdosage of estrogens may
cause nausea and vomiting, and withdrawal bleeding may occur in females.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-216/S-054
NDA 10-402/S-048
Page 18
DOSAGE AND ADMINISTRATION
Use of Premarin Vaginal Cream, alone or in combination with a progestin, should be limited to
the shortest duration consistent with treatment goals and risks for the individual woman. Patients
should be re-evaluated periodically as clinically appropriate (e.g., at 3-month to 6-month
intervals) to determine if treatment is still necessary (See BOXED WARNINGS and
WARNINGS). For women who have a uterus, adequate diagnostic measures, such as
endometrial sampling, when indicated, should be undertaken to rule out malignancy in cases of
undiagnosed persistent or recurring abnormal vaginal bleeding.
Given cyclically for short-term use only:
For treatment of atrophic vaginitis, or kraurosis vulvae. The lowest dose that will control
symptoms should be chosen and medication should be discontinued as promptly as possible.
Administration should be cyclic (e.g., three weeks on and one week off).
Usual Dosage Range:
½ to 2 g daily, intravaginally, depending on the severity of the condition.
Instructions For Use Of Gentle Measure Applicator
1. Remove cap from tube.
2. Screw nozzle end of applicator onto tube.
3. Gently squeeze tube from the bottom to force sufficient cream into the barrel to provide the
prescribed dose. Use the marked stopping points on the applicator as a guideline to measure the
correct dose.
4. Unscrew applicator from tube.
5. Lie on back with knees drawn up. To deliver medication, gently insert applicator deeply into
vagina and press plunger downward to its original position.
To Cleanse: Pull plunger to remove it from barrel. Wash with mild soap and warm water.
DO NOT BOIL OR USE HOT WATER.
HOW SUPPLIED
Premarin (conjugated estrogens) Vaginal CreamEach gram contains 0.625 mg conjugated
estrogens, USP.
Combination package: Each contains Net Wt. 1 ½ oz (42.5 g) tube with one plastic applicator
calibrated in ½ g increments to a maximum of 2 g (NDC 0046-0872-93).
Also Available Refill package: Each contains Net Wt. 1 ½ oz (42.5 g) tube
(NDC 0046-0872-01).
Store at room temperature (approximately 25° C).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-216/S-054
NDA 10-402/S-048
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PATIENT INFORMATION
(Updated August, 2005)
Premarin (conjugated estrogens) Vaginal Cream
Read this PATIENT INFORMATION before you start using Premarin Vaginal Cream and read
what you get each time you refill Premarin Vaginal Cream. There may be new information. This
information does not take the place of talking to your healthcare provider about your medical
condition or your treatment.
What is the most important information I should know about Premarin (an estrogen
mixture)?
• Estrogens increase the chances of getting cancer of the uterus.
Report any unusual vaginal bleeding right away while you are taking Premarin. Vaginal
bleeding after menopause may be a warning sign of cancer of the uterus (womb). Your
healthcare provider should check any unusual vaginal bleeding to find out the cause.
• Do not use estrogens with or without progestins to prevent heart disease, heart attacks,
strokes, or dementia.
Using estrogens with or without progestins may increase your chances of getting heart
attacks, strokes, breast cancer, and blood clots. Using estrogens, with or without progestins,
may increase your risk of dementia based on a study of women age 65 years or older. You
and your healthcare provider should talk regularly about whether you still need treatment
with Premarin Vaginal Cream.
What is Premarin Vaginal Cream?
Premarin Vaginal Cream is a medicine that contains a mixture of estrogen hormones.
What is Premarin Vaginal Cream used for?
Premarin Vaginal Cream is used after menopause to:
• treat dryness, itching, and burning, in and around the vagina. You and your healthcare
provider should talk regularly about whether you still need treatment with Premarin Vaginal
Cream to control these problems.
Who should not use Premarin Vaginal Cream?
Do not start using Premarin Vaginal Cream if you:
• have unusual vaginal bleeding.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-216/S-054
NDA 10-402/S-048
Page 20
• currently have or have had certain cancers.
Estrogens may increase the chances of getting certain types of cancers, including cancer of
the breast or uterus. If you have or have had cancer, talk with your healthcare provider about
whether you should use Premarin Vaginal Cream.
• had a stroke or heart attack in the past year.
• currently have or had blood clots.
• currently have liver problems.
• are allergic to Premarin Vaginal Cream or any of its ingredients.
See the end of this leaflet for a list of all the ingredients in Premarin Vaginal Cream.
• think you may be pregnant.
Tell your healthcare provider:
• if you are breast feeding. The hormones in Premarin Vaginal Cream can pass into your
milk.
• about all of your medical problems. Your healthcare provider may need to check you more
carefully if you have certain conditions, such as asthma (wheezing), epilepsy (seizures),
migraine, endometriosis, lupus, or problems with your heart, liver, thyroid, kidneys, or have
high calcium levels in your blood.
• about all the medicines you take, including prescription and nonprescription medicines,
vitamins, and herbal supplements. Some medicines may affect how Premarin Vaginal Cream
works. Premarin Vaginal Cream may also affect how your other medicines work.
• if you are going to have surgery or will be on bedrest. You may need to stop using
Premarin Vaginal Cream.
How should I use Premarin Vaginal Cream?
The Gentle Measure Applicator has been specifically designed for comfortable, easy use.
1. Remove cap from tube.
2. Screw nozzle end of applicator onto tube.
3. Gently squeeze tube from the bottom to force sufficient cream into the barrel to provide the
prescribed dose. Use the marked stopping points on the applicator as a guideline to measure the
correct dose, as prescribed by your healthcare provider.
4. Unscrew applicator from tube.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-216/S-054
NDA 10-402/S-048
Page 21
5. Lie on back with knees drawn up. To deliver medication, gently insert applicator deeply into
vagina and press plunger downward to its original position.
TO CLEANSE: Pull plunger to remove it from barrel. Wash with mild soap and warm water.
DO NOT BOIL OR USE HOT WATER.
Premarin Vaginal Cream should be used at the lowest possible dose for your treatment and only
as long as needed. You and your healthcare provider should talk regularly (for example, every
3 to 6 months) about the dose you are taking and whether you still need treatment with Premarin
Vaginal Cream.
What are the possible side effects of Premarin Vaginal Cream?
Although Premarin Vaginal Cream is only used in and around the vagina, the risks associated
with Premarin tablets should be taken into account.
Less common but serious side effects of estrogens include:
• Breast cancer
• Cancer of the uterus
• Stroke
• Heart attack
• Blood clots
• Dementia
• Gallbladder disease
• Ovarian cancer
These are some of the warning signs of serious side effects:
• Breast lumps
• Unusual vaginal bleeding
• Dizziness and faintness
• Changes in speech
• Severe headaches
• Chest pain
• Shortness of breath
• Pains in your legs
• Changes in vision
• Vomiting
Call your healthcare provider right away if you get any of these warning signs, or any other
unusual symptom that concerns you.
Common side effects of estrogens include:
• Headache
• Breast tenderness
• Irregular vaginal bleeding or spotting
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-216/S-054
NDA 10-402/S-048
Page 22
• Stomach/abdominal cramps, bloating
• Nausea and vomiting
• Hair loss
• Reactions from inserting Premarin Vaginal Cream such as vaginal burning, irritation, and
itching
Other side effects of estrogens include:
• High blood pressure
• Liver problems
• High blood sugar
• Fluid retention
• Enlargement of benign tumors of the uterus (“fibroids”)
• Vaginal yeast infections
• Allergic Reactions
These are not all the possible side effects of Premarin Vaginal Cream. For more information, ask
your healthcare provider or pharmacist.
What can I do to lower my chances of getting a serious side effect with Premarin Vaginal
Cream?
• Talk with your healthcare provider regularly about whether you should continue using
Premarin Vaginal Cream.
• See your healthcare provider right away if you get vaginal bleeding while using Premarin
Vaginal Cream.
• Have a breast exam and mammogram (breast X-ray) every year unless your healthcare
provider tells you something else. If members of your family have had breast cancer or if you
have ever had breast lumps or an abnormal mammogram, you may need to have breast exams
more often.
• If you have high blood pressure, high cholesterol (fat in the blood), diabetes, are overweight,
or if you use tobacco, you may have higher chances for getting heart disease. Ask your health
care provider for ways to lower your chances for getting heart disease.
General information about the safe and effective use of Premarin Vaginal Cream
Medicines are sometimes prescribed for conditions that are not mentioned in patient information
leaflets. Do not use Premarin Vaginal Cream for conditions for which it was not prescribed. Do
not give Premarin Vaginal Cream to other people, even if they have the same symptoms you
have. It may harm them. Keep Premarin Vaginal Cream out of the reach of children.
This leaflet provides a summary of the most important information about Premarin Vaginal
Cream. If you would like more information, talk with your healthcare provider or pharmacist.
You can ask for information about Premarin Vaginal Cream that is written for health
professionals. You can get more information by calling the toll free number 1-800-934-5556.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-216/S-054
NDA 10-402/S-048
Page 23
What are the ingredients in Premarin Vaginal Cream?
Premarin Vaginal Cream contains a mixture of conjugated estrogens, which are a mixture of
sodium estrone sulfate and sodium equilin sulfate and other components including sodium
sulfate conjugates: 17 α-dihydroequilin, 17 α-estradiol, and 17 β-dihydroequilin. Premarin
Vaginal Cream also contains cetyl esters wax, cetyl alcohol, white wax, glyceryl monostearate,
propylene glycol monostearate, methyl stearate, benzyl alcohol, sodium lauryl sulfate, glycerin,
and mineral oil.
Premarin (conjugated estrogens) Vaginal CreamEach gram contains 0.625 mg conjugated
estrogens, USP.
Combination package: Each contains Net Wt. 1 ½ oz (42.5 g) tube with one plastic applicator
calibrated in ½ g increments to a maximum of 2 g (NDC 0046-0872-93).
Also AvailableRefill package: Each contains Net Wt. 1 ½ oz (42.5 g) tube
(NDC 0046-0872-01).
Store at room temperature (approximately 25° C).
Wyeth Pharmaceuticals Inc.
Philadelphia, PA 19101 Revised August , 2005
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-216/S-054
NDA 10-402/S-048
Page 24
Premarin(conjugated estrogens)
Vaginal Cream in a nonliquefying base
℞ only
◄TEAR HERE
PATIENT INFORMATION
Read this PATIENT INFORMATION before you start using Premarin Vaginal Cream and read
what you get each time you refill Premarin Vaginal Cream. There may be new information. This
information does not take the place of talking to your healthcare provider about your medical
condition or your treatment.
What is the most important information I should know about Premarin (an estrogen
mixture)?
• Estrogens increase the chances of getting cancer of the uterus.
Report any unusual vaginal bleeding right away while you are taking Premarin. Vaginal
bleeding after menopause may be a warning sign of cancer of the uterus (womb). Your
healthcare provider should check any unusual vaginal bleeding to find out the cause.
• Do not use estrogens with or without progestins to prevent heart disease, heart attacks,
strokes, or dementia.
Using estrogens with or without progestins may increase your chances of getting heart
attacks, strokes, breast cancer, and blood clots. Using estrogens, with or without progestins,
may increase your risk of dementia based on a study of women age 65 years or older. You
and your healthcare provider should talk regularly about whether you still need treatment
with Premarin Vaginal Cream.
What is Premarin Vaginal Cream?
Premarin Vaginal Cream is a medicine that contains a mixture of estrogen hormones.
What is Premarin Vaginal Cream used for?
Premarin Vaginal Cream is used after menopause to:
• treat dryness, itching, and burning, in and around the vagina.
You and your healthcare provider should talk regularly about whether you still need treatment
with Premarin Vaginal Cream to control these problems.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-216/S-054
NDA 10-402/S-048
Page 25
Who should not use Premarin Vaginal Cream?
Do not start using Premarin Vaginal Cream if you:
• have unusual vaginal bleeding.
• currently have or have had certain cancers.
Estrogens may increase the chances of getting certain types of cancers, including cancer of
the breast or uterus. If you have or have had cancer, talk with your healthcare provider about
whether you should use Premarin Vaginal Cream.
• had a stroke or heart attack in the past year.
• currently have or had blood clots.
• currently have liver problems.
• are allergic to Premarin Vaginal Cream or any of its ingredients.
See the end of this leaflet for a list of all the ingredients in Premarin Vaginal Cream.
• think you may be pregnant.
Tell your healthcare provider:
• if you are breast feeding. The hormones in Premarin Vaginal Cream can pass into your
milk.
• about all of your medical problems. Your healthcare provider may need to check you more
carefully if you have certain conditions, such as asthma (wheezing), epilepsy (seizures),
migraine, endometriosis, lupus, problems with your heart, liver, thyroid, kidneys, or have
high calcium levels in your blood.
• about all the medicines you take, including prescription and nonprescription medicines,
vitamins, and herbal supplements. Some medicines may affect how Premarin Vaginal Cream
works. Premarin Vaginal Cream may also affect how your other medicines work.
• if you are going to have surgery or will be on bedrest. You may need to stop using
Premarin Vaginal Cream.
How should I use Premarin Vaginal Cream?
The Gentle MeasureApplicator has been specifically designed for comfortable, easy use.
1. Remove cap from tube.
2. Screw nozzle end of applicator onto tube.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-216/S-054
NDA 10-402/S-048
Page 26
3. Gently squeeze tube from the bottom to force sufficient cream into the barrel to provide the
prescribed dose. Use the marked stopping points on the applicator as a guideline to measure
the correct dose as prescribed by your healthcare provider.
4. Unscrew applicator from tube.
5. Lie on back with knees drawn up. To deliver medication, gently insert applicator deeply into
vagina and press plunger downward to its original position.
TO CLEANSE: Pull plunger to remove it from barrel. Wash with mild soap and warm water.
DO NOT BOIL OR USE HOT WATER.
Premarin Vaginal Cream should be used at the lowest possible dose for your treatment and only
as long as needed. You and your healthcare provider should talk regularly (for example, every
3 to 6 months) about the dose you are taking and about whether you still need treatment with
Premarin Vaginal Cream.
What are the possible side effects of Premarin Vaginal Cream?
Although Premarin Vaginal Cream is only used in and around the vagina, the risks associated
with Premarin tablets should be taken into account.
Less common but serious side effects of estrogens include:
• Breast cancer
• Cancer of the uterus
• Stroke
• Heart attack
• Blood clots
• Dementia
• Gallbladder disease
• Ovarian cancer
These are some of the warning signs of serious side effects:
• Breast lumps
• Unusual vaginal bleeding
• Dizziness and faintness
• Changes in speech
• Severe headaches
• Chest pain
• Shortness of breath
• Pains in your legs
• Changes in vision
• Vomiting
Call your healthcare provider right away if you get any of these warning signs, or any other
unusual symptom that concerns you.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-216/S-054
NDA 10-402/S-048
Page 27
Common side effects of estrogens include:
• Headache
• Breast tenderness
• Irregular vaginal bleeding or spotting
• Stomach/abdominal cramps, bloating
• Nausea and vomiting
• Hair loss
• Reactions from inserting Premarin Vaginal Cream such as vaginal burning, irritation, and
itching
Other side effects of estrogens include:
• High blood pressure
• Liver problems
• High blood sugar
• Fluid retention
• Enlargement of benign tumors of the uterus (“fibroids”)
• Vaginal yeast infections
• Allergic reactions
These are not all the possible side effects of Premarin Vaginal Cream. For more information, ask
your healthcare provider or pharmacist.
What can I do to lower my chances of getting a serious side effect with Premarin Vaginal
Cream?
• Talk with your healthcare provider regularly about whether you should continue using
Premarin Vaginal Cream.
• See your healthcare provider right away if you get vaginal bleeding while using Premarin
Vaginal Cream.
• Have a breast exam and mammogram (breast X-ray) every year unless your healthcare
provider tells you something else. If members of your family have had breast cancer or if you
have ever had breast lumps or an abnormal mammogram, you may need to have breast exams
more often.
• If you have high blood pressure, high cholesterol (fat in the blood), diabetes, are overweight,
or if you use tobacco, you may have higher chances for getting heart disease. Ask your health
care provider for ways to lower your chances for getting heart disease.
General information about the safe and effective use of Premarin Vaginal Cream
Medicines are sometimes prescribed for conditions that are not mentioned in patient information
leaflets. Do not use Premarin Vaginal Cream for conditions for which it was not prescribed. Do
not give Premarin Vaginal Cream to other people, even if they have the same symptoms you
have. It may harm them. Keep Premarin Vaginal Cream out of the reach of children.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-216/S-054
NDA 10-402/S-048
Page 28
This leaflet provides a summary of the most important information about Premarin Vaginal
Cream. If you would like more information, talk with your healthcare provider or pharmacist.
You can ask for information about Premarin Vaginal Cream that is written for health
professionals. You can get more information by calling the toll free number 800-934-5556.
What are the ingredients in Premarin Vaginal Cream?
Premarin Vaginal Cream contains a mixture of conjugated estrogens, which are a mixture of
sodium estrone sulfate and sodium equilin sulfate and other components including sodium
sulfate conjugates: 17 α-dihydroequilin, 17 α-estradiol, and 17 β-dihydroequilin. Premarin
Vaginal Cream also contains cetyl esters wax, cetyl alcohol, white wax, glyceryl monostearate,
propylene glycol monostearate, methyl stearate, benzyl alcohol, sodium lauryl sulfate, glycerin,
and mineral oil.
Premarin (conjugated estrogens) Vaginal CreamEach gram contains 0.625 mg conjugated
estrogens, USP.
Combination package: Each contains Net Wt. 1 ½ oz (42.5 g) tube with one plastic applicator
calibrated in ½ g increments to a maximum of 2 g (NDC 0046-0872-93).
Also AvailableRefill package: Each contains Net Wt. 1 ½ oz (42.5 g) tube
(NDC 0046-0872-01).
Store at room temperature (approximately 25° C).
This product’s label may have been revised after this insert was used
in production. For further product information and current package
insert, please visit www.wyeth.com or call our medical
communications department toll-free at 1-800-934-5556.
Wyeth Pharmaceuticals Inc.
Philadelphia, PA 19101 AUGUST, 2005
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-216/S-054
NDA 10-402/S-048
Page 29
Premarin
Intravenous
(conjugated estrogens, USP) for injection
Specially prepared for Intravenous & Intramuscular use
] only
ESTROGENS INCREASE THE RISK OF ENDOMETRIAL CANCER
Close clinical surveillance of all women taking estrogens is important. Adequate diagnostic
measures, including endometrial sampling when indicated, should be undertaken to rule out
malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal bleeding. There
is no evidence that the use of “natural” estrogens results in a different endometrial risk profile
than synthetic estrogens of equivalent estrogen doses. (See WARNINGS, Malignant
neoplasms, Endometrial cancer.)
CARDIOVASCULAR AND OTHER RISKS
Estrogens with or without progestins should not be used for the prevention of cardiovascular
disease or dementia. (See WARNINGS, Cardiovascular disorders and Dementia.)
The Women’s Health Initiative (WHI) study reported increased risks of stroke and deep vein
thrombosis in postmenopausal women (50 to 79 years of age) during 6.8 years of treatment with
conjugated estrogens (0.625 mg) relative to placebo. (See CLINICAL PHARMACOLOGY,
Clinical Studies and WARNINGS, Cardiovascular disorders.)
The WHI study reported increased risks of myocardial infarction, stroke, invasive breast cancer,
pulmonary emboli, and deep vein thrombosis in postmenopausal women (50 to 79 years of age)
during 5 years of treatment with conjugated estrogens (0.625 mg) combined with
medroxyprogesterone acetate (2.5 mg) relative to placebo. (See CLINICAL
PHARMACOLOGY, Clinical Studies and WARNINGS, Cardiovascular disorders and
Malignant neoplasms, Breast cancer.)
The Women’s Health Initiative Memory Study (WHIMS), a substudy of WHI, reported
increased risk of developing probable dementia in postmenopausal women 65 years of age or
older during 5.2 years of treatment with conjugated estrogens alone and during 4 years of
treatment with conjugated estrogens combined with medroxyprogesterone acetate, relative to
placebo. It is unknown whether this finding applies to younger postmenopausal women. (See
CLINICAL PHARMACOLOGY, Clinical Studies, WARNINGS, Dementia and
PRECAUTIONS, Geriatric Use.)
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-216/S-054
NDA 10-402/S-048
Page 30
Other doses of conjugated estrogens and medroxyprogesterone acetate, and other combinations
and dosage forms of estrogens and progestins were not studied in the WHI clinical trials and, in
the absence of comparable data, these risks should be assumed to be similar. Because of these
risks, estrogens with or without progestins should be prescribed at the lowest effective doses and
for the shortest duration consistent with treatment goals and risks for the individual woman.
DESCRIPTION
Premarin Intravenous (conjugated estrogens, USP) for injection contains a mixture of
conjugated estrogens obtained exclusively from natural sources, occurring as the sodium salts of
water-soluble estrogen sulfates blended to represent the average composition of materials
derived from pregnant mares’ urine. It is a mixture of sodium estrone sulfate and sodium equilin
sulfate. It contains as concomitant components, as sodium sulfate conjugates,
17α-dihydroequilin, 17α-estradiol, and 17β-dihydroequilin.
Each Secule vial contains 25 mg of conjugated estrogens, USP, in a sterile lyophilized cake
which also contains lactose 200 mg, sodium citrate 12.2 mg, and simethicone 0.2 mg. The pH is
adjusted with sodium hydroxide or hydrochloric acid. A sterile diluent (5 mL) containing
2% benzyl alcohol in sterile water is provided for reconstitution. The reconstituted solution is
suitable for intravenous or intramuscular injection.
CLINICAL PHARMACOLOGY
Endogenous estrogens are largely responsible for the development and maintenance of the
female reproductive system and secondary sexual characteristics. Although circulating estrogens
exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal
intracellular human estrogen and is substantially more potent than its metabolites, estrone and
estriol, at the receptor level. The primary source of estrogen in normally cycling adult women is
the ovarian follicle, which secretes 70 to 500 mcg of estradiol daily, depending on the phase of
the menstrual cycle. After menopause, most endogenous estrogen is produced by conversion of
androstenedione, secreted by the adrenal cortex, to estrone by peripheral tissues. Thus, estrone
and the sulfate-conjugated form, estrone sulfate, are the most abundant circulating estrogen in
postmenopausal women.
Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, two
estrogen receptors have been identified. These vary in proportion from tissue to tissue.
Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone
(LH) and follicle stimulating hormone (FSH) through a negative feedback mechanism. Estrogens
act to reduce the elevated levels of these gonadotropins seen in postmenopausal women.
Pharmacokinetics
Absorption
Conjugated estrogens are soluble in water and are well absorbed through the skin, mucous
membranes, and gastrointestinal tract after release from the drug formulation.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-216/S-054
NDA 10-402/S-048
Page 31
Distribution
The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are
widely distributed in the body and are generally found in higher concentration in the sex
hormone target organs. Estrogens circulate in the blood largely bound to sex hormone-binding
globulin (SHBG) and albumin.
Metabolism
Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating
estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations
take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be
converted to estriol, which is the major urinary metabolite. Estrogens also undergo enterohepatic
recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates
into the intestine, and hydrolysis in the gut followed by reabsorption. In postmenopausal women
a significant proportion of the circulating estrogens exists as sulfate conjugates, especially
estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens.
Excretion
Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate
conjugates.
Special Populations
No pharmacokinetic studies were conducted in special populations, including patients with renal
or hepatic impairment.
Drug Interactions
Data from a single-dose drug-drug interaction study involving oral conjugated estrogens and
medroxyprogesterone acetate indicate that the pharmacokinetic dispositions of both drugs are not
altered when the drugs are coadministered. No other clinical drug-drug interaction studies have
been conducted with conjugated estrogens.
In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome
P450 3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen drug
metabolism. Inducers of CYP3A4 such as St. John’s Wort preparations (Hypericum perforatum),
phenobarbital, carbamazepine, and rifampin may reduce plasma concentrations of estrogens,
possibly resulting in a decrease in therapeutic effects and/or changes in the uterine bleeding
profile. Inhibitors of CYP3A4 such as erythromycin, clarithromycin, ketoconazole, itraconazole,
ritonavir and grapefruit juice may increase plasma concentrations of estrogens and may result in
side effects.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-216/S-054
NDA 10-402/S-048
Page 32
Clinical Studies
Women’s Health Initiative Studies.
The Women’s Health Initiative (WHI) enrolled a total of 27,000 predominantly healthy
postmenopausal women to assess the risks and benefits of either the use of Premarin tablets
(0.625 mg conjugated estrogens per day) alone or the use of PREMPROTM tablets (0.625 mg
conjugated estrogens plus 2.5 mg medroxyprogesterone acetate per day) compared to placebo in
the prevention of certain chronic diseases. The primary endpoint was the incidence of coronary
heart disease (CHD) (nonfatal myocardial infarction and CHD death), with invasive breast
cancer as the primary adverse outcome studied. A “global index” included the earliest occurrence
of CHD, invasive breast cancer, stroke, pulmonary embolism (PE), endometrial cancer,
colorectal cancer, hip fracture, or death due to other cause. The study did not evaluate the effects
of Premarin tablets or PREMPRO on menopausal symptoms.
The estrogen alone substudy was stopped early because an increased risk of stroke was observed
and it was deemed that no further information would be obtained regarding the risks and benefits
of estrogen alone in predetermined primary endpoints. Results of the estrogen alone substudy,
which included 10,739 women (average age of 63 years, range 50 to 79; 75.3% White,
15% Black, 6.1% Hispanic), after an average follow-up of 6.8 years are presented in Table 1
below.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-216/S-054
NDA 10-402/S-048
Page 33
TABLE 1. RELATIVE AND ABSOLUTE RISK SEEN IN THE ESTROGEN ALONE
SUBSTUDY OF WHIa
Placebo
n = 5429
Premarin
n = 5310
Eventc
Relative Risk*
Premarin vs Placebo
at 6.8 Years
(95% CI)
Absolute Risk per 10,000
Women-years
CHD events
0.91 (0.75-1.12)
54
49
Non-fatal MI
0.89 (0.70-1.12)
41
37
CHD death
0.94 (0.65-1.36)
16
15
Invasive breast cancer
0.77 (0.59-1.01)
33
26
Stroke
1.39 (1.10-1.77)
32
44
Pulmonary embolism
1.34 (0.87-2.06)
10
13
Colorectal cancer
1.08 (0.75-1.55)
16
17
Hip fracture
0.61 (0.41-0.91)
17
11
Death due to other causes than
the events above
1.08 (0.88-1.32)
50
53
Global Indexb
1.01 (0.91-1.12)
190
192
Deep vein thrombosisc
1.47 (1.04-2.08)
15
21
Vertebral fracturesc
0.62 (0.42-0.93)
17
11
Total fracturesc
0.70 (0.63-0.79)
195
139
a: adapted from JAMA, 2004; 291:1701-1712
b: a subset of the events was combined in a “global index,” defined as the earliest occurrence of
CHD events, invasive breast cancer, stroke, pulmonary embolism, endometrial cancer,
colorectal cancer, hip fracture, or death due to other causes
c: not included in Global Index
* nominal confidence intervals unadjusted for multiple looks and multiple comparisons.
For those outcomes included in the WHI “global index” that reached statistical significance, the
absolute excess risk per 10,000 women-years in the group treated with Premarin alone were 12
more strokes while the absolute risk reduction per 10,000 women-years was 6 fewer hip
fractures. The absolute excess risk of events included in the “global index” was a nonsignificant
2 events per 10,000 women-years. There was no difference between the groups in terms of
all-cause mortality. (See BOXED WARNINGS, WARNINGS, and PRECAUTIONS.)
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-216/S-054
NDA 10-402/S-048
Page 34
The estrogen plus progestin substudy was also stopped early because, according to the
predefined stopping rule, the increased risk of breast cancer and cardiovascular events exceeded
the specified benefits included in the “global index.” Results of the estrogen plus progestin
substudy, which included 16,608 women (average age of 63 years, range 50 to 79; 83.9% White,
6.5% Black, 5.5% Hispanic), after an average follow-up of 5.2 years, are presented in Table 2
below:
Table 2. RELATIVE AND ABSOLUTE RISK SEEN IN THE ESTROGEN PLUS
PROGESTIN SUBSTUDY OF WHIa
Placebo
Prempro
n = 8102
n = 8506
Event c
Relative Risk
Prempro vs Placebo
at 5.2 Years
(95% CI*)
Absolute Risk per 10,000
Women-years
CHD events
1.29 (1.02-1.63)
30
37
Non-fatal MI
1.32 (1.02-1.72)
23
30
CHD death
1.18 (0.70-1.97)
6
7
Invasive breast cancer b
1.26 (1.00-1.59)
30
38
Stroke
1.41 (1.07-1.85)
21
29
Pulmonary embolism
2.13 (1.39-3.25)
8
16
Colorectal cancer
0.63 (0.43-0.92)
16
10
Endometrial cancer
0.83 (0.47-1.47)
6
5
Hip fracture
0.66 (0.45-0.98)
15
10
Death due to causes other
than the events above
0.92 (0.74-1.14)
40
37
Global Index c
1.15 (1.03-1.28)
151
170
Deep vein thrombosis d
2.07 (1.49-2.87)
13
26
Vertebral fractures d
0.66 (0.44-0.98)
15
9
Other osteoporotic
fractures d
0.77 (0.69-0.86)
170
131
a
adapted from JAMA, 2002; 288:321-333
b
includes metastatic and non-metastatic breast cancer with the exception of in situ breast
cancer
c
a subset of the events was combined in a “global index”, defined as the earliest occurrence
of CHD events, invasive breast cancer, stroke, pulmonary embolism, endometrial cancer,
colorectal cancer, hip fracture, or death due to other causes
d
not included in Global Index
∗ nominal confidence intervals unadjusted for multiple looks and multiple comparisons
For those outcomes included in the WHI “global index,” the absolute excess risks per
10,000 women-years in the group treated with PREMPRO were 7 more CHD events, 8 more
strokes, 8 more PEs, and 8 more invasive breast cancers, while the absolute risk reductions per
10,000 women-years were 6 fewer colorectal cancers and 5 fewer hip fractures. The absolute
excess risk of events included in the “global index” was 19 per 10,000 women-years. There was
no difference between the groups in terms of all-cause mortality. (See BOXED WARNINGS,
WARNINGS, and PRECAUTIONS.)
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-216/S-054
NDA 10-402/S-048
Page 35
Women’s Health Initiative Memory Study.
The estrogen alone Women’s Health Initiative Memory Study (WHIMS), a substudy of WHI,
enrolled 2,947 predominantly healthy postmenopausal women 65 years of age and older (45%
were age 65 to 69 years, 36% were 70 to 74 years, and 19% were 75 years of age and older) to
evaluate the effects of Premarin (0.625 mg conjugated estrogens) on the incidence of probable
dementia (primary outcome) compared with placebo.
After an average follow-up of 5.2 years, 28 women in the estrogen alone group (37 per
10,000 women-years) and 19 in the placebo group (25 per 10,000 women-years) were diagnosed
with probable dementia. The relative risk of probable dementia in the estrogen alone group was
1.49 (95% CI, 0.83 to 2.66) compared to placebo. It is unknown whether these findings apply to
younger postmenopausal women. (See BOXED WARNINGS, WARNINGS, Dementia and
PRECAUTIONS, Geriatric Use.)
The estrogen plus progestin WHIMS substudy enrolled 4,532 predominantly healthy
postmenopausal women 65 years of age and older (47% were age 65 to 69 years, 35% were
70 to 74 years, and 18% were 75 years of age and older) to evaluate the effects of PREMPRO
(0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate) on the incidence of
probable dementia (primary outcome) compared with placebo.
After an average follow-up of 4 years, 40 women in the estrogen/progestin group (45 per
10,000 women-years) and 21 in the placebo group (22 per 10,000 women-years) were diagnosed
with probable dementia. The relative risk of probable dementia in the hormone therapy group
was 2.05 (95% CI, 1.21 to 3.48) compared to placebo. Differences between groups became
apparent in the first year of treatment. It is unknown whether these findings apply to younger
postmenopausal women. (See BOXED WARNINGS, WARNINGS, Dementia and
PRECAUTIONS, Geriatric Use.)
INDICATIONS AND USAGE
Premarin Intravenous (conjugated estrogens, USP) for injection is indicated in the treatment of
abnormal uterine bleeding due to hormonal imbalance in the absence of organic pathology.
Premarin Intravenous is indicated for short-term use only, to provide a rapid and temporary
increase in estrogen levels.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-216/S-054
NDA 10-402/S-048
Page 36
CONTRAINDICATIONS
Premarin Intravenous should not be used in individuals with any of the following conditions:
1. Undiagnosed abnormal genital bleeding.
2. Known, suspected, or history of cancer of the breast.
3. Known or suspected estrogen-dependent neoplasia.
4. Active deep vein thrombosis, pulmonary embolism or a history of these conditions.
5. Active or recent (e.g., within past year) arterial thromboembolic disease (e.g., stroke,
myocardial infarction).
6. Liver dysfunction or disease.
7. Premarin Intravenous for injection should not be used in patients with known
hypersensitivity to its ingredients.
8. Known or suspected pregnancy. There is no indication for Premarin Intravenous in
pregnancy. There appears to be little or no increased risk of birth defects in children born to
women who have used estrogen and progestins from oral contraceptives inadvertently during
pregnancy. (See PRECAUTIONS.)
WARNINGS
See BOXED WARNINGS.
Premarin Intravenous is indicated for short-term use. However, warnings, precautions and
adverse reactions associated with Premarin tablets should be taken into account.
1. Cardiovascular disorders.
Estrogen and estrogen/progestin therapy have been associated with an increased risk of
cardiovascular events such as myocardial infarction and stroke, as well as venous thrombosis and
pulmonary embolism (venous thromboembolism or VTE). Should any of these occur or be
suspected, estrogens should be discontinued immediately.
Risk factors for arterial vascular disease (e.g., hypertension, diabetes mellitus, tobacco use,
hypercholesterolemia, and obesity) and/or venous thromboembolism (e.g., personal history or
family history of VTE, obesity, and systemic lupus erythematosus) should be managed
appropriately.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
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Page 37
a. Coronary heart disease and stroke. In the estrogen alone substudy of the Women’s Health
Initiative (WHI) study, an increased risk of stroke was observed in women receiving Premarin
(0.625 mg conjugated estrogens) per day compared to women receiving placebo (44 vs 32 per
10,000 women-years). The increase in risk was observed in year one and persisted. (See
CLINICAL PHARMACOLOGY, Clinical Studies.)
In the estrogen plus progestin substudy of WHI, an increased risk of coronary heart disease
(CHD) events (defined as nonfatal myocardial infarction and CHD death) was observed in
women receiving PREMPRO (0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone
acetate) per day compared to women receiving placebo (37 vs 30 per 10,000 women-years). The
increase in risk was observed in year one and persisted.
In the same estrogen plus progestin substudy of WHI, an increased risk of stroke was observed in
women receiving PREMPRO compared to women receiving placebo (29 vs 21 per 10,000
women-years). The increase in risk was observed after the first year and persisted.
In postmenopausal women with documented heart disease (n = 2,763, average age 66.7 years) a
controlled clinical trial of secondary prevention of cardiovascular disease (Heart and
Estrogen/progestin Replacement Study; HERS) treatment with PREMPRO (0.625 mg conjugated
estrogen plus 2.5 mg medroxyprogesterone acetate per day) demonstrated no cardiovascular
benefit. During an average follow-up of 4.1 years, treatment with PREMPRO did not reduce the
overall rate of CHD events in postmenopausal women with established coronary heart disease.
There were more CHD events in the PREMPRO-treated group than in the placebo group in year
1, but not during the subsequent years. Two thousand three hundred and twenty one women from
the original HERS trial agreed to participate in an open label extension of HERS, HERS II.
Average follow-up in HERS II was an additional 2.7 years, for a total of 6.8 years overall. Rates
of CHD events were comparable among women in the PREMPRO group and the placebo group
in HERS, HERS II, and overall.
Large doses of estrogen (5 mg conjugated estrogens per day), comparable to those used to treat
cancer of the prostate and breast, have been shown in a large prospective clinical trial in men to
increase the risks of nonfatal myocardial infarction, pulmonary embolism, and thrombophlebitis.
b. Venous thromboembolism (VTE). In the estrogen alone substudy of the Women’s Health
Initiative (WHI) study, an increased risk of deep vein thrombosis was observed in women
receiving Premarin compared to placebo (21 vs 15 per 10,000 women-years. The increase in
VTE risk was observed during the first year. (See CLINICAL PHARMACOLOGY, Clinical
Studies.)
In the estrogen plus progestin substudy of WHI, a 2-fold greater rate of VTE, including deep
venous thrombosis and pulmonary embolism, was observed in women receiving PREMPRO
compared to women receiving placebo. The rate of VTE was 34 per 10,000 women-years in the
PREMPRO group compared to 16 per 10,000 women-years in the placebo group. The increase in
VTE risk was observed during the first year and persisted.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
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Page 38
2. Malignant neoplasms.
a. Endometrial cancer. The use of unopposed estrogens in women with intact uteri has been
associated with an increased risk of endometrial cancer. The reported endometrial cancer risk
among unopposed estrogen users is about 2- to 12-fold greater than in non-users, and appears
dependent on duration of treatment and on estrogen dose. Most studies show no significant
increased risk associated with use of estrogens for less than one year. The greatest risk appears
associated with prolonged use, with increased risks of 15- to 24-fold for five to ten years or more
and this risk has been shown to persist for at least 8 to 15 years after estrogen therapy is
discontinued.
b. Breast cancer. In some studies, the use of estrogens and progestins by postmenopausal
women has been reported to increase the risk of breast cancer. The most important randomized
clinical trial providing information about this issue is the Women’s Health Initiative (WHI) trial
of estrogen plus progestin (see CLINICAL PHARMACOLOGY, Clinical Studies). The
results from observational studies are generally consistent with those of the WHI clinical trial.
After a mean follow-up of 5.6 years, the WHI trial reported an increased risk of breast cancer in
women who took estrogen plus progestin. Observational studies have also reported an increased
risk for estrogen/progestin combination therapy, and a smaller increased risk for estrogen alone
therapy, after several years of use. For both findings, the excess risk increased with duration of
use, and appeared to return to baseline over about five years after stopping treatment (only the
observational studies have substantial data on risk after stopping). In these studies, the risk of
breast cancer was greater, and became apparent earlier, with estrogen/progestin combination
therapy as compared to estrogen alone therapy. However, these studies have not found
significant variation in the risk of breast cancer among different estrogens or among different
estrogen/progestin combinations, doses, or routes of administration.
In the WHI trial of estrogen plus progestin, 26% of the women reported prior use of estrogen
alone and/or estrogen/progestin combination hormone therapy. After a mean follow-up of
5.6 years during the clinical trial, the overall relative risk of invasive breast cancer was
1.24 (95% confidence interval 1.01-1.54), and the overall absolute risk was 41 vs. 33 cases per
10,000 women-years, for estrogen plus progestin compared with placebo. Among women who
reported prior use of hormone therapy, the relative risk of invasive breast cancer was 1.86, and
the absolute risk was 46 vs. 25 cases per 10,000 women-years, for estrogen plus progestin
compared with placebo. Among women who reported no prior use of hormone therapy, the
relative risk of invasive breast cancer was 1.09, and the absolute risk was 40 vs. 36 cases
per 10,000 women-years for estrogen plus progestin compared with placebo. In the WHI trial,
invasive breast cancers were larger and diagnosed at a more advanced stage in the estrogen plus
progestin group compared with the placebo group. Metastatic disease was rare with no apparent
difference between the two groups. Other prognostic factors such as histologic subtype, grade
and hormone receptor status did not differ between the groups.
The observational Million Women Study in Europe reported an increased risk of mortality due to
breast cancer among current users of estrogens alone or estrogens plus progestins compared to
never users, while the estrogen plus progestin sub-study of WHI showed no effect on breast
cancer mortality with a mean follow-up of 5.6 years.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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NDA 10-402/S-048
Page 39
The use of estrogen plus progestin has been reported to result in an increase in abnormal
mammograms requiring further evaluation. All women should receive yearly breast
examinations by a healthcare provider and perform monthly breast self-examinations. In
addition, mammography examinations should be scheduled based on patient age, risk factors,
and prior mammogram results.
3. Dementia.
In the estrogen alone Women’s Health Initiative Memory Study (WHIMS), a substudy of WHI, a
population of 2,947 hysterectomized women aged 65 to 79 years was randomized to Premarin
(0.625 mg) or placebo. In the estrogen plus progestin WHIMS substudy, a population of 4,532
postmenopausal women aged 65 to 79 years was randomized to PREMPRO (0.625 mg/2.5 mg)
or placebo.
In the estrogen alone substudy, after an average follow-up of 5.2 years, 28 women in the
estrogen alone group and 19 women in the placebo group were diagnosed with probable
dementia. The relative risk of probable dementia for Premarin alone versus placebo was
1.49 (95% CI 0.83-2.66). The absolute risk of probable dementia for Premarin alone versus
placebo was 37 versus 25 cases per 10,000 women-years.
In the estrogen plus progestin substudy, after an average follow-up of 4 years, 40 women in the
estrogen plus progestin group and 21 women in the placebo group were diagnosed with probable
dementia. The relative risk of probable dementia for estrogen plus progestin versus placebo was
2.05 (95% CI 1.21-3.48). The absolute risk of probable dementia for PREMPRO versus placebo
was 45 versus 22 cases per 10,000 women-years.
Since both substudies were conducted in women aged 65 to 79 years, it is unknown whether
these findings apply to younger postmenopausal women. (See BOXED WARNINGS and
PRECAUTIONS, Geriatric Use.)
4. Gallbladder disease.
A 2- to 4-fold increase in the risk of gallbladder disease requiring surgery in postmenopausal
women receiving postmenopausal estrogens has been reported.
5. Hypercalcemia.
Estrogen administration may lead to severe hypercalcemia in patients with breast cancer and
bone metastases. If hypercalcemia occurs, use of the drug should be stopped and appropriate
measures taken to reduce the serum calcium level.
6. Visual abnormalities.
Retinal vascular thrombosis has been reported in patients receiving estrogens. Discontinue
medication pending examination if there is sudden partial or complete loss of vision, or a sudden
onset of proptosis, diplopia, or migraine. If examination reveals papilledema or retinal vascular
lesions, estrogens should be discontinued.
PRECAUTIONS
A. General
Premarin Intravenous is indicated for short-term use. However, warnings, precautions and
adverse reactions associated with Premarin tablets should be taken into account.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-216/S-054
NDA 10-402/S-048
Page 40
1. Addition of a progestin when a woman has not had a hysterectomy.
Studies of the addition of a progestin for 10 or more days of a cycle of estrogen administration or
daily with estrogen in a continuous regimen have reported a lowered incidence of endometrial
hyperplasia than would be induced by estrogen treatment alone. Endometrial hyperplasia may be
a precursor to endometrial cancer.
There are, however, possible risks which may be associated with the use of progestins with
estrogens compared to estrogen-alone regimens. These include a possible increased risk of breast
cancer, adverse effects on lipoprotein metabolism (e.g., lowering HDL, raising LDL) and
impairment of glucose tolerance.
2. Elevated blood pressure.
In a small number of case reports, substantial increases in blood pressure have been attributed to
idiosyncratic reactions to estrogens. In a large, randomized, placebo-controlled clinical trial, a
generalized effect of estrogen therapy on blood pressure was not seen. Blood pressure should be
monitored at regular intervals with estrogen use.
3. Hypertriglyceridemia.
In patients with pre-existing hypertriglyceridemia, estrogen therapy may be associated with
elevations of plasma triglycerides leading to pancreatitis and other complications.
4. Impaired liver function and past history of cholestatic jaundice.
Estrogens may be poorly metabolized in patients with impaired liver function. For patients with a
history of cholestatic jaundice associated with past estrogen use or with pregnancy, caution
should be exercised and in the case of recurrence, medication should be discontinued.
5. Hypothyroidism.
Estrogen administration leads to increased thyroid-binding globulin (TBG) levels. Patients with
normal thyroid function can compensate for the increased TBG by making more thyroid
hormone, thus maintaining free T4 and T3 serum concentrations in the normal range. Patients
dependent on thyroid hormone replacement therapy who are also receiving estrogens may
require increased doses of their thyroid replacement therapy. These patients should have their
thyroid function monitored in order to maintain their free thyroid hormone levels in an
acceptable range.
6. Fluid retention.
Because estrogens may cause some degree of fluid retention, patients with conditions that might
be influenced by this factor, such as a cardiac or renal dysfunction, warrant careful observation
when estrogens are prescribed.
7. Hypocalcemia.
Estrogens should be used with caution in individuals with severe hypocalcemia.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-216/S-054
NDA 10-402/S-048
Page 41
8. Ovarian cancer.
The estrogen plus progestin substudy of WHI reported that after an average follow-up of
5.6 years, the relative risk of ovarian cancer for estrogen plus progestin versus placebo was
1.58 (95% confidence interval 0.77 – 3.24) but was not statistically significant. The absolute risk
for estrogen plus progestin versus placebo was 4.2 versus 2.7 cases per 10,000 women-years. In
some epidemiologic studies, the use of estrogen-only products, in particular for ten or more
years, has been associated with an increased risk of ovarian cancer. Other epidemiologic studies
have not found these associations.
9. Exacerbation of endometriosis.
Endometriosis may be exacerbated with administration of estrogen therapy.
A few cases of malignant transformation of residual endometrial implants have been reported in
women treated post-hysterectomy with estrogen alone therapy. For patients known to have
residual endometriosis post-hysterectomy, the addition of progestin should be considered.
10. Exacerbation of other conditions.
Estrogen therapy may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine,
porphyria, systemic lupus erythematosus, and hepatic hemangiomas and should be used with
caution in women with these conditions.
B. Patient Information
Physicians are advised to discuss the contents of the PATIENT INFORMATION leaflet with
patients who are being treated with Premarin Intravenous.
C. Laboratory Tests
Estrogen administration should be guided by clinical response at the lowest dose, rather than
laboratory monitoring.
D. Drug/Laboratory Test Interactions
1. Accelerated prothrombin time, partial thromboplastin time, and platelet aggregation time;
increased platelet count; increased factors II, VII antigen, VIII antigen, VIII coagulant activity,
IX, X, XII, VII-X complex, II-VII-X complex, and beta-thromboglobulin; decreased levels of
anti-factor Xa and antithrombin III, decreased antithrombin III activity; increased levels of
fibrinogen and fibrinogen activity; increased plasminogen antigen and activity.
2. Increased thyroid-binding globulin (TBG) leading to increased circulating total thyroid
hormone, as measured by protein-bound iodine (PBI), T4 levels (by column or by
radioimmunoassay) or T3 levels by radioimmunoassay. T3 resin uptake is decreased, reflecting
the elevated TBG. Free T4 and free T3 concentrations are unaltered. Patients on thyroid
replacement therapy may require higher doses of thyroid hormone.
3. Other binding proteins may be elevated in serum, i.e., corticosteroid binding globulin (CBG),
sex hormone-binding globulin (SHBG), leading to increased total circulating corticosteroids and
sex steroids respectively. Free hormone concentrations may be decreased. Other plasma proteins
may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin).
4. Increased plasma HDL and HDL2 subfraction concentrations, reduced LDL cholesterol
concentration, increased triglyceride levels.
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Page 42
5. Impaired glucose tolerance.
6. Reduced response to metyrapone test.
E. Carcinogenesis, Mutagenesis, and Impairment of Fertility
(See BOXED WARNINGS, WARNINGS, and PRECAUTIONS.)
Long-term continuous administration of natural and synthetic estrogens in certain animal species
increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis, and liver.
F. Pregnancy
Premarin Intravenous should not be used during pregnancy. (See CONTRAINDICATIONS.)
G. Nursing Mothers
Estrogen administration to nursing mothers has been shown to decrease the quantity and quality
of breast milk. Detectable amounts of estrogens have been identified in the milk of mothers
receiving the drug. Caution should be exercised when Premarin Intravenous is administered to a
nursing woman.
H. Pediatric Use
Estrogen therapy has been used for the induction of puberty in adolescents with some forms of
pubertal delay. Safety and effectiveness in pediatric patients have not otherwise been established.
Large and repeated doses of estrogen over an extended time period have been shown to
accelerate epiphyseal closure, which could result in short adult stature if treatment is initiated
before the completion of physiologic puberty in normally developing children. If estrogen is
administered to patients whose bone growth is not complete, periodic monitoring of bone
maturation and effects on epiphyseal centers is recommended during estrogen administration.
Estrogen treatment of prepubertal girls also induces premature breast development and vaginal
cornification, and may induce vaginal bleeding. In boys, estrogen treatment may modify the
normal pubertal process and induce gynecomastia.
I. Geriatric Use
Of the total number of subjects in the estrogen alone substudy of the Women’s Health Initiative
(WHI) study, 46% (n=4,943) were 65 years and over, while 7.1% (n=767) were 75 years and
over. There was a higher relative risk (Premarin vs. placebo) of stroke in women less than 75
years of age compared to women 75 years and over.
In the estrogen alone substudy of the Women’s Health Initiative Memory Study (WHIMS), a
substudy of WHI, a population of 2,947 hysterectomized women, aged 65 to 79 years, was
randomized to Premarin (0.625 mg) or placebo. In the estrogen alone group, after an average
follow-up of 5.2 years, the relative risk (Premarin versus placebo) of probable dementia was
1.49 (95% CI 0.83-2.66).
Of the total number of subjects in the estrogen plus progestin substudy of the Women’s Health
Initiative study, 44% (n=7,320) were 65 years and over, while 6.6% (n=1,095) were 75 years and
over. There was a higher relative risk (PREMPRO vs placebo) of stroke and invasive breast
cancer in women 75 and over compared to women less than 75 years of age.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-216/S-054
NDA 10-402/S-048
Page 43
In the estrogen plus progestin substudy of WHIMS, a population of 4,532 postmenopausal
women, aged 65 to 79 years, was randomized to PREMPRO (0.625 mg/2.5 mg) or placebo. In
the estrogen plus progestin group, after an average follow-up of 4 years, the relative risk
(PREMPRO versus placebo) of probable dementia was 2.05 (95% CI 1.21-3.48).
Pooling the events in women receiving Premarin or PREMPRO in comparison to those in
women on placebo, the overall relative risk for probable dementia was 1.76 (95% CI 1.19-2.60).
Since both substudies were conducted in women aged 65 to 79 years, it is unknown whether
these findings apply to younger postmenopausal women. (See BOXED WARNINGS and
WARNINGS, Dementia.)
There have not been sufficient numbers of geriatric patients involved in studies utilizing
Premarin to determine whether those over 65 years of age differ from younger subjects in their
response to Premarin.
ADVERSE REACTIONS
See BOXED WARNINGS, WARNINGS, and PRECAUTIONS.
Premarin Intravenous is indicated for short-term use. However, the warnings, precautions and
adverse reactions associated with Premarin tablets should be taken into account.
1. Genitourinary system.
Changes in vaginal bleeding pattern and abnormal withdrawal bleeding or flow;
breakthrough bleeding, spotting
Increase in size of uterine leiomyomata.
Vaginal candidiasis.
Change in amount of cervical secretion.
Ovarian cancer.
Endometrial hyperplasia.
Endometrial cancer.
2. Breasts.
Pain, tenderness, enlargement.
Breast cancer.
3. Cardiovascular.
Deep and superficial venous thrombosis.
Pulmonary embolism.
Thrombophlebitis.
Hypotension.
Myocardial infarction.
Stroke.
4. Gastrointestinal.
Nausea, vomiting.
Abdominal cramps, bloating.
Cholestatic jaundice.
Increased incidence of gallbladder disease.
Pancreatitis.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
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NDA 10-402/S-048
Page 44
Enlargement of hepatic hemangiomas.
5. Skin.
Chloasma or melasma that may persist when drug is discontinued.
Erythema multiforme.
Erythema nodosum.
Hemorrhagic eruption.
Loss of scalp hair.
Hirsutism.
Pruritis.
Rash.
6. Eyes.
Retinal vascular thrombosis.
Intolerance to contact lenses.
7. Central Nervous System.
Headache.
Migraine.
Dizziness.
Mental depression.
Chorea.
Nervousness.
Exacerbation of epilepsy.
Dementia.
8. Miscellaneous.
Increase or decrease in weight.
Reduced carbohydrate tolerance.
Aggravation of porphyria.
Edema.
Changes in libido.
Anaphylactoid/anaphylactic reactions.
Urticaria.
Angioedema.
Injection site pain.
Injection site edema.
Phlebitis (injection site).
Exacerbation of asthma.
Increased triglycerides.
OVERDOSAGE
Serious ill effects have not been reported following acute ingestion of large doses of
estrogen-containing drug products by young children. Overdosage of estrogen may cause nausea
and vomiting, and withdrawal bleeding may occur in females.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
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NDA 10-402/S-048
Page 45
DOSAGE AND ADMINISTRATION
For treatment of abnormal uterine bleeding due to hormonal imbalance in the absence of organic
pathology:
One 25 mg injection, intravenously or intramuscularly. Intravenous use is preferred since more
rapid response can be expected from this mode of administration. Repeat in 6 to 12 hours if
necessary. The use of Premarin Intravenous for injection does not preclude the advisability of
other appropriate measures.
One should adhere to the usual precautionary measures governing intravenous administration.
Injection should be made SLOWLY to obviate the occurrence of flushes.
Infusion of Premarin Intravenous for injection with other agents is not generally recommended.
In emergencies, however, when an infusion has already been started it may be expedient to make
the injection into the tubing just distal to the infusion needle. If so used, compatibility of
solutions must be considered.
COMPATIBILITY OF SOLUTIONS: Premarin Intravenous is compatible with normal saline,
dextrose, and invert sugar solutions. It is not compatible with protein hydrolysate, ascorbic
acid, or any solution with an acid pH.
DIRECTIONS FOR STORAGE AND RECONSTITUTION
STORAGE BEFORE RECONSTITUTION: Store package in refrigerator, 2° to 8°C
(36° to 46°F).
TO RECONSTITUTE: First withdraw air from Secule vial so as to facilitate introduction of
sterile diluent. Then, flow the sterile diluent slowly against the side of Secule vial and agitate
gently. Do not shake violently.
STORAGE AFTER RECONSTITUTION: It is common practice to utilize the reconstituted
solution within a few hours. If it is necessary to keep the reconstituted solution for more than a
few hours, store the reconstituted solution under refrigeration (2° to 8°C). Under these
conditions, the solution is stable for 60 days, and is suitable for use unless darkening or
precipitation occurs.
HOW SUPPLIED
NDC 0046-0749-05−Each package provides: (1) One Secule vial containing 25 mg of
conjugated estrogens, USP, for injection (also lactose 200 mg, sodium citrate 12.2 mg, and
simethicone 0.2 mg). The pH is adjusted with sodium hydroxide or hydrochloric acid.
(2) One 5 mL ampul of sterile diluent with 2% benzyl alcohol in sterile water.
Premarin Intravenous (conjugated estrogens, USP) for injection is prepared by cryodesiccation.
SECULE-Registered trademark to designate a vial containing an injectable preparation in dry
form.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-216/S-054
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PATIENT INFORMATION
(Updated August, 2005)
Premarin Intravenous (conjugated estrogens, USP) for injection
Read this PATIENT INFORMATION which describes the benefit and major risks of your
treatment, as well as how and when treatment should be used. This information does not take the
place of talking to your healthcare provider about your medical condition or your treatment.
What is the most important information I should know about Premarin Intravenous (an
estrogen mixture)?
• Estrogens increase the chances of getting cancer of the uterus.
Report any unusual vaginal bleeding right away while you are taking Premarin. Vaginal
bleeding after menopause may be a warning sign of cancer of the uterus (womb). Your
healthcare provider should check any unusual vaginal bleeding to find out the cause.
• Do not use estrogens with or without progestins to prevent heart disease, heart attacks,
strokes, or dementia.
Using estrogens with or without progestins may increase your chances of getting heart
attacks, strokes, breast cancer, and blood clots. Using estrogens, with or without progestins,
may increase your risk of dementia, based on a study of women age 65 years or older. You
and your healthcare provider should talk regularly about whether you still need treatment
with estrogens.
What is Premarin Intravenous?
Premarin Intravenous is a medicine that contains a mixture of estrogen hormones.
Premarin Intravenous is used to:
• treat certain types of abnormal uterine bleeding due to hormonal imbalance when your doctor
has found no other cause of bleeding.
Who should not use Premarin Intravenous?
Premarin Intravenous should not be used if you:
• have unusual vaginal bleeding that has not been evaluated by your healthcare provider.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-216/S-054
NDA 10-402/S-048
Page 47
• currently have or have had certain cancers.
Estrogens may increase the chances of getting certain types of cancers, including cancer of
the breast or uterus. If you have or have had cancer, talk with your healthcare provider about
whether you should use Premarin Intravenous.
• had a stroke or heart attack in the past year.
• currently have or have had blood clots.
• currently have liver problems.
• are allergic to Premarin Intravenous or any of its ingredients.
See the end of this leaflet for a list of all the ingredients in Premarin Intravenous.
• think you may be pregnant.
Tell your healthcare provider:
• if you are breast feeding. The hormones in Premarin Intravenous can pass into your milk.
• about all of your medical problems. Your healthcare provider may need to check you more
carefully if you have certain conditions, such as asthma (wheezing), epilepsy (seizures),
migraine, endometriosis, lupus, problems with your heart, liver, thyroid, kidneys, or have high
calcium levels in your blood.
• about all the medicines you take, including prescription and nonprescription medicines,
vitamins, and herbal supplements. Some medicines may affect how Premarin Intravenous works.
What are the possible side effects of Premarin Intravenous?
Premarin Intravenous is for short-term use only. However, the risks associated with Premarin
tablets should be taken into account.
Less common but serious side effects include:
• Breast cancer
• Cancer of the uterus
• Stroke
• Heart attack
• Blood clots
• Dementia
• Gallbladder disease
• Ovarian cancer
These are some of the warning signs of serious side effects:
• Breast lumps
• Unusual vaginal bleeding
• Dizziness and faintness
• Changes in speech
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-216/S-054
NDA 10-402/S-048
Page 48
• Severe headaches
• Chest pain
• Shortness of breath
• Pains in your legs
• Changes in vision
• Vomiting
Call your healthcare provider right away if you get any of these warning signs, or any other
unusual symptom that concerns you.
Common side effects include:
• Headache
• Breast tenderness
• Irregular vaginal bleeding or spotting
• Stomach/abdominal cramps, bloating
• Nausea and vomiting
• Hair loss
Other side effects include:
• High blood pressure
• Liver problems
• High blood sugar
• Fluid retention
• Enlargement of benign tumors of the uterus (“fibroids”)
• Vaginal yeast infections
These are not all the possible side effects of Premarin. For more information, ask your healthcare
provider or pharmacist.
What can I do to lower my chances of getting a serious side effect with Premarin
Intravenous?
• If you have high blood pressure, high cholesterol (fat in the blood), diabetes, are overweight,
or if you use tobacco, you may have higher chances for getting heart disease. Ask your
healthcare provider for ways to lower your chances for getting heart disease.
General information about the safe and effective use of Premarin Intravenous
Medicines are sometimes prescribed for conditions that are not mentioned in patient information
leaflets. Do not use Premarin Intravenous for conditions for which it was not prescribed. Do not
give Premarin Intravenous to other people, even if they have the same symptoms you have. It
may harm them. Keep Premarin Intravenous out of the reach of children.
This leaflet provides a summary of the most important information about Premarin Intravenous.
If you would like more information, talk with your healthcare provider or pharmacist. You can
ask for information about Premarin Intravenous that is written for health professionals. You can
get more information by calling the toll free number 1-800-934-5556.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-216/S-054
NDA 10-402/S-048
Page 49
What are the ingredients in Premarin IV?
Premarin Intravenous for injection contains a mixture of conjugated estrogens, which are a
mixture of sodium estrone sulfate and sodium equilin sulfate and other components including
sodium sulfate conjugates: 17α-dihydroequilin, 17α-estradiol, and 17β-dihydroequilin.
Premarin Intravenous for injection also contains lactose, sodium citrate, simethicone, and sodium
hydroxide or hydrochloric acid in dry form. A sterile diluent containing benzyl alcohol in sterile
water is provided for reconstitution. The reconstituted solution is suitable for intravenous or
intramuscular injection.
Each Premarin Intravenous (conjugated estrogens, USP) for injection package provides 25 mg of
conjugated estrogens, USP, in dry form and 5 mL of sterile diluent for intravenous or
intramuscular use.
This product’s label may have been revised after this insert was used
in production. For further product information and current package
insert, please visit www.wyeth.com or call our medical
communications department toll-free at 1-800-934-5556.
Wyeth Pharmaceuticals Inc.
Philadelphia, PA 19101
Revised August, 2005
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
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|
12,323
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HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to
use PREMARIN Vaginal Cream safely and effectively. See full
prescribing information for PREMARIN Vaginal Cream.
PREMARIN (conjugated estrogens) Vaginal Cream
Initial U.S. approval: 1946
WARNING: ENDOMETRIAL CANCER,
CARDIOVASCULAR DISORDERS AND PROBABLE
DEMENTIA FOR ESTROGEN-ALONE THERAPY
See full prescribing information for complete boxed warning.
●
There is an increased risk of endometrial cancer in a
woman with a uterus who uses unopposed estrogens. (5.3)
●
Estrogen-alone therapy should not be used for the
prevention of cardiovascular disease or dementia. (5.2,
5.4)
●
The Women’s Health Initiative (WHI) estrogen-alone
substudy reported increased risks of stroke and deep vein
thrombosis. (5.2)
●
The Women’s Health Initiative Memory Study (WHIMS)
estrogen-alone ancillary study of WHI reported an
increased risk of probable dementia in postmenopausal
women 65 years of age and older. (5.4)
WARNING: CARDIOVASCULAR DISORDERS, BREAST
CANCER AND PROBABLE DEMENTIA FOR ESTROGEN
PLUS PROGESTIN THERAPY
See full prescribing information for complete boxed warning.
●
Estrogen plus progestin therapy should not be used for
the prevention of cardiovascular disease or dementia.
(5.2, 5.4)
●
The WHI estrogen plus progestin substudy reported
increased risks of stroke, deep vein thrombosis,
pulmonary embolism, and myocardial infarction. (5.2)
●
The WHI estrogen plus progestin substudy reported
increased risks of invasive breast cancer. (5.3)
●
The WHIMS estrogen plus progestin ancillary study of
WHI reported an increased risk of probable dementia in
postmenopausal women 65 years of age and older. (5.4)
-------------------------- RECENT MAJOR CHANGES-------------------------
Indications and Usage (1)
11/2008
Dosage and Administration (2.3)
11/2008
Warnings and Precautions:
- Malignant Neoplasms, Ovarian Cancer (5.3)
3/2008
-------------------------- INDICATIONS AND USAGE --------------------------
PREMARIN (conjugated estrogens) Vaginal Cream is a mixture of
estrogens indicated for:
•
Treatment of Atrophic Vaginitis and Kraurosis Vulvae (1.1)
•
Treatment of Moderate to Severe Dyspareunia, a Symptom of
Vulvar and Vaginal Atrophy, due to Menopause (1.2)
---------------------DOSAGE AND ADMINISTRATION ------------------
•
Cyclic administration of 0.5 to 2 g intravaginally [daily for
21 days then off for 7 days] for Treatment of Atrophic
Vaginitis and Kraurosis Vulvae (2.2)
•
Cyclic administration of 0.5 g intravaginally [daily for 21
days then off for 7 days] for Treatment of Moderate to Severe
Dyspareunia, a Symptom of Vulvar and Vaginal Atrophy,
due to Menopause (2.3)
•
Twice-weekly administration of 0.5 g intravaginally [for
example, Monday and Thursday] for Treatment of Moderate
to Severe Dyspareunia, a Symptom of Vulvar and Vaginal
Atrophy, due to Menopause (2.3)
--------------------- DOSAGE FORMS AND STRENGTHS ---------------
•
Each gram contains 0.625 mg conjugated estrogens, USP (3)
•
Combination package: Each contains a net wt.
1.5 oz (42.5 g) tube with one plastic applicator calibrated in
0.5 g increments to a maximum of 2 g (3)
--------------------- CONTRAINDICATIONS --------------------------------
•
Undiagnosed abnormal genital bleeding (4)
•
Known, suspected, or history of breast cancer (4, 5.3)
•
Known or suspected estrogen-dependent neoplasia (4, 5.3)
•
Active deep vein thrombosis, pulmonary embolism or a
history of these conditions (4, 5.2)
•
Active arterial thromboembolic disease (for example, stroke,
myocardial infarction) or a history of these conditions (4, 5.2)
•
Known liver dysfunction or disease (4, 5.10)
•
Known or suspected pregnancy (4, 8.1)
--------------------- WARNINGS AND PRECAUTIONS-------------------
•
Estrogens increase the risk of gallbladder disease (5.5)
•
Discontinue estrogen if severe hypercalcemia, loss of vision,
severe hypertriglyceridemia or cholestatic jaundice occurs
(5.6, 5.7, 5.10, 5.11)
•
Monitor thyroid function in women on thyroid replacement
therapy (5.12, 5.19)
--------------------- ADVERSE REACTIONS---------------------------------
In a prospective, randomized, placebo-controlled, double-blind
study, the most common adverse reactions ≥ 5 percent are
headache, infection, abdominal pain, back pain, accidental injury,
and vaginitis. (6.1, 14.1)
To report SUSPECTED ADVERSE REACTIONS, contact
Wyeth Pharmaceuticals Inc. at 1-800-934-5556 or FDA at
1-800-FDA-1088 or www.fda.gov/medwatch
--------------------- DRUG INTERACTIONS ---------------------------------
Inducers and/or inhibitors of CYP3A4 may affect estrogen drug
metabolism (7)
--------------------- USE IN SPECIFIC POPULATIONS ------------------
•
Nursing Women: Estrogen administration to nursing women
has been shown to decrease the quantity and quality of breast
milk. (8.3)
•
Geriatric Use: An increased risk of probable dementia in
women over 65 years of age was reported in the Women’s
Health Initiative Memory ancillary studies of the Women’s
Health Initiative. (5.4, 8.5)
See 17 for Patient Counseling Information and FDA-approved
patient labeling
Revised: 11/2008
1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
FULL PRESCRIBING INFORMATION: CONTENTS*
BOXED WARNING
1
INDICATIONS AND USAGE
1.1 Treatment of Atrophic Vaginitis and Kraurosis Vulvae
1.2 Treatment of Moderate to Severe Dyspareunia, a
Symptom of Vulvar and Vaginal Atrophy, due to
Menopause
2
DOSAGE AND ADMINISTRATION
2.1 General Dosing Information
2.2 Treatment of Atrophic Vaginitis and Kraurosis Vulvae
2.3 Treatment of Moderate to Severe Dyspareunia, a
Symptom of Vulvar and Vaginal Atrophy, due to
Menopause
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1 Risks From Systemic Absorption
5.2 Cardiovascular Disorders
5.3 Malignant Neoplasms
5.4 Probable Dementia
5.5 Gallbladder Disease
5.6 Hypercalcemia
5.7 Visual Abnormalities
5.8 Addition of a Progestin When a Woman Has Not Had a
Hysterectomy
5.9 Elevated Blood Pressure
5.10 Hypertrigylceridemia
5.11 Hepatic Impairment and/or Past History of Cholestatic
Jaundice
5.12 Hypothyroidism
5.13 Fluid Retention
5.14 Hypocalcemia
5.15 Exacerbation of Endometriosis
5.16 Exacerbation of Other Conditions
5.17 Effect on Barrier Contraception
5.18 Laboratory Tests
5.19 Drug/Laboratory Test Interactions
6
ADVERSE REACTIONS
6.1 Clinical Study Experience
6.2 Postmarketing Experience
7
DRUG INTERACTIONS
7.1 Metabolic Interactions
8
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Renal Impairment
8.7 Hepatic Impairment
10
OVERDOSAGE
11
DESCRIPTION
12
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14
CLINICAL STUDIES
14.1 Effects on Vulvar and Vaginal Atrophy
14.2 Women’s Health Initiative Studies
14.3 Women’s Health Initiative Memory Study
15
REFERENCES
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
17.1 Vaginal Bleeding
17.2 Possible Serious Adverse Reactions With Estrogens
17.3 Possible Less Serious But Common Adverse Reactions
With Estrogens
17.4 Instructions for Use of Applicator
17.5 FDA-Approved Patient Labeling
*Sections or subsections omitted from the full prescribing
information are not listed
2
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
FULL PRESCRIBING INFORMATION
WARNING: ENDOMETRIAL CANCER,
CARDIOVASCULAR DISORDERS AND PROBABLE
DEMENTIA FOR ESTROGEN-ALONE THERAPY
ENDOMETRIAL CANCER
There is an increased risk of endometrial cancer in a woman
with a uterus who uses unopposed estrogens. Adding a
progestin to estrogen therapy has been shown to reduce the
risk of endometrial hyperplasia, which may be a precursor to
endometrial cancer. Adequate diagnostic measures, including
directed or random endometrial sampling when indicated,
should be undertaken to rule out malignancy in
postmenopausal women with undiagnosed persistent or
recurring abnormal genital bleeding [see Warnings and
Precautions (5.3)].
CARDIOVASCULAR DISORDERS AND PROBABLE
DEMENTIA
Estrogen-alone therapy should not be used for the prevention
of cardiovascular disease or dementia [see Warnings and
Precautions (5.2, 5.4), and Clinical Studies (14.2, 14.3)].
The Women’s Health Initiative (WHI) estrogen-alone substudy
reported increased risks of stroke and deep vein thrombosis
(DVT) in postmenopausal women (50 to 79 years of age) during
7.1 years of treatment with daily oral conjugated estrogens
(CE) [0.625 mg], relative to placebo [see Warnings and
Precautions (5.2), and Clinical Studies (14.2)].
The Women’s Health Initiative Memory Study (WHIMS)
estrogen-alone ancillary study of WHI reported an increased
risk of developing probable dementia in postmenopausal
women 65 years of age or older during 5.2 years of treatment
with daily CE (0.625 mg) alone, relative to placebo. It is
unknown whether this finding applies to younger
postmenopausal women [see Warnings and Precautions (5.4),
Use in Specific Populations (8.5), and Clinical Studies (14.3)].
In the absence of comparable data, these risks should be
assumed to be similar for other doses of CE and other dosage
forms of estrogens.
Estrogens with or without progestins should be prescribed at
the lowest effective doses and for the shortest duration
consistent with treatment goals and risks for the individual
woman.
WARNING: CARDIOVASCULAR DISORDERS, BREAST
CANCER AND PROBABLE DEMENTIA FOR ESTROGEN
PLUS PROGESTIN THERAPY
Estrogen plus progestin therapy should not be used for the
prevention of cardiovascular disease or dementia [see
Warnings and Precautions (5.2, 5.4), and Clinical Studies (14.2,
14.3)].
The WHI estrogen plus progestin substudy reported increased
risks of DVT, pulmonary embolism, stroke and myocardial
infarction in postmenopausal women (50 to 79 years of age)
during 5.6 years of treatment with daily oral CE (0.625 mg)
combined with medroxyprogesterone acetate (MPA) [2.5 mg],
relative to placebo [see Warnings and Precautions (5.2), and
Clinical Studies (14.2)].
The WHI estrogen plus progestin substudy also demonstrated
an increased risk of invasive breast cancer [see Warnings and
Precautions (5.3), and Clinical Studies (14.2)].
The WHIMS estrogen plus progestin ancillary study of the
WHI, reported an increased risk of developing probable
dementia in postmenopausal women 65 years of age or older
during 4 years of treatment with daily CE (0.625 mg)
combined with MPA (2.5 mg), relative to placebo. It is
unknown whether this finding applies to younger
postmenopausal women [see Warnings and Precautions (5.4),
Use in Specific Populations (8.5), and Clinical Studies (14.3)].
In the absence of comparable data, these risks should be
assumed to be similar for other doses of CE and MPA, and
other combinations and dosage forms of estrogens and
progestins.
Estrogens with or without progestins should be prescribed at
the lowest effective doses and for the shortest duration
consistent with treatment goals and risks for the individual
woman.
1
INDICATIONS AND USAGE
1.1 Treatment of Atrophic Vaginitis and Kraurosis Vulvae
1.2 Treatment of Moderate to Severe Dyspareunia, a
Symptom of Vulvar and Vaginal Atrophy, due to
Menopause
2
DOSAGE AND ADMINISTRATION
2.1 General Dosing Information
Generally, when estrogen is prescribed for a postmenopausal
woman with a uterus, a progestin should also be considered to
reduce the risk of endometrial cancer.
A woman without a uterus does not need a progestin. In some
cases, however, hysterectomized women with a history of
endometriosis may need a progestin [see Warnings and
Precautions (5.3, 5.15)].
Use of estrogen-alone, or in combination with a progestin, should
be with the lowest effective dose and for the shortest duration
consistent with treatment goals and risks for the individual woman.
Postmenopausal women should be re-evaluated periodically as
clinically appropriate to determine if treatment is still necessary.
2.2 Treatment of Atrophic Vaginitis and Kraurosis Vulvae
PREMARIN Vaginal Cream is administered intravaginally in a
cyclic regimen (daily for 21 days and then off for 7 days).
Generally, women should be started at the 0.5 g dosage strength.
Dosage adjustments (0.5 to 2 g) may be made based on individual
response [see Dosage Forms and Strengths (3)].
2.3 Treatment of Moderate to Severe Dyspareunia, a
Symptom of Vulvar and Vaginal Atrophy, due to
Menopause
PREMARIN Vaginal Cream (0.5 g) is administered intravaginally
in a twice-weekly (for example, Monday and Thursday)
continuous regimen or in a cyclic regimen of 21 days of therapy
followed by 7 days off of therapy [see Dosage Forms and
Strengths (3)].
3
DOSAGE FORMS AND STRENGTHS
Each gram contains 0.625 mg conjugated estrogens, USP.
Combination package: Each contains a net wt. 1.5 oz (42.5 g) tube
with one plastic applicator calibrated in 0.5 g increments to a
maximum of 2 g.
3
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
4
CONTRAINDICATIONS
PREMARIN Vaginal Cream therapy should not be used in women
with any of the following conditions:
•
Undiagnosed abnormal genital bleeding
•
Known, suspected, or history of breast cancer
•
Known or suspected estrogen-dependent neoplasia
•
Active deep vein thrombosis, pulmonary embolism or a
history of these conditions
•
Active arterial thromboembolic disease (for example, stroke,
and myocardial infarction), or a history of these conditions
•
Known liver dysfunction or disease
•
Known or suspected pregnancy
5
WARNINGS AND PRECAUTIONS
5.1 Risks From Systemic Absorption
Systemic absorption occurs with the use of PREMARIN Vaginal
Cream. The warnings, precautions, and adverse reactions
associated with oral PREMARIN treatment should be taken into
account.
5.2 Cardiovascular Disorders
An increased risk of stroke and deep vein thrombosis (DVT) has
been reported with estrogen-alone therapy. An increased risk of
pulmonary embolism, DVT, stroke and myocardial infarction has
been reported with estrogen plus progestin therapy. Should any of
these occur or be suspected, estrogens with or without progestins
should be discontinued immediately.
Risk factors for arterial vascular disease (for example,
hypertension, diabetes mellitus, tobacco use, hypercholesterolemia,
and obesity) and/or venous thromboembolism (for example,
personal history of venous thromboembolism [VTE], obesity, and
systemic lupus erythematosus) should be managed appropriately.
Stroke
In the Women's Health Initiative (WHI) estrogen-alone substudy, a
statistically significant increased risk of stroke was reported in
women 50 to 79 years of age receiving daily CE (0.625 mg)
compared to women in the same age group receiving placebo (45
versus 33 per 10,000 women-years). The increase in risk was
demonstrated in year one and persisted [see Clinical Studies
(14.2)]. Should a stroke occur or be suspected, estrogens should be
discontinued immediately.
Subgroup analyses of women 50 to 59 years of age suggest no
increased risk of stroke for those women receiving CE (0.625 mg)
versus those receiving placebo (18 versus 21 per 10,000 women
years).1
In the WHI estrogen plus progestin substudy, a statistically
significant increased risk of stroke was reported in all women
receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to
placebo (33 versus 25 per 10,000 women-years) [see Clinical
Studies (14.2)]. The increase in risk was demonstrated after the
first year and persisted.1
Coronary Heart Disease
In the WHI estrogen-alone substudy, no overall effect on coronary
heart disease (CHD) events (defined as nonfatal myocardial
infarction [MI], silent MI, or CHD death) was reported in women
receiving estrogen alone compared to placebo2 [see Clinical
Studies (14.2)].
Subgroup analyses of women 50 to 59 years of age suggest a
statistically non-significant reduction in CHD events (CE 0.625 mg
compared to placebo) in women with less than 10 years since
menopause (8 versus 16 per 10,000 women-years).1
In the WHI estrogen plus progestin substudy, there was a
statistically non-significant increased risk of CHD events in
women receiving daily CE (0.625 mg) plus MPA (2.5 mg)
compared to women receiving placebo (41 versus 34 per 10,000
women-years).1 An increase in relative risk was demonstrated in
year 1, and a trend toward decreasing relative risk was reported in
years 2 through 5 [see Clinical Studies (14.2)].
In postmenopausal women with documented heart disease
(n = 2,763), average age 66.7 years, in a controlled clinical trial of
secondary prevention of cardiovascular disease (Heart and
Estrogen/Progestin Replacement Study [HERS]), treatment with
daily CE (0.625 mg) plus MPA (2.5 mg) demonstrated no
cardiovascular benefit. During an average follow-up of 4.1 years,
treatment with CE plus MPA did not reduce the overall rate of
CHD events in postmenopausal women with established coronary
heart disease. There were more CHD events in the CE plus
MPA-treated group than in the placebo group in year 1, but not
during subsequent users. Two thousand, three hundred and
twenty-one (2,321) women from the original HERS trial agreed to
participate in an open label extension of HERS, HERS II. Average
follow-up in HERS II was an additional 2.7 years, for a total of 6.8
years overall. Rates of CHD events were comparable among
women in the CE (0.625 mg) plus MPA (2.5 mg) group and the
placebo group in HERS, HERS II, and overall.
Venous Thromboembolism (VTE)
In the WHI estrogen-alone substudy, the risk of VTE (DVT and
pulmonary embolism [PE]) was increased for women receiving
daily CE (0.625 mg) compared to placebo (30 versus 22 per 10,000
women-years), although only the increased risk of DVT reached
statistical significance (23 versus 15 per 10,000 women-years).
The increase in VTE risk was demonstrated during the first 2
years3 [see Clinical Studies (14.2)]. Should a VTE occur or be
suspected, estrogens should be discontinued immediately.
In the WHI estrogen plus progestin substudy, a statistically
significant 2-fold greater rate of VTE was reported in women
receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to
women receiving placebo (35 versus 17 per 10,000 women-years).
Statistically significant increases in risk for both DVT (26 versus
13 per 10,000 women-years) and PE (18 versus 8 per 10,000
women-years) were also demonstrated. The increase in VTE risk
was observed during the first year and persisted4 [see Clinical
Studies (14.2)]. Should a VTE occur or be suspected, estrogens
should be discontinued immediately.
If feasible, estrogens should be discontinued at least 4 to 6 weeks
before surgery of the type associated with an increased risk of
thromboembolism, or during periods of prolonged immobilization.
4
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5.3 Malignant Neoplasms
Endometrial Cancer
An increased risk of endometrial cancer has been reported with the
use of unopposed estrogen therapy in a woman with a uterus. The
reported endometrial cancer risk among unopposed estrogen users
is about 2- to 12-fold greater than in non-users, and appears
dependent on duration of treatment and on estrogen dose. Most
studies show no significant increased risk associated with use of
estrogens for less than 1 year. The greatest risk appears to be
associated with prolonged use, with increased risks of 15- to
24-fold for 5 to 10 years or more, and this risk has been shown to
persist for at least 8 to 15 years after estrogen therapy is
discontinued.
Clinical surveillance of all women using estrogen-alone or
estrogen plus progestin therapy is important. Adequate diagnostic
measures, including directed or random endometrial sampling
when indicated, should be undertaken to rule out malignancy in
postmenopausal women with undiagnosed persistent or recurring
abnormal genital bleeding.
There is no evidence that the use of natural estrogens results in a
different endometrial risk profile than synthetic estrogens of
equivalent estrogen dose. Adding a progestin to postmenopausal
estrogen therapy has been shown to reduce the risk of endometrial
hyperplasia, which may be a precursor to endometrial cancer.
In a 52-week clinical trial using PREMARIN Vaginal Cream alone
(0.5 g inserted twice weekly or daily for 21 days, then off for 7
days), there was no evidence of endometrial hyperplasia or
endometrial carcinoma.
Breast Cancer
The most important randomized clinical trial providing
information about breast cancer in estrogen-alone users is the
Women's Health Initiative (WHI) substudy of daily CE
(0.625 mg). In the WHI estrogen-alone substudy, after an average
follow-up of 7.1 years, daily CE (0.625 mg) was not associated
with an increased risk of invasive breast cancer (relative risk [RR]
0.80)5 [see Clinical Studies (14.2)].
The most important randomized clinical trial providing
information about breast cancer in estrogen plus progestin users is
the WHI substudy of daily CE (0.625 mg) plus MPA (2.5 mg).
After a mean follow-up of 5.6 years, the estrogen plus progestin
substudy reported an increased risk of breast cancer in women who
took daily CE plus MPA. In this substudy, prior use of estrogen-
alone or estrogen plus progestin therapy was reported by 26
percent of the women. The relative risk of invasive breast cancer
was 1.24, and the absolute risk was 41 versus 33 cases per 10,000
women-years, for estrogen plus progestin compared with placebo.6
Among women who reported prior use of hormone therapy, the
relative risk of invasive breast cancer was 1.86, and the absolute
risk was 46 versus 25 cases per 10,000 women-years for estrogen
plus progestin compared with placebo. Among women who
reported no prior use of hormone therapy, the relative risk of
invasive breast cancer was 1.09, and the absolute risk was 40
versus 36 cases per 10,000 women-years for estrogen plus
progestin compared with placebo. In the same substudy, invasive
breast cancers were larger and diagnosed at a more advanced stage
in the CE (0.625 mg) plus MPA (2.5 mg) group compared with the
placebo group. Metastatic disease was rare, with no apparent
difference between the two groups. Other prognostic factors, such
as histologic subtype, grade and hormone receptor status did not
differ between the groups [see Clinical Studies (14.2)].
Consistent with the WHI clinical trial, observational studies have
also reported an increased risk of breast cancer for estrogen plus
progestin therapy, and a smaller increased risk for estrogen-alone
therapy, after several years of use. The risk increased with duration
of use, and appeared to return to baseline over about 5 years after
stopping treatment (only the observational studies have substantial
data on risk after stopping). Observational studies also suggest that
the risk of breast cancer was greater, and became apparent earlier,
with estrogen plus progestin therapy as compared to estrogen-alone
therapy. However, these studies have not generally found
significant variation in the risk of breast cancer among different
estrogen plus progestin combinations, doses, or routes of
administration.
The use of estrogen-alone and estrogen plus progestin therapy has
been reported to result in an increase in abnormal mammograms,
requiring further evaluation.
All women should receive yearly breast examinations by a
healthcare provider and perform monthly breast self-examinations.
In addition, mammography examinations should be scheduled
based on patient age, risk factors, and prior mammogram results.
Ovarian Cancer
The WHI estrogen plus progestin substudy reported a statistically
non-significant increased risk of ovarian cancer. After an average
follow-up of 5.6 years, the relative risk for ovarian cancer for CE
plus MPA versus placebo, was 1.58 (95 percent nCI 0.77-3.24).
The absolute risk for CE plus MPA versus placebo was 4 versus 3
cases per 10,000 women-years.7 In some epidemiologic studies, the
use of estrogen-only products, in particular for 5 or more years, has
been associated with an increased risk of ovarian cancer. However,
the duration of exposure associated with increased risk is not
consistent across all epidemiologic studies, and some report no
association.
5.4 Probable Dementia
In the estrogen-alone Women's Health Initiative Memory Study
(WHIMS), an ancillary study of WHI, a population of 2,947
hysterectomized women 65 to 79 years of age was randomized to
daily CE (0.625 mg) or placebo. In the WHIMS estrogen plus
progestin ancillary study, a population of 4,532 postmenopausal
women 65 to 79 years of age was randomized to daily CE
(0.625 mg) plus MPA (2.5 mg) or placebo.
In the WHIMS estrogen-alone ancillary study, after an average
follow-up of 5.2 years, 28 women in the estrogen-alone group and
19 women in the placebo group were diagnosed with probable
dementia. The relative risk of probable dementia for CE-alone
versus placebo was 1.49 (95 percent nCI 0.83-2.66). The absolute
risk of probable dementia for CE alone versus placebo was 37
versus 25 cases per 10,000 women-years8 [see Use in Specific
Populations (8.3), and Clinical Studies (14.3)].
In the WHIMS estrogen plus progestin ancillary study, after an
average follow-up of 4 years, 40 women in the CE plus MPA
group and 21 women in the placebo group were diagnosed with
probable dementia. The relative risk of probable dementia for CE
plus MPA versus placebo was 2.05 (95 percent nCI 1.21-3.48).
The absolute risk of probable dementia for CE plus MPA versus
placebo was 45 versus 22 cases per 10,000 women-years8 [see Use
in Specific Populations (8.3), and Clinical Studies (14.3)].
When data from the two populations were pooled as planned in the
WHIMS protocol, the reported overall relative risk for probable
dementia was 1.76 (95 percent nCI 1.19-2.60). Since both
substudies were conducted in women 65 to 79 years of age, it is
unknown whether these findings apply to younger postmenopausal
women8 [see Use in Specific Populations (8.5), and Clinical
Studies (14.3)].
5
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5.5 Gallbladder Disease
5.13 Fluid Retention
A 2- to 4-fold increase in the risk of gallbladder disease requiring
surgery in postmenopausal women receiving estrogens has been
reported.
5.6 Hypercalcemia
Estrogen administration may lead to severe hypercalcemia in
women with breast cancer and bone metastases. If hypercalcemia
occurs, use of the drug should be stopped and appropriate
measures taken to reduce the serum calcium level.
5.7 Visual Abnormalities
Retinal vascular thrombosis has been reported in patients receiving
estrogens. Discontinue medication pending examination if there is
sudden partial or complete loss of vision, or a sudden onset of
proptosis, diplopia, or migraine. If examination reveals
papilledema or retinal vascular lesions, estrogens should be
permanently discontinued.
5.8 Addition of a Progestin When a Woman Has Not Had a
Hysterectomy
Studies of the addition of a progestin for 10 or more days of a
cycle of estrogen administration or daily with estrogen in a
continuous regimen have reported a lowered incidence of
endometrial hyperplasia than would be induced by estrogen
treatment alone. Endometrial hyperplasia may be a precursor to
endometrial cancer.
There are, however, possible risks that may be associated with the
use of progestins with estrogens compared to estrogen-alone
regimens. These include an increased risk of breast cancer.
5.9 Elevated Blood Pressure
In a small number of case reports, substantial increases in blood
pressure have been attributed to idiosyncratic reactions to
estrogens. In a large, randomized, placebo-controlled clinical trial,
a generalized effect of estrogen therapy on blood pressure was not
seen.
5.10 Hypertriglyceridemia
In patients with pre-existing hypertriglyceridemia, estrogen
therapy may be associated with elevations of plasma triglycerides
leading to pancreatitis. Consider discontinuation of treatment if
pancreatitis occurs.
5.11 Hepatic Impairment and/or Past History of Cholestatic
Jaundice
Estrogens may be poorly metabolized in women with impaired
liver function. For women with a history of cholestatic jaundice
associated with past estrogen use or with pregnancy, caution
should be exercised, and in the case of recurrence, medication
should be discontinued.
5.12 Hypothyroidism
Estrogen administration leads to increased thyroid-binding
globulin (TBG) levels. Women with normal thyroid function can
compensate for the increased TBG by making more thyroid
hormone, thus maintaining free T4 and T3 serum concentrations in
the normal range. Women dependent on thyroid hormone
replacement therapy who are also receiving estrogens may require
increased doses of their thyroid replacement therapy. These
women should have their thyroid function monitored in order to
maintain their free thyroid hormone levels in an acceptable range.
Estrogens may cause some degree of fluid retention. Patients with
conditions that might be influenced by this factor, such as cardiac
or renal dysfunction, warrant careful observation when estrogens
are prescribed.
5.14 Hypocalcemia
Estrogens should be used with caution in individuals with
hypoparathyroidism as estrogen-induced hypocalcemia may occur.
5.15 Exacerbation of Endometriosis
A few cases of malignant transformation of residual endometrial
implants have been reported in women treated post-hysterectomy
with estrogen-alone therapy. For women known to have residual
endometriosis post-hysterectomy, the addition of progestin should
be considered.
5.16 Exacerbation of Other Conditions
Estrogen therapy may cause an exacerbation of asthma, diabetes
mellitus, epilepsy, migraine, porphyria, systemic lupus
erythematosus, and hepatic hemangiomas and should be used with
caution in women with these conditions.
5.17 Effects on Barrier Contraception
PREMARIN Vaginal Cream exposure has been reported to weaken
latex condoms. The potential for PREMARIN Vaginal Cream to
weaken and contribute to the failure of condoms, diaphragms, or
cervical caps made of latex or rubber should be considered.
5.18 Laboratory Tests
Serum follicle stimulating hormone and estradiol levels have not
been shown to be useful in the management of moderate to severe
symptoms of vulvar and vaginal atrophy.
5.19 Drug/Laboratory Test Interactions
Accelerated prothrombin time, partial thromboplastin time, and
platelet aggregation time; increased platelet count; increased
factors II, VII antigen, VIII antigen, VIII coagulant activity, IX, X,
XII, VII-X complex, II-VII-X complex, and beta-thromboglobulin;
decreased levels of antifactor Xa and antithrombin III, decreased
antithrombin III activity; increased levels of fibrinogen and
fibrinogen activity; increased plasminogen antigen and activity.
Increased thyroid-binding globulin (TBG) leading to increased
circulating total thyroid hormone, as measured by protein-bound
iodine (PBI), T4 levels (by column or by radioimmunoassay) or T3
levels by radioimmunoassay. T3 resin uptake is decreased,
reflecting the elevated TBG. Free T4 and free T3 concentrations are
unaltered. Women on thyroid replacement therapy may require
higher doses of thyroid hormone.
Other binding proteins may be elevated in serum, for example,
corticosteroid binding globulin (CBG), sex hormone-binding
globulin (SHBG), leading to increased total circulating
corticosteroids and sex steroids, respectively. Free hormone
concentrations, such as testosterone and estradiol, may be
decreased. Other plasma proteins may be increased
(angiotensinogen/renin substrate, alpha-1-antitrypsin,
ceruloplasmin).
Increased plasma HDL and HDL2 cholesterol subfraction
concentrations, reduced LDL cholesterol concentrations, increased
triglyceride levels.
Impaired glucose tolerance.
6
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
6
ADVERSE REACTIONS
6.1 Clinical Study Experience
Because clinical trials are conducted under widely varying
conditions, adverse reaction rates observed in the clinical trial of a
drug cannot be directly compared to rates in the clinical trials of
another drug and may not reflect the rates observed in practice.
In a 12-week, randomized, double-blind, placebo-controlled trial of
PREMARIN Vaginal Cream (PVC), a total of 423 postmenopausal
women received at least 1 dose of study medication and were
included in all safety analyses: 143 women in the PVC-21/7
treatment group (0.5 g PVC daily for 21 days, then 7 days off), 72
women in the matching placebo treatment group; 140 women in
the PVC-2x/wk treatment group (0.5 g PVC twice weekly), 68
women in the matching placebo treatment group. A 40-week,
open-label extension followed, in which a total of 394 women
received treatment with PVC, including those subjects randomized
at baseline to placebo. In this study, the most common adverse
reactions ≥ 5 percent are shown below (Table 1) [see Clinical
Studies (14.1)].
Table 1: Number (%) of Patients Reporting Treatment Emergent
Adverse Events ≥ 5 Percent Only
Treatment
Body Systema
Adverse Event
PVC
21/7
(n=143)
Placebo
21/7
(n=72)
PVC
2x/wk
(n=140)
Placebo
2x/wk
(n=68)
Number (%) of Patients with Adverse Event
Any Adverse
Event
95 (66.4)
45 (62.5)
97 (69.3)
46 (67.6)
Body As A Whole
Abdominal Pain
11 (7.7)
2 (2.8)
9 (6.4)
6 (8.8)
Accidental
Injury
4 (2.8)
5 (6.9)
9 (6.4)
3 (4.4)
Asthenia
8 (5.6)
0
2 (1.4)
1 (1.5)
Back Pain
7 (4.9)
3 (4.2)
13 (9.3)
5 (7.4)
Headache
16 (11.2)
9 (12.5)
25 (17.9)
12 (17.6)
Infection
7 (4.9)
5 (6.9)
16 (11.4)
5 (7.4)
Pain
10 (7.0)
3 (4.2)
4 (2.9)
4 (5.9)
Cardiovascular System
Vasodilatation
5 (3.5)
4 (5.6)
7 (5.0)
1 (1.5)
Digestive System
Diarrhea
4 (2.8)
2 (2.8)
10 (7.1)
1 (1.5)
Nausea
5 (3.5)
4 (5.6)
3 (2.1)
3 (4.4)
Musculoskeletal System
Arthralgia
5 (3.5)
5 (6.9)
6 (4.3)
4 (5.9)
Nervous System
Insomnia
6 (4.2)
3 (4.2)
4 (2.9)
4 (5.9)
Respiratory System
Cough Increased
0
1 (1.4)
7 (5.0)
3 (4.4)
Pharyngitis
3 (2.1)
2 (2.8)
7 (5.0)
3 (4.4)
Sinusitis
1 (0.7)
3 (4.2)
2 (1.4)
4 (5.9)
Skin And
Appendages
12 (8.4)
7 (9.7)
16 (11.4)
3 (4.4)
Urogenital System
Breast Pain
8 (5.6)
1 (1.4)
4 (2.9)
0
Leukorrhea
3 (2.1)
2 (2.8)
4 (2.9)
6 (8.8)
Vaginitis
8 (5.6)
3 (4.2)
7 (5.0)
3 (4.4)
a Body system totals are not necessarily the sum of the individual adverse
events, since a patient may report two or more different adverse events in
the same body system.
6.2 Postmarketing Experience
The following adverse reactions have been reported with
PREMARIN Vaginal Cream. Because these reactions are reported
voluntarily from a population of uncertain size, it is not always
possible to reliably estimate their frequency or establish a causal
relationship to drug exposure.
Genitourinary System
Abnormal uterine bleeding/spotting, dysmenorrhea/pelvic pain,
increase in size of uterine leiomyomata, vaginitis (including
vaginal candidiasis), change in cervical secretion, cystitis-like
syndrome, application site reactions of vulvovaginal discomfort,
(including burning, irritation, and genital pruritus), endometrial
hyperplasia, endometrial cancer, precocious puberty, leukorrhea.
Breasts
Tenderness, enlargement, pain, discharge, fibrocystic breast
changes, breast cancer, gynecomastia in males.
Cardiovascular
Deep venous thrombosis, pulmonary embolism, myocardial
infarction, stroke, increase in blood pressure.
Gastrointestinal
Nausea, vomiting, abdominal cramps, bloating, increased
incidence of gallbladder disease.
Skin
Chloasma that may persist when drug is discontinued, loss of scalp
hair, hirsutism, rash.
Eyes
Retinal vascular thrombosis, intolerance to contact lenses.
Central Nervous System
Headache, migraine, dizziness, mental depression, nervousness,
mood disturbances, irritability, dementia.
Miscellaneous
Increase or decrease in weight, glucose intolerance, edema,
arthralgias, leg cramps, changes in libido, urticaria, anaphylactic
reactions, exacerbation of asthma, increased triglycerides,
hypersensitivity.
Additional postmarketing adverse reactions have been reported in
patients receiving other forms of hormone therapy.
7
DRUG INTERACTIONS
No formal drug interaction studies have been conducted for
PREMARIN Vaginal Cream.
7.1 Metabolic Interactions
In vitro and in vivo studies have shown that estrogens are
metabolized partially by cytochrome P450 3A4 (CYP3A4).
Therefore, inducers or inhibitors of CYP3A4 may affect estrogen
drug metabolism. Inducers of CYP3A4, such as St. John's Wort
(Hypericum perforatum) preparations, phenobarbital,
carbamazepine, and rifampin, may reduce plasma concentrations
of estrogens, possibly resulting in a decrease in therapeutic effects
and/or changes in the uterine bleeding profile. Inhibitors of
CYP3A4, such as erythromycin, clarithromycin, ketoconazole,
itraconazole, ritonavir and grapefruit juice, may increase plasma
concentrations of estrogens and may result in side effects.
7
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
8
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
PREMARIN Vaginal Cream should not be used during pregnancy
[see Contraindications (4)]. There appears to be little or no
increased risk of birth defects in children born to women who have
used estrogens and progestins as an oral contraceptive
inadvertently during early pregnancy.
8.3 Nursing Mothers
PREMARIN Vaginal Cream should not be used during lactation.
Estrogen administration to nursing mothers has been shown to
decrease the quantity and quality of the breast milk. Detectable
amounts of estrogens have been identified in the breast milk of
mothers receiving estrogens. Caution should be exercised when
PREMARIN Vaginal Cream is administered to a nursing woman.
8.4 Pediatric Use
PREMARIN Vaginal Cream is not indicated in children. Clinical
studies have not been conducted in the pediatric population.
8.5 Geriatric Use
There have not been sufficient numbers of geriatric women
involved in clinical studies utilizing PREMARIN Vaginal Cream
to determine whether those over 65 years of age differ from
younger subjects in their response to PREMARIN Vaginal Cream.
The Women’s Health Initiative Study
In the Women’s Health Initiative (WHI) estrogen-alone substudy
(daily conjugated estrogens 0.625 mg versus placebo), there was a
higher relative risk of stroke in women greater than 65 years of age
[see Clinical Studies (14.2)].
In the WHI estrogen plus progestin substudy, there was a higher
relative risk of nonfatal stroke and invasive breast cancer in
women greater than 65years of age [see Clinical Studies (14.2)].
The Women’s Health Initiative Memory Study
In the Women’s Health Initiative Memory Study (WHIMS) of
postmenopausal women 65 to 79 years of age, there was an
increased risk of developing probable dementia in the estrogen-
alone and the estrogen plus progestin substudies when compared to
placebo [see Clinical Studies (14.3)].
Since both substudies were conducted in women 65 to 79 years of
age, it is unknown whether these findings apply to younger
postmenopausal women8 [see Clinical Studies (14.3)].
8.6 Renal Impairment
The effect of renal impairment on PREMARIN Vaginal Cream
pharmacokinetics has not been studied.
8.7 Hepatic Impairment
The effect of hepatic impairment on PREMARIN Vaginal Cream
pharmacokinetics has not been studied.
10
OVERDOSAGE
Overdosage of estrogen may cause nausea and vomiting, breast
tenderness, dizziness, abdominal pain, drowsiness/fatigue, and
withdrawal bleeding in females. Treatment of overdose consists of
discontinuation of PREMARIN therapy with institution of
appropriate symptomatic care.
11
DESCRIPTION
Each gram of PREMARIN (conjugated estrogens) Vaginal Cream
contains 0.625 mg conjugated estrogens, USP in a nonliquefying
base containing cetyl esters wax, cetyl alcohol, white wax, glyceryl
monostearate, propylene glycol monostearate, methyl stearate,
benzyl alcohol, sodium lauryl sulfate, glycerin, and mineral oil.
PREMARIN Vaginal Cream is applied intravaginally.
PREMARIN Vaginal Cream contains a mixture of conjugated
estrogens obtained exclusively from natural sources, occurring as
the sodium salts of water-soluble estrogen sulfates blended to
represent the average composition of material derived from
pregnant mares' urine. It is a mixture of sodium estrone sulfate and
sodium equilin sulfate. It contains as concomitant components,
sodium sulfate conjugates, 17 α-dihydroequilin, 17 α-estradiol, and
17 β-dihydroequilin.
12
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Endogenous estrogens are largely responsible for the development
and maintenance of the female reproductive system and secondary
sexual characteristics. Although circulating estrogens exist in a
dynamic equilibrium of metabolic interconversions, estradiol is the
principal intracellular human estrogen and is substantially more
potent than its metabolites, estrone and estriol, at the receptor
level.
The primary source of estrogen in normally cycling adult women is
the ovarian follicle, which secretes 70 to 500 mcg of estradiol
daily, depending on the phase of the menstrual cycle. After
menopause, most endogenous estrogen is produced by conversion
of androstenedione, which is secreted by the adrenal cortex, to
estrone by peripheral tissues. Thus, estrone and the sulfate-
conjugated form, estrone sulfate, are the most abundant circulating
estrogens in postmenopausal women.
Estrogens act through binding to nuclear receptors in estrogen-
responsive tissues. To date, two estrogen receptors have been
identified. These vary in proportion from tissue to tissue.
Circulating estrogens modulate the pituitary secretion of the
gonadotropins, luteinizing hormone (LH) and follicle stimulating
hormone (FSH), through a negative feedback mechanism.
Estrogens act to reduce the elevated levels of these gonadotropins
seen in postmenopausal women.
12.2 Pharmacodynamics
Currently, there are no pharmacodynamic data known for
PREMARIN Vaginal Cream.
12.3 Pharmacokinetics
Absorption
Conjugated estrogens are water soluble and are well-absorbed
through the skin, mucous membranes, and the gastrointestinal (GI)
tract. The vaginal delivery of estrogens circumvents first-pass
metabolism.
A bioavailability study was conducted in 24 postmenopausal
women with atrophic vaginitis. The mean (SD) pharmacokinetic
parameters for unconjugated estrone, unconjugated estradiol, total
estrone, total estradiol and total equilin following 7 once-daily
doses of PREMARIN Vaginal Cream 0.5 g is shown in Table 2.
8
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 2: Mean ± SD Pharmacokinetic Parameters of PREMARIN
Following Daily Administration (7 Days) of PREMARIN Vaginal
Cream 0.5 g in 24 Postmenopausal Women
Pharmacokinetic Profiles of Unconjugated Estrogens
PREMARIN Vaginal Cream 0.5 g
PK Parameters
Arithmetic Mean ± SD
Cmax
(pg/mL)
Tmax
(hr)
AUCss
(pg•hr/mL)
Estrone
42.0 ± 13.9
7.4 ± 6.2
826 ± 295
Baseline-adjusted
estrone
21.9 ± 13.1
7.4 ± 6.2
365 ± 255
Estradiol
12.8 ± 16.6
8.5 ± 6.2
231 ± 285
Baseline-adjusted
estradiol
9.14 ± 14.7
8.5 ± 6.2
161 ± 252
Pharmacokinetic Profiles of Conjugated Estrogens
PREMARIN Vaginal Cream 0.5 g
PK Parameters
Arithmetic Mean ± SD
Cmax
(ng/mL)
Tmax
(hr)
AUCss
(ng•hr/mL)
Total estrone
0.60 ± 0.32
6.0 ± 4.0
9.75 ± 4.99
Baseline-adjusted total
estrone
0.40 ± 0.28
6.0 ± 4.0
5.79 ± 3.7
Total estradiol
0.04 ± 0.04
7.7 ± 5.9
0.70 ± 0.42
Baseline-adjusted total
estradiol
0.04 ± 0.04
7.7 ± 6.0
0.49 ± 0.38
Total equilin
0.12 ± 0.15
6.1 ± 4.7
3.09 ± 1.37
Distribution
The distribution of exogenous estrogens is similar to that of
endogenous estrogens. Estrogens are widely distributed in the body
and are generally found in higher concentration in the sex hormone
target organs. Estrogens circulate in the blood largely bound to sex
hormone-binding globulin (SHBG) and albumin.
Metabolism
Exogenous estrogens are metabolized in the same manner as
endogenous estrogens. Circulating estrogens exist in a dynamic
equilibrium of metabolic interconversions. These transformations
take place mainly in the liver. Estradiol is converted reversibly to
estrone, and both can be converted to estriol, which is a major
urinary metabolite. Estrogens also undergo enterohepatic
recirculation via sulfate and glucuronide conjugation in the liver,
biliary secretion of conjugates into the intestine, and hydrolysis in
the intestine followed by reabsorption. In postmenopausal women,
a significant portion of the circulating estrogens exists as sulfate
conjugates, especially estrone sulfate, which serves as a circulating
reservoir for the formation of more active estrogens.
Excretion
Estradiol, estrone, and estriol are excreted in the urine, along with
glucuronide and sulfate conjugates.
Specific Populations
No pharmacokinetic studies were conducted in specific
populations, including patients with renal or hepatic impairment.
13
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term continuous administration of natural and synthetic
estrogens in certain animal species increases the frequency of
carcinomas of the breast, uterus, cervix, vagina, testis, and liver.
14
CLINICAL STUDIES
14.1 Effects on Vulvar and Vaginal Atrophy
A 12-week, prospective, randomized, double-blind placebo-
controlled study was conducted to compare the safety and efficacy
of 2 PREMARIN Vaginal Cream (PVC) regimens 0.5 g
(0.3 mg CE) administered twice weekly and 0.5 g (0.3 mg CE)
administered sequentially for 21 days on drug followed by 7 days
off drug to matching placebo regimens in the treatment of
moderate to severe symptoms of vulvar and vaginal atrophy due to
menopause. The initial 12-week, double-blind, placebo-controlled
phase was followed by an open-label phase to assess endometrial
safety through week 52. The study randomized 423 generally
healthy postmenopausal women between 44 to 77 years of age
(mean 57.8 years), who at baseline had ≤ 5 percent superficial cells
on a vaginal smear, a vaginal pH ≥ 5.0, and who identified a most
bothersome moderate to severe symptom of vulvar and vaginal
atrophy. The majority (92.2 percent) of the women were Caucasian
(n = 390); 7.8 percent were Other (n = 33). All subjects were
assessed for improvement in the mean change from baseline to
Week 12 for the co-primary efficacy variables of: most bothersome
symptom of vulvar and vaginal atrophy (defined as the moderate to
severe symptom that had been identified by the woman as most
bothersome to her at baseline); percentage of vaginal superficial
cells and percentage of vaginal parabasal cells; and vaginal pH.
In the 12-week, double-blind phase, a statistically significant mean
change between baseline and Week 12 in the symptom of
dyspareunia was observed for both of the PREMARIN Vaginal
Cream regimens (0.5 g twice weekly and 0.5 g daily for 21 days,
then 7 days off) compared to matching placebo, see Table 3. Also
demonstrated for each PREMARIN Vaginal Cream regimen
compared to placebo was a statistically significant increase in the
percentage of superficial cells at Week 12 (28 percent and 26
percent, respectively, compared to 3 percent and 1 percent for
matching placebo), a statistically significant decrease in parabasal
cells (-61 percent and -58 percent, respectively, compared to -21
percent and -7 percent for matching placebo) and statistically
significant mean reduction between baseline and Week 12 in
vaginal pH (-1.62 and -1.57, respectively, compared to -0.36 and
-0.26 for matching placebo).
Endometrial safety was assessed by endometrial biopsy for all
randomly assigned subjects at week 52. For the 155 subjects (83 on
the 21/7 regimen, 72 on the twice-weekly regimen) completing the
52-week period with complete follow-up and evaluable
endometrial biopsies, there were no reports of endometrial
hyperplasia or endometrial carcinoma.
9
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 3: Mean Change in Most Bothersome Symptom of Dyspareunia
Compared to Placebo MITT Populationa
Dyspareunia*
PVC
0.5 g
2x/wkb
Placebo
0.5 g
2x/wkb
PVC
0.5 g
21/7c
Placebo
0.5 g
21/7c
Baseline
n
mean (SD)*
52
2.43 (0.76)
22
2.28 (1.04)
50
2.26 (0.99)
18
2.32 (0.88)
Week 12
n
mean (SD)*
52
0.88 (0.96)
21
1.63 (1.16)
50
0.77 (1.05)
18
1.92 (1.03)
Change from
Baseline at Week 12
n
52
21
50
18
LS meand
-1. 45
-0.69
-1.51
-0.36
(SD)*
P-value
(0.16)
(0.24)
(0.17)
(0.26)
vs.
Placebo
0.01e
--
<0.001f
--
a Women at baseline had ≤5 percent superficial cells on a vaginal smear, a
vaginal pH >5.0, and who identified dyspareunia as the most bothersome
symptom.
b PVC 2x/wk = apply PVC twice a week
c PVC 21/7 = apply PVC for 21 days and then 7 days of no therapy
d Least square mean from ANCOVA adjusting for study site and baseline
dyspareunia
e Comparison of PVC 2x/wk with placebo 2x/wk
f Comparison of PVC 21/7 with placebo 21/7
* Symptom Assessment Scale: 0 (none), 1 (mild), 2 (moderate), 3 (severe).
14.2 Women's Health Initiative Studies
The Women’s Health Initiative (WHI) enrolled approximately
27,000 predominantly healthy postmenopausal women in two
substudies to assess the risks and benefits of daily oral CE
(0.625 mg)-alone or in combination with MPA (2.5 mg) compared
to placebo in the prevention of certain chronic diseases. The
primary endpoint was the incidence of coronary heart disease
[(CHD) defined as nonfatal myocardial infarction (MI), silent MI
and CHD death], with invasive breast cancer as the primary
adverse outcome. A “global index” included the earliest
occurrence of CHD, invasive breast cancer, stroke, pulmonary
embolism (PE), endometrial cancer (only in the CE plus MPA
substudy), colorectal cancer, hip fracture, or death due to other
causes. The study did not evaluate the effects of CE or CE plus
MPA on menopausal symptoms.
WHI Estrogen-Alone Substudy
The WHI estrogen-alone substudy was stopped early because an
increased risk of stroke was observed, and it was deemed that no
further information would be obtained regarding the risks and
benefits of estrogen alone in predetermined primary endpoints.
Results of the estrogen-alone substudy, which included 10,739
women (average age of 63 years, range 50 to 79; 75.3 percent
White, 15.1 percent Black, 6.1 percent Hispanic, 3.6 percent
Other) after an average follow-up of 7.1 years, are presented in
Table 4.
Table 4: Relative and Absolute Risk Seen in the Estrogen-Alone
Substudy of WHI
Event
Relative Risk
CE vs. Placebo
(95% nCIa)
CE
n = 5,310
Placebo
n = 5,429
Absolute Risk per 10,000
Women-Years
CHD eventsb
0.95 (0.78–1.16)
54
57
Non-fatal MI b
0.91 (0.73–1.14)
40
43
CHD deathb
1.01 (0.71–1.43)
16
16
All Strokeb
1.33 (1.05–1.68)
45
33
Ischemicb
1.55 (1.19–2.01)
38
25
Deep vein
thrombosisb,c
1.47 (1.06–2.06)
23
15
Pulmonary embolismb
1.37 (0.90–2.07)
14
10
Invasive breast
cancerb
0.80 (0.62–1.04)
28
34
Colorectal cancerd
1.08 (0.75–1.55)
17
16
Hip fractureb
0.65 (0.45–0.94)
12
19
Vertebral fracturesb,c
0.64 (0.44–0.93)
11
18
Lower arm/wrist
fracturesb,c
0.58 (0.47–0.72)
35
59
Total fracturesb,c
0.71 (0.64–0.80)
144
197
Death due to other
causesd,e
1.08 (0.88–1.32)
53
50
Overall mortalityb,c
1.04 (0.88–1.22)
79
75
Global Indexf
1.02 (0.92–1.13)
206
201
a Nominal confidence intervals unadjusted for multiple looks and multiple
comparisons.
b Results are based on centrally adjudicated data for an average follow-up of
7.1 years.
c Not included in “global index.”
d Results are based on an average follow-up of 6.8 years.
e All deaths, except from breast or colorectal cancer, definite/probable CHD,
PE or cerebrovascular disease.
f A subset of the events was combined in a “global index” defined as the
earliest occurrence of CHD events, invasive breast cancer, stroke,
pulmonary embolism, colorectal cancer, hip fracture, or death due to other
causes.
For those outcomes included in the WHI “global index” that
reached statistical significance, the absolute excess risk per 10,000
women-years in the group treated with CE-alone was 12 more
strokes while the absolute risk reduction per 10,000 women-years
was 7 fewer hip fractures.9 The absolute excess risk of events
included in the “global index” was a non-significant 5 events per
10,000 women-years. There was no difference between the groups
in terms of all-cause mortality [see Boxed Warnings, and Warnings
and Precautions (5)].
No overall difference for primary CHD events (nonfatal MI, silent
MI and CHD death) and invasive breast cancer incidence in
women receiving CE-alone compared with placebo was reported in
final centrally adjudicated results from the estrogen-alone
substudy, after an average follow up of 7.1 years.
Centrally adjudicated results for stroke events from the estrogen-
alone substudy, after an average follow-up of 7.1 years, reported
no significant difference in distribution of stroke subtype or
severity, including fatal strokes, in women receiving CE-alone
compared to placebo. Estrogen-alone increased the risk for
ischemic stroke, and this excess risk was present in all subgroups
of women examined, see Table 4.10
10
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Timing of the initiation of estrogen therapy relative to the start of
menopause may affect the overall risk benefit profile. The WHI
estrogen-alone substudy stratified by age showed in women 50-59
years of age, a non-significant trend toward reduced risk for CHD
[HR 0.63 (95 percent CI 0.36-1.09)] and overall mortality [HR
0.71 (95 percent CI 0.46-1.11)].
WHI Estrogen Plus Progestin Substudy
The WHI estrogen plus progestin substudy was stopped early.
According to the predefined stopping rule, after an average follow-
up of 5.6 years of treatment, the increased risk of breast cancer and
cardiovascular events exceeded the specified benefits included in
the “global index.” The absolute excess risk of events included in
the “global index” was 19 per 10,000 women-years.
For those outcomes included in the WHI “global index” that
reached statistical significance after 5.6 years of follow-up, the
absolute excess risks per 10,000 women-years in the group treated
with CE plus MPA were 7 more CHD events, 8 more strokes, 10
more PEs, and 8 more invasive breast cancers, while the absolute
risk reductions per 10,000 women-years were 6 fewer colorectal
cancers and 5 fewer hip fractures.
Results of the estrogen plus progestin substudy, which included
16,608 women (average 63 years of age, range 50 to 79; 83.9
percent White, 6.8 percent Black, 5.4 percent Hispanic, 3.9 percent
Other) are presented in Table 5. These results reflect centrally
adjudicated data after an average follow-up of 5.6 years.
Table 5: Relative and Absolute Risk Seen in the Estrogen Plus
Progestin Substudy of WHI at an Average of 5.6 Yearsa
Event
Relative Risk
CE/MPA vs.
Placebo
(95% nCIb)
CE/MPA
n = 8,506
Placebo
n = 8,102
Absolute Risk per 10,000
Women-Years
CHD events
1.23 (0.99–1.53)
41
34
Non-fatal MIb
1.28 (1.00–1.63)
31
25
CHD death
1.10 (0.70–1.75)
8
8
All Strokes
1.31 (1.03–1.68)
33
25
Ischemic stroke
1.44 (1.09–1.90)
26
18
Deep vein
thrombosisc
1.95 (1.43–2.67)
26
13
Pulmonary embolism
2.13 (1.45–3.11)
18
8
Invasive breast
cancerd
1.24 (1.01–1.54)
41
33
Colorectal cancer
0.61 (0.42–0.87)
10
16
Endometrial cancerc
0.81 (0.48–1.36)
6
7
Table 5: Relative and Absolute Risk Seen in the Estrogen Plus
Progestin Substudy of WHI at an Average of 5.6 Yearsa
Event
Relative Risk
CE/MPA vs.
Placebo
(95% nCIb)
CE/MPA
n = 8,506
Placebo
n = 8,102
Absolute Risk per 10,000
Women-Years
Cervical cancerc
1.44 (0.47–4.42)
2
1
Hip fractureb
0.67 (0.47–0.96)
11
16
Vertebral fracturesc
0.65 (0.46–0.92)
11
17
Lower arm/wrist
fracturesc
0.71 (0.59–0.85)
44
62
Total fracturesc
0.76 (0.69–0.83)
152
199
Overall Mortalitye
1.00 (0.83–1.19)
52
52
Global Indexf
1.13 (1.02–1.25)
184
165
a Results are based on centrally adjudicated data.
b Nominal confidence intervals unadjusted for multiple looks and
multiple comparisons.
c Not included in “global index.”
d Includes metastatic and non-metastatic breast cancer, with the
exception of in situ cancer.
e All deaths, except from breast or colorectal cancer, definite/probable
CHD, PE or cerebrovascular disease.
f A subset of the events was combined in a “global index” defined as the
earliest occurrence of CHD events, invasive breast cancer, stroke,
pulmonary embolism, colorectal cancer, hip fracture, or death due to
other causes.
Timing of the initiation of estrogen therapy relative to the start of
menopause may affect the overall risk benefit profile. The WHI
estrogen plus progestin substudy stratified by age showed in
women 50-59 years of age, a non-significant trend toward reduced
risk for overall mortality [HR 0.69 (95 percent CI 0.44-1.07)].
14.3 Women's Health Initiative Memory Study
The estrogen-alone Women's Health Initiative Memory Study
(WHIMS), an ancillary study of WHI, enrolled 2,947
predominantly healthy hysterectomized postmenopausal women 65
to 79 years of age and older (45 percent were 65 to 69 years of age;
36 percent were 70 to 74 years of age; 19 percent were 75 years of
age and older) to evaluate the effects of daily CE (0.625 mg) on the
incidence of probable dementia (primary outcome) compared to
placebo.
After an average follow-up of 5.2 years, the relative risk of
probable dementia for CE-alone versus placebo was 1.49 (95
percent CI 0.83-2.66). The absolute risk of probable dementia for
CE-alone versus placebo was 37 versus 25 cases per 10,000
women-years. Probable dementia as defined in this study included
Alzheimer’s disease (AD), vascular dementia (VaD) and mixed
types (having features of both AD and VaD). The most common
classification of probable dementia in both the treatment and
placebo groups was AD. Since the ancillary study was conducted
in women 65 to 79 years of age, it is unknown whether these
findings apply to younger postmenopausal women [see Warnings
and Precautions (5.4), and Use in Specific Populations (8.3)].
The WHIMS estrogen plus progestin substudy enrolled 4,532
predominantly healthy postmenopausal women 65 years of age and
older (47 percent were 65 to 69 years of age; 35 percent were 70 to
74 years; 18 percent were 75 years of age and older) to evaluate
the effects of daily CE (0.625 mg) plus MPA (2.5 mg) on the
incidence of probable dementia (primary outcome) compared to
placebo.
11
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
After an average follow-up of 4 years, the relative risk of probable
dementia for CE (0.625 mg) plus MPA (2.5 mg) versus placebo
was 2.05 (95 percent CI 1.21-3.48). The absolute risk of probable
dementia for CE (0.625 mg) plus MPA (2.5 mg) versus placebo
was 45 versus 22 per 10,000 women-years. Probable dementia as
defined in this study included Alzheimer’s disease, vascular
dementia and mixed types (having features of both AD and VaD).
The most common classification of probable dementia in both the
treatment and placebo groups was AD. Since the ancillary study
was conducted in women 65 to 79 years of age, it is unknown
whether these findings apply to younger postmenopausal women
[see Warnings and Precautions (5.4), and Use in Specific
Populations (8.5)].
When data from the two populations were pooled as planned in the
WHIMS protocol, the reported overall relative risk for probable
dementia was 1.76 (95 percent CI 1.19-2.60). Differences between
groups became apparent in the first year of treatment. It is
unknown whether these findings apply to younger postmenopausal
women [see Warnings and Precautions (5.4), and Use in Specific
Populations (8.5)].
15
REFERENCES
1.
Rossouw JE, et al. Postmenopausal Hormone Therapy and
Risk of Cardiovascular Disease by Age and Years Since
Menopause. JAMA. 2007;297:1465-1477.
2.
Hsia J, et al. Conjugated Equine Estrogens and Coronary
Heart Disease. Arch Int Med. 2006;166:357-365.
3.
Curb JD, et al. Venous Thrombosis and Conjugated Equine
Estrogen in Women Without a Uterus. Arch Int Med.
2006;166:772-780.
4.
Cushman M, et al. Estrogen Plus Progestin and Risk of
Venous Thrombosis. JAMA. 2004;292:1573-1580.
5.
Stefanick ML, et al. Effects of Conjugated Equine Estrogens
on Breast Cancer and Mammography Screening in
Postmenopausal Women With Hysterectomy. JAMA.
2006;295:1647-1657.
6.
Chlebowski RT, et al. Influence of Estrogen Plus Progestin
on Breast Cancer and Mammography in Healthy
Postmenopausal Women. JAMA. 2003;289:3234-3253.
7.
Anderson GL, et al. Effects of Estrogen Plus Progestin on
Gynecologic cancers and Associated Diagnostic Procedures.
JAMA. 2003;290:1739-1748.
8.
Shumaker SA, et al. Conjugated Equine Estrogens and
Incidence of Probable Dementia and Mild Cognitive
Impairment in Postmenopausal Women. JAMA.
2004;291:2947-2958.
9.
Jackson RD, et al. Effects of Conjugated Equine Estrogen on
Risk of Fractures and BMD in Postmenopausal Women With
Hysterectomy: Results From the Women’s Health Initiative
Randomized Trial. J Bone Miner Res. 2006;21:817-828.
10. Hendrix SL, et al. Effects of Conjugated Equine Estrogen on
Stroke in the Women’s Health Initiative. Circulation.
2006;113:2425-2434.
16 HOW SUPPLIED/STORAGE AND HANDLING
PREMARIN (conjugated estrogens) Vaginal Cream—Each gram
contains 0.625 mg conjugated estrogens, USP.
Combination package: Each contains a net wt. 1.5 oz (42.5 g) tube
with one plastic applicator calibrated in 0.5 g increments to a
maximum of 2 g (NDC 0046-0872-93).
Store at 20° to 25°C (68° to 77°F); excursions permitted to 15°
to 30°C (59° to 86°F) [see USP Controlled Room
Temperature].
17 PATIENT COUNSELING INFORMATION
See Section 17.5 for FDA-Approved Patient Labeling.
17.1 Vaginal Bleeding
Inform postmenopausal women of the importance of reporting
vaginal bleeding to their healthcare provider as soon as possible
[see Warnings and Precautions (5.3)]
17.2 Possible Serious Adverse Reactions With Estrogens
Inform postmenopausal women of possible serious adverse
reactions of estrogen therapy including Cardiovascular Disorders,
Malignant Neoplasms, and Probable Dementia [see Warnings and
Precautions (5.2, 5.3, 5.4)].
17.3 Possible Less Serious But Common Adverse Reactions
With Estrogens
Inform postmenopausal women of possible less serious but
common adverse reactions of estrogen therapy such as headache,
breast pain and tenderness, nausea and vomiting.
17.4 Instructions for Use of Applicator
1.
Remove cap from tube.
2.
Screw nozzle end of applicator onto tube.
3.
Gently squeeze tube from the bottom to force sufficient
cream into the barrel to provide the prescribed dose. Use the
marked stopping points on the applicator to measure the
correct dose, as prescribed by your healthcare provider.
4.
Unscrew applicator from tube.
5.
Lie on back with knees drawn up. To deliver medication,
gently insert applicator deeply into vagina and press plunger
downward to its original position.
TO CLEANSE: Pull plunger to remove it from barrel. Wash with
mild soap and warm water.
DO NOT BOIL OR USE HOT WATER.
17.5 FDA-Approved Patient Labeling
PREMARIN® (conjugated estrogens) Vaginal Cream
Read this PATIENT INFORMATION before you start using
PREMARIN Vaginal Cream and read what you get each time you
refill your PREMARIN Vaginal Cream prescription. There may be
new information. This information does not take the place of
12
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
talking to your healthcare provider about your menopausal
symptoms and their treatment.
What is the most important information I should know about
PREMARIN Vaginal Cream (an estrogen mixture)?
•
Estrogens may increase the chance of getting cancer of the
uterus.
•
Report any unusual vaginal bleeding right away while you
are using PREMARIN Vaginal Cream. Vaginal bleeding
after menopause may be a warning sign of cancer of the
uterus (womb). Your healthcare provider should check any
unusual vaginal bleeding to find the cause.
•
Do not use estrogens with or without progestins to prevent
heart disease, heart attacks, strokes or dementia.
Using estrogens, with or without progestins, may increase
your chance of getting heart attacks, strokes, breast cancer,
and blood clots. Using estrogens, with or without
progestins, may increase your chance of getting dementia,
based on a study of women age 65 years or older. You and
your healthcare provider should talk regularly about
whether you still need treatment with PREMARIN Vaginal
Cream.
What is PREMARIN Vaginal Cream?
PREMARIN Vaginal Cream is a medicine that contains a mixture
of estrogen hormones.
What is PREMARIN Vaginal Cream used for?
PREMARIN Vaginal Cream is used after menopause to:
•
Treat menopausal changes in and around the vagina. You
and your healthcare provider should talk regularly about
whether you still need treatment with PREMARIN Vaginal
Cream to control these problems.
•
Treat painful intercourse caused by menopausal changes
of the vagina.
Who should not use PREMARIN Vaginal Cream?
Do not start using PREMARIN Vaginal Cream if you:
•
Have unusual vaginal bleeding.
•
Currently have or have had certain cancers.
Estrogens may increase the chance of getting certain types of
cancers, including cancer of the breast or uterus. If you have
or have had cancer, talk with your healthcare provider about
whether you should use PREMARIN Vaginal Cream.
•
Had a stroke or heart attack.
•
Currently have or have had blood clots.
•
Currently have or have had liver problems.
•
Are allergic to PREMARIN Vaginal Cream or any of its
ingredients.
See the list of ingredients in PREMARIN Vaginal Cream at
the end of this leaflet.
•
Think you may be pregnant.
Tell your healthcare provider:
•
If you have any unusual vaginal bleeding. Vaginal
bleeding after menopause may be a warning sign of cancer of
the uterus (womb). Your healthcare provider should check
any unusual vaginal bleeding to find the cause.
•
About all of your medical problems. Your healthcare
provider may need to check you more carefully if you have
certain conditions, such as asthma (wheezing), epilepsy
(seizures), diabetes, migraine, endometriosis, lupus, or
problems with your heart, liver, thyroid, kidneys, or have
high calcium levels in your blood.
•
About all the medicines you take. This includes
prescription and nonprescription medicines, vitamins, and
herbal supplements. Some medicines may affect how
PREMARIN Vaginal Cream works. PREMARIN Vaginal
Cream may also affect how your other medicines work.
•
If you are going to have surgery or will be on bedrest.
You may need to stop using PREMARIN Vaginal Cream.
•
If you are breast feeding. The hormones in PREMARIN
Vaginal Cream can pass into your milk.
How should I use PREMARIN Vaginal Cream?
PREMARIN Vaginal Cream is a cream that you place in your
vagina with the applicator provided with the cream.
•
Take the dose recommended by your healthcare provider and
talk to him or her about how well that dose is working for
you.
•
Estrogens should be used at the lowest dose possible for your
treatment only as long as needed. You and your healthcare
provider should talk regularly (for example, every 3 to 6
months) about the dose you are taking and whether you still
need treatment with PREMARIN Vaginal Cream.
1.
Remove cap from tube.
2.
Screw nozzle end of applicator onto tube.
3.
Gently squeeze tube from the bottom to force sufficient
cream into the barrel to provide the prescribed dose. Use the
marked stopping points on the applicator to measure the
correct dose, as prescribed by your healthcare provider.
4.
Unscrew applicator from tube.
5.
Lie on back with knees drawn up. To deliver medication,
gently insert applicator deeply into vagina and press plunger
downward to its original position.
TO CLEANSE: Pull plunger to remove it from barrel. Wash with
mild soap and warm water.
13
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
DO NOT BOIL OR USE HOT WATER.
What are the possible side effects of PREMARIN Vaginal
Cream?
PREMARIN Vaginal Cream is only used in and around the vagina;
however, the risks associated with oral estrogens should be taken
into account.
Side effects are grouped by how serious they are and how often
they happen when you are treated.
Serious, but less common side effects include:
•
Breast cancer
•
Cancer of the uterus
•
Stroke
•
Heart attack
•
Blood clots
•
Dementia
•
Gallbladder disease
•
Ovarian cancer
•
High blood pressure
•
Liver problems
•
High blood sugar
•
Enlargement of benign tumors of the uterus (“fibroids”)
Some of the warning signs of these serious side effects include:
•
Breast lumps
•
Unusual vaginal bleeding
•
Dizziness and faintness
•
Changes in speech
•
Severe headaches
•
Chest pain
•
Shortness of breath
•
Pains in your legs
•
Changes in vision
•
Vomiting
Call your healthcare provider right away if you get any of these
warning signs, or any other unusual symptoms that concern you.
Less serious, but common, side effects include:
•
Headache
•
Breast pain
•
Irregular vaginal bleeding or spotting
•
Stomach/abdominal cramps, bloating
•
Nausea and vomiting
•
Hair loss
•
Fluid retention
•
Vaginal yeast infection
•
Reactions from inserting PREMARIN Vaginal Cream, such
as vaginal burning, irritation, and itching
These are not all the possible side effects of PREMARIN Vaginal
Cream. For more information, ask your healthcare provider or
pharmacist.
What can I do to lower my chances of getting a serious side
effect with PREMARIN Vaginal Cream?
•
Talk with your healthcare provider regularly about whether
you should continue using PREMARIN Vaginal Cream.
•
If you have a uterus, talk with your healthcare provider about
whether the addition of a progestin is right for you. The
addition of a progestin is generally recommended for a
woman with a uterus to reduce the chance of getting cancer
of the uterus. See your healthcare provider right away if you
get vaginal bleeding while using PREMARIN Vaginal
Cream.
•
Have a pelvic exam, breast exam and mammogram (breast
X-ray) every year unless your healthcare provider tells you
something else. If members of your family have had breast
cancer or if you have ever had breast lumps or an abnormal
mammogram, you may need to have breast exams more
often.
•
If you have high blood pressure, high cholesterol (fat in the
blood), diabetes, are overweight, or if you use tobacco, you
may have higher chances for getting heart disease. Ask your
healthcare provider for ways to lower your chances for
getting heart disease.
General information about the safe and effective use of
PREMARIN Vaginal Cream
Medicines are sometimes prescribed for conditions that are not
mentioned in patient information leaflets. Do not use PREMARIN
Vaginal Cream for conditions for which it was not prescribed. Do
not give PREMARIN Vaginal Cream to other people, even if they
have the same symptoms you have. It may harm them. Keep
PREMARIN Vaginal Cream out of the reach of children.
•
Yellowing of the skin, eyes, or nail beds
14
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Latex or rubber condoms, diaphragms and cervical caps may be
weakened and fail when they come into contact with PREMARIN
Vaginal Cream.
This leaflet provides a summary of the most important information
about PREMARIN Vaginal Cream. If you would like more
information, talk with your healthcare provider or pharmacist. You
can ask for information about PREMARIN Vaginal Cream that is
written for health professionals. You can get more information by
calling the toll free number 1-800-934-5556.
What are the ingredients in PREMARIN Vaginal Cream?
PREMARIN Vaginal Cream contains a mixture of conjugated
estrogens, which are a mixture of sodium estrone sulfate and
sodium equilin sulfate and other components, including sodium
sulfate conjugates: 17 α-dihydroequilin, 17 α-estradiol, and
17 β-dihydroequilin. PREMARIN Vaginal Cream also contains
cetyl esters wax, cetyl alcohol, white wax, glyceryl monostearate,
propylene glycol monostearate, methyl stearate, benzyl alcohol,
sodium lauryl sulfate, glycerin, and mineral oil.
PREMARIN (conjugated estrogens) Vaginal Cream—Each gram
contains 0.625 mg conjugated estrogens, USP.
Combination package: Each contains a net wt. 1.5 oz (42.5 g) tube
with one plastic applicator calibrated in 0.5 g increments to a
maximum of 2 g (NDC 0046-0872-93).
Store at 20° to 25°C (68° to 77°F); excursions permitted to 15°
to 30°C (59° to 86°F) [see USP Controlled Room
Temperature].
Wyeth®
Wyeth Pharmaceuticals Inc.
Philadelphia, PA 19101
«TEAR HERE
PATIENT INFORMATION
PREMARIN® (conjugated estrogens) Vaginal Cream
Read this PATIENT INFORMATION before you start using
PREMARIN Vaginal Cream and read what you get each time you
refill your PREMARIN Vaginal Cream prescription. There may be
new information. This information does not take the place of
talking to your healthcare provider about your menopausal
symptoms and their treatment.
What is the most important information I should know about
PREMARIN Vaginal Cream (an estrogen mixture)?
•
Estrogens may increase the chances of getting cancer of the
uterus.
Report any unusual vaginal bleeding right away while you
are using PREMARIN Vaginal Cream. Vaginal bleeding
after menopause may be a warning sign of cancer of the
uterus (womb). Your healthcare provider should check any
unusual vaginal bleeding to find the cause.
•
Do not use estrogens with or without progestins to prevent
heart disease, heart attacks, strokes or dementia.
Using estrogens, with or without progestins, may increase
your chance of getting heart attacks, strokes, breast cancer,
and blood clots. Using estrogens, with or without
progestins, may increase your chance of getting dementia,
based on a study of women age 65 years or older. You and
your healthcare provider should talk regularly about
whether you still need treatment with PREMARIN Vaginal
Cream.
What is PREMARIN Vaginal Cream?
PREMARIN Vaginal Cream is a medicine that contains a mixture
of estrogen hormones.
What is PREMARIN Vaginal Cream used for?
PREMARIN Vaginal Cream is used after menopause to:
•
Treat menopausal changes in and around the vagina. You
and your healthcare provider should talk regularly about
whether you still need treatment with PREMARIN Vaginal
Cream to control these problems.
•
Treat painful intercourse caused by menopausal changes
of the vagina.
Who should not use PREMARIN Vaginal Cream?
Do not start using PREMARIN Vaginal Cream if you:
•
Have unusual vaginal bleeding.
15
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
•
Currently have or have had certain cancers.
Estrogens may increase the chance of getting certain types of
cancers, including cancer of the breast or uterus. If you have
or have had cancer, talk with your healthcare provider about
whether you should use PREMARIN Vaginal Cream.
•
Had a stroke or heart attack.
•
Currently have or have had blood clots.
•
Currently have or have had liver problems.
•
Are allergic to PREMARIN Vaginal Cream or any of its
ingredients.
See the list of ingredients in PREMARIN Vaginal Cream at
the end of this leaflet.
•
Think you may be pregnant.
Tell your healthcare provider:
•
If you have any unusual vaginal bleeding. Vaginal
bleeding after menopause may be a warning sign of cancer of
the uterus (womb). Your healthcare provider should check
any unusual vaginal bleeding to find the cause.
•
About all of your medical problems. Your healthcare
provider may need to check you more carefully if you have
certain conditions, such as asthma (wheezing), epilepsy
(seizures), diabetes, migraine, endometriosis, lupus, or
problems with your heart, liver, thyroid, kidneys, or have
high calcium levels in your blood.
•
About all the medicines you take. This includes
prescription and nonprescription medicines, vitamins, and
herbal supplements. Some medicines may affect how
PREMARIN Vaginal Cream works. PREMARIN Vaginal
Cream may also affect how your other medicines work.
•
If you are going to have surgery or will be on bedrest.
You may need to stop using PREMARIN Vaginal Cream.
•
If you are breast feeding. The hormones in PREMARIN
Vaginal Cream can pass into your milk.
How should I use PREMARIN Vaginal Cream?
PREMARIN Vaginal Cream is a cream that you place in your
vagina with the applicator provided with the cream.
•
Take the dose recommended by your healthcare provider and
talk to him or her about how well that dose is working for
you.
•
Estrogens should be used at the lowest dose possible for your
treatment only as long as needed. You and your healthcare
provider should talk regularly (for example, every 3 to 6
months) about the dose you are taking and whether you still
need treatment with PREMARIN Vaginal Cream.
1.
Remove cap from tube.
2.
Screw nozzle end of applicator onto tube.
3.
Gently squeeze tube from the bottom to force sufficient
cream into the barrel to provide the prescribed dose. Use the
marked stopping points on the applicator to measure the
correct dose, as prescribed by your healthcare provider.
4.
Unscrew applicator from tube.
5.
Lie on back with knees drawn up. To deliver medication,
gently insert applicator deeply into vagina and press plunger
downward to its original position.
TO CLEANSE: Pull plunger to remove it from barrel. Wash with
mild soap and warm water.
DO NOT BOIL OR USE HOT WATER.
What are the possible side effects of PREMARIN Vaginal
Cream?
PREMARIN Vaginal Cream is only used in and around the vagina;
however, the risks associated with oral estrogens should be taken
into account.
Side effects are grouped by how serious they are and how often
they happen when you are treated.
Serious, but less common side effects include:
•
Breast cancer
•
Cancer of the uterus
•
Stroke
•
Heart attack
•
Blood clots
•
Dementia
•
Gallbladder disease
•
Ovarian cancer
•
High blood pressure
•
Liver problems
•
High blood sugar
•
Enlargement of benign tumors of the uterus (“fibroids”)
Some of the warning signs of these serious side effects include:
•
Breast lumps
•
Unusual vaginal bleeding
•
Dizziness and faintness
•
Changes in speech
•
Severe headaches
16
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
•
Chest pain
•
Shortness of breath
•
Pains in your legs
•
Changes in vision
•
Vomiting
•
Yellowing of the skin, eyes, or nail beds
Call your healthcare provider right away if you get any of these
warning signs, or any other unusual symptoms that concern you.
Less serious, but common, side effects include:
•
Headache
•
Breast pain
•
Irregular vaginal bleeding or spotting
•
Stomach/abdominal cramps, bloating
•
Nausea and vomiting
•
Hair loss
•
Fluid retention
•
Vaginal yeast infection
•
Reactions from inserting PREMARIN Vaginal Cream, such
as vaginal burning, irritation, and itching
These are not all the possible side effects of PREMARIN Vaginal
Cream. For more information, ask your healthcare provider or
pharmacist.
What can I do to lower my chances of getting a serious side
effect with PREMARIN Vaginal Cream?
•
Talk with your healthcare provider regularly about whether
you should continue using PREMARIN Vaginal Cream.
•
If you have a uterus, talk with your healthcare provider about
whether the addition of a progestin is right for you. The
addition of a progestin is generally recommended for a
woman with a uterus to reduce the chance of getting cancer
of the uterus. See your healthcare provider right away if you
get vaginal bleeding while using PREMARIN Vaginal
Cream.
•
Have a pelvic exam, breast exam and mammogram (breast
X-ray) every year unless your healthcare provider tells you
something else. If members of your family have had breast
cancer or if you have ever had breast lumps or an abnormal
mammogram, you may need to have breast exams more
often.
•
If you have high blood pressure, high cholesterol (fat in the
blood), diabetes, are overweight, or if you use tobacco, you
may have higher chances for getting heart disease. Ask your
healthcare provider for ways to lower your chances for
getting heart disease.
General information about the safe and effective use of
PREMARIN Vaginal Cream
Medicines are sometimes prescribed for conditions that are not
mentioned in patient information leaflets. Do not use PREMARIN
Vaginal Cream for conditions for which it was not prescribed. Do
not give PREMARIN Vaginal Cream to other people, even if they
have the same symptoms you have. It may harm them. Keep
PREMARIN Vaginal Cream out of the reach of children.
Latex or rubber condoms, diaphragms and cervical caps may be
weakened and fail when they come into contact with PREMARIN
Vaginal Cream.
This leaflet provides a summary of the most important information
about PREMARIN Vaginal Cream. If you would like more
information, talk with your healthcare provider or pharmacist. You
can ask for information about PREMARIN Vaginal Cream that is
written for health professionals. You can get more information by
calling the toll free number 1-800-934-5556.
What are the ingredients in PREMARIN Vaginal Cream?
PREMARIN Vaginal Cream contains a mixture of conjugated
estrogens, which are a mixture of sodium estrone sulfate and
sodium equilin sulfate and other components, including sodium
sulfate conjugates: 17 α-dihydroequilin, 17 α-estradiol, and
17 β-dihydroequilin. PREMARIN Vaginal Cream also contains
cetyl esters wax, cetyl alcohol, white wax, glyceryl monostearate,
propylene glycol monostearate, methyl stearate, benzyl alcohol,
sodium lauryl sulfate, glycerin, and mineral oil.
PREMARIN (conjugated estrogens) Vaginal Cream—Each gram
contains 0.625 mg conjugated estrogens, USP.
Combination package: Each contains a net wt. 1.5 oz (42.5 g) tube
with one plastic applicator calibrated in 0.5 g increments to a
maximum of 2 g (NDC 0046-0872-93).
Store at 20° to 25°C (68° to 77°F); excursions permitted to 15°
to 30°C (59° to 86°F) [see USP Controlled Room
Temperature].
This product's label may have
been updated. For current
package insert and further
product information, please
visit www.wyeth.com or call
our medical communications
department toll-free at
1-800-934-5556. ComputerTelephone
Wyeth®
Wyeth Pharmaceuticals Inc.
Philadelphia, PA 19101
(Update W10413C012)
(Update ET01)
Rev Date: November 2008
17
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:47:02.574360
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/020216s060lbl.pdf', 'application_number': 20216, 'submission_type': 'SUPPL ', 'submission_number': 60}
|
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&;
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
PREMARIN VAGINAL CREAM safely and effectively. See full
prescribing information for PREMARIN VAGINAL CREAM.
PREMARIN (conjugated estrogens) Vaginal Cream.
Initial U.S. Approval: 1946
WARNING: ENDOMETRIAL CANCER, CARDIOVASCULAR
DISORDERS, BREAST CANCER and PROBABLE DEMENTIA
See full prescribing information for complete boxed warning.
Estrogen-Alone Therapy
There is an increased risk of endometrial cancer in a woman
with a uterus who uses unopposed estrogens (5.3)
Estrogen-alone therapy should not be used for the prevention
of cardiovascular disease or dementia (5.2, 5.4)
The Women’s Health Initiative (WHI) estrogen-alone substudy
reported increased risks of stroke and deep vein thrombosis
(DVT) (5.2)
The WHI Memory Study (WHIMS) estrogen-alone ancillary
study of WHI reported an increased risk of probable dementia
in postmenopausal women 65 years of age and older (5.4)
Estrogen Plus Progestin Therapy
Estrogen plus progestin therapy should not be used for the
prevention of cardiovascular disease or dementia (5.2, 5.4)
The WHI estrogen plus progestin substudy reported increased
risks of stroke, DVT, pulmonary embolism (PE), and
myocardial infarction (MI) (5.2)
The WHI estrogen plus progestin substudy reported increased
risks of invasive breast cancer (5.3)
The WHIMS estrogen plus progestin ancillary study of WHI
reported an increased risk of probable dementia in
postmenopausal women 65 years of age and older (5.4)
———————— RECENT MAJOR CHANGES ————————
Contraindications (4)
02/2012
Warnings and Precautions
02/2012
Anaphylactic Reaction and Angioedema (5.16)
Hereditary Angioedema (5.17)
02/2012
———————— INDICATIONS AND USAGE————————
PREMARIN (conjugated estrogens) Vaginal Cream is a mixture of
estrogens indicated for:
Treatment of Atrophic Vaginitis and Kraurosis Vulvae (1.1)
Treatment of Moderate to Severe Dyspareunia, a Symptom of
Vulvar and Vaginal Atrophy, due to Menopause (1.2)
——————— DOSAGE AND ADMINISTRATION——————
Cyclic administration of 0.5 to 2 g intravaginally [daily for 21 days
then off for 7 days] for Treatment of Atrophic Vaginitis and
Kraurosis Vulvae (2.1)
Cyclic administration of 0.5 g intravaginally [daily for 21 days
then off for 7 days] for Treatment of Moderate to Severe
Dyspareunia, a Symptom of Vulvar and Vaginal Atrophy, due to
Menopause (2.2)
Twice-weekly administration of 0.5 g intravaginally [for example,
Monday and Thursday] for Treatment of Moderate to Severe
Dyspareunia, a Symptom of Vulvar and Vaginal Atrophy, due to
Menopause (2.2)
—————— DOSAGE FORMS AND STRENGTHS——————
Each gram contains 0.625 mg conjugated estrogens, USP (3)
Combination package: Each contains a net wt. 1.5 oz (42.5 g) tube
with one plastic applicator calibrated in 0.5 g increments to a
maximum of 2 g (3)
————————— CONTRAINDICATIONS————————
Undiagnosed abnormal genital bleeding (4)
Known, suspected, or history of breast cancer (4, 5.3)
Known or suspected estrogen-dependent neoplasia (4, 5.3)
Active DVT, PE, or a history of these conditions (4, 5.2)
Active arterial thromboembolic disease (for example, stroke and
MI), or a history of these conditions (4, 5.2)
Known anaphylactic reaction or angioedema to PREMARIN
Vaginal Cream (5.16, 5.17)
Known liver dysfunction or disease (4, 5.10)
Known protein C, protein S, or antithrombin deficiency, or other
known thrombophilic disorders (4)
Known or suspected pregnancy (4, 8.1)
——————— WARNINGS AND PRECAUTIONS——————
Estrogens increase the risk of gallbladder disease (5.5)
Discontinue estrogen if severe hypercalcemia, loss of vision,
severe hypertriglyceridemia or cholestatic jaundice occurs (5.6,
5.7, 5.10, 5.11)
Monitor thyroid function in women on thyroid replacement therapy
(5.12, 5.21)
————————— ADVERSE REACTIONS—————————
In a prospective, randomized, placebo-controlled, double-blind study, the
most common adverse reactions ≥ 2 percent are headache, pelvic pain,
vasodilation, breast pain, leucorrhea, metrorrhagia, vaginitis, vulvovaginal
disorder. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc.
at 1-800-438-1985 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch
————————— DRUG INTERACTIONS—————————
Inducers and/or inhibitors of CYP3A4 may affect estrogen drug
metabolism. (7.1)
——————— USE IN SPECIFIC POPULATIONS——————
Nursing Mothers: Estrogen administration to nursing women has
been shown to decrease the quantity and quality of breast milk
(8.3)
Geriatric Use: An increased risk of probable dementia in women
over 65 years of age was reported in the Women’s Health Initiative
Memory ancillary studies of the Women’s Health Initiative (5.4,
8.5)
See 17 for PATIENT COUNSELING INFORMATION and
FDA-approved patient labeling
Revised: 02/2012
1
Reference ID: 3087017
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
FULL PRESCRIBING INFORMATION: CONTENTS *
WARNING: ENDOMETRIAL CANCER, CARDIOVASCULAR
DISORDERS, BREAST CANCER and PROBABLE DEMENTIA
1 INDICATIONS AND USAGE
1.1 Treatment of Atrophic Vaginitis and Kraurosis Vulvae
1.2 Treatment of Moderate to Severe Dyspareunia, a Symptom of Vulvar
and Vaginal Atrophy, due to Menopause
2 DOSAGE AND ADMINISTRATION
2.1 Treatment of Atrophic Vaginitis and Kraurosis Vulvae
2.2 Treatment of Moderate to Severe Dyspareunia, a Symptom of Vulvar
and Vaginal Atrophy, due to Menopause
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Risks from Systemic Abso ption
r
e
5.2 Cardiovascular Disord rs
5.3 Malignant Neoplasms
5.4 Probable Dementia
5.5 Gallbladder Disease
5.6 Hypercalcemia
5.7 Visual Abnormalities
5.8 Addition of a Progestin When a Woman Has Not Had a Hysterectomy
5.9 Elevated Blood Pressure
5.10 Hypertriglyceridemia
5.11 Hepatic Impairm nt and/or Past History of Cholestatic Jaundice
e
5.12 Hypothyroidism
5.13 Fluid Retention
5.14 Hypocalcemia
5.15 Exacerbation of Endometriosis
5.16 Anaphylactic Reaction and Angioedema
5.17 Hereditary Angioedema
5.18 Exacerbation of Other Conditions
5.19 Effects on Barrier Contraception
5.20 Laboratory Tests
5.21 Drug-Laboratory Test I teractions
n
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
6.2 Postmarketing Experience
7 DRUG INTERACTIONS
* Sections or subsections omitted from the full prescribing information are not listed
7.1 Metabolic Interactions
8 USE IN SPEC FIC POPULATIONS
I
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Renal Impairment
8.7 Hepatic Impairment
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
14.1 Effects on Vulvar and Vaginal Atro hy
p
14.2 Women’s Health Initiative Studies
14.3 Women’s Hea th Initiative Memory Study
l
15 REFERENCES
16 HOW SUPPLIED/STORAGE AND HANDLING
16.1 How Supplied
16.2 Storage and Handling
17 PATIENT COUNSELING INFORMATION
17.1 Vaginal Bleeding
17.2 Possible Serious Adverse Reactions with Estrogen-Alone Therapy
17.3 Possible Less Serious but Common Adverse Reactions with
Estrogen-Alone Therapy
17.4 Instructions for Use of Applicator
FDA-Approved Patient Labeling
2
Reference ID: 3087017
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
FULL PRESCRIBING INFORMATION
WARNING: ENDOMETRIAL CANCER, CARDIOVASCULAR DISORDERS, BREAST
CANCER and PROBABLE DEMENTIA
Estrogen-Alone Therapy
Endometrial Cancer
There is an increased risk of endometrial cancer in a woman with a uterus who uses
unopposed estrogens. Adding a progestin to estrogen therapy has been shown to reduce the
risk of endometrial hyperplasia, which may be a precursor to endometrial cancer.
Adequate diagnostic measures, including directed or random endometrial sampling when
indicated, should be undertaken to rule out malignancy in postmenopausal women with
undiagnosed persistent or recurring abnormal genital bleeding [see Warnings and
Precautions (5.3)].
Cardiovascular Disorders and Probable Dementia
Estrogen-alone therapy should not be used for the prevention of cardiovascular disease or
dementia [see Warnings and Precautions (5.2, 5.4), and Clinical Studies (14.2, 14.3)].
The Women’s Health Initiative (WHI) estrogen-alone substudy reported increased risks of
stroke and deep vein thrombosis (DVT) in postmenopausal women (50 to 79 years of age)
during 7.1 years of treatment with daily oral conjugated estrogens (CE) [0.625 mg]-alone,
relative to placebo [see Warnings and Precautions (5.2), and Clinical Studies (14.2)].
The WHI Memory Study (WHIMS) estrogen-alone ancillary study of WHI reported an
increased risk of developing probable dementia in postmenopausal women 65 years of age
or older during 5.2 years of treatment with daily CE (0.625 mg)-alone, relative to placebo.
It is unknown whether this finding applies to younger postmenopausal women [see
Warnings and Precautions (5.4), Use in Specific Populations (8.5), and Clinical Studies
(14.3)].
In the absence of comparable data, these risks should be assumed to be similar for other
doses of CE and other dosage forms of estrogens.
Estrogens with or without progestins should be prescribed at the lowest effective doses and
for the shortest duration consistent with treatment goals and risks for the individual
woman.
Estrogen Plus Progestin Therapy
Cardiovascular Disorders and Probable Dementia
Estrogen plus progestin therapy should not be used for the prevention of cardiovascular
disease or dementia [see Warnings and Precautions (5.2, 5.4), and Clinical Studies (14.2,
14.3)].
3
Reference ID: 3087017
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
The WHI estrogen plus progestin substudy reported increased risks of DVT, pulmonary
embolism (PE), stroke and myocardial infarction (MI) in postmenopausal women (50 to 79
years of age) during 5.6 years of treatment with daily oral CE (0.625 mg) combined with
medroxyprogesterone acetate (MPA) [2.5 mg], relative to placebo [see Warnings and
Precautions (5.2), and Clinical Studies (14.2)].
The WHIMS estrogen plus progestin ancillary study of the WHI reported an increased risk
of developing probable dementia in postmenopausal women 65 years of age or older during
4 years of treatment with daily CE (0.625 mg) combined with MPA (2.5 mg), relative to
placebo. It is unknown whether this finding applies to younger postmenopausal women [see
Warnings and Precautions (5.4), Use in Specific Populations (8.5), and Clinical Studies
(14.3)].
Breast Cancer
The WHI estrogen plus progestin substudy also demonstrated an increased risk of invasive
breast cancer [see Warnings and Precautions (5.3), and Clinical Studies (14.2)].
In the absence of comparable data, these risks should be assumed to be similar for other
doses of CE and MPA, and other combinations and dosage forms of estrogens and
progestins.
Estrogens with or without progestins should be prescribed at the lowest effective doses and
for the shortest duration consistent with treatment goals and risks for the individual
woman.
1 INDICATIONS AND USAGE
1.1 Treatment of Atrophic Vaginitis and Kraurosis Vulvae
1.2 Treatment of Moderate to Severe Dyspareunia, a Symptom of Vulvar and Vaginal
Atrophy, due to Menopause
2 DOSAGE AND ADMINISTRATION
Generally, when estrogen is prescribed for a postmenopausal woman with a uterus, a progestin
should also be considered to reduce the risk of endometrial cancer.
A woman without a uterus does not need a progestin. In some cases, however, hysterectomized
women with a history of endometriosis may need a progestin [see Warnings and Precautions
(5.3, 5.15)].
Use of estrogen-alone, or in combination with a progestin, should be with the lowest effective
dose and for the shortest duration consistent with treatment goals and risks for the individual
woman. Postmenopausal women should be re-evaluated periodically as clinically appropriate to
determine if treatment is still necessary.
4
Reference ID: 3087017
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2.1 Treatment of Atrophic Vaginitis and Kraurosis Vulvae
PREMARIN Vaginal Cream is administered intravaginally in a cyclic regimen (daily for 21 days
and then off for 7 days). Generally, women should be started at the 0.5 g dosage strength.
Dosage adjustments (0.5 to 2 g) may be made based on individual response [see Dosage Forms
and Strengths (3)].
2.2 Treatment of Moderate to Severe Dyspareunia, a Symptom of Vulvar and Vaginal
Atrophy, due to Menopause
PREMARIN Vaginal Cream (0.5 g) is administered intravaginally in a twice-weekly (for
example, Monday and Thursday) continuous regimen or in a cyclic regimen of 21 days of
therapy followed by 7 days off of therapy [see Dosage Forms and Strengths (3)].
3 DOSAGE FORMS AND STRENGTHS
Each gram contains 0.625 mg conjugated estrogens, USP.
Combination package: Each contains a net wt. 1.5 oz (42.5 g) tube with one plastic applicator
calibrated in 0.5 g increments to a maximum of 2 g.
4 CONTRAINDICATIONS
PREMARIN Vaginal Cream therapy should not be used in women with any of the following
conditions:
Undiagnosed abnormal genital bleeding
Known, suspected, or history of breast cancer
Known or suspected estrogen-dependent neoplasia
Active DVT, PE, or a history of these conditions
Active arterial thromboembolic disease (for example, stroke and MI), or a history of
these conditions
Known anaphylactic reaction or angioedema to PREMARIN Vaginal Cream
Known liver dysfunction or disease
Known protein C, protein S or antithrombin deficiency, or other known
thrombophilic disorders
Known or suspected pregnancy
5
Reference ID: 3087017
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5 WARNINGS AND PRECAUTIONS
5.1 Risks from Systemic Absorption
Systemic absorption occurs with the use of PREMARIN Vaginal Cream. The warnings,
precautions, and adverse reactions associated with oral PREMARIN treatment should be taken
into account.
5.2 Cardiovascular Disorders
An increased risk of stroke and DVT has been reported with estrogen-alone therapy. An
increased risk of PE, DVT, stroke and MI has been reported with estrogen plus progestin
therapy. Should any of these occur or be suspected, estrogen with or without progestin therapy
should be discontinued immediately.
Risk factors for arterial vascular disease (for example, hypertension, diabetes mellitus, tobacco
use, hypercholesterolemia, and obesity) and/or venous thromboembolism (VTE) (for example,
personal history or family history of VTE, obesity, and systemic lupus erythematosus) should be
managed appropriately.
Stroke
In the WHI estrogen-alone substudy, a statistically significant increased risk of stroke was
reported in women 50 to 79 years of age receiving daily CE (0.625 mg)-alone compared to
women in the same age group receiving placebo (45 versus 33 per 10,000 women-years). The
increase in risk was demonstrated in year 1 and persisted [see Clinical Studies (14.2)]. Should a
stroke occur or be suspected, estrogen-alone therapy should be discontinued immediately.
Subgroup analyses of women 50 to 59 years of age suggest no increased risk of stroke for those
women receiving CE (0.625 mg)-alone versus those receiving placebo (18 versus 21 per 10,000
women-years).1
In the WHI estrogen plus progestin substudy, a statistically significant increased risk of stroke
was reported in women 50 to 79 years of age receiving daily CE (0.625 mg) plus MPA (2.5 mg)
compared to women in the same age group receiving placebo (33 versus 25 per 10,000 women-
years) [see Clinical Studies (14.2)]. The increase in risk was demonstrated after the first year and
persisted.1 Should a stroke occur or be suspected, estrogen plus progestin therapy should be
discontinued immediately.
Coronary Heart Disease
In the WHI estrogen-alone substudy, no overall effect on coronary heart disease (CHD) events
(defined as nonfatal MI, silent MI, or CHD death) was reported in women receiving estrogen-
alone compared to placebo2 [see Clinical Studies (14.2)].
Subgroup analyses of women 50 to 59 years of age suggest a statistically non-significant
reduction in CHD events (CE [0.625 mg]-alone compared to placebo) in women with less than
10 years since menopause (8 versus 16 per 10,000 women-years).1
Reference ID: 3087017
6
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
In the WHI estrogen plus progestin substudy, there was a statistically non-significant increased
risk of CHD events reported in women receiving daily CE (0.625 mg) plus MPA (2.5 mg)
compared to women receiving placebo (41 versus 34 per 10,000 women-years).1 An increase in
relative risk was demonstrated in year 1, and a trend toward decreasing relative risk was reported
in years 2 through 5 [see Clinical Studies (14.2)].
In postmenopausal women with documented heart disease (n = 2,763), average 66.7 years of age,
in a controlled clinical trial of secondary prevention of cardiovascular disease (Heart and
Estrogen/Progestin Replacement Study [HERS]), treatment with daily CE (0.625 mg) plus MPA
(2.5 mg) demonstrated no cardiovascular benefit. During an average follow-up of 4.1 years,
treatment with CE plus MPA did not reduce the overall rate of CHD events in postmenopausal
women with established coronary heart disease. There were more CHD events in the CE plus
MPA-treated group than in the placebo group in year 1, but not during subsequent years. Two
thousand, three hundred and twenty-one (2,321) women from the original HERS trial agreed to
participate in an open label extension of HERS, HERS II. Average follow-up in HERS II was an
additional 2.7 years, for a total of 6.8 years overall. Rates of CHD events were comparable
among women in the CE plus MPA group and the placebo group in HERS, HERS II, and overall.
Venous Thromboembolism
In the WHI estrogen-alone substudy, the risk of VTE (DVT and PE) was increased for women
receiving daily CE (0.625 mg)-alone compared to placebo (30 versus 22 per 10,000 women-
years), although only the increased risk of DVT reached statistical significance (23 versus 15 per
10,000 women-years). The increase in VTE risk was demonstrated during the first 2 years3 [see
Clinical Studies (14.2)]. Should a VTE occur or be suspected, estrogen-alone therapy should be
discontinued immediately.
In the WHI estrogen plus progestin substudy, a statistically significant 2-fold greater rate of VTE
was reported in women receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women
receiving placebo (35 versus 17 per 10,000 women-years). Statistically significant increases in
risk for both DVT (26 versus 13 per 10,000 women-years) and PE (18 versus 8 per 10,000
women-years) were also demonstrated. The increase in VTE risk was observed during the first
year and persisted4 [see Clinical Studies (14.2)]. Should a VTE occur or be suspected, estrogen
plus progestin therapy should be discontinued immediately.
If feasible, estrogens should be discontinued at least 4 to 6 weeks before surgery of the type
associated with an increased risk of thromboembolism, or during periods of prolonged
immobilization.
5.3 Malignant Neoplasms
Endometrial Cancer
An increased risk of endometrial cancer has been reported with the use of unopposed estrogen
therapy in a woman with a uterus. The reported endometrial cancer risk among unopposed
estrogen users is about 2 to 12 times greater than in non-users, and appears dependent on
duration of treatment and on estrogen dose. Most studies show no significant increased risk
associated with use of estrogens for less than 1 year. The greatest risk appears to be associated
7
Reference ID: 3087017
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
with prolonged use, with increased risks of 15- to 24-fold for 5 to 10 years or more, and this risk
has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued.
Clinical surveillance of all women using estrogen-alone or estrogen plus progestin therapy is
important. Adequate diagnostic measures, including directed or random endometrial sampling
when indicated, should be undertaken to rule out malignancy in postmenopausal women with
undiagnosed persistent or recurring abnormal genital bleeding.
There is no evidence that the use of natural estrogens results in a different endometrial risk
profile than synthetic estrogens of equivalent estrogen dose. Adding a progestin to
postmenopausal estrogen therapy has been shown to reduce the risk of endometrial hyperplasia,
which may be a precursor to endometrial cancer.
In a 52-week clinical trial using PREMARIN Vaginal Cream alone (0.5 g inserted twice weekly
or daily for 21 days, then off for 7 days), there was no evidence of endometrial hyperplasia or
endometrial carcinoma.
Breast Cancer
The most important randomized clinical trial providing information about breast cancer in
estrogen-alone users is the WHI substudy of daily CE (0.625 mg)-alone. In the WHI estrogen-
alone substudy, after an average follow-up of 7.1 years, daily CE-alone was not associated with
an increased risk of invasive breast cancer [relative risk (RR) 0.80]5 [see Clinical Studies
(14.2)].
The most important randomized clinical trial providing information about breast cancer in
estrogen plus progestin users is the WHI substudy of daily CE (0.625 mg) plus MPA (2.5 mg).
After a mean follow-up of 5.6 years, the estrogen plus progestin substudy reported an increased
risk of invasive breast cancer in women who took daily CE plus MPA. In this substudy, prior use
of estrogen-alone or estrogen plus progestin therapy was reported by 26 percent of the women.
The relative risk of invasive breast cancer was 1.24, and the absolute risk was 41 versus 33 cases
per 10,000 women-years, for CE plus MPA compared with placebo. Among women who
reported prior use of hormone therapy, the relative risk of invasive breast cancer was 1.86, and
the absolute risk was 46 versus 25 cases per 10,000 women-years, for CE plus MPA compared
with placebo. Among women who reported no prior use of hormone therapy, the relative risk of
invasive breast cancer was 1.09, and the absolute risk was 40 versus 36 cases per 10,000 women-
years for CE plus MPA compared with placebo. In the same substudy, invasive breast cancers
were larger, were more likely to be node positive, and were diagnosed at a more advanced stage
in the CE (0.625 mg) plus MPA (2.5 mg) group compared with the placebo group. Metastatic
disease was rare, with no apparent difference between the two groups. Other prognostic factors,
such as histologic subtype, grade and hormone receptor status did not differ between the groups6
[see Clinical Studies (14.2)].
Consistent with the WHI clinical trial, observational studies have also reported an increased risk
of breast cancer for estrogen plus progestin therapy, and a smaller increased risk for estrogen-
alone therapy, after several years of use. The risk increased with duration of use, and appeared to
return to baseline over about 5 years after stopping treatment (only the observational studies have
8
Reference ID: 3087017
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For current labeling information, please visit https://www.fda.gov/drugsatfda
substantial data on risk after stopping). Observational studies also suggest that the risk of breast
cancer was greater, and became apparent earlier, with estrogen plus progestin therapy as
compared to estrogen-alone therapy. However, these studies have not generally found significant
variation in the risk of breast cancer among different estrogen plus progestin combinations,
doses, or routes of administration.
The use of estrogen-alone and estrogen plus progestin therapy has been reported to result in an
increase in abnormal mammograms, requiring further evaluation.
All women should receive yearly breast examinations by a healthcare provider and perform
monthly breast self-examinations. In addition, mammography examinations should be scheduled
based on patient age, risk factors, and prior mammogram results.
Ovarian Cancer
The WHI estrogen plus progestin substudy reported a statistically non-significant increased risk
of ovarian cancer. After an average follow-up of 5.6 years, the relative risk for ovarian cancer for
CE plus MPA versus placebo was 1.58 (95 percent CI, 0.77-3.24). The absolute risk for CE plus
MPA versus placebo was 4 versus 3 cases per 10,000 women-years.7 In some epidemiologic
studies, the use of estrogen plus progestin and estrogen-only products, in particular for 5 or more
years, has been associated with an increased risk of ovarian cancer. However, the duration of
exposure associated with increased risk is not consistent across all epidemiologic studies, and
some report no association.
5.4 Probable Dementia
In the WHIMS estrogen-alone ancillary study of WHI, a population of 2,947 hysterectomized
women 65 to 79 years of age was randomized to daily CE (0.625 mg)-alone or placebo.
After an average follow-up of 5.2 years, 28 women in the estrogen-alone group and 19 women in
the placebo group were diagnosed with probable dementia. The relative risk of probable
dementia for CE-alone versus placebo was 1.49 (95 percent CI, 0.83-2.66). The absolute risk of
probable dementia for CE-alone versus placebo was 37 versus 25 cases per 10,000 women-years8
[see Use in Specific Populations (8.5), and Clinical Studies (14.3)].
In the WHIMS estrogen plus progestin ancillary study of WHI, a population of 4,532
postmenopausal women 65 to 79 years of age was randomized to daily CE (0.625 mg) plus MPA
(2.5 mg) or placebo.
After an average follow-up of 4 years, 40 women in the CE plus MPA group and 21 women in
the placebo group were diagnosed with probable dementia. The relative risk of probable
dementia for CE plus MPA versus placebo was 2.05 (95 percent CI, 1.21-3.48). The absolute risk
of probable dementia for CE plus MPA versus placebo was 45 versus 22 cases per 10,000
women-years8 [see Use in Specific Populations (8.5), and Clinical Studies (14.3)].
When data from the two populations in the WHIMS estrogen-alone and estrogen plus progestin
ancillary studies were pooled as planned in the WHIMS protocol, the reported overall relative
risk for probable dementia was 1.76 (95 percent CI, 1.19-2.60). Since both ancillary studies were
9
Reference ID: 3087017
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For current labeling information, please visit https://www.fda.gov/drugsatfda
conducted in women 65 to 79 years of age, it is unknown whether these findings apply to
younger postmenopausal women8 [see Use in Specific Populations (8.5), and Clinical Studies
(14.3)].
5.5 Gallbladder Disease
A 2- to 4-fold increase in the risk of gallbladder disease requiring surgery in postmenopausal
women receiving estrogens has been reported.
5.6 Hypercalcemia
Estrogen administration may lead to severe hypercalcemia in women with breast cancer and
bone metastases. If hypercalcemia occurs, use of the drug should be stopped and appropriate
measures taken to reduce the serum calcium level.
5.7 Visual Abnormalities
Retinal vascular thrombosis has been reported in patients receiving estrogens. Discontinue
medication pending examination if there is sudden partial or complete loss of vision, or a sudden
onset of proptosis, diplopia, or migraine. If examination reveals papilledema or retinal vascular
lesions, estrogens should be permanently discontinued.
5.8 Addition of a Progestin When a Woman Has Not Had a Hysterectomy
Studies of the addition of a progestin for 10 or more days of a cycle of estrogen administration,
or daily with estrogen in a continuous regimen, have reported a lowered incidence of endometrial
hyperplasia than would be induced by estrogen treatment alone. Endometrial hyperplasia may be
a precursor to endometrial cancer.
There are, however, possible risks that may be associated with the use of progestins with
estrogens compared to estrogen-alone regimens. These include an increased risk of breast cancer.
5.9 Elevated Blood Pressure
In a small number of case reports, substantial increases in blood pressure have been attributed to
idiosyncratic reactions to estrogens. In a large, randomized, placebo-controlled clinical trial, a
generalized effect of estrogen therapy on blood pressure was not seen.
5.10 Hypertriglyceridemia
In women with pre-existing hypertriglyceridemia, estrogen therapy may be associated with
elevations of plasma triglycerides leading to pancreatitis. Consider discontinuation of treatment
if pancreatitis occurs.
10
Reference ID: 3087017
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5.11 Hepatic Impairment and/or Past History of Cholestatic Jaundice
Estrogens may be poorly metabolized in women with impaired liver function. For women with a
history of cholestatic jaundice associated with past estrogen use or with pregnancy, caution
should be exercised, and in the case of recurrence, medication should be discontinued.
5.12 Hypothyroidism
Estrogen administration leads to increased thyroid-binding globulin (TBG) levels. Women with
normal thyroid function can compensate for the increased TBG by making more thyroid
hormone, thus maintaining free T4 and T3 serum concentrations in the normal range. Women
dependent on thyroid hormone replacement therapy who are also receiving estrogens may
require increased doses of their thyroid replacement therapy. These women should have their
thyroid function monitored in order to maintain their free thyroid hormone levels in an
acceptable range.
5.13 Fluid Retention
Estrogens may cause some degree of fluid retention. Women with conditions that might be
influenced by this factor, such as cardiac or renal dysfunction, warrant careful observation when
estrogen-alone is prescribed.
5.14 Hypocalcemia
Estrogen therapy should be used with caution in women with hypoparathyroidism as estrogen-
induced hypocalcemia may occur.
5.15 Exacerbation of Endometriosis
A few cases of malignant transformation of residual endometrial implants have been reported in
women treated post-hysterectomy with estrogen-alone therapy. For women known to have
residual endometriosis post-hysterectomy, the addition of progestin should be considered.
5.16 Anaphylactic Reaction and Angioedema
Cases of anaphylaxis, which develop within minutes to hours after taking orally-administered
PREMARIN and require emergency management, have been reported in the postmarketing
setting. Skin (hives, pruritus, swollen lips-tongue-face) and either respiratory tract (respiratory
compromise) or gastrointestinal tract (abdominal pain, vomiting) involvement has been noted.
Angioedema involving the tongue, larynx, face, and feet requiring medical intervention has
occurred postmarketing in patients taking orally-administered PREMARIN. If angioedema
involves the tongue, glottis, or larynx, airway obstruction may occur. Patients who develop an
anaphylactic reaction with or without angioedema after treatment with oral PREMARIN should
not receive oral PREMARIN again.
11
Reference ID: 3087017
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5.17 Hereditary Angioedema
Exogenous estrogens may exacerbate symptoms of angioedema in women with hereditary
angioedema.
5.18 Exacerbation of Other Conditions
Estrogen therapy may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine,
porphyria, systemic lupus erythematosus, and hepatic hemangiomas and should be used with
caution in women with these conditions.
5.19 Effects on Barrier Contraception
PREMARIN Vaginal Cream exposure has been reported to weaken latex condoms. The potential
for PREMARIN Vaginal Cream to weaken and contribute to the failure of condoms, diaphragms,
or cervical caps made of latex or rubber should be considered.
5.20 Laboratory Tests
Serum follicle stimulating hormone (FSH) and estradiol levels have not been shown to be useful
in the management of moderate to severe symptoms of vulvar and vaginal atrophy.
5.21 Drug-Laboratory Test Interactions
Accelerated prothrombin time, partial thromboplastin time, and platelet aggregation time;
increased platelet count; increased factors II, VII antigen, VIII antigen, VIII coagulant activity,
IX, X, XII, VII-X complex, II-VII-X complex, and beta-thromboglobulin; decreased levels of
antifactor Xa and antithrombin III, decreased antithrombin III activity; increased levels of
fibrinogen and fibrinogen activity; increased plasminogen antigen and activity.
Increased thyroid-binding globulin (TBG) leading to increased circulating total thyroid hormone,
as measured by protein-bound iodine (PBI), T4 levels (by column or by radioimmunoassay) or T3
levels by radioimmunoassay. T3 resin uptake is decreased, reflecting the elevated TBG. Free T4
and free T3 concentrations are unaltered. Women on thyroid replacement therapy may require
higher doses of thyroid hormone.
Other binding proteins may be elevated in serum, for example, corticosteroid binding globulin
(CBG), sex hormone-binding globulin (SHBG), leading to increased total circulating
corticosteroids and sex steroids, respectively. Free hormone concentrations, such as testosterone
and estradiol, may be decreased. Other plasma proteins may be increased (angiotensinogen/renin
substrate, alpha-1-antitrypsin, ceruloplasmin).
Increased plasma high-density lipoprotein (HDL) and HDL2 cholesterol subfraction
concentrations, reduced low-density lipoprotein (LDL) cholesterol concentrations, increased
triglyceride levels.
Impaired glucose tolerance.
12
Reference ID: 3087017
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
6 ADVERSE REACTIONS
The following serious adverse reactions are discussed elsewhere in the labeling:
Cardiovascular Disorders [see Boxed Warning, Warnings and Precautions (5.2)]
Malignant Neoplasms [see Boxed Warning, Warnings and Precautions (5.3)]
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates
observed in the clinical trial of a drug cannot be directly compared to rates in the clinical trials of
another drug and may not reflect the rates observed in practice.
In a 12-week, randomized, double-blind, placebo-controlled trial of PREMARIN Vaginal Cream
(PVC), a total of 423 postmenopausal women received at least 1 dose of study medication and
were included in all safety analyses: 143 women in the PVC-21/7 treatment group (0.5 g PVC
daily for 21 days, then 7 days off), 72 women in the matching placebo treatment group; 140
women in the PVC-2x/wk treatment group (0.5 g PVC twice weekly), 68 women in the matching
placebo treatment group. A 40-week, open-label extension followed, in which a total of 394
women received treatment with PVC, including those subjects randomized at baseline to
placebo. In this study, the most common adverse reactions ≥ 1 percent in the double blind phase
are shown below (Table 1) [see Clinical Studies (14.1)].
13
Reference ID: 3087017
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For current labeling information, please visit https://www.fda.gov/drugsatfda
&
Table 1: Number (%) of Patients Reporting Treatment Emergent Adverse Reactions ≥ 1
Percent Only
Treatment
Body Systema/Adverse
Reaction
PVC 21/7
N=143
Placebo 21/7
N=72
PVC 2x/week
N=140
Placebo
2x/week
N=68
Number (%) of Patients with Adverse Reaction
Body As A Whole
Abdominal Pain
1 (0.7)
1 (1.4)
0
1 (1.5)
Headache
5 (3.5)
1 (1.4)
3 (2.1)
1 (1.5)
Moniliasis
2 (1.4)
1 (1.4)
1 (0.7)
0
Pain
2 (1.4)
0
1 (0.7)
0
Pelvic Pain
4 (2.8)
2 (2.8)
4 (2.9)
0
Cardiovascular System
Migraine
0
0
0
1 (1.5)
Vasodilation
3 (2.1)
2 (2.8)
2 (1.4)
0
Musculoskeletal System
Muscle Cramp
2 (1.4)
0
0
0
Nervous System
Dizziness
1 (0.7)
0
0
1 (1.5)
Skin and Appendages
Acne
0
0
2 (1.4)
0
Erythema
0
1 (1.4)
0
0
Pruritus
2 (1.4)
1 (1.4)
1 (0.7)
0
Urogenital System
Breast Enlargement
1 (0.7)
1 (1.4)
0
0
Breast Pain
7 (4.9)
0
3 (2.1)
0
Dysuria
2 (1.4)
0
0
0
Leukorrhea
3 (2.1)
1 (1.4)
4 (2.9)
5 (7.4)
Metrorrhagia
0
0
0
2 (2.9)
Urinary Frequency
0
1 (1.4)
0
0
Urinary Tract Infection
0
1 (1.4)
0
0
Urinary Urgency
1 (0.7)
1 (1.4)
0
0
Vaginal Hemorrhage
2 (1.4)
0
1 (0.7)
1 (1.5)
Vaginal Moniliasis
2 (1.4)
0
0
0
Vaginitis
2 (1.4)
1 (1.4)
3 (2.1)
3 (4.4)
Vulvovaginal Disorder
4 (2.8)
0
3 (2.1)
2 (2.9)
a Body system totals are not necessarily the sum of individual adverse events, since a patient may
report two or more different adverse reactions in the same body system.
14
Reference ID: 3087017
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
6.2 Postmarketing Experience
The following adverse reactions have been identified during post-approval use of PREMARIN
Vaginal Cream. Because these reactions are reported voluntarily from a population of uncertain
size, it is not always possible to reliably estimate their frequency or establish a causal
relationship to drug exposure.
Genitourinary System
Abnormal uterine bleeding or spotting, dysmenorrhea or pelvic pain, increase in size of uterine
leiomyomata, vaginitis (including vaginal candidiasis), change in cervical secretion, cystitis-like
syndrome, application site reactions of vulvovaginal discomfort, (including burning, irritation,
and genital pruritus), endometrial hyperplasia, endometrial cancer, precocious puberty,
leukorrhea.
Breasts
Tenderness, enlargement, pain, discharge, fibrocystic breast changes, breast cancer,
gynecomastia in males.
Cardiovascular
Deep venous thrombosis, pulmonary embolism, myocardial infarction, stroke, increase in blood
pressure.
Gastrointestinal
Nausea, vomiting, abdominal cramps, bloating, increased incidence of gallbladder disease.
Skin
Chloasma that may persist when drug is discontinued, loss of scalp hair, hirsutism, rash.
Eyes
Retinal vascular thrombosis, intolerance to contact lenses.
Central Nervous System
Headache, migraine, dizziness, mental depression, nervousness, mood disturbances, irritability,
dementia.
Miscellaneous
Increase or decrease in weight, glucose intolerance, edema, arthralgias, leg cramps, changes in
libido, urticaria, exacerbation of asthma, increased triglycerides, hypersensitivity.
Reference ID: 3087017
15
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Additional postmarketing adverse reactions have been reported in patients receiving other forms
of hormone therapy.
7 DRUG INTERACTIONS
No drug interaction studies have been conducted for PREMARIN Vaginal Cream.
7.1 Metabolic Interactions
In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome
P450 3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen drug
metabolism. Inducers of CYP3A4, such as St. John’s wort (Hypericum perforatum) preparations,
phenobarbital, carbamazepine, and rifampin, may reduce plasma concentrations of estrogens,
possibly resulting in a decrease in therapeutic effects and/or changes in the uterine bleeding
profile. Inhibitors of CYP3A4, such as erythromycin, clarithromycin, ketoconazole, itraconazole,
ritonavir and grapefruit juice, may increase plasma concentrations of estrogens and may result in
side effects.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
PREMARIN Vaginal Cream should not be used during pregnancy [see Contraindications (4)].
There appears to be little or no increased risk of birth defects in children born to women who
have used estrogens and progestins as an oral contraceptive inadvertently during early
pregnancy.
8.3 Nursing Mothers
PREMARIN Vaginal Cream should not be used during lactation. Estrogen administration to
nursing women has been shown to decrease the quantity and quality of the breast milk.
Detectable amounts of estrogens have been identified in the breast milk of women receiving
estrogen therapy. Caution should be exercised when PREMARIN Vaginal Cream is administered
to a nursing woman.
8.4 Pediatric Use
PREMARIN Vaginal Cream is not indicated in children. Clinical studies have not been
conducted in the pediatric population.
8.5 Geriatric Use
There have not been sufficient numbers of geriatric women involved in clinical studies utilizing
PREMARIN Vaginal Cream to determine whether those over 65 years of age differ from
younger subjects in their response to PREMARIN Vaginal Cream.
The Women’s Health Initiative Studies
16
Reference ID: 3087017
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
In the WHI estrogen-alone substudy (daily CE [0.625 mg]-alone versus placebo), there was a
higher relative risk of stroke in women greater than 65 years of age [see Clinical Studies (14.2)].
In the WHI estrogen plus progestin substudy (daily CE [0.625 mg] plus MPA [2.5 mg] versus
placebo), there was a higher relative risk of nonfatal stroke and invasive breast cancer in women
greater than 65 years of age [see Clinical Studies (14.2)].
The Women’s Health Initiative Memory Study
In the WHIMS ancillary studies of postmenopausal women 65 to 79 years of age, there was an
increased risk of developing probable dementia in women receiving estrogen-alone or estrogen
plus progestin when compared to placebo [see Warnings and Precautions (5.4), and Clinical
Studies (14.3)].
Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown
whether these findings apply to younger postmenopausal women8 [see Warnings and
Precautions (5.4), and Clinical Studies (14.3)].
8.6 Renal Impairment
The effect of renal impairment on the pharmacokinetics of PREMARIN Vaginal Cream has not
been studied.
8.7 Hepatic Impairment
The effect of hepatic impairment on the pharmacokinetics of PREMARIN Vaginal Cream has
not been studied.
10 OVERDOSAGE
Overdosage of estrogen may cause nausea, vomiting, breast tenderness, abdominal pain,
drowsiness and fatigue, and withdrawal bleeding may occur in women. Treatment of overdose
consists of discontinuation of PREMARIN therapy with institution of appropriate symptomatic
care.
11 DESCRIPTION
Each gram of PREMARIN (conjugated estrogens) Vaginal Cream contains 0.625 mg conjugated
estrogens, USP in a nonliquefying base containing cetyl esters wax, cetyl alcohol, white wax,
glyceryl monostearate, propylene glycol monostearate, methyl stearate, benzyl alcohol, sodium
lauryl sulfate, glycerin, and mineral oil. PREMARIN Vaginal Cream is applied intravaginally.
PREMARIN Vaginal Cream contains a mixture of conjugated estrogens obtained exclusively
from natural sources, occurring as the sodium salts of water-soluble estrogen sulfates blended to
represent the average composition of material derived from pregnant mares’ urine. It is a mixture
of sodium estrone sulfate and sodium equilin sulfate. It contains as concomitant components,
sodium sulfate conjugates, 17 α-dihydroequilin, 17 α-estradiol, and 17 β-dihydroequilin.
17
Reference ID: 3087017
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For current labeling information, please visit https://www.fda.gov/drugsatfda
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Endogenous estrogens are largely responsible for the development and maintenance of the
female reproductive system and secondary sexual characteristics. Although circulating estrogens
exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal
intracellular human estrogen and is substantially more potent than its metabolites, estrone and
estriol, at the receptor level.
The primary source of estrogen in normally cycling adult women is the ovarian follicle, which
secretes 70 to 500 mcg of estradiol daily, depending on the phase of the menstrual cycle. After
menopause, most endogenous estrogen is produced by conversion of androstenedione, which is
secreted by the adrenal cortex, to estrone in the peripheral tissues. Thus, estrone and the sulfate-
conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal
women.
Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, two
estrogen receptors have been identified. These vary in proportion from tissue to tissue.
Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone
(LH) and FSH, through a negative feedback mechanism. Estrogens act to reduce the elevated
levels of these gonadotropins seen in postmenopausal women.
12.2 Pharmacodynamics
Currently, there are no pharmacodynamic data known for PREMARIN Vaginal Cream.
12.3 Pharmacokinetics
Absorption
Conjugated estrogens are water soluble and are well-absorbed through the skin, mucous
membranes, and the gastrointestinal (GI) tract. The vaginal delivery of estrogens circumvents
first-pass metabolism.
A bioavailability study was conducted in 24 postmenopausal women with atrophic vaginitis. The
mean (SD) pharmacokinetic parameters for unconjugated estrone, unconjugated estradiol, total
estrone, total estradiol and total equilin following 7 once-daily doses of PREMARIN Vaginal
Cream 0.5 g is shown in Table 2.
18
Reference ID: 3087017
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
&;
Table 2: Mean ± SD Pharmacokinetic Parameters of PREMARIN Following Daily
Administration (7 Days) of PREMARIN Vaginal Cream 0.5 g in 24 Postmenopausal
Women
Pharmacokinetic Profiles of Unconjugated Estrogens
PREMARIN Vaginal Cream 0.5 g
PK Parameters
Arithmetic Mean ± SD
Cmax
(pg/mL)
Tmax
(hr)
AUCss
(pg•hr/mL)
Estrone
42.0 ± 13.9
7.4 ± 6.2
826 ± 295
Baseline-adjusted estrone
21.9 ± 13.1
7.4 ± 6.2
365 ± 255
Estradiol
12.8 ± 16.6
8.5 ± 6.2
231 ± 285
Baseline-adjusted estradiol
9.14 ± 14.7
8.5 ± 6.2
161 ± 252
Pharmacokinetic Profiles of Conjugated Estrogens
PREMARIN Vaginal Cream 0.5 g
PK Parameters
Arithmetic Mean ± SD
Cmax
(ng/mL)
Tmax
(hr)
AUCss
(ng•hr/mL)
Total estrone
0.60 ± 0.32
6.0 ± 4.0
9.75 ± 4.99
Baseline-adjusted total estrone
0.40 ± 0.28
6.0 ± 4.0
5.79 ± 3.7
Total estradiol
0.04 ± 0.04
7.7 ± 5.9
0.70 ± 0.42
Baseline-adjusted total estradiol
0.04 ± 0.04
7.7 ± 6.0
0.49 ± 0.38
Total equilin
0.12 ± 0.15
6.1 ± 4.7
3.09 ± 1.37
Distribution
The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are
widely distributed in the body and are generally found in higher concentration in the sex
hormone target organs. Estrogens circulate in the blood largely bound to SHBG and albumin.
Metabolism
Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating
estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations
take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be
converted to estriol, which is a major urinary metabolite. Estrogens also undergo enterohepatic
recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates
into the intestine, and hydrolysis in the intestine followed by reabsorption. In postmenopausal
women, a significant portion of the circulating estrogens exists as sulfate conjugates, especially
estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens.
Excretion
Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate
conjugates.
Use in Specific Populations
19
Reference ID: 3087017
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For current labeling information, please visit https://www.fda.gov/drugsatfda
No pharmacokinetic studies were conducted in specific populations, including patients with renal
or hepatic impairment.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term continuous administration of natural and synthetic estrogens in certain animal species
increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis, and liver.
14 CLINICAL STUDIES
14.1 Effects on Vulvar and Vaginal Atrophy
A 12-week, prospective, randomized, double-blind placebo-controlled study was conducted to
compare the safety and efficacy of 2 PREMARIN Vaginal Cream (PVC) regimens 0.5 g
(0.3 mg CE) administered twice weekly and 0.5 g (0.3 mg CE) administered sequentially for 21
days on drug followed by 7 days off drug to matching placebo regimens in the treatment of
moderate to severe symptoms of vulvar and vaginal atrophy due to menopause. The initial 12
week, double-blind, placebo-controlled phase was followed by an open-label phase to assess
endometrial safety through week 52. The study randomized 423 generally healthy
postmenopausal women between 44 to 77 years of age (mean 57.8 years), who at baseline had ≤
5 percent superficial cells on a vaginal smear, a vaginal pH ≥ 5.0, and who identified a most
bothersome moderate to severe symptom of vulvar and vaginal atrophy. The majority (92.2
percent) of the women were Caucasian (n = 390); 7.8 percent were Other (n = 33). All subjects
were assessed for improvement in the mean change from baseline to Week 12 for the co-primary
efficacy variables of: most bothersome symptom of vulvar and vaginal atrophy (defined as the
moderate to severe symptom that had been identified by the woman as most bothersome to her at
baseline); percentage of vaginal superficial cells and percentage of vaginal parabasal cells; and
vaginal pH.
In the 12-week, double-blind phase, a statistically significant mean change between baseline and
Week 12 in the symptom of dyspareunia was observed for both of the PREMARIN Vaginal
Cream regimens (0.5 g twice weekly and 0.5 g daily for 21 days, then 7 days off) compared to
matching placebo, see Table 3. Also demonstrated for each PREMARIN Vaginal Cream regimen
compared to placebo was a statistically significant increase in the percentage of superficial cells
at Week 12 (28 percent and 26 percent, respectively, compared to 3 percent and 1 percent for
matching placebo), a statistically significant decrease in parabasal cells (-61 percent and -58
percent, respectively, compared to -21 percent and -7 percent for matching placebo) and
statistically significant mean reduction between baseline and Week 12 in vaginal pH (-1.62 and
1.57, respectively, compared to -0.36 and -0.26 for matching placebo).
Endometrial safety was assessed by endometrial biopsy for all randomly assigned subjects at
week 52. For the 155 subjects (83 on the 21/7 regimen, 72 on the twice-weekly regimen)
completing the 52-week period with complete follow-up and evaluable endometrial biopsies,
there were no reports of endometrial hyperplasia or endometrial carcinoma.
20
Reference ID: 3087017
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
&
Table 3: Mean Change in Dyspareunia Severity Compared to Placebo MITT Population of
Most Bothersome Symptom Score for Dyspareunia, LOCF
Dyspareunia
PVC
0.5 g
2x/wka
Placebo
0.5 g
2x/wka
PVC
0.5 g
21/7b
Placebo
0.5 g
21/7b
Baseline
n
Mean (SD)
52
2.43 (0.76)
n
Mean (SD)
22
2.28 (1.04)
n
Mean (SD)
50
2.26 (0.99)
n
Mean (SD)
18
2.32 (0.88)
Week 12
52
0.88 (0.96)
21
1.63 (1.16)
50
0.77 (1.05)
18
1.93 (1.03)
Change from
Baseline at Week 12
52
-1.55 (0.92)
21
-0.62 (1.23)
50
-1.48 (1.17)
18
-0.40 (1.01)
P-value
vs.
Placebo
<0.001c
--
<0.001d
--
a PVC 2x/wk = apply PVC twice a week
b PVC 21/7 = apply PVC for 21 days and then 7 days of no therapy
c Comparison of PVC 2x/wk with placebo 2x/wk
d Comparison of PVC 21/7 with placebo 21/7
14.2 Women’s Health Initiative Studies
The WHI enrolled approximately 27,000 predominantly healthy postmenopausal women in two
substudies to assess the risks and benefits of daily oral CE (0.625 mg)-alone or in combination
with MPA (2.5 mg) compared to placebo in the prevention of certain chronic diseases. The
primary endpoint was the incidence of CHD (defined as nonfatal MI, silent MI and CHD death),
with invasive breast cancer as the primary adverse outcome. A “global index” included the
earliest occurrence of CHD, invasive breast cancer, stroke, PE, endometrial cancer (only in the
CE plus MPA substudy), colorectal cancer, hip fracture, or death due to other causes. These
substudies did not evaluate the effects of CE-alone or CE plus MPA on menopausal symptoms.
WHI Estrogen-Alone Substudy
The WHI estrogen-alone substudy was stopped early because an increased risk of stroke was
observed, and it was deemed that no further information would be obtained regarding the risks
and benefits of estrogen-alone in predetermined primary endpoints.
21
Reference ID: 3087017
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For current labeling information, please visit https://www.fda.gov/drugsatfda
&
Results of the estrogen-alone substudy, which included 10,739 women (average 63 years of age,
range 50 to 79; 75.3 percent White, 15.1 percent Black, 6.1 percent Hispanic, 3.6 percent Other)
after an average follow-up of 7.1 years, are presented in Table 4.
Table 4: Relative and Absolute Risk Seen in the Estrogen-Alone Substudy of WHIa
Event
Relative Risk
CE vs. Placebo
(95% nCIb)
CE
n = 5,310
Placebo
n = 5,429
Absolute Risk per 10,000 Women-
Years
CHD eventsc
0.95 (0.78–1.16)
54
57
Non-fatal MIc
0.91 (0.73–1.14)
40
43
CHD deathc
1.01 (0.71–1.43)
16
16
All Strokesc
1.33 (1.05–1.68)
45
33
Ischemic strokec
1.55 (1.19–2.01)
38
25
Deep vein thrombosisc,d
1.47 (1.06–2.06)
23
15
Pulmonary embolismc
1.37 (0.90–2.07)
14
10
Invasive breast cancerc
0.80 (0.62–1.04)
28
34
Colorectal cancere
1.08 (0.75–1.55)
17
16
Hip fracturec
0.65 (0.45–0.94)
12
19
Vertebral fracturesc,d
0.64 (0.44–0.93)
11
18
Lower arm/wrist fracturesc,d
0.58 (0.47–0.72)
35
59
Total fracturesc,d
0.71 (0.64–0.80)
144
197
Death due to other causese,f
1.08 (0.88–1.32)
53
50
Overall mortalityc,d
1.04 (0.88–1.22)
79
75
Global Indexg
1.02 (0.92–1.13)
206
201
a Adapted from numerous WHI publications. WHI publications can be viewed at
www.nhlbi.nih.gov/whi.
b Nominal confidence intervals unadjusted for multiple looks and multiple comparisons.
c Results are based on centrally adjudicated data for an average follow-up of 7.1 years.
d Not included in “global index.”
e Results are based on an average follow-up of 6.8 years.
f All deaths, except from breast or colorectal cancer, definite or probable CHD, PE or
cerebrovascular disease.
g A subset of the events was combined in a “global index” defined as the earliest occurrence of
CHD events, invasive breast cancer, stroke, pulmonary embolism, colorectal cancer, hip fracture,
or death due to other causes.
For those outcomes included in the WHI “global index” that reached statistical significance, the
absolute excess risk per 10,000 women-years in the group treated with CE-alone was 12 more
strokes while the absolute risk reduction per 10,000 women-years was 7 fewer hip fractures.9
The absolute excess risk of events included in the “global index” was a non-significant 5 events
per 10,000 women-years. There was no difference between the groups in terms of all-cause
mortality.
Reference ID: 3087017
22
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
No overall difference for primary CHD events (nonfatal MI, silent MI and CHD death) and
invasive breast cancer incidence in women receiving CE-alone compared with placebo was
reported in final centrally adjudicated results from the estrogen-alone substudy, after an average
follow up of 7.1 years.
Centrally adjudicated results for stroke events from the estrogen-alone substudy, after an average
follow-up of 7.1 years, reported no significant difference in distribution of stroke subtype or
severity, including fatal strokes, in women receiving CE-alone compared to placebo. Estrogen-
alone increased the risk for ischemic stroke, and this excess risk was present in all subgroups of
women examined.10
Timing of the initiation of estrogen-alone therapy relative to the start of menopause may affect
the overall risk benefit profile. The WHI estrogen-alone substudy, stratified by age, showed in
women 50 to 59 years of age a non-significant trend toward reduced risk for CHD [hazard ratio
(HR) 0.63 (95 percent CI, 0.36-1.09)] and overall mortality [HR 0.71 (95 percent CI, 0.46
1.11)].
WHI Estrogen Plus Progestin Substudy
The WHI estrogen plus progestin substudy was stopped early. According to the predefined
stopping rule, after an average follow-up of 5.6 years of treatment, the increased risk of invasive
breast cancer and cardiovascular events exceeded the specified benefits included in the “global
index.” The absolute excess risk of events included in the “global index” was 19 per 10,000
women-years.
For those outcomes included in the WHI “global index” that reached statistical significance after
5.6 years of follow-up, the absolute excess risks per 10,000 women-years in the group treated
with CE plus MPA were 7 more CHD events, 8 more strokes, 10 more PEs, and 8 more invasive
breast cancers, while the absolute risk reductions per 10,000 women-years were 6 fewer
colorectal cancers and 5 fewer hip fractures.
Results of the CE plus MPA substudy, which included 16,608 women (average 63 years of age,
range 50 to 79; 83.9 percent White, 6.8 percent Black, 5.4 percent Hispanic, 3.9 percent Other)
are presented in Table 5. These results reflect centrally adjudicated data after an average follow-
up of 5.6 years.
23
Reference ID: 3087017
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For current labeling information, please visit https://www.fda.gov/drugsatfda
&;
Table 5: Relative and Absolute Risk Seen in the Estrogen Plus Progestin Substudy of WHI
at an Average of 5.6 Yearsa,b
Event
Relative Risk
CE/MPA vs. Placebo
(95% nCIc)
CE/MPA
n = 8,506
Placebo
n = 8,102
Absolute Risk per 10,000
Women-Years
CHD events
1.23 (0.99–1.53)
41
34
Non-fatal MI
1.28 (1.00–1.63)
31
25
CHD death
1.10 (0.70–1.75)
8
8
All Strokes
1.31 (1.03–1.68)
33
25
Ischemic stroke
1.44 (1.09–1.90)
26
18
Deep vein thrombosisd
1.95 (1.43–2.67)
26
13
Pulmonary embolism
2.13 (1.45–3.11)
18
8
Invasive breast cancere
1.24 (1.01–1.54)
41
33
Colorectal cancer
0.61 (0.42–0.87)
10
16
Endometrial cancerd
0.81 (0.48–1.36)
6
7
Cervical cancerd
1.44 (0.47–4.42)
2
1
Hip fracture
0.67 (0.47–0.96)
11
16
Vertebral fracturesd
0.65 (0.46–0.92)
11
17
Lower arm/wrist fracturesd
0.71 (0.59–0.85)
44
62
Total fracturesd
0.76 (0.69–0.83)
152
199
Overall Mortalityf
1.00 (0.83–1.19)
52
52
Global Indexg
1.13 (1.02–1.25)
184
165
a Adapted from numerous WHI publications. WHI publications can be viewed at
www.nhlbi.nih.gov/whi.
b Results are based on centrally adjudicated data.
c Nominal confidence intervals unadjusted for multiple looks and multiple comparisons.
d Not included in “global index.”
e Includes metastatic and non-metastatic breast cancer, with the exception of in situ cancer.
f All deaths, except from breast or colorectal cancer, definite or probable CHD, PE or
cerebrovascular disease.
g A subset of the events was combined in a “global index” defined as the earliest occurrence of
CHD events, invasive breast cancer, stroke, pulmonary embolism, colorectal cancer, hip fracture,
or death due to other causes.
Timing of the initiation of estrogen plus progestin therapy relative to the start of menopause may
affect the overall risk benefit profile. The WHI estrogen plus progestin substudy stratified by age
showed in women 50 to 59 years of age, a non-significant trend toward reduced risk for overall
mortality [HR 0.69 (95 percent CI, 0.44-1.07)].
14.3 Women’s Health Initiative Memory Study
The WHIMS estrogen-alone ancillary study of WHI enrolled 2,947 predominantly healthy
hysterectomized postmenopausal women 65 to 79 years of age and older (45 percent were
24
Reference ID: 3087017
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For current labeling information, please visit https://www.fda.gov/drugsatfda
65 to 69 years of age; 36 percent were 70 to 74 years of age; 19 percent were 75 years of age and
older) to evaluate the effects of daily CE (0.625 mg)-alone on the incidence of probable dementia
(primary outcome) compared to placebo.
After an average follow-up of 5.2 years, the relative risk of probable dementia for CE-alone
versus placebo was 1.49 (95 percent CI, 0.83-2.66). The absolute risk of probable dementia for
CE-alone versus placebo was 37 versus 25 cases per 10,000 women-years. Probable dementia as
defined in this study included Alzheimer’s disease (AD), vascular dementia (VaD) and mixed
types (having features of both AD and VaD). The most common classification of probable
dementia in the treatment group and the placebo group was AD. Since the ancillary study was
conducted in women 65 to 79 years of age, it is unknown whether these findings apply to
younger postmenopausal women [see Warnings and Precautions (5.4), and Use in Specific
Populations (8.5)].
The WHIMS estrogen plus progestin ancillary study of WHI enrolled 4,532 predominantly
healthy postmenopausal women 65 years of age and older (47 percent were 65 to 69 years of
age; 35 percent were 70 to 74 years; 18 percent were 75 years of age and older) to evaluate the
effects of daily CE (0.625 mg) plus MPA (2.5 mg) on the incidence of probable dementia
(primary outcome) compared to placebo.
After an average follow-up of 4 years, the relative risk of probable dementia for CE plus MPA
versus placebo was 2.05 (95 percent CI, 1.21-3.48). The absolute risk of probable dementia for
CE plus MPA versus placebo was 45 versus 22 per 10,000 women-years. Probable dementia as
defined in this study included AD, VaD and mixed types (having features of both AD and VaD).
The most common classification of probable dementia in the treatment group and the placebo
group was AD. Since the ancillary study was conducted in women 65 to 79 years of age, it is
unknown whether these findings apply to younger postmenopausal women [see Warnings and
Precautions (5.4), and Use in Specific Populations (8.5)].
When data from the two populations were pooled as planned in the WHIMS protocol, the
reported overall relative risk for probable dementia was 1.76 (95 percent CI, 1.19-2.60).
Differences between groups became apparent in the first year of treatment. It is unknown
whether these findings apply to younger postmenopausal women [see Warnings and Precautions
(5.4), and Use in Specific Populations (8.5)].
15 REFERENCES
1. Rossouw JE, et al. Postmenopausal Hormone Therapy and Risk of Cardiovascular
Disease by Age and Years Since Menopause. JAMA. 2007;297:1465-1477.
2. Hsia J, et al. Conjugated Equine Estrogens and Coronary Heart Disease. Arch Int Med.
2006;166:357-365.
3. Curb JD, et al. Venous Thrombosis and Conjugated Equine Estrogen in Women Without
a Uterus. Arch Int Med. 2006;166:772-780.
4. Cushman M, et al. Estrogen Plus Progestin and Risk of Venous Thrombosis. JAMA.
2004;292:1573-1580.
25
Reference ID: 3087017
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5. Stefanick ML, et al. Effects of Conjugated Equine Estrogens on Breast Cancer and
Mammography Screening in Postmenopausal Women With Hysterectomy. JAMA.
2006;295:1647-1657.
6. Chlebowski RT, et al. Influence of Estrogen Plus Progestin on Breast Cancer and
Mammography in Healthy Postmenopausal Women. JAMA. 2003;289:3234-3253.
7. Anderson GL, et al. Effects of Estrogen Plus Progestin on Gynecologic Cancers and
Associated Diagnostic Procedures. JAMA. 2003;290:1739-1748.
8. Shumaker SA, et al. Conjugated Equine Estrogens and Incidence of Probable Dementia
and Mild Cognitive Impairment in Postmenopausal Women. JAMA. 2004;291:2947
2958.
9. Jackson RD, et al. Effects of Conjugated Equine Estrogen on Risk of Fractures and BMD
in Postmenopausal Women With Hysterectomy: Results From the Women’s Health
Initiative Randomized Trial. J Bone Miner Res. 2006;21:817-828.
10. Hendrix SL, et al. Effects of Conjugated Equine Estrogen on Stroke in the Women’s
Health Initiative. Circulation. 2006;113:2425-2434.
16 HOW SUPPLIED/STORAGE AND HANDLING
16.1 How Supplied
PREMARIN (conjugated estrogens) Vaginal Cream—Each gram contains 0.625 mg conjugated
estrogens, USP.
Combination package: Each contains a net wt. 1.5 oz (42.5 g) tube with one plastic applicator
calibrated in 0.5 g increments to a maximum of 2 g (NDC 0046-0872-93). 16.2 Storage and
Handling
Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F)
[see USP Controlled Room Temperature].
17 PATIENT COUNSELING INFORMATION
See FDA-Approved Patient Labeling.
17.1 Vaginal Bleeding
Inform postmenopausal women of the importance of reporting vaginal bleeding to their
healthcare provider as soon as possible [see Warnings and Precautions (5.3)].
17.2 Possible Serious Adverse Reactions with Estrogen-Alone Therapy
Inform postmenopausal women of possible serious adverse reactions of estrogen-alone therapy
including Cardiovascular Disorders, Malignant Neoplasms, and Probable Dementia [see
Warnings and Precautions (5.2, 5.3, 5.4)].
26
Reference ID: 3087017
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
17.3 Possible Less Serious but Common Adverse Reactions with Estrogen-Alone Therapy
Inform postmenopausal women of possible less serious but common adverse reactions of
estrogen-alone therapy such as headache, breast pain and tenderness, nausea and vomiting.
17.4 Instructions for Use of Applicator
Step 1.
Remove cap from tube.
Step 2.
Screw nozzle end of applicator onto tube (Figure A). usage illustration
Figure A
Step 3.
Gently squeeze tube from the bottom to force sufficient cream into the barrel to
provide the prescribed dose. Use the marked stopping points on the applicator to
measure the correct dose, as prescribed by your healthcare provider (Figure B). usage illustration
Figure B
Step 4. Unscrew applicator from tube.
27
Reference ID: 3087017
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Step 5.
Lie on back with knees drawn up. To deliver medication, gently insert applicator
deeply into vagina and press plunger downward to its original position (Figure C). usage illustration
Figure C
Step 6. TO CLEANSE: Pull plunger to remove it from barrel. Wash with mild soap and
warm water (Figure D).
DO NOT BOIL OR USE HOT WATER. usage illustration
Figure D
28
Reference ID: 3087017
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
FDA-Approved Patient Labeling
PREMARIN® (conjugated estrogens) Vaginal Cream
Read this PATIENT INFORMATION before you start using PREMARIN Vaginal Cream and
read what you get each time you refill your PREMARIN Vaginal Cream prescription. There may
be new information. This information does not take the place of talking to your healthcare
provider about your menopausal symptoms or your treatment.
What is the most important information I should know about PREMARIN Vaginal Cream
(an estrogen mixture)?
Using estrogen-alone may increase your chance of getting cancer of the uterus (womb)
Report any unusual vaginal bleeding right away while you are using PREMARIN
Vaginal Cream. Vaginal bleeding after menopause may be a warning sign of cancer of
the uterus (womb). Your healthcare provider should check any unusual vaginal
bleeding to find out the cause.
Do not use estrogen-alone to prevent heart disease, heart attacks, strokes or dementia
(decline in brain function)
Using estrogen-alone may increase your chances of getting strokes or blood clots
Using estrogen-alone may increase your chance of getting dementia, based on a study
of women 65 years of age or older
Do not use estrogens with progestins to prevent heart disease, heart attacks, strokes or
dementia
Using estrogens with progestins may increase your chances of getting heart attacks,
strokes, breast cancer, or blood clots
Using estrogens with progestins may increase your chance of getting dementia, based
on a study of women age 65 years of age or older
You and your healthcare provider should talk regularly about whether you still need
treatment with PREMARIN Vaginal Cream
What is PREMARIN Vaginal Cream?
PREMARIN Vaginal Cream is a medicine that contains a mixture of estrogen hormones.
29
Reference ID: 3087017
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
What is PREMARIN Vaginal Cream used for?
PREMARIN Vaginal Cream is used after menopause to:
Treat menopausal changes in and around the vagina
You and your healthcare provider should talk regularly about whether you still need
treatment with PREMARIN Vaginal Cream to control these problems.
Treat painful intercourse caused by menopausal changes of the vagina
Who should not use PREMARIN Vaginal Cream?
Do not start using PREMARIN Vaginal Cream if you:
Have unusual vaginal bleeding
Currently have or have had certain cancers
Estrogens may increase the chance of getting certain types of cancers, including cancer of
the breast or uterus. If you have or have had cancer, talk with your healthcare provider
about whether you should use PREMARIN Vaginal Cream.
Had a stroke or heart attack
Currently have or have had blood clots
Currently have or have had liver problems
Have been diagnosed with a bleeding disorder
Are allergic to PREMARIN Vaginal Cream or any of its ingredients
See the list of ingredients in PREMARIN Vaginal Cream at the end of this leaflet.
Think you may be pregnant
Tell your healthcare provider:
If you have unusual vaginal bleeding
Vaginal bleeding after menopause may be a warning sign of cancer of the uterus (womb).
Your healthcare provider should check any unusual vaginal bleeding to find out the cause.
About all of your medical problems
Your healthcare provider may need to check you more carefully if you have certain
conditions, such as asthma (wheezing), epilepsy (seizures), diabetes, migraine,
endometriosis, lupus, or problems with your heart, liver, thyroid, kidneys, or have high
calcium levels in your blood.
30
Reference ID: 3087017
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
About all the medicines you take
This includes prescription and nonprescription medicines, vitamins, and herbal
supplements. Some medicines may affect how PREMARIN Vaginal Cream works.
PREMARIN Vaginal Cream may also affect how your other medicines work.
If you are going to have surgery or will be on bedrest
You may need to stop using PREMARIN Vaginal Cream.
If you are breast feeding
The estrogen hormones in PREMARIN Vaginal Cream can pass into your breast milk.
How should I use PREMARIN Vaginal Cream?
PREMARIN Vaginal Cream is a cream that you place in your vagina with the applicator
provided with the cream.
Take the dose recommended by your healthcare provider and talk to him or her about
how well that dose is working for you
Estrogens should be used at the lowest dose possible for your treatment only as long as
needed. You and your healthcare provider should talk regularly (for example, every 3 to 6
months) about the dose you are taking and whether you still need treatment with
PREMARIN Vaginal Cream
Step 1.
Remove cap from tube.
Step 2.
Screw nozzle end of applicator onto tube (Figure A). usage illustration
Figure A
Step 3.
Gently squeeze tube from the bottom to force sufficient cream into the barrel to
provide the prescribed dose. Use the marked stopping points on the applicator to
measure the correct dose, as prescribed by your healthcare provider (Figure B).
31
Reference ID: 3087017
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
usage illustration
Step 4.
Figure B
Unscrew applicator from tube.
Step 5.
Lie on back with knees drawn up. To deliver medication, gently insert applicator
deeply into vagina and press plunger downward to its original position (Figure C). usage illustration
Figure C
Step 6. TO CLEANSE: Pull plunger to remove it from barrel. Wash with mild soap and
warm water (Figure D).
32
Reference ID: 3087017
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For current labeling information, please visit https://www.fda.gov/drugsatfda
DO NOT BOIL OR USE HOT WATER. usage illustration
Figure D
What are the possible side effects of PREMARIN Vaginal Cream?
PREMARIN Vaginal Cream is only used in and around the vagina; however, the risks associated
with oral estrogens should be taken into account.
Side effects are grouped by how serious they are and how often they happen when you are
treated.
Serious, but less common side effects include:
Heart attack
Stroke
Blood clots
Dementia
Breast cancer
Cancer of the lining of the uterus (womb)
Cancer of the ovary
High blood pressure
High blood sugar
Gallbladder disease
33
Reference ID: 3087017
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Liver problems
Enlargement of benign tumors of the uterus (“fibroids”)
Severe allergic reaction
Call your healthcare provider right away if you get any of the following warning signs or
any other unusual symptoms that concern you:
New breast lumps
Unusual vaginal bleeding
Changes in vision or speech
Sudden new severe headaches
Severe pains in your chest or legs with or without shortness of breath, weakness and
fatigue
Swollen lips, tongue or face
Less serious, but common side effects include:
Headache
Breast pain
Irregular vaginal bleeding or spotting
Stomach or abdominal cramps, bloating
Nausea and vomiting
Hair loss
Fluid retention
Vaginal yeast infection
Reactions from inserting PREMARIN Vaginal Cream, such as vaginal burning, irritation,
and itching
These are not all the possible side effects of PREMARIN Vaginal Cream. For more information,
ask your healthcare provider or pharmacist for advice about side effects. You may report side
effects to Pfizer Inc. at 1-800-438-1985 or to FDA at 1-800-FDA-1088.
34
Reference ID: 3087017
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
What can I do to lower my chances of getting a serious side effect with PREMARIN
Vaginal Cream?
Talk with your healthcare provider regularly about whether you should continue using
PREMARIN Vaginal Cream
If you have a uterus, talk with your healthcare provider about whether the addition of a
progestin is right for you
The addition of a progestin is generally recommended for a woman with a uterus to reduce
the chance of getting cancer of the uterus. See your healthcare provider right away if you
get vaginal bleeding while using PREMARIN Vaginal Cream.
Have a pelvic exam, breast exam and mammogram (breast X-ray) every year unless your
healthcare provider tells you something else
If members of your family have had breast cancer or if you have ever had breast lumps or
an abnormal mammogram, you may need to have breast exams more often.
If you have high blood pressure, high cholesterol (fat in the blood), diabetes, are
overweight, or if you use tobacco, you may have higher chances for getting heart disease
Ask your healthcare provider for ways to lower your chances for getting heart disease.
General information about the safe and effective use of PREMARIN Vaginal Cream
Medicines are sometimes prescribed for conditions that are not mentioned in patient information
leaflets. Do not use PREMARIN Vaginal Cream for conditions for which it was not prescribed.
Do not give PREMARIN Vaginal Cream to other people, even if they have the same symptoms
you have. It may harm them.
Keep PREMARIN Vaginal Cream out of the reach of children.
Latex or rubber condoms, diaphragms and cervical caps may be weakened and fail when they
come into contact with PREMARIN Vaginal Cream.
This leaflet provides a summary of the most important information about PREMARIN Vaginal
Cream. If you would like more information, talk with your healthcare provider or pharmacist.
You can ask for information about PREMARIN Vaginal Cream that is written for health
professionals. You can get more information by calling the toll free number 1-800-438-1985.
35
Reference ID: 3087017
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
What are the ingredients in PREMARIN Vaginal Cream?
PREMARIN Vaginal Cream contains a mixture of conjugated estrogens, which are a mixture of
sodium estrone sulfate and sodium equilin sulfate and other components, including sodium
sulfate conjugates: 17 α-dihydroequilin, 17 α-estradiol, and 17 β-dihydroequilin. PREMARIN
Vaginal Cream also contains cetyl esters wax, cetyl alcohol, white wax, glyceryl monostearate,
propylene glycol monostearate, methyl stearate, benzyl alcohol, sodium lauryl sulfate, glycerin,
and mineral oil.
PREMARIN (conjugated estrogens) Vaginal Cream—Each gram contains 0.625 mg conjugated
estrogens, USP.
Combination package: Each contains a net wt. 1.5 oz (42.5 g) tube with one plastic applicator
calibrated in 0.5 g increments to a maximum of 2 g (NDC 0046-0872-93).
Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F)
[see USP Controlled Room Temperature]. company logo
LAB-0498-2.0
Rev 0X/2011
36
Reference ID: 3087017
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
«TEAR HERE
FDA-Approved Patient Labeling
PREMARIN® (conjugated estrogens) Vaginal Cream
Read this PATIENT INFORMATION before you start using PREMARIN Vaginal Cream and
read what you get each time you refill your PREMARIN Vaginal Cream prescription. There may
be new information. This information does not take the place of talking to your healthcare
provider about your menopausal symptoms or your treatment.
What is the most important information I should know about PREMARIN Vaginal Cream
(an estrogen mixture)?
Using estrogen-alone may increase your chance of getting cancer of the uterus (womb)
Report any unusual vaginal bleeding right away while you are using PREMARIN
Vaginal Cream. Vaginal bleeding after menopause may be a warning sign of cancer of
the uterus (womb). Your healthcare provider should check any unusual vaginal bleeding
to find out the cause.
Do not use estrogen-alone to prevent heart disease, heart attacks, strokes or dementia
(decline in brain function)
Using estrogen-alone may increase your chances of getting strokes or blood clots
Using estrogen-alone may increase your chance of getting dementia, based on a study of
women age 65 years of age or older
Do not use estrogens with progestins to prevent heart disease, heart attacks, strokes or
dementia
Using estrogens with progestins may increase your chances of getting heart attacks,
strokes, breast cancer, or blood clots
Using estrogens with progestins may increase your chance of getting dementia, based on
a study of women age 65 years of age or older
You and your healthcare provider should talk regularly about whether you still need
treatment with PREMARIN Vaginal Cream
What is PREMARIN Vaginal Cream?
PREMARIN Vaginal Cream is a medicine that contains a mixture of estrogen hormones.
37
Reference ID: 3087017
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For current labeling information, please visit https://www.fda.gov/drugsatfda
What is PREMARIN Vaginal Cream used for?
PREMARIN Vaginal Cream is used after menopause to:
Treat menopausal changes in and around the vagina
You and your healthcare provider should talk regularly about whether you still need
treatment with PREMARIN Vaginal Cream to control these problems.
Treat painful intercourse caused by menopausal changes of the vagina
Who should not use PREMARIN Vaginal Cream?
Do not start using PREMARIN Vaginal Cream if you:
Have unusual vaginal bleeding
Currently have or have had certain cancers
Estrogens may increase the chance of getting certain types of cancers, including cancer of
the breast or uterus. If you have or have had cancer, talk with your healthcare provider
about whether you should use PREMARIN Vaginal Cream.
Had a stroke or heart attack
Currently have or have had blood clots
Currently have or have had liver problems
Have been diagnosed with a bleeding disorder
Are allergic to PREMARIN Vaginal Cream or any of its ingredients
See the list of ingredients in PREMARIN Vaginal Cream at the end of this leaflet.
Think you may be pregnant
Tell your healthcare provider:
If you have unusual vaginal bleeding
Vaginal bleeding after menopause may be a warning sign of cancer of the uterus (womb).
Your healthcare provider should check any unusual vaginal bleeding to find out the cause.
About all of your medical problems
Your healthcare provider may need to check you more carefully if you have certain
conditions, such as asthma (wheezing), epilepsy (seizures), diabetes, migraine,
endometriosis, lupus, or problems with your heart, liver, thyroid, kidneys, or have high
calcium levels in your blood.
38
Reference ID: 3087017
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For current labeling information, please visit https://www.fda.gov/drugsatfda
About all the medicines you take
This includes prescription and nonprescription medicines, vitamins, and herbal
supplements. Some medicines may affect how PREMARIN Vaginal Cream works.
PREMARIN Vaginal Cream may also affect how your other medicines work.
If you are going to have surgery or will be on bedrest
You may need to stop using PREMARIN Vaginal Cream.
If you are breast feeding
The estrogen hormones in PREMARIN Vaginal Cream can pass into your breast milk.
How should I use PREMARIN Vaginal Cream?
PREMARIN Vaginal Cream is a cream that you place in your vagina with the applicator
provided with the cream.
Take the dose recommended by your healthcare provider and talk to him or her about
how well that dose is working for you
Estrogens should be used at the lowest dose possible for your treatment only as long as
needed. You and your healthcare provider should talk regularly (for example, every 3 to 6
months) about the dose you are taking and whether you still need treatment with
PREMARIN Vaginal Cream
Step 1.
Remove cap from tube.
Step 2.
Screw nozzle end of applicator onto tube (Figure A). usage illustration
Figure A
Step 3.
Gently squeeze tube from the bottom to force sufficient cream into the barrel to
provide the prescribed dose. Use the marked stopping points on the applicator to
measure the correct dose, as prescribed by your healthcare provider (Figure B).
39
Reference ID: 3087017
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For current labeling information, please visit https://www.fda.gov/drugsatfda
usage illustration
Figure B
Step 4.
Step 5.
Unscrew applicator from tube.
Lie on back with knees drawn up. To deliver medication, gently insert applicator
deeply into vagina and press plunger downward to its original position (Figure C). usage illustration
Figure C
40
Reference ID: 3087017
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Step 6. TO CLEANSE: Pull plunger to remove it from barrel. Wash with mild soap and
warm water (Figure D).
DO NOT BOIL OR USE HOT WATER. usage illustration
Figure D
What are the possible side effects of PREMARIN Vaginal Cream?
PREMARIN Vaginal Cream is only used in and around the vagina; however, the risks associated
with oral estrogens should be taken into account.
Side effects are grouped by how serious they are and how often they happen when you are
treated.
Serious, but less common side effects include:
Heart attack
Stroke
Blood clots
Dementia
Breast cancer
Cancer of the lining of the uterus (womb)
Cancer of the ovary
High blood pressure
High blood sugar
Gallbladder disease
Liver problems
Reference ID: 3087017
41
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Enlargement of benign tumors of the uterus (“fibroids”)
Severe allergic reaction
Call your healthcare provider right away if you get any of the following warning signed or
any other unusual symptoms that concern you:
New breast lumps
Unusual vaginal bleeding
Changes in vision or speech
Sudden new severe headaches
Severe pains in your chest or legs with or without shortness of breath, weakness and
fatigue
Swollen lips, tongue or face
Less serious, but common side effects include:
Headache
Breast pain
Irregular vaginal bleeding or spotting
Stomach or abdominal cramps, bloating
Nausea and vomiting
Hair loss
Fluid retention
Vaginal yeast infection
Reactions from inserting PREMARIN Vaginal Cream, such as vaginal burning, irritation,
and itching
These are not all the possible side effects of PREMARIN Vaginal Cream. For more information,
ask your healthcare provider or pharmacist for advice about side effects. You may report side
effects to Pfizer Inc. at 1-800-438-1985 or to FDA at 1-800-FDA-1088.
What can I do to lower my chances of getting a serious side effect with PREMARIN
Vaginal Cream?
42
Reference ID: 3087017
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Talk with your healthcare provider regularly about whether you should continue using
PREMARIN Vaginal Cream
If you have a uterus, talk with your healthcare provider about whether the addition of a
progestin is right for you
The addition of a progestin is generally recommended for a woman with a uterus to reduce
the chance of getting cancer of the uterus. See your healthcare provider right away if you
get vaginal bleeding while using PREMARIN Vaginal Cream.
Have a pelvic exam, breast exam and mammogram (breast X-ray) every year unless your
healthcare provider tells you something else
If members of your family have had breast cancer or if you have ever had breast lumps or
an abnormal mammogram, you may need to have breast exams more often.
If you have high blood pressure, high cholesterol (fat in the blood), diabetes, are
overweight, or if you use tobacco, you may have higher chances for getting heart disease
Ask your healthcare provider for ways to lower your chances for getting heart disease.
General information about the safe and effective use of PREMARIN Vaginal Cream
Medicines are sometimes prescribed for conditions that are not mentioned in patient information
leaflets. Do not use PREMARIN Vaginal Cream for conditions for which it was not prescribed.
Do not give PREMARIN Vaginal Cream to other people, even if they have the same symptoms
you have. It may harm them.
Keep PREMARIN Vaginal Cream out of the reach of children.
Latex or rubber condoms, diaphragms and cervical caps may be weakened and fail when they
come into contact with PREMARIN Vaginal Cream.
This leaflet provides a summary of the most important information about PREMARIN Vaginal
Cream. If you would like more information, talk with your healthcare provider or pharmacist.
You can ask for information about PREMARIN Vaginal Cream that is written for health
professionals. You can get more information by calling the toll free number 1-800-438-1985.
What are the ingredients in PREMARIN Vaginal Cream?
PREMARIN Vaginal Cream contains a mixture of conjugated estrogens, which are a mixture of
sodium estrone sulfate and sodium equilin sulfate and other components, including sodium
sulfate conjugates: 17 α-dihydroequilin, 17 α-estradiol, and 17 β-dihydroequilin. PREMARIN
Vaginal Cream also contains cetyl esters wax, cetyl alcohol, white wax, glyceryl monostearate,
propylene glycol monostearate, methyl stearate, benzyl alcohol, sodium lauryl sulfate, glycerin,
and mineral oil.
43
Reference ID: 3087017
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PREMARIN (conjugated estrogens) Vaginal Cream—Each gram contains 0.625 mg conjugated
estrogens, USP.
Combination package: Each contains a net wt. 1.5 oz (42.5 g) tube with one plastic applicator
calibrated in 0.5 g increments to a maximum of 2 g (NDC 0046-0872-93).
Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F)
[see USP Controlled Room Temperature].
This product’s label may have been updated. For current package insert and
further product information, please visit www.pfizer.com or call our m edical
communications department toll-free at 1-800-438-1985. company logo
LAB-0519-2.0
Rev 02/2012
44
Reference ID: 3087017
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For current labeling information, please visit https://www.fda.gov/drugsatfda
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12,325
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&;
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
PREMARIN VAGINAL CREAM safely and effectively. See full
prescribing information for PREMARIN VAGINAL CREAM.
PREMARIN (conjugated estrogens) Vaginal Cream.
Initial U.S. Approval: 1946
WARNING: ENDOMETRIAL CANCER, CARDIOVASCULAR
DISORDERS, BREAST CANCER and PROBABLE DEMENTIA
See full prescribing information for complete boxed warning.
Estrogen-Alone Therapy
There is an increased risk of endometrial cancer in a woman
with a uterus who uses unopposed estrogens (5.3)
Estrogen-alone therapy should not be used for the prevention
of cardiovascular disease or dementia (5.2, 5.4)
The Women’s Health Initiative (WHI) estrogen-alone substudy
reported increased risks of stroke and deep vein thrombosis
(DVT) (5.2)
The WHI Memory Study (WHIMS) estrogen-alone ancillary
study of WHI reported an increased risk of probable dementia
in postmenopausal women 65 years of age and older (5.4)
Estrogen Plus Progestin Therapy
Estrogen plus progestin therapy should not be used for the
prevention of cardiovascular disease or dementia (5.2, 5.4)
The WHI estrogen plus progestin substudy reported increased
risks of stroke, DVT, pulmonary embolism (PE), and
myocardial infarction (MI) (5.2)
The WHI estrogen plus progestin substudy reported increased
risks of invasive breast cancer (5.3)
The WHIMS estrogen plus progestin ancillary study of WHI
reported an increased risk of probable dementia in
postmenopausal women 65 years of age and older (5.4)
———————— RECENT MAJOR CHANGES ————————
Contraindications (4)
02/2012
Warnings and Precautions
02/2012
Anaphylactic Reaction and Angioedema (5.16)
Hereditary Angioedema (5.17)
02/2012
———————— INDICATIONS AND USAGE————————
PREMARIN (conjugated estrogens) Vaginal Cream is a mixture of
estrogens indicated for:
Treatment of Atrophic Vaginitis and Kraurosis Vulvae (1.1)
Treatment of Moderate to Severe Dyspareunia, a Symptom of
Vulvar and Vaginal Atrophy, due to Menopause (1.2)
——————— DOSAGE AND ADMINISTRATION——————
Cyclic administration of 0.5 to 2 g intravaginally [daily for 21 days
then off for 7 days] for Treatment of Atrophic Vaginitis and
Kraurosis Vulvae (2.1)
Cyclic administration of 0.5 g intravaginally [daily for 21 days
then off for 7 days] for Treatment of Moderate to Severe
Dyspareunia, a Symptom of Vulvar and Vaginal Atrophy, due to
Menopause (2.2)
Twice-weekly administration of 0.5 g intravaginally [for example,
Monday and Thursday] for Treatment of Moderate to Severe
Dyspareunia, a Symptom of Vulvar and Vaginal Atrophy, due to
Menopause (2.2)
—————— DOSAGE FORMS AND STRENGTHS——————
Each gram contains 0.625 mg conjugated estrogens, USP (3)
Combination package: Each contains a net wt. 1.5 oz (42.5 g) tube
with one plastic applicator calibrated in 0.5 g increments to a
maximum of 2 g (3)
————————— CONTRAINDICATIONS————————
Undiagnosed abnormal genital bleeding (4)
Known, suspected, or history of breast cancer (4, 5.3)
Known or suspected estrogen-dependent neoplasia (4, 5.3)
Active DVT, PE, or a history of these conditions (4, 5.2)
Active arterial thromboembolic disease (for example, stroke and
MI), or a history of these conditions (4, 5.2)
Known anaphylactic reaction or angioedema to PREMARIN
Vaginal Cream (5.16, 5.17)
Known liver dysfunction or disease (4, 5.10)
Known protein C, protein S, or antithrombin deficiency, or other
known thrombophilic disorders (4)
Known or suspected pregnancy (4, 8.1)
——————— WARNINGS AND PRECAUTIONS——————
Estrogens increase the risk of gallbladder disease (5.5)
Discontinue estrogen if severe hypercalcemia, loss of vision,
severe hypertriglyceridemia or cholestatic jaundice occurs (5.6,
5.7, 5.10, 5.11)
Monitor thyroid function in women on thyroid replacement therapy
(5.12, 5.21)
————————— ADVERSE REACTIONS—————————
In a prospective, randomized, placebo-controlled, double-blind study, the
most common adverse reactions ≥ 2 percent are headache, pelvic pain,
vasodilation, breast pain, leucorrhea, metrorrhagia, vaginitis, vulvovaginal
disorder. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc.
at 1-800-438-1985 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch
————————— DRUG INTERACTIONS—————————
Inducers and/or inhibitors of CYP3A4 may affect estrogen drug
metabolism. (7.1)
——————— USE IN SPECIFIC POPULATIONS——————
Nursing Mothers: Estrogen administration to nursing women has
been shown to decrease the quantity and quality of breast milk
(8.3)
Geriatric Use: An increased risk of probable dementia in women
over 65 years of age was reported in the Women’s Health Initiative
Memory ancillary studies of the Women’s Health Initiative (5.4,
8.5)
See 17 for PATIENT COUNSELING INFORMATION and
FDA-approved patient labeling
Revised: 02/2012
1
Reference ID: 3087017
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
FULL PRESCRIBING INFORMATION: CONTENTS *
WARNING: ENDOMETRIAL CANCER, CARDIOVASCULAR
DISORDERS, BREAST CANCER and PROBABLE DEMENTIA
1 INDICATIONS AND USAGE
1.1 Treatment of Atrophic Vaginitis and Kraurosis Vulvae
1.2 Treatment of Moderate to Severe Dyspareunia, a Symptom of Vulvar
and Vaginal Atrophy, due to Menopause
2 DOSAGE AND ADMINISTRATION
2.1 Treatment of Atrophic Vaginitis and Kraurosis Vulvae
2.2 Treatment of Moderate to Severe Dyspareunia, a Symptom of Vulvar
and Vaginal Atrophy, due to Menopause
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Risks from Systemic Abso ption
r
e
5.2 Cardiovascular Disord rs
5.3 Malignant Neoplasms
5.4 Probable Dementia
5.5 Gallbladder Disease
5.6 Hypercalcemia
5.7 Visual Abnormalities
5.8 Addition of a Progestin When a Woman Has Not Had a Hysterectomy
5.9 Elevated Blood Pressure
5.10 Hypertriglyceridemia
5.11 Hepatic Impairm nt and/or Past History of Cholestatic Jaundice
e
5.12 Hypothyroidism
5.13 Fluid Retention
5.14 Hypocalcemia
5.15 Exacerbation of Endometriosis
5.16 Anaphylactic Reaction and Angioedema
5.17 Hereditary Angioedema
5.18 Exacerbation of Other Conditions
5.19 Effects on Barrier Contraception
5.20 Laboratory Tests
5.21 Drug-Laboratory Test I teractions
n
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
6.2 Postmarketing Experience
7 DRUG INTERACTIONS
* Sections or subsections omitted from the full prescribing information are not listed
7.1 Metabolic Interactions
8 USE IN SPEC FIC POPULATIONS
I
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Renal Impairment
8.7 Hepatic Impairment
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
14.1 Effects on Vulvar and Vaginal Atro hy
p
14.2 Women’s Health Initiative Studies
14.3 Women’s Hea th Initiative Memory Study
l
15 REFERENCES
16 HOW SUPPLIED/STORAGE AND HANDLING
16.1 How Supplied
16.2 Storage and Handling
17 PATIENT COUNSELING INFORMATION
17.1 Vaginal Bleeding
17.2 Possible Serious Adverse Reactions with Estrogen-Alone Therapy
17.3 Possible Less Serious but Common Adverse Reactions with
Estrogen-Alone Therapy
17.4 Instructions for Use of Applicator
FDA-Approved Patient Labeling
2
Reference ID: 3087017
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For current labeling information, please visit https://www.fda.gov/drugsatfda
FULL PRESCRIBING INFORMATION
WARNING: ENDOMETRIAL CANCER, CARDIOVASCULAR DISORDERS, BREAST
CANCER and PROBABLE DEMENTIA
Estrogen-Alone Therapy
Endometrial Cancer
There is an increased risk of endometrial cancer in a woman with a uterus who uses
unopposed estrogens. Adding a progestin to estrogen therapy has been shown to reduce the
risk of endometrial hyperplasia, which may be a precursor to endometrial cancer.
Adequate diagnostic measures, including directed or random endometrial sampling when
indicated, should be undertaken to rule out malignancy in postmenopausal women with
undiagnosed persistent or recurring abnormal genital bleeding [see Warnings and
Precautions (5.3)].
Cardiovascular Disorders and Probable Dementia
Estrogen-alone therapy should not be used for the prevention of cardiovascular disease or
dementia [see Warnings and Precautions (5.2, 5.4), and Clinical Studies (14.2, 14.3)].
The Women’s Health Initiative (WHI) estrogen-alone substudy reported increased risks of
stroke and deep vein thrombosis (DVT) in postmenopausal women (50 to 79 years of age)
during 7.1 years of treatment with daily oral conjugated estrogens (CE) [0.625 mg]-alone,
relative to placebo [see Warnings and Precautions (5.2), and Clinical Studies (14.2)].
The WHI Memory Study (WHIMS) estrogen-alone ancillary study of WHI reported an
increased risk of developing probable dementia in postmenopausal women 65 years of age
or older during 5.2 years of treatment with daily CE (0.625 mg)-alone, relative to placebo.
It is unknown whether this finding applies to younger postmenopausal women [see
Warnings and Precautions (5.4), Use in Specific Populations (8.5), and Clinical Studies
(14.3)].
In the absence of comparable data, these risks should be assumed to be similar for other
doses of CE and other dosage forms of estrogens.
Estrogens with or without progestins should be prescribed at the lowest effective doses and
for the shortest duration consistent with treatment goals and risks for the individual
woman.
Estrogen Plus Progestin Therapy
Cardiovascular Disorders and Probable Dementia
Estrogen plus progestin therapy should not be used for the prevention of cardiovascular
disease or dementia [see Warnings and Precautions (5.2, 5.4), and Clinical Studies (14.2,
14.3)].
3
Reference ID: 3087017
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
The WHI estrogen plus progestin substudy reported increased risks of DVT, pulmonary
embolism (PE), stroke and myocardial infarction (MI) in postmenopausal women (50 to 79
years of age) during 5.6 years of treatment with daily oral CE (0.625 mg) combined with
medroxyprogesterone acetate (MPA) [2.5 mg], relative to placebo [see Warnings and
Precautions (5.2), and Clinical Studies (14.2)].
The WHIMS estrogen plus progestin ancillary study of the WHI reported an increased risk
of developing probable dementia in postmenopausal women 65 years of age or older during
4 years of treatment with daily CE (0.625 mg) combined with MPA (2.5 mg), relative to
placebo. It is unknown whether this finding applies to younger postmenopausal women [see
Warnings and Precautions (5.4), Use in Specific Populations (8.5), and Clinical Studies
(14.3)].
Breast Cancer
The WHI estrogen plus progestin substudy also demonstrated an increased risk of invasive
breast cancer [see Warnings and Precautions (5.3), and Clinical Studies (14.2)].
In the absence of comparable data, these risks should be assumed to be similar for other
doses of CE and MPA, and other combinations and dosage forms of estrogens and
progestins.
Estrogens with or without progestins should be prescribed at the lowest effective doses and
for the shortest duration consistent with treatment goals and risks for the individual
woman.
1 INDICATIONS AND USAGE
1.1 Treatment of Atrophic Vaginitis and Kraurosis Vulvae
1.2 Treatment of Moderate to Severe Dyspareunia, a Symptom of Vulvar and Vaginal
Atrophy, due to Menopause
2 DOSAGE AND ADMINISTRATION
Generally, when estrogen is prescribed for a postmenopausal woman with a uterus, a progestin
should also be considered to reduce the risk of endometrial cancer.
A woman without a uterus does not need a progestin. In some cases, however, hysterectomized
women with a history of endometriosis may need a progestin [see Warnings and Precautions
(5.3, 5.15)].
Use of estrogen-alone, or in combination with a progestin, should be with the lowest effective
dose and for the shortest duration consistent with treatment goals and risks for the individual
woman. Postmenopausal women should be re-evaluated periodically as clinically appropriate to
determine if treatment is still necessary.
4
Reference ID: 3087017
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2.1 Treatment of Atrophic Vaginitis and Kraurosis Vulvae
PREMARIN Vaginal Cream is administered intravaginally in a cyclic regimen (daily for 21 days
and then off for 7 days). Generally, women should be started at the 0.5 g dosage strength.
Dosage adjustments (0.5 to 2 g) may be made based on individual response [see Dosage Forms
and Strengths (3)].
2.2 Treatment of Moderate to Severe Dyspareunia, a Symptom of Vulvar and Vaginal
Atrophy, due to Menopause
PREMARIN Vaginal Cream (0.5 g) is administered intravaginally in a twice-weekly (for
example, Monday and Thursday) continuous regimen or in a cyclic regimen of 21 days of
therapy followed by 7 days off of therapy [see Dosage Forms and Strengths (3)].
3 DOSAGE FORMS AND STRENGTHS
Each gram contains 0.625 mg conjugated estrogens, USP.
Combination package: Each contains a net wt. 1.5 oz (42.5 g) tube with one plastic applicator
calibrated in 0.5 g increments to a maximum of 2 g.
4 CONTRAINDICATIONS
PREMARIN Vaginal Cream therapy should not be used in women with any of the following
conditions:
Undiagnosed abnormal genital bleeding
Known, suspected, or history of breast cancer
Known or suspected estrogen-dependent neoplasia
Active DVT, PE, or a history of these conditions
Active arterial thromboembolic disease (for example, stroke and MI), or a history of
these conditions
Known anaphylactic reaction or angioedema to PREMARIN Vaginal Cream
Known liver dysfunction or disease
Known protein C, protein S or antithrombin deficiency, or other known
thrombophilic disorders
Known or suspected pregnancy
5
Reference ID: 3087017
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5 WARNINGS AND PRECAUTIONS
5.1 Risks from Systemic Absorption
Systemic absorption occurs with the use of PREMARIN Vaginal Cream. The warnings,
precautions, and adverse reactions associated with oral PREMARIN treatment should be taken
into account.
5.2 Cardiovascular Disorders
An increased risk of stroke and DVT has been reported with estrogen-alone therapy. An
increased risk of PE, DVT, stroke and MI has been reported with estrogen plus progestin
therapy. Should any of these occur or be suspected, estrogen with or without progestin therapy
should be discontinued immediately.
Risk factors for arterial vascular disease (for example, hypertension, diabetes mellitus, tobacco
use, hypercholesterolemia, and obesity) and/or venous thromboembolism (VTE) (for example,
personal history or family history of VTE, obesity, and systemic lupus erythematosus) should be
managed appropriately.
Stroke
In the WHI estrogen-alone substudy, a statistically significant increased risk of stroke was
reported in women 50 to 79 years of age receiving daily CE (0.625 mg)-alone compared to
women in the same age group receiving placebo (45 versus 33 per 10,000 women-years). The
increase in risk was demonstrated in year 1 and persisted [see Clinical Studies (14.2)]. Should a
stroke occur or be suspected, estrogen-alone therapy should be discontinued immediately.
Subgroup analyses of women 50 to 59 years of age suggest no increased risk of stroke for those
women receiving CE (0.625 mg)-alone versus those receiving placebo (18 versus 21 per 10,000
women-years).1
In the WHI estrogen plus progestin substudy, a statistically significant increased risk of stroke
was reported in women 50 to 79 years of age receiving daily CE (0.625 mg) plus MPA (2.5 mg)
compared to women in the same age group receiving placebo (33 versus 25 per 10,000 women-
years) [see Clinical Studies (14.2)]. The increase in risk was demonstrated after the first year and
persisted.1 Should a stroke occur or be suspected, estrogen plus progestin therapy should be
discontinued immediately.
Coronary Heart Disease
In the WHI estrogen-alone substudy, no overall effect on coronary heart disease (CHD) events
(defined as nonfatal MI, silent MI, or CHD death) was reported in women receiving estrogen-
alone compared to placebo2 [see Clinical Studies (14.2)].
Subgroup analyses of women 50 to 59 years of age suggest a statistically non-significant
reduction in CHD events (CE [0.625 mg]-alone compared to placebo) in women with less than
10 years since menopause (8 versus 16 per 10,000 women-years).1
Reference ID: 3087017
6
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
In the WHI estrogen plus progestin substudy, there was a statistically non-significant increased
risk of CHD events reported in women receiving daily CE (0.625 mg) plus MPA (2.5 mg)
compared to women receiving placebo (41 versus 34 per 10,000 women-years).1 An increase in
relative risk was demonstrated in year 1, and a trend toward decreasing relative risk was reported
in years 2 through 5 [see Clinical Studies (14.2)].
In postmenopausal women with documented heart disease (n = 2,763), average 66.7 years of age,
in a controlled clinical trial of secondary prevention of cardiovascular disease (Heart and
Estrogen/Progestin Replacement Study [HERS]), treatment with daily CE (0.625 mg) plus MPA
(2.5 mg) demonstrated no cardiovascular benefit. During an average follow-up of 4.1 years,
treatment with CE plus MPA did not reduce the overall rate of CHD events in postmenopausal
women with established coronary heart disease. There were more CHD events in the CE plus
MPA-treated group than in the placebo group in year 1, but not during subsequent years. Two
thousand, three hundred and twenty-one (2,321) women from the original HERS trial agreed to
participate in an open label extension of HERS, HERS II. Average follow-up in HERS II was an
additional 2.7 years, for a total of 6.8 years overall. Rates of CHD events were comparable
among women in the CE plus MPA group and the placebo group in HERS, HERS II, and overall.
Venous Thromboembolism
In the WHI estrogen-alone substudy, the risk of VTE (DVT and PE) was increased for women
receiving daily CE (0.625 mg)-alone compared to placebo (30 versus 22 per 10,000 women-
years), although only the increased risk of DVT reached statistical significance (23 versus 15 per
10,000 women-years). The increase in VTE risk was demonstrated during the first 2 years3 [see
Clinical Studies (14.2)]. Should a VTE occur or be suspected, estrogen-alone therapy should be
discontinued immediately.
In the WHI estrogen plus progestin substudy, a statistically significant 2-fold greater rate of VTE
was reported in women receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women
receiving placebo (35 versus 17 per 10,000 women-years). Statistically significant increases in
risk for both DVT (26 versus 13 per 10,000 women-years) and PE (18 versus 8 per 10,000
women-years) were also demonstrated. The increase in VTE risk was observed during the first
year and persisted4 [see Clinical Studies (14.2)]. Should a VTE occur or be suspected, estrogen
plus progestin therapy should be discontinued immediately.
If feasible, estrogens should be discontinued at least 4 to 6 weeks before surgery of the type
associated with an increased risk of thromboembolism, or during periods of prolonged
immobilization.
5.3 Malignant Neoplasms
Endometrial Cancer
An increased risk of endometrial cancer has been reported with the use of unopposed estrogen
therapy in a woman with a uterus. The reported endometrial cancer risk among unopposed
estrogen users is about 2 to 12 times greater than in non-users, and appears dependent on
duration of treatment and on estrogen dose. Most studies show no significant increased risk
associated with use of estrogens for less than 1 year. The greatest risk appears to be associated
7
Reference ID: 3087017
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
with prolonged use, with increased risks of 15- to 24-fold for 5 to 10 years or more, and this risk
has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued.
Clinical surveillance of all women using estrogen-alone or estrogen plus progestin therapy is
important. Adequate diagnostic measures, including directed or random endometrial sampling
when indicated, should be undertaken to rule out malignancy in postmenopausal women with
undiagnosed persistent or recurring abnormal genital bleeding.
There is no evidence that the use of natural estrogens results in a different endometrial risk
profile than synthetic estrogens of equivalent estrogen dose. Adding a progestin to
postmenopausal estrogen therapy has been shown to reduce the risk of endometrial hyperplasia,
which may be a precursor to endometrial cancer.
In a 52-week clinical trial using PREMARIN Vaginal Cream alone (0.5 g inserted twice weekly
or daily for 21 days, then off for 7 days), there was no evidence of endometrial hyperplasia or
endometrial carcinoma.
Breast Cancer
The most important randomized clinical trial providing information about breast cancer in
estrogen-alone users is the WHI substudy of daily CE (0.625 mg)-alone. In the WHI estrogen-
alone substudy, after an average follow-up of 7.1 years, daily CE-alone was not associated with
an increased risk of invasive breast cancer [relative risk (RR) 0.80]5 [see Clinical Studies
(14.2)].
The most important randomized clinical trial providing information about breast cancer in
estrogen plus progestin users is the WHI substudy of daily CE (0.625 mg) plus MPA (2.5 mg).
After a mean follow-up of 5.6 years, the estrogen plus progestin substudy reported an increased
risk of invasive breast cancer in women who took daily CE plus MPA. In this substudy, prior use
of estrogen-alone or estrogen plus progestin therapy was reported by 26 percent of the women.
The relative risk of invasive breast cancer was 1.24, and the absolute risk was 41 versus 33 cases
per 10,000 women-years, for CE plus MPA compared with placebo. Among women who
reported prior use of hormone therapy, the relative risk of invasive breast cancer was 1.86, and
the absolute risk was 46 versus 25 cases per 10,000 women-years, for CE plus MPA compared
with placebo. Among women who reported no prior use of hormone therapy, the relative risk of
invasive breast cancer was 1.09, and the absolute risk was 40 versus 36 cases per 10,000 women-
years for CE plus MPA compared with placebo. In the same substudy, invasive breast cancers
were larger, were more likely to be node positive, and were diagnosed at a more advanced stage
in the CE (0.625 mg) plus MPA (2.5 mg) group compared with the placebo group. Metastatic
disease was rare, with no apparent difference between the two groups. Other prognostic factors,
such as histologic subtype, grade and hormone receptor status did not differ between the groups6
[see Clinical Studies (14.2)].
Consistent with the WHI clinical trial, observational studies have also reported an increased risk
of breast cancer for estrogen plus progestin therapy, and a smaller increased risk for estrogen-
alone therapy, after several years of use. The risk increased with duration of use, and appeared to
return to baseline over about 5 years after stopping treatment (only the observational studies have
8
Reference ID: 3087017
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For current labeling information, please visit https://www.fda.gov/drugsatfda
substantial data on risk after stopping). Observational studies also suggest that the risk of breast
cancer was greater, and became apparent earlier, with estrogen plus progestin therapy as
compared to estrogen-alone therapy. However, these studies have not generally found significant
variation in the risk of breast cancer among different estrogen plus progestin combinations,
doses, or routes of administration.
The use of estrogen-alone and estrogen plus progestin therapy has been reported to result in an
increase in abnormal mammograms, requiring further evaluation.
All women should receive yearly breast examinations by a healthcare provider and perform
monthly breast self-examinations. In addition, mammography examinations should be scheduled
based on patient age, risk factors, and prior mammogram results.
Ovarian Cancer
The WHI estrogen plus progestin substudy reported a statistically non-significant increased risk
of ovarian cancer. After an average follow-up of 5.6 years, the relative risk for ovarian cancer for
CE plus MPA versus placebo was 1.58 (95 percent CI, 0.77-3.24). The absolute risk for CE plus
MPA versus placebo was 4 versus 3 cases per 10,000 women-years.7 In some epidemiologic
studies, the use of estrogen plus progestin and estrogen-only products, in particular for 5 or more
years, has been associated with an increased risk of ovarian cancer. However, the duration of
exposure associated with increased risk is not consistent across all epidemiologic studies, and
some report no association.
5.4 Probable Dementia
In the WHIMS estrogen-alone ancillary study of WHI, a population of 2,947 hysterectomized
women 65 to 79 years of age was randomized to daily CE (0.625 mg)-alone or placebo.
After an average follow-up of 5.2 years, 28 women in the estrogen-alone group and 19 women in
the placebo group were diagnosed with probable dementia. The relative risk of probable
dementia for CE-alone versus placebo was 1.49 (95 percent CI, 0.83-2.66). The absolute risk of
probable dementia for CE-alone versus placebo was 37 versus 25 cases per 10,000 women-years8
[see Use in Specific Populations (8.5), and Clinical Studies (14.3)].
In the WHIMS estrogen plus progestin ancillary study of WHI, a population of 4,532
postmenopausal women 65 to 79 years of age was randomized to daily CE (0.625 mg) plus MPA
(2.5 mg) or placebo.
After an average follow-up of 4 years, 40 women in the CE plus MPA group and 21 women in
the placebo group were diagnosed with probable dementia. The relative risk of probable
dementia for CE plus MPA versus placebo was 2.05 (95 percent CI, 1.21-3.48). The absolute risk
of probable dementia for CE plus MPA versus placebo was 45 versus 22 cases per 10,000
women-years8 [see Use in Specific Populations (8.5), and Clinical Studies (14.3)].
When data from the two populations in the WHIMS estrogen-alone and estrogen plus progestin
ancillary studies were pooled as planned in the WHIMS protocol, the reported overall relative
risk for probable dementia was 1.76 (95 percent CI, 1.19-2.60). Since both ancillary studies were
9
Reference ID: 3087017
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For current labeling information, please visit https://www.fda.gov/drugsatfda
conducted in women 65 to 79 years of age, it is unknown whether these findings apply to
younger postmenopausal women8 [see Use in Specific Populations (8.5), and Clinical Studies
(14.3)].
5.5 Gallbladder Disease
A 2- to 4-fold increase in the risk of gallbladder disease requiring surgery in postmenopausal
women receiving estrogens has been reported.
5.6 Hypercalcemia
Estrogen administration may lead to severe hypercalcemia in women with breast cancer and
bone metastases. If hypercalcemia occurs, use of the drug should be stopped and appropriate
measures taken to reduce the serum calcium level.
5.7 Visual Abnormalities
Retinal vascular thrombosis has been reported in patients receiving estrogens. Discontinue
medication pending examination if there is sudden partial or complete loss of vision, or a sudden
onset of proptosis, diplopia, or migraine. If examination reveals papilledema or retinal vascular
lesions, estrogens should be permanently discontinued.
5.8 Addition of a Progestin When a Woman Has Not Had a Hysterectomy
Studies of the addition of a progestin for 10 or more days of a cycle of estrogen administration,
or daily with estrogen in a continuous regimen, have reported a lowered incidence of endometrial
hyperplasia than would be induced by estrogen treatment alone. Endometrial hyperplasia may be
a precursor to endometrial cancer.
There are, however, possible risks that may be associated with the use of progestins with
estrogens compared to estrogen-alone regimens. These include an increased risk of breast cancer.
5.9 Elevated Blood Pressure
In a small number of case reports, substantial increases in blood pressure have been attributed to
idiosyncratic reactions to estrogens. In a large, randomized, placebo-controlled clinical trial, a
generalized effect of estrogen therapy on blood pressure was not seen.
5.10 Hypertriglyceridemia
In women with pre-existing hypertriglyceridemia, estrogen therapy may be associated with
elevations of plasma triglycerides leading to pancreatitis. Consider discontinuation of treatment
if pancreatitis occurs.
10
Reference ID: 3087017
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For current labeling information, please visit https://www.fda.gov/drugsatfda
5.11 Hepatic Impairment and/or Past History of Cholestatic Jaundice
Estrogens may be poorly metabolized in women with impaired liver function. For women with a
history of cholestatic jaundice associated with past estrogen use or with pregnancy, caution
should be exercised, and in the case of recurrence, medication should be discontinued.
5.12 Hypothyroidism
Estrogen administration leads to increased thyroid-binding globulin (TBG) levels. Women with
normal thyroid function can compensate for the increased TBG by making more thyroid
hormone, thus maintaining free T4 and T3 serum concentrations in the normal range. Women
dependent on thyroid hormone replacement therapy who are also receiving estrogens may
require increased doses of their thyroid replacement therapy. These women should have their
thyroid function monitored in order to maintain their free thyroid hormone levels in an
acceptable range.
5.13 Fluid Retention
Estrogens may cause some degree of fluid retention. Women with conditions that might be
influenced by this factor, such as cardiac or renal dysfunction, warrant careful observation when
estrogen-alone is prescribed.
5.14 Hypocalcemia
Estrogen therapy should be used with caution in women with hypoparathyroidism as estrogen-
induced hypocalcemia may occur.
5.15 Exacerbation of Endometriosis
A few cases of malignant transformation of residual endometrial implants have been reported in
women treated post-hysterectomy with estrogen-alone therapy. For women known to have
residual endometriosis post-hysterectomy, the addition of progestin should be considered.
5.16 Anaphylactic Reaction and Angioedema
Cases of anaphylaxis, which develop within minutes to hours after taking orally-administered
PREMARIN and require emergency management, have been reported in the postmarketing
setting. Skin (hives, pruritus, swollen lips-tongue-face) and either respiratory tract (respiratory
compromise) or gastrointestinal tract (abdominal pain, vomiting) involvement has been noted.
Angioedema involving the tongue, larynx, face, and feet requiring medical intervention has
occurred postmarketing in patients taking orally-administered PREMARIN. If angioedema
involves the tongue, glottis, or larynx, airway obstruction may occur. Patients who develop an
anaphylactic reaction with or without angioedema after treatment with oral PREMARIN should
not receive oral PREMARIN again.
11
Reference ID: 3087017
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5.17 Hereditary Angioedema
Exogenous estrogens may exacerbate symptoms of angioedema in women with hereditary
angioedema.
5.18 Exacerbation of Other Conditions
Estrogen therapy may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine,
porphyria, systemic lupus erythematosus, and hepatic hemangiomas and should be used with
caution in women with these conditions.
5.19 Effects on Barrier Contraception
PREMARIN Vaginal Cream exposure has been reported to weaken latex condoms. The potential
for PREMARIN Vaginal Cream to weaken and contribute to the failure of condoms, diaphragms,
or cervical caps made of latex or rubber should be considered.
5.20 Laboratory Tests
Serum follicle stimulating hormone (FSH) and estradiol levels have not been shown to be useful
in the management of moderate to severe symptoms of vulvar and vaginal atrophy.
5.21 Drug-Laboratory Test Interactions
Accelerated prothrombin time, partial thromboplastin time, and platelet aggregation time;
increased platelet count; increased factors II, VII antigen, VIII antigen, VIII coagulant activity,
IX, X, XII, VII-X complex, II-VII-X complex, and beta-thromboglobulin; decreased levels of
antifactor Xa and antithrombin III, decreased antithrombin III activity; increased levels of
fibrinogen and fibrinogen activity; increased plasminogen antigen and activity.
Increased thyroid-binding globulin (TBG) leading to increased circulating total thyroid hormone,
as measured by protein-bound iodine (PBI), T4 levels (by column or by radioimmunoassay) or T3
levels by radioimmunoassay. T3 resin uptake is decreased, reflecting the elevated TBG. Free T4
and free T3 concentrations are unaltered. Women on thyroid replacement therapy may require
higher doses of thyroid hormone.
Other binding proteins may be elevated in serum, for example, corticosteroid binding globulin
(CBG), sex hormone-binding globulin (SHBG), leading to increased total circulating
corticosteroids and sex steroids, respectively. Free hormone concentrations, such as testosterone
and estradiol, may be decreased. Other plasma proteins may be increased (angiotensinogen/renin
substrate, alpha-1-antitrypsin, ceruloplasmin).
Increased plasma high-density lipoprotein (HDL) and HDL2 cholesterol subfraction
concentrations, reduced low-density lipoprotein (LDL) cholesterol concentrations, increased
triglyceride levels.
Impaired glucose tolerance.
12
Reference ID: 3087017
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
6 ADVERSE REACTIONS
The following serious adverse reactions are discussed elsewhere in the labeling:
Cardiovascular Disorders [see Boxed Warning, Warnings and Precautions (5.2)]
Malignant Neoplasms [see Boxed Warning, Warnings and Precautions (5.3)]
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates
observed in the clinical trial of a drug cannot be directly compared to rates in the clinical trials of
another drug and may not reflect the rates observed in practice.
In a 12-week, randomized, double-blind, placebo-controlled trial of PREMARIN Vaginal Cream
(PVC), a total of 423 postmenopausal women received at least 1 dose of study medication and
were included in all safety analyses: 143 women in the PVC-21/7 treatment group (0.5 g PVC
daily for 21 days, then 7 days off), 72 women in the matching placebo treatment group; 140
women in the PVC-2x/wk treatment group (0.5 g PVC twice weekly), 68 women in the matching
placebo treatment group. A 40-week, open-label extension followed, in which a total of 394
women received treatment with PVC, including those subjects randomized at baseline to
placebo. In this study, the most common adverse reactions ≥ 1 percent in the double blind phase
are shown below (Table 1) [see Clinical Studies (14.1)].
13
Reference ID: 3087017
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For current labeling information, please visit https://www.fda.gov/drugsatfda
&
Table 1: Number (%) of Patients Reporting Treatment Emergent Adverse Reactions ≥ 1
Percent Only
Treatment
Body Systema/Adverse
Reaction
PVC 21/7
N=143
Placebo 21/7
N=72
PVC 2x/week
N=140
Placebo
2x/week
N=68
Number (%) of Patients with Adverse Reaction
Body As A Whole
Abdominal Pain
1 (0.7)
1 (1.4)
0
1 (1.5)
Headache
5 (3.5)
1 (1.4)
3 (2.1)
1 (1.5)
Moniliasis
2 (1.4)
1 (1.4)
1 (0.7)
0
Pain
2 (1.4)
0
1 (0.7)
0
Pelvic Pain
4 (2.8)
2 (2.8)
4 (2.9)
0
Cardiovascular System
Migraine
0
0
0
1 (1.5)
Vasodilation
3 (2.1)
2 (2.8)
2 (1.4)
0
Musculoskeletal System
Muscle Cramp
2 (1.4)
0
0
0
Nervous System
Dizziness
1 (0.7)
0
0
1 (1.5)
Skin and Appendages
Acne
0
0
2 (1.4)
0
Erythema
0
1 (1.4)
0
0
Pruritus
2 (1.4)
1 (1.4)
1 (0.7)
0
Urogenital System
Breast Enlargement
1 (0.7)
1 (1.4)
0
0
Breast Pain
7 (4.9)
0
3 (2.1)
0
Dysuria
2 (1.4)
0
0
0
Leukorrhea
3 (2.1)
1 (1.4)
4 (2.9)
5 (7.4)
Metrorrhagia
0
0
0
2 (2.9)
Urinary Frequency
0
1 (1.4)
0
0
Urinary Tract Infection
0
1 (1.4)
0
0
Urinary Urgency
1 (0.7)
1 (1.4)
0
0
Vaginal Hemorrhage
2 (1.4)
0
1 (0.7)
1 (1.5)
Vaginal Moniliasis
2 (1.4)
0
0
0
Vaginitis
2 (1.4)
1 (1.4)
3 (2.1)
3 (4.4)
Vulvovaginal Disorder
4 (2.8)
0
3 (2.1)
2 (2.9)
a Body system totals are not necessarily the sum of individual adverse events, since a patient may
report two or more different adverse reactions in the same body system.
14
Reference ID: 3087017
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
6.2 Postmarketing Experience
The following adverse reactions have been identified during post-approval use of PREMARIN
Vaginal Cream. Because these reactions are reported voluntarily from a population of uncertain
size, it is not always possible to reliably estimate their frequency or establish a causal
relationship to drug exposure.
Genitourinary System
Abnormal uterine bleeding or spotting, dysmenorrhea or pelvic pain, increase in size of uterine
leiomyomata, vaginitis (including vaginal candidiasis), change in cervical secretion, cystitis-like
syndrome, application site reactions of vulvovaginal discomfort, (including burning, irritation,
and genital pruritus), endometrial hyperplasia, endometrial cancer, precocious puberty,
leukorrhea.
Breasts
Tenderness, enlargement, pain, discharge, fibrocystic breast changes, breast cancer,
gynecomastia in males.
Cardiovascular
Deep venous thrombosis, pulmonary embolism, myocardial infarction, stroke, increase in blood
pressure.
Gastrointestinal
Nausea, vomiting, abdominal cramps, bloating, increased incidence of gallbladder disease.
Skin
Chloasma that may persist when drug is discontinued, loss of scalp hair, hirsutism, rash.
Eyes
Retinal vascular thrombosis, intolerance to contact lenses.
Central Nervous System
Headache, migraine, dizziness, mental depression, nervousness, mood disturbances, irritability,
dementia.
Miscellaneous
Increase or decrease in weight, glucose intolerance, edema, arthralgias, leg cramps, changes in
libido, urticaria, exacerbation of asthma, increased triglycerides, hypersensitivity.
Reference ID: 3087017
15
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Additional postmarketing adverse reactions have been reported in patients receiving other forms
of hormone therapy.
7 DRUG INTERACTIONS
No drug interaction studies have been conducted for PREMARIN Vaginal Cream.
7.1 Metabolic Interactions
In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome
P450 3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen drug
metabolism. Inducers of CYP3A4, such as St. John’s wort (Hypericum perforatum) preparations,
phenobarbital, carbamazepine, and rifampin, may reduce plasma concentrations of estrogens,
possibly resulting in a decrease in therapeutic effects and/or changes in the uterine bleeding
profile. Inhibitors of CYP3A4, such as erythromycin, clarithromycin, ketoconazole, itraconazole,
ritonavir and grapefruit juice, may increase plasma concentrations of estrogens and may result in
side effects.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
PREMARIN Vaginal Cream should not be used during pregnancy [see Contraindications (4)].
There appears to be little or no increased risk of birth defects in children born to women who
have used estrogens and progestins as an oral contraceptive inadvertently during early
pregnancy.
8.3 Nursing Mothers
PREMARIN Vaginal Cream should not be used during lactation. Estrogen administration to
nursing women has been shown to decrease the quantity and quality of the breast milk.
Detectable amounts of estrogens have been identified in the breast milk of women receiving
estrogen therapy. Caution should be exercised when PREMARIN Vaginal Cream is administered
to a nursing woman.
8.4 Pediatric Use
PREMARIN Vaginal Cream is not indicated in children. Clinical studies have not been
conducted in the pediatric population.
8.5 Geriatric Use
There have not been sufficient numbers of geriatric women involved in clinical studies utilizing
PREMARIN Vaginal Cream to determine whether those over 65 years of age differ from
younger subjects in their response to PREMARIN Vaginal Cream.
The Women’s Health Initiative Studies
16
Reference ID: 3087017
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
In the WHI estrogen-alone substudy (daily CE [0.625 mg]-alone versus placebo), there was a
higher relative risk of stroke in women greater than 65 years of age [see Clinical Studies (14.2)].
In the WHI estrogen plus progestin substudy (daily CE [0.625 mg] plus MPA [2.5 mg] versus
placebo), there was a higher relative risk of nonfatal stroke and invasive breast cancer in women
greater than 65 years of age [see Clinical Studies (14.2)].
The Women’s Health Initiative Memory Study
In the WHIMS ancillary studies of postmenopausal women 65 to 79 years of age, there was an
increased risk of developing probable dementia in women receiving estrogen-alone or estrogen
plus progestin when compared to placebo [see Warnings and Precautions (5.4), and Clinical
Studies (14.3)].
Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown
whether these findings apply to younger postmenopausal women8 [see Warnings and
Precautions (5.4), and Clinical Studies (14.3)].
8.6 Renal Impairment
The effect of renal impairment on the pharmacokinetics of PREMARIN Vaginal Cream has not
been studied.
8.7 Hepatic Impairment
The effect of hepatic impairment on the pharmacokinetics of PREMARIN Vaginal Cream has
not been studied.
10 OVERDOSAGE
Overdosage of estrogen may cause nausea, vomiting, breast tenderness, abdominal pain,
drowsiness and fatigue, and withdrawal bleeding may occur in women. Treatment of overdose
consists of discontinuation of PREMARIN therapy with institution of appropriate symptomatic
care.
11 DESCRIPTION
Each gram of PREMARIN (conjugated estrogens) Vaginal Cream contains 0.625 mg conjugated
estrogens, USP in a nonliquefying base containing cetyl esters wax, cetyl alcohol, white wax,
glyceryl monostearate, propylene glycol monostearate, methyl stearate, benzyl alcohol, sodium
lauryl sulfate, glycerin, and mineral oil. PREMARIN Vaginal Cream is applied intravaginally.
PREMARIN Vaginal Cream contains a mixture of conjugated estrogens obtained exclusively
from natural sources, occurring as the sodium salts of water-soluble estrogen sulfates blended to
represent the average composition of material derived from pregnant mares’ urine. It is a mixture
of sodium estrone sulfate and sodium equilin sulfate. It contains as concomitant components,
sodium sulfate conjugates, 17 α-dihydroequilin, 17 α-estradiol, and 17 β-dihydroequilin.
17
Reference ID: 3087017
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Endogenous estrogens are largely responsible for the development and maintenance of the
female reproductive system and secondary sexual characteristics. Although circulating estrogens
exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal
intracellular human estrogen and is substantially more potent than its metabolites, estrone and
estriol, at the receptor level.
The primary source of estrogen in normally cycling adult women is the ovarian follicle, which
secretes 70 to 500 mcg of estradiol daily, depending on the phase of the menstrual cycle. After
menopause, most endogenous estrogen is produced by conversion of androstenedione, which is
secreted by the adrenal cortex, to estrone in the peripheral tissues. Thus, estrone and the sulfate-
conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal
women.
Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, two
estrogen receptors have been identified. These vary in proportion from tissue to tissue.
Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone
(LH) and FSH, through a negative feedback mechanism. Estrogens act to reduce the elevated
levels of these gonadotropins seen in postmenopausal women.
12.2 Pharmacodynamics
Currently, there are no pharmacodynamic data known for PREMARIN Vaginal Cream.
12.3 Pharmacokinetics
Absorption
Conjugated estrogens are water soluble and are well-absorbed through the skin, mucous
membranes, and the gastrointestinal (GI) tract. The vaginal delivery of estrogens circumvents
first-pass metabolism.
A bioavailability study was conducted in 24 postmenopausal women with atrophic vaginitis. The
mean (SD) pharmacokinetic parameters for unconjugated estrone, unconjugated estradiol, total
estrone, total estradiol and total equilin following 7 once-daily doses of PREMARIN Vaginal
Cream 0.5 g is shown in Table 2.
18
Reference ID: 3087017
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
&;
Table 2: Mean ± SD Pharmacokinetic Parameters of PREMARIN Following Daily
Administration (7 Days) of PREMARIN Vaginal Cream 0.5 g in 24 Postmenopausal
Women
Pharmacokinetic Profiles of Unconjugated Estrogens
PREMARIN Vaginal Cream 0.5 g
PK Parameters
Arithmetic Mean ± SD
Cmax
(pg/mL)
Tmax
(hr)
AUCss
(pg•hr/mL)
Estrone
42.0 ± 13.9
7.4 ± 6.2
826 ± 295
Baseline-adjusted estrone
21.9 ± 13.1
7.4 ± 6.2
365 ± 255
Estradiol
12.8 ± 16.6
8.5 ± 6.2
231 ± 285
Baseline-adjusted estradiol
9.14 ± 14.7
8.5 ± 6.2
161 ± 252
Pharmacokinetic Profiles of Conjugated Estrogens
PREMARIN Vaginal Cream 0.5 g
PK Parameters
Arithmetic Mean ± SD
Cmax
(ng/mL)
Tmax
(hr)
AUCss
(ng•hr/mL)
Total estrone
0.60 ± 0.32
6.0 ± 4.0
9.75 ± 4.99
Baseline-adjusted total estrone
0.40 ± 0.28
6.0 ± 4.0
5.79 ± 3.7
Total estradiol
0.04 ± 0.04
7.7 ± 5.9
0.70 ± 0.42
Baseline-adjusted total estradiol
0.04 ± 0.04
7.7 ± 6.0
0.49 ± 0.38
Total equilin
0.12 ± 0.15
6.1 ± 4.7
3.09 ± 1.37
Distribution
The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are
widely distributed in the body and are generally found in higher concentration in the sex
hormone target organs. Estrogens circulate in the blood largely bound to SHBG and albumin.
Metabolism
Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating
estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations
take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be
converted to estriol, which is a major urinary metabolite. Estrogens also undergo enterohepatic
recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates
into the intestine, and hydrolysis in the intestine followed by reabsorption. In postmenopausal
women, a significant portion of the circulating estrogens exists as sulfate conjugates, especially
estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens.
Excretion
Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate
conjugates.
Use in Specific Populations
19
Reference ID: 3087017
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
No pharmacokinetic studies were conducted in specific populations, including patients with renal
or hepatic impairment.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term continuous administration of natural and synthetic estrogens in certain animal species
increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis, and liver.
14 CLINICAL STUDIES
14.1 Effects on Vulvar and Vaginal Atrophy
A 12-week, prospective, randomized, double-blind placebo-controlled study was conducted to
compare the safety and efficacy of 2 PREMARIN Vaginal Cream (PVC) regimens 0.5 g
(0.3 mg CE) administered twice weekly and 0.5 g (0.3 mg CE) administered sequentially for 21
days on drug followed by 7 days off drug to matching placebo regimens in the treatment of
moderate to severe symptoms of vulvar and vaginal atrophy due to menopause. The initial 12
week, double-blind, placebo-controlled phase was followed by an open-label phase to assess
endometrial safety through week 52. The study randomized 423 generally healthy
postmenopausal women between 44 to 77 years of age (mean 57.8 years), who at baseline had ≤
5 percent superficial cells on a vaginal smear, a vaginal pH ≥ 5.0, and who identified a most
bothersome moderate to severe symptom of vulvar and vaginal atrophy. The majority (92.2
percent) of the women were Caucasian (n = 390); 7.8 percent were Other (n = 33). All subjects
were assessed for improvement in the mean change from baseline to Week 12 for the co-primary
efficacy variables of: most bothersome symptom of vulvar and vaginal atrophy (defined as the
moderate to severe symptom that had been identified by the woman as most bothersome to her at
baseline); percentage of vaginal superficial cells and percentage of vaginal parabasal cells; and
vaginal pH.
In the 12-week, double-blind phase, a statistically significant mean change between baseline and
Week 12 in the symptom of dyspareunia was observed for both of the PREMARIN Vaginal
Cream regimens (0.5 g twice weekly and 0.5 g daily for 21 days, then 7 days off) compared to
matching placebo, see Table 3. Also demonstrated for each PREMARIN Vaginal Cream regimen
compared to placebo was a statistically significant increase in the percentage of superficial cells
at Week 12 (28 percent and 26 percent, respectively, compared to 3 percent and 1 percent for
matching placebo), a statistically significant decrease in parabasal cells (-61 percent and -58
percent, respectively, compared to -21 percent and -7 percent for matching placebo) and
statistically significant mean reduction between baseline and Week 12 in vaginal pH (-1.62 and
1.57, respectively, compared to -0.36 and -0.26 for matching placebo).
Endometrial safety was assessed by endometrial biopsy for all randomly assigned subjects at
week 52. For the 155 subjects (83 on the 21/7 regimen, 72 on the twice-weekly regimen)
completing the 52-week period with complete follow-up and evaluable endometrial biopsies,
there were no reports of endometrial hyperplasia or endometrial carcinoma.
20
Reference ID: 3087017
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
&
Table 3: Mean Change in Dyspareunia Severity Compared to Placebo MITT Population of
Most Bothersome Symptom Score for Dyspareunia, LOCF
Dyspareunia
PVC
0.5 g
2x/wka
Placebo
0.5 g
2x/wka
PVC
0.5 g
21/7b
Placebo
0.5 g
21/7b
Baseline
n
Mean (SD)
52
2.43 (0.76)
n
Mean (SD)
22
2.28 (1.04)
n
Mean (SD)
50
2.26 (0.99)
n
Mean (SD)
18
2.32 (0.88)
Week 12
52
0.88 (0.96)
21
1.63 (1.16)
50
0.77 (1.05)
18
1.93 (1.03)
Change from
Baseline at Week 12
52
-1.55 (0.92)
21
-0.62 (1.23)
50
-1.48 (1.17)
18
-0.40 (1.01)
P-value
vs.
Placebo
<0.001c
--
<0.001d
--
a PVC 2x/wk = apply PVC twice a week
b PVC 21/7 = apply PVC for 21 days and then 7 days of no therapy
c Comparison of PVC 2x/wk with placebo 2x/wk
d Comparison of PVC 21/7 with placebo 21/7
14.2 Women’s Health Initiative Studies
The WHI enrolled approximately 27,000 predominantly healthy postmenopausal women in two
substudies to assess the risks and benefits of daily oral CE (0.625 mg)-alone or in combination
with MPA (2.5 mg) compared to placebo in the prevention of certain chronic diseases. The
primary endpoint was the incidence of CHD (defined as nonfatal MI, silent MI and CHD death),
with invasive breast cancer as the primary adverse outcome. A “global index” included the
earliest occurrence of CHD, invasive breast cancer, stroke, PE, endometrial cancer (only in the
CE plus MPA substudy), colorectal cancer, hip fracture, or death due to other causes. These
substudies did not evaluate the effects of CE-alone or CE plus MPA on menopausal symptoms.
WHI Estrogen-Alone Substudy
The WHI estrogen-alone substudy was stopped early because an increased risk of stroke was
observed, and it was deemed that no further information would be obtained regarding the risks
and benefits of estrogen-alone in predetermined primary endpoints.
21
Reference ID: 3087017
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
&
Results of the estrogen-alone substudy, which included 10,739 women (average 63 years of age,
range 50 to 79; 75.3 percent White, 15.1 percent Black, 6.1 percent Hispanic, 3.6 percent Other)
after an average follow-up of 7.1 years, are presented in Table 4.
Table 4: Relative and Absolute Risk Seen in the Estrogen-Alone Substudy of WHIa
Event
Relative Risk
CE vs. Placebo
(95% nCIb)
CE
n = 5,310
Placebo
n = 5,429
Absolute Risk per 10,000 Women-
Years
CHD eventsc
0.95 (0.78–1.16)
54
57
Non-fatal MIc
0.91 (0.73–1.14)
40
43
CHD deathc
1.01 (0.71–1.43)
16
16
All Strokesc
1.33 (1.05–1.68)
45
33
Ischemic strokec
1.55 (1.19–2.01)
38
25
Deep vein thrombosisc,d
1.47 (1.06–2.06)
23
15
Pulmonary embolismc
1.37 (0.90–2.07)
14
10
Invasive breast cancerc
0.80 (0.62–1.04)
28
34
Colorectal cancere
1.08 (0.75–1.55)
17
16
Hip fracturec
0.65 (0.45–0.94)
12
19
Vertebral fracturesc,d
0.64 (0.44–0.93)
11
18
Lower arm/wrist fracturesc,d
0.58 (0.47–0.72)
35
59
Total fracturesc,d
0.71 (0.64–0.80)
144
197
Death due to other causese,f
1.08 (0.88–1.32)
53
50
Overall mortalityc,d
1.04 (0.88–1.22)
79
75
Global Indexg
1.02 (0.92–1.13)
206
201
a Adapted from numerous WHI publications. WHI publications can be viewed at
www.nhlbi.nih.gov/whi.
b Nominal confidence intervals unadjusted for multiple looks and multiple comparisons.
c Results are based on centrally adjudicated data for an average follow-up of 7.1 years.
d Not included in “global index.”
e Results are based on an average follow-up of 6.8 years.
f All deaths, except from breast or colorectal cancer, definite or probable CHD, PE or
cerebrovascular disease.
g A subset of the events was combined in a “global index” defined as the earliest occurrence of
CHD events, invasive breast cancer, stroke, pulmonary embolism, colorectal cancer, hip fracture,
or death due to other causes.
For those outcomes included in the WHI “global index” that reached statistical significance, the
absolute excess risk per 10,000 women-years in the group treated with CE-alone was 12 more
strokes while the absolute risk reduction per 10,000 women-years was 7 fewer hip fractures.9
The absolute excess risk of events included in the “global index” was a non-significant 5 events
per 10,000 women-years. There was no difference between the groups in terms of all-cause
mortality.
Reference ID: 3087017
22
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
No overall difference for primary CHD events (nonfatal MI, silent MI and CHD death) and
invasive breast cancer incidence in women receiving CE-alone compared with placebo was
reported in final centrally adjudicated results from the estrogen-alone substudy, after an average
follow up of 7.1 years.
Centrally adjudicated results for stroke events from the estrogen-alone substudy, after an average
follow-up of 7.1 years, reported no significant difference in distribution of stroke subtype or
severity, including fatal strokes, in women receiving CE-alone compared to placebo. Estrogen-
alone increased the risk for ischemic stroke, and this excess risk was present in all subgroups of
women examined.10
Timing of the initiation of estrogen-alone therapy relative to the start of menopause may affect
the overall risk benefit profile. The WHI estrogen-alone substudy, stratified by age, showed in
women 50 to 59 years of age a non-significant trend toward reduced risk for CHD [hazard ratio
(HR) 0.63 (95 percent CI, 0.36-1.09)] and overall mortality [HR 0.71 (95 percent CI, 0.46
1.11)].
WHI Estrogen Plus Progestin Substudy
The WHI estrogen plus progestin substudy was stopped early. According to the predefined
stopping rule, after an average follow-up of 5.6 years of treatment, the increased risk of invasive
breast cancer and cardiovascular events exceeded the specified benefits included in the “global
index.” The absolute excess risk of events included in the “global index” was 19 per 10,000
women-years.
For those outcomes included in the WHI “global index” that reached statistical significance after
5.6 years of follow-up, the absolute excess risks per 10,000 women-years in the group treated
with CE plus MPA were 7 more CHD events, 8 more strokes, 10 more PEs, and 8 more invasive
breast cancers, while the absolute risk reductions per 10,000 women-years were 6 fewer
colorectal cancers and 5 fewer hip fractures.
Results of the CE plus MPA substudy, which included 16,608 women (average 63 years of age,
range 50 to 79; 83.9 percent White, 6.8 percent Black, 5.4 percent Hispanic, 3.9 percent Other)
are presented in Table 5. These results reflect centrally adjudicated data after an average follow-
up of 5.6 years.
23
Reference ID: 3087017
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
&;
Table 5: Relative and Absolute Risk Seen in the Estrogen Plus Progestin Substudy of WHI
at an Average of 5.6 Yearsa,b
Event
Relative Risk
CE/MPA vs. Placebo
(95% nCIc)
CE/MPA
n = 8,506
Placebo
n = 8,102
Absolute Risk per 10,000
Women-Years
CHD events
1.23 (0.99–1.53)
41
34
Non-fatal MI
1.28 (1.00–1.63)
31
25
CHD death
1.10 (0.70–1.75)
8
8
All Strokes
1.31 (1.03–1.68)
33
25
Ischemic stroke
1.44 (1.09–1.90)
26
18
Deep vein thrombosisd
1.95 (1.43–2.67)
26
13
Pulmonary embolism
2.13 (1.45–3.11)
18
8
Invasive breast cancere
1.24 (1.01–1.54)
41
33
Colorectal cancer
0.61 (0.42–0.87)
10
16
Endometrial cancerd
0.81 (0.48–1.36)
6
7
Cervical cancerd
1.44 (0.47–4.42)
2
1
Hip fracture
0.67 (0.47–0.96)
11
16
Vertebral fracturesd
0.65 (0.46–0.92)
11
17
Lower arm/wrist fracturesd
0.71 (0.59–0.85)
44
62
Total fracturesd
0.76 (0.69–0.83)
152
199
Overall Mortalityf
1.00 (0.83–1.19)
52
52
Global Indexg
1.13 (1.02–1.25)
184
165
a Adapted from numerous WHI publications. WHI publications can be viewed at
www.nhlbi.nih.gov/whi.
b Results are based on centrally adjudicated data.
c Nominal confidence intervals unadjusted for multiple looks and multiple comparisons.
d Not included in “global index.”
e Includes metastatic and non-metastatic breast cancer, with the exception of in situ cancer.
f All deaths, except from breast or colorectal cancer, definite or probable CHD, PE or
cerebrovascular disease.
g A subset of the events was combined in a “global index” defined as the earliest occurrence of
CHD events, invasive breast cancer, stroke, pulmonary embolism, colorectal cancer, hip fracture,
or death due to other causes.
Timing of the initiation of estrogen plus progestin therapy relative to the start of menopause may
affect the overall risk benefit profile. The WHI estrogen plus progestin substudy stratified by age
showed in women 50 to 59 years of age, a non-significant trend toward reduced risk for overall
mortality [HR 0.69 (95 percent CI, 0.44-1.07)].
14.3 Women’s Health Initiative Memory Study
The WHIMS estrogen-alone ancillary study of WHI enrolled 2,947 predominantly healthy
hysterectomized postmenopausal women 65 to 79 years of age and older (45 percent were
24
Reference ID: 3087017
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
65 to 69 years of age; 36 percent were 70 to 74 years of age; 19 percent were 75 years of age and
older) to evaluate the effects of daily CE (0.625 mg)-alone on the incidence of probable dementia
(primary outcome) compared to placebo.
After an average follow-up of 5.2 years, the relative risk of probable dementia for CE-alone
versus placebo was 1.49 (95 percent CI, 0.83-2.66). The absolute risk of probable dementia for
CE-alone versus placebo was 37 versus 25 cases per 10,000 women-years. Probable dementia as
defined in this study included Alzheimer’s disease (AD), vascular dementia (VaD) and mixed
types (having features of both AD and VaD). The most common classification of probable
dementia in the treatment group and the placebo group was AD. Since the ancillary study was
conducted in women 65 to 79 years of age, it is unknown whether these findings apply to
younger postmenopausal women [see Warnings and Precautions (5.4), and Use in Specific
Populations (8.5)].
The WHIMS estrogen plus progestin ancillary study of WHI enrolled 4,532 predominantly
healthy postmenopausal women 65 years of age and older (47 percent were 65 to 69 years of
age; 35 percent were 70 to 74 years; 18 percent were 75 years of age and older) to evaluate the
effects of daily CE (0.625 mg) plus MPA (2.5 mg) on the incidence of probable dementia
(primary outcome) compared to placebo.
After an average follow-up of 4 years, the relative risk of probable dementia for CE plus MPA
versus placebo was 2.05 (95 percent CI, 1.21-3.48). The absolute risk of probable dementia for
CE plus MPA versus placebo was 45 versus 22 per 10,000 women-years. Probable dementia as
defined in this study included AD, VaD and mixed types (having features of both AD and VaD).
The most common classification of probable dementia in the treatment group and the placebo
group was AD. Since the ancillary study was conducted in women 65 to 79 years of age, it is
unknown whether these findings apply to younger postmenopausal women [see Warnings and
Precautions (5.4), and Use in Specific Populations (8.5)].
When data from the two populations were pooled as planned in the WHIMS protocol, the
reported overall relative risk for probable dementia was 1.76 (95 percent CI, 1.19-2.60).
Differences between groups became apparent in the first year of treatment. It is unknown
whether these findings apply to younger postmenopausal women [see Warnings and Precautions
(5.4), and Use in Specific Populations (8.5)].
15 REFERENCES
1. Rossouw JE, et al. Postmenopausal Hormone Therapy and Risk of Cardiovascular
Disease by Age and Years Since Menopause. JAMA. 2007;297:1465-1477.
2. Hsia J, et al. Conjugated Equine Estrogens and Coronary Heart Disease. Arch Int Med.
2006;166:357-365.
3. Curb JD, et al. Venous Thrombosis and Conjugated Equine Estrogen in Women Without
a Uterus. Arch Int Med. 2006;166:772-780.
4. Cushman M, et al. Estrogen Plus Progestin and Risk of Venous Thrombosis. JAMA.
2004;292:1573-1580.
25
Reference ID: 3087017
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5. Stefanick ML, et al. Effects of Conjugated Equine Estrogens on Breast Cancer and
Mammography Screening in Postmenopausal Women With Hysterectomy. JAMA.
2006;295:1647-1657.
6. Chlebowski RT, et al. Influence of Estrogen Plus Progestin on Breast Cancer and
Mammography in Healthy Postmenopausal Women. JAMA. 2003;289:3234-3253.
7. Anderson GL, et al. Effects of Estrogen Plus Progestin on Gynecologic Cancers and
Associated Diagnostic Procedures. JAMA. 2003;290:1739-1748.
8. Shumaker SA, et al. Conjugated Equine Estrogens and Incidence of Probable Dementia
and Mild Cognitive Impairment in Postmenopausal Women. JAMA. 2004;291:2947
2958.
9. Jackson RD, et al. Effects of Conjugated Equine Estrogen on Risk of Fractures and BMD
in Postmenopausal Women With Hysterectomy: Results From the Women’s Health
Initiative Randomized Trial. J Bone Miner Res. 2006;21:817-828.
10. Hendrix SL, et al. Effects of Conjugated Equine Estrogen on Stroke in the Women’s
Health Initiative. Circulation. 2006;113:2425-2434.
16 HOW SUPPLIED/STORAGE AND HANDLING
16.1 How Supplied
PREMARIN (conjugated estrogens) Vaginal Cream—Each gram contains 0.625 mg conjugated
estrogens, USP.
Combination package: Each contains a net wt. 1.5 oz (42.5 g) tube with one plastic applicator
calibrated in 0.5 g increments to a maximum of 2 g (NDC 0046-0872-93). 16.2 Storage and
Handling
Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F)
[see USP Controlled Room Temperature].
17 PATIENT COUNSELING INFORMATION
See FDA-Approved Patient Labeling.
17.1 Vaginal Bleeding
Inform postmenopausal women of the importance of reporting vaginal bleeding to their
healthcare provider as soon as possible [see Warnings and Precautions (5.3)].
17.2 Possible Serious Adverse Reactions with Estrogen-Alone Therapy
Inform postmenopausal women of possible serious adverse reactions of estrogen-alone therapy
including Cardiovascular Disorders, Malignant Neoplasms, and Probable Dementia [see
Warnings and Precautions (5.2, 5.3, 5.4)].
26
Reference ID: 3087017
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
17.3 Possible Less Serious but Common Adverse Reactions with Estrogen-Alone Therapy
Inform postmenopausal women of possible less serious but common adverse reactions of
estrogen-alone therapy such as headache, breast pain and tenderness, nausea and vomiting.
17.4 Instructions for Use of Applicator
Step 1.
Remove cap from tube.
Step 2.
Screw nozzle end of applicator onto tube (Figure A). usage illustration
Figure A
Step 3.
Gently squeeze tube from the bottom to force sufficient cream into the barrel to
provide the prescribed dose. Use the marked stopping points on the applicator to
measure the correct dose, as prescribed by your healthcare provider (Figure B). usage illustration
Figure B
Step 4. Unscrew applicator from tube.
27
Reference ID: 3087017
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Step 5.
Lie on back with knees drawn up. To deliver medication, gently insert applicator
deeply into vagina and press plunger downward to its original position (Figure C). usage illustration
Figure C
Step 6. TO CLEANSE: Pull plunger to remove it from barrel. Wash with mild soap and
warm water (Figure D).
DO NOT BOIL OR USE HOT WATER. usage illustration
Figure D
28
Reference ID: 3087017
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
FDA-Approved Patient Labeling
PREMARIN® (conjugated estrogens) Vaginal Cream
Read this PATIENT INFORMATION before you start using PREMARIN Vaginal Cream and
read what you get each time you refill your PREMARIN Vaginal Cream prescription. There may
be new information. This information does not take the place of talking to your healthcare
provider about your menopausal symptoms or your treatment.
What is the most important information I should know about PREMARIN Vaginal Cream
(an estrogen mixture)?
Using estrogen-alone may increase your chance of getting cancer of the uterus (womb)
Report any unusual vaginal bleeding right away while you are using PREMARIN
Vaginal Cream. Vaginal bleeding after menopause may be a warning sign of cancer of
the uterus (womb). Your healthcare provider should check any unusual vaginal
bleeding to find out the cause.
Do not use estrogen-alone to prevent heart disease, heart attacks, strokes or dementia
(decline in brain function)
Using estrogen-alone may increase your chances of getting strokes or blood clots
Using estrogen-alone may increase your chance of getting dementia, based on a study
of women 65 years of age or older
Do not use estrogens with progestins to prevent heart disease, heart attacks, strokes or
dementia
Using estrogens with progestins may increase your chances of getting heart attacks,
strokes, breast cancer, or blood clots
Using estrogens with progestins may increase your chance of getting dementia, based
on a study of women age 65 years of age or older
You and your healthcare provider should talk regularly about whether you still need
treatment with PREMARIN Vaginal Cream
What is PREMARIN Vaginal Cream?
PREMARIN Vaginal Cream is a medicine that contains a mixture of estrogen hormones.
29
Reference ID: 3087017
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
What is PREMARIN Vaginal Cream used for?
PREMARIN Vaginal Cream is used after menopause to:
Treat menopausal changes in and around the vagina
You and your healthcare provider should talk regularly about whether you still need
treatment with PREMARIN Vaginal Cream to control these problems.
Treat painful intercourse caused by menopausal changes of the vagina
Who should not use PREMARIN Vaginal Cream?
Do not start using PREMARIN Vaginal Cream if you:
Have unusual vaginal bleeding
Currently have or have had certain cancers
Estrogens may increase the chance of getting certain types of cancers, including cancer of
the breast or uterus. If you have or have had cancer, talk with your healthcare provider
about whether you should use PREMARIN Vaginal Cream.
Had a stroke or heart attack
Currently have or have had blood clots
Currently have or have had liver problems
Have been diagnosed with a bleeding disorder
Are allergic to PREMARIN Vaginal Cream or any of its ingredients
See the list of ingredients in PREMARIN Vaginal Cream at the end of this leaflet.
Think you may be pregnant
Tell your healthcare provider:
If you have unusual vaginal bleeding
Vaginal bleeding after menopause may be a warning sign of cancer of the uterus (womb).
Your healthcare provider should check any unusual vaginal bleeding to find out the cause.
About all of your medical problems
Your healthcare provider may need to check you more carefully if you have certain
conditions, such as asthma (wheezing), epilepsy (seizures), diabetes, migraine,
endometriosis, lupus, or problems with your heart, liver, thyroid, kidneys, or have high
calcium levels in your blood.
30
Reference ID: 3087017
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
About all the medicines you take
This includes prescription and nonprescription medicines, vitamins, and herbal
supplements. Some medicines may affect how PREMARIN Vaginal Cream works.
PREMARIN Vaginal Cream may also affect how your other medicines work.
If you are going to have surgery or will be on bedrest
You may need to stop using PREMARIN Vaginal Cream.
If you are breast feeding
The estrogen hormones in PREMARIN Vaginal Cream can pass into your breast milk.
How should I use PREMARIN Vaginal Cream?
PREMARIN Vaginal Cream is a cream that you place in your vagina with the applicator
provided with the cream.
Take the dose recommended by your healthcare provider and talk to him or her about
how well that dose is working for you
Estrogens should be used at the lowest dose possible for your treatment only as long as
needed. You and your healthcare provider should talk regularly (for example, every 3 to 6
months) about the dose you are taking and whether you still need treatment with
PREMARIN Vaginal Cream
Step 1.
Remove cap from tube.
Step 2.
Screw nozzle end of applicator onto tube (Figure A). usage illustration
Figure A
Step 3.
Gently squeeze tube from the bottom to force sufficient cream into the barrel to
provide the prescribed dose. Use the marked stopping points on the applicator to
measure the correct dose, as prescribed by your healthcare provider (Figure B).
31
Reference ID: 3087017
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
usage illustration
Step 4.
Figure B
Unscrew applicator from tube.
Step 5.
Lie on back with knees drawn up. To deliver medication, gently insert applicator
deeply into vagina and press plunger downward to its original position (Figure C). usage illustration
Figure C
Step 6. TO CLEANSE: Pull plunger to remove it from barrel. Wash with mild soap and
warm water (Figure D).
32
Reference ID: 3087017
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
DO NOT BOIL OR USE HOT WATER. usage illustration
Figure D
What are the possible side effects of PREMARIN Vaginal Cream?
PREMARIN Vaginal Cream is only used in and around the vagina; however, the risks associated
with oral estrogens should be taken into account.
Side effects are grouped by how serious they are and how often they happen when you are
treated.
Serious, but less common side effects include:
Heart attack
Stroke
Blood clots
Dementia
Breast cancer
Cancer of the lining of the uterus (womb)
Cancer of the ovary
High blood pressure
High blood sugar
Gallbladder disease
33
Reference ID: 3087017
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Liver problems
Enlargement of benign tumors of the uterus (“fibroids”)
Severe allergic reaction
Call your healthcare provider right away if you get any of the following warning signs or
any other unusual symptoms that concern you:
New breast lumps
Unusual vaginal bleeding
Changes in vision or speech
Sudden new severe headaches
Severe pains in your chest or legs with or without shortness of breath, weakness and
fatigue
Swollen lips, tongue or face
Less serious, but common side effects include:
Headache
Breast pain
Irregular vaginal bleeding or spotting
Stomach or abdominal cramps, bloating
Nausea and vomiting
Hair loss
Fluid retention
Vaginal yeast infection
Reactions from inserting PREMARIN Vaginal Cream, such as vaginal burning, irritation,
and itching
These are not all the possible side effects of PREMARIN Vaginal Cream. For more information,
ask your healthcare provider or pharmacist for advice about side effects. You may report side
effects to Pfizer Inc. at 1-800-438-1985 or to FDA at 1-800-FDA-1088.
34
Reference ID: 3087017
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
What can I do to lower my chances of getting a serious side effect with PREMARIN
Vaginal Cream?
Talk with your healthcare provider regularly about whether you should continue using
PREMARIN Vaginal Cream
If you have a uterus, talk with your healthcare provider about whether the addition of a
progestin is right for you
The addition of a progestin is generally recommended for a woman with a uterus to reduce
the chance of getting cancer of the uterus. See your healthcare provider right away if you
get vaginal bleeding while using PREMARIN Vaginal Cream.
Have a pelvic exam, breast exam and mammogram (breast X-ray) every year unless your
healthcare provider tells you something else
If members of your family have had breast cancer or if you have ever had breast lumps or
an abnormal mammogram, you may need to have breast exams more often.
If you have high blood pressure, high cholesterol (fat in the blood), diabetes, are
overweight, or if you use tobacco, you may have higher chances for getting heart disease
Ask your healthcare provider for ways to lower your chances for getting heart disease.
General information about the safe and effective use of PREMARIN Vaginal Cream
Medicines are sometimes prescribed for conditions that are not mentioned in patient information
leaflets. Do not use PREMARIN Vaginal Cream for conditions for which it was not prescribed.
Do not give PREMARIN Vaginal Cream to other people, even if they have the same symptoms
you have. It may harm them.
Keep PREMARIN Vaginal Cream out of the reach of children.
Latex or rubber condoms, diaphragms and cervical caps may be weakened and fail when they
come into contact with PREMARIN Vaginal Cream.
This leaflet provides a summary of the most important information about PREMARIN Vaginal
Cream. If you would like more information, talk with your healthcare provider or pharmacist.
You can ask for information about PREMARIN Vaginal Cream that is written for health
professionals. You can get more information by calling the toll free number 1-800-438-1985.
35
Reference ID: 3087017
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
What are the ingredients in PREMARIN Vaginal Cream?
PREMARIN Vaginal Cream contains a mixture of conjugated estrogens, which are a mixture of
sodium estrone sulfate and sodium equilin sulfate and other components, including sodium
sulfate conjugates: 17 α-dihydroequilin, 17 α-estradiol, and 17 β-dihydroequilin. PREMARIN
Vaginal Cream also contains cetyl esters wax, cetyl alcohol, white wax, glyceryl monostearate,
propylene glycol monostearate, methyl stearate, benzyl alcohol, sodium lauryl sulfate, glycerin,
and mineral oil.
PREMARIN (conjugated estrogens) Vaginal Cream—Each gram contains 0.625 mg conjugated
estrogens, USP.
Combination package: Each contains a net wt. 1.5 oz (42.5 g) tube with one plastic applicator
calibrated in 0.5 g increments to a maximum of 2 g (NDC 0046-0872-93).
Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F)
[see USP Controlled Room Temperature]. company logo
LAB-0498-2.0
Rev 0X/2011
36
Reference ID: 3087017
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
«TEAR HERE
FDA-Approved Patient Labeling
PREMARIN® (conjugated estrogens) Vaginal Cream
Read this PATIENT INFORMATION before you start using PREMARIN Vaginal Cream and
read what you get each time you refill your PREMARIN Vaginal Cream prescription. There may
be new information. This information does not take the place of talking to your healthcare
provider about your menopausal symptoms or your treatment.
What is the most important information I should know about PREMARIN Vaginal Cream
(an estrogen mixture)?
Using estrogen-alone may increase your chance of getting cancer of the uterus (womb)
Report any unusual vaginal bleeding right away while you are using PREMARIN
Vaginal Cream. Vaginal bleeding after menopause may be a warning sign of cancer of
the uterus (womb). Your healthcare provider should check any unusual vaginal bleeding
to find out the cause.
Do not use estrogen-alone to prevent heart disease, heart attacks, strokes or dementia
(decline in brain function)
Using estrogen-alone may increase your chances of getting strokes or blood clots
Using estrogen-alone may increase your chance of getting dementia, based on a study of
women age 65 years of age or older
Do not use estrogens with progestins to prevent heart disease, heart attacks, strokes or
dementia
Using estrogens with progestins may increase your chances of getting heart attacks,
strokes, breast cancer, or blood clots
Using estrogens with progestins may increase your chance of getting dementia, based on
a study of women age 65 years of age or older
You and your healthcare provider should talk regularly about whether you still need
treatment with PREMARIN Vaginal Cream
What is PREMARIN Vaginal Cream?
PREMARIN Vaginal Cream is a medicine that contains a mixture of estrogen hormones.
37
Reference ID: 3087017
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
What is PREMARIN Vaginal Cream used for?
PREMARIN Vaginal Cream is used after menopause to:
Treat menopausal changes in and around the vagina
You and your healthcare provider should talk regularly about whether you still need
treatment with PREMARIN Vaginal Cream to control these problems.
Treat painful intercourse caused by menopausal changes of the vagina
Who should not use PREMARIN Vaginal Cream?
Do not start using PREMARIN Vaginal Cream if you:
Have unusual vaginal bleeding
Currently have or have had certain cancers
Estrogens may increase the chance of getting certain types of cancers, including cancer of
the breast or uterus. If you have or have had cancer, talk with your healthcare provider
about whether you should use PREMARIN Vaginal Cream.
Had a stroke or heart attack
Currently have or have had blood clots
Currently have or have had liver problems
Have been diagnosed with a bleeding disorder
Are allergic to PREMARIN Vaginal Cream or any of its ingredients
See the list of ingredients in PREMARIN Vaginal Cream at the end of this leaflet.
Think you may be pregnant
Tell your healthcare provider:
If you have unusual vaginal bleeding
Vaginal bleeding after menopause may be a warning sign of cancer of the uterus (womb).
Your healthcare provider should check any unusual vaginal bleeding to find out the cause.
About all of your medical problems
Your healthcare provider may need to check you more carefully if you have certain
conditions, such as asthma (wheezing), epilepsy (seizures), diabetes, migraine,
endometriosis, lupus, or problems with your heart, liver, thyroid, kidneys, or have high
calcium levels in your blood.
38
Reference ID: 3087017
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
About all the medicines you take
This includes prescription and nonprescription medicines, vitamins, and herbal
supplements. Some medicines may affect how PREMARIN Vaginal Cream works.
PREMARIN Vaginal Cream may also affect how your other medicines work.
If you are going to have surgery or will be on bedrest
You may need to stop using PREMARIN Vaginal Cream.
If you are breast feeding
The estrogen hormones in PREMARIN Vaginal Cream can pass into your breast milk.
How should I use PREMARIN Vaginal Cream?
PREMARIN Vaginal Cream is a cream that you place in your vagina with the applicator
provided with the cream.
Take the dose recommended by your healthcare provider and talk to him or her about
how well that dose is working for you
Estrogens should be used at the lowest dose possible for your treatment only as long as
needed. You and your healthcare provider should talk regularly (for example, every 3 to 6
months) about the dose you are taking and whether you still need treatment with
PREMARIN Vaginal Cream
Step 1.
Remove cap from tube.
Step 2.
Screw nozzle end of applicator onto tube (Figure A). usage illustration
Figure A
Step 3.
Gently squeeze tube from the bottom to force sufficient cream into the barrel to
provide the prescribed dose. Use the marked stopping points on the applicator to
measure the correct dose, as prescribed by your healthcare provider (Figure B).
39
Reference ID: 3087017
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
usage illustration
Figure B
Step 4.
Step 5.
Unscrew applicator from tube.
Lie on back with knees drawn up. To deliver medication, gently insert applicator
deeply into vagina and press plunger downward to its original position (Figure C). usage illustration
Figure C
40
Reference ID: 3087017
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Step 6. TO CLEANSE: Pull plunger to remove it from barrel. Wash with mild soap and
warm water (Figure D).
DO NOT BOIL OR USE HOT WATER. usage illustration
Figure D
What are the possible side effects of PREMARIN Vaginal Cream?
PREMARIN Vaginal Cream is only used in and around the vagina; however, the risks associated
with oral estrogens should be taken into account.
Side effects are grouped by how serious they are and how often they happen when you are
treated.
Serious, but less common side effects include:
Heart attack
Stroke
Blood clots
Dementia
Breast cancer
Cancer of the lining of the uterus (womb)
Cancer of the ovary
High blood pressure
High blood sugar
Gallbladder disease
Liver problems
Reference ID: 3087017
41
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Enlargement of benign tumors of the uterus (“fibroids”)
Severe allergic reaction
Call your healthcare provider right away if you get any of the following warning signed or
any other unusual symptoms that concern you:
New breast lumps
Unusual vaginal bleeding
Changes in vision or speech
Sudden new severe headaches
Severe pains in your chest or legs with or without shortness of breath, weakness and
fatigue
Swollen lips, tongue or face
Less serious, but common side effects include:
Headache
Breast pain
Irregular vaginal bleeding or spotting
Stomach or abdominal cramps, bloating
Nausea and vomiting
Hair loss
Fluid retention
Vaginal yeast infection
Reactions from inserting PREMARIN Vaginal Cream, such as vaginal burning, irritation,
and itching
These are not all the possible side effects of PREMARIN Vaginal Cream. For more information,
ask your healthcare provider or pharmacist for advice about side effects. You may report side
effects to Pfizer Inc. at 1-800-438-1985 or to FDA at 1-800-FDA-1088.
What can I do to lower my chances of getting a serious side effect with PREMARIN
Vaginal Cream?
42
Reference ID: 3087017
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Talk with your healthcare provider regularly about whether you should continue using
PREMARIN Vaginal Cream
If you have a uterus, talk with your healthcare provider about whether the addition of a
progestin is right for you
The addition of a progestin is generally recommended for a woman with a uterus to reduce
the chance of getting cancer of the uterus. See your healthcare provider right away if you
get vaginal bleeding while using PREMARIN Vaginal Cream.
Have a pelvic exam, breast exam and mammogram (breast X-ray) every year unless your
healthcare provider tells you something else
If members of your family have had breast cancer or if you have ever had breast lumps or
an abnormal mammogram, you may need to have breast exams more often.
If you have high blood pressure, high cholesterol (fat in the blood), diabetes, are
overweight, or if you use tobacco, you may have higher chances for getting heart disease
Ask your healthcare provider for ways to lower your chances for getting heart disease.
General information about the safe and effective use of PREMARIN Vaginal Cream
Medicines are sometimes prescribed for conditions that are not mentioned in patient information
leaflets. Do not use PREMARIN Vaginal Cream for conditions for which it was not prescribed.
Do not give PREMARIN Vaginal Cream to other people, even if they have the same symptoms
you have. It may harm them.
Keep PREMARIN Vaginal Cream out of the reach of children.
Latex or rubber condoms, diaphragms and cervical caps may be weakened and fail when they
come into contact with PREMARIN Vaginal Cream.
This leaflet provides a summary of the most important information about PREMARIN Vaginal
Cream. If you would like more information, talk with your healthcare provider or pharmacist.
You can ask for information about PREMARIN Vaginal Cream that is written for health
professionals. You can get more information by calling the toll free number 1-800-438-1985.
What are the ingredients in PREMARIN Vaginal Cream?
PREMARIN Vaginal Cream contains a mixture of conjugated estrogens, which are a mixture of
sodium estrone sulfate and sodium equilin sulfate and other components, including sodium
sulfate conjugates: 17 α-dihydroequilin, 17 α-estradiol, and 17 β-dihydroequilin. PREMARIN
Vaginal Cream also contains cetyl esters wax, cetyl alcohol, white wax, glyceryl monostearate,
propylene glycol monostearate, methyl stearate, benzyl alcohol, sodium lauryl sulfate, glycerin,
and mineral oil.
43
Reference ID: 3087017
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PREMARIN (conjugated estrogens) Vaginal Cream—Each gram contains 0.625 mg conjugated
estrogens, USP.
Combination package: Each contains a net wt. 1.5 oz (42.5 g) tube with one plastic applicator
calibrated in 0.5 g increments to a maximum of 2 g (NDC 0046-0872-93).
Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F)
[see USP Controlled Room Temperature].
This product’s label may have been updated. For current package insert and
further product information, please visit www.pfizer.com or call our m edical
communications department toll-free at 1-800-438-1985. company logo
LAB-0519-2.0
Rev 02/2012
44
Reference ID: 3087017
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:47:02.749493
|
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|
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______________________________________________________________________________________________________________________________
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to
use ULTRAVIST Injection safely and effectively. See full
prescribing information for ULTRAVIST Injection.
ULTRAVIST (iopromide) Injection, for intravenous or intra
arterial use
Initial U.S. Approval: 1995
WARNING: NOT FOR INTRATHECAL USE
Inadvertent intrathecal administration may cause death,
convulsions, cerebral hemorrhage, coma, paralysis,
arachnoiditis, acute renal failure, cardiac arrest, seizures,
rhabdomyolysis, hyperthermia, and brain edema.
------------------------RECENT MAJOR CHANGES--------------
Indications and Usage (1.2)
12/2009
Dosage and Administration (2.2)
12/2009
------------------------INDICATIONS AND USAGE--------------
ULTRAVIST (iopromide) Injection is a radiographic contrast
agent indicated for:
• Intra-arterial digital subtraction angiography (IA-DSA)
(150 mgI/mL) (1.1)
• Cerebral arteriography and peripheral arteriography
(300 mgI/mL) (1.1)
• Coronary arteriography and left ventriculography, visceral
angiography and aortography (370 mgI/mL) (1.1)
• Peripheral venography (240 mgI/mL) (1.2)
• Contrast computed tomography (CT) imaging of head and
body (300 mgI/mL and 370 mgI/mL) (1.2)
• Excretory urography (300 mgI/mL) (1.2)
----------------------DOSAGE AND ADMINISTRATION-----------
Carefully individualize the volume and concentration of
ULTRAVIST Injection to be used for a vascular procedure,
according to the specific dosing tables. Adjust the dose accounting
for factors such as age, body weight, size of the vessel and the rate
of blood flow within the vessel. (2)
---------------------DOSAGE FORMS AND STRENGTHS---------
ULTRAVIST Injection is available in four strengths: 150 mgI/mL;
240 mgI/mL; 300 mgI/mL; 370 mgI/mL. (3)
-------------------------------CONTRAINDICATIONS----------------
•
ULTRAVIST Injection is contraindicated for intrathecal use.
(4)
•
Preparatory dehydration (e.g. prolonged fasting and the
administration of a laxative before ULTRAVIST Injection) is
contraindicated in pediatric patients because of risk of renal
failure. (4)
-----------------------WARNINGS AND PRECAUTIONS----------
•
Anaphylactoid Reactions: Life-threatening or fatal
anaphylactoid reactions may occur during or after Ultravist
administration, particularly in patients with allergic disorders.
(5.1)
•
Acute Renal Failure: Acute renal failure may occur following
ULTRAVIST administration, particularly in patients with
renal insufficiency, diabetes, multiple myeloma. Exercise
caution and use the lowest necessary dose of ULTRAVIST in
patients with renal dysfunction. (5.2)
•
Cardiovascular Reactions: Hemodynamic disturbances
including shock and cardiac arrest may occur during or
shortly after administration of ULTRAVIST.(5.3)
•
Thromboembolic Complications: Angiography may be
associated with local and distal organ damage, ischemia,
thromboembolism and organ failure. In angiographic
procedures, consider the possibility of dislodging plaques or
damaging or perforating the vessel wall. The
physicochemical properties of the contrast agent, the dose
and the speed of injection can influence the reactions. (5.4)
------------------------------ADVERSE REACTIONS------------------
Most common adverse reactions (>1%) are headache, dysguesia,
abnormal vision, chest pain, vasodilatation, nausea, vomiting, back
pain, urinary urgency, injection site and infusion site reactions, and
pain. (6)
To report SUSPECTED ADVERSE REACTIONS, contact
Bayer HealthCare Pharmaceuticals Inc. at 1-888-842-2937 or
FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
------------------------------DRUG INTERACTIONS------------------
•
Do not mix other drugs with ULTRAVIST Injection. (7)
•
Stop biguanides (e.g. metformin) 48 hours before the
contrast medium examination and withhold 48 hours after the
procedure. (7)
-----------------------USE IN SPECIFIC POPULATIONS----------
•
Adequate and well-controlled studies in pregnant women
have not been conducted. Because animal reproduction
studies are not always predictive of human response, this
drug should be used during pregnancy only if clearly needed.
(8.1)
•
The safety and efficacy of ULTRAVIST Injection have been
established in the pediatric population over 2 years of age.
(8.4)
See 17 for PATIENT COUNSELING INFORMATION.
Revised: 11/2009
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
______________________________________________________________________________________________________________________________
FULL PRESCRIBING INFORMATION: CONTENTS*
7
DRUG INTERACTIONS
7.1 Drug-Drug Interactions
WARNING: NOT FOR INTRATHECAL USE
7.2 Drug/Laboratory Test Interactions
8
USE IN SPECIFIC POPULATIONS
1
INDICATIONS AND USAGE
8.1 Pregnancy
1.1 Intra-Arterial Procedures
8.3 Nursing Mothers
1.2 Intravenous Procedures
8.4 Pediatric Use
2
DOSAGE AND ADMINISTRATION
8.5 Geriatric Use
2.1 Intra-Arterial Procedures
8.6 Renal Impairment
2.2 Intravenous Procedures
10 OVERDOSAGE
2.3 Pediatric Dosing
11 DESCRIPTION
3
DOSAGE FORMS AND STRENGTHS
12 CLINICAL PHARMACOLOGY
4
CONTRAINDICATIONS
12.1
Mechanism of Action
5
WARNINGS AND PRECAUTIONS
12.2
Pharmacodynamics
5.1 Anaphylactoid Reactions
12.3
Pharmacokinetics
5.2 Acute Renal Failure
13 NONCLINICAL TOXICOLOGY
5.3 Cardiovascular Reactions
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
5.4 Thromboembolic Complications
14 CLINICAL STUDIES
5.5 Reactions in Patients with Hyperthyroidism,
16 HOW SUPPLIED/STORAGE AND HANDLING
Pheochromocytoma, or Sickle Cell Disease
17 PATIENT COUNSELING INFORMATION
5.6 Extravasation
5.7 Increased Radiation Exposure
5.8 Interference with Image Interpretation
6
ADVERSE REACTIONS
6.1 Clinical Trials Experience
6.2 Postmarketing Experience
*Sections or subsections omitted from the full prescribing
6.3 Pediatrics
information are not listed.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
FULL PRESCRIBING INFORMATION
1
INDICATIONS AND USAGE
ULTRAVIST
® Injection is an iodinated contrast agent indicated for:
1.1
Intra-arterial Procedures*
• 150 mgI/mL for intra-arterial digital subtraction angiography (IA-DSA)
• 300 mgI/mL for cerebral arteriography and peripheral arteriography
• 370 mgI/mL for coronary arteriography and left ventriculography, visceral angiography, and aortography
1.2
Intravenous Procedures*
• 240 mgI/mL for peripheral venography
• 300 mgI/mL for excretory urography
• 300 mgI/mL and 370 mgl/mL for contrast Computed Tomography (CT) of the head and body (intrathoracic, intra-abdominal and retroperitoneal
regions) for the evaluation of neoplastic and non-neoplastic lesions. The usefulness of contrast enhancement for the investigation of the
retrobulbar space and of low grade or infiltrative glioma has not been demonstrated
*For information on the concentrations and doses for the Pediatric Population [see Dosage and Administration (2.3) and Use in Specific
Populations (8.4)].
2. DOSAGE AND ADMINISTRATION
•
Visually inspect ULTRAVIST for particulate matter and/or discoloration, whenever solution and container permit. Do not administer
ULTRAVIST if particulate matter and/or discoloration is observed.
•
Determine the volume and concentration of ULTRAVIST Injection to be used taking into account factors such as age, body weight, size
of the vessel and the rate of blood flow within the vessel; consider also extent of opacification required, structure(s) or area to be
examined, disease processes affecting the patient, and equipment and technique to be employed. Specific dose adjustments for age,
gender, weight and renal function have not been studied for ULTRAVIST Injection. As with all iodinated contrast agents, lower doses
may have less risk. The efficacy of ULTRAVIST Injection below doses recommended has not been established.
•
The maximum recommended total dose of iodine in adults is 86 grams; a maximum recommended total dose of iodine has not been
established for pediatric patients.
•
Hydrate patients adequately prior to and following the intravascular administration of ULTRAVIST. [See Warnings and Precautions
(5.2).]
2.1 Intra-Arterial Procedures
The volume and rate of injection of the contrast agent will vary depending on the injection site and the area being examined. Inject contrast at
rates approximately equal to the flow rate in the vessel being injected.
•
Cerebral Arteriography (300 mgI/mL), Coronary Arteriography and Left Ventriculography (370 mgI/mL), Peripheral Arteriography
(300 mgI/mL), Intra-arterial Digital Subtraction Angiography (IA-DSA) (150 mgI/mL): see Table 1.
•
Aortography and Visceral Angiography (370 mgI/mL):
Use a volume and rate of contrast injection proportional to the blood flow and related to the vascular and pathological characteristics of
the specific vessels being studied. Do not exceed 225 ml as total dose for the procedure.
Table 1: Suggested Single Injection Doses for Adult Intra-Arterial Procedures
IA-DSA*
(150 mgI/mL)
Cerebral
Arteriography
(300 mgI/mL)
Peripheral
Arteriography
(300 mgI/mL)
Coronary Arteriography
and Left Ventriculography
(370 mgI/mL)
Intra-Arterial Injection
Sites
Carotid Arteries
Vertebral Arteries
Aortic Arch Injection (4 vessel study)
6-10 mL
4-8 mL
-
3-12 mL
4-12 mL
20-50 mL
-
-
-
-
-
-
Right Coronary Artery
Left Coronary Artery
Left Ventricle
-
-
-
-
-
-
-
-
-
3-14 mL
3-14 mL
30-60 mL
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Aorta
Major Branches of the Abdominal Aorta
20-50 mL
2-20 mL
-
-
-
-
-
-
Subclavian or Femoral Artery
Aortic Bifurcation (distal runoff)
-
-
-
-
5-40 mL
25-50 mL
-
-
Maximum Total Dose
250 mL
150 mL
250 mL
225 mL
*IA-DSA = Intra-Arterial Digital Subtraction Angiography
2.2 Intravenous Procedures
•
Peripheral Venography (240 mgI/mL):
Inject the minimum volume necessary to visualize satisfactorily the structures under examination. Do not exceed 250 mL as total dose for
the procedure.
•
Contrast Computed Tomography (CT) (300 mgI/mL and 370 mgI/mL) and Excretory Urography (300 mgI/mL): see Table 2.
Table 2: Suggested Ultravist Injection Dosing for Adult Intravenous Contrast Administration
Excretory Urography
(300 mgI/mL)
Contrast Computed
Tomography (300 mgI/mL)
Contrast Computed
Tomography (370 mgI/mL)
Excretory Urography
Approximately 300
mgI/kg body wt.
(Adults with normal
renal function)
-
-
Head
-
50-200 mL
41-162 mL
Body: Bolus Injection
Rapid Infusion
-
-
50-200 mL
100-200 mL
41-162 mL
81-162 mL
Maximum Total Dose
100 mL
200 mL (60 g iodine)
162 mL (60 g iodine)
2.3 Pediatric Dosing
The recommended dose in children over 2 years of age for the following evaluations is:
•
Intra-arterial:
Cardiac chambers and related arteries (370 mgI/mL):
Inject 1 to 2 milliliters per kilogram (mL/kg). Do not exceed 4 mL/kg as total dose.
•
Intravenous:
Contrast Computerized Tomography or Excretory Urography (300 mgI/mL):
Inject 1 to 2 mL/kg. Do not exceed 3mL/kg as total dose.
The safety and efficacy relationships of other doses, concentrations or procedures have not been established. [See Use in Specific Populations
(8.4) and Clinical Pharmacology (12.3).]
3. DOSAGE FORMS AND STRENGTHS
ULTRAVIST Injection is a nonionic, sterile, clear, colorless to slightly yellow, odorless, pyrogen-free aqueous solution of iopromide, containing
2.42 mg/mL tromethamine buffer and 0.1 mg/mL edetate calcium disodium stabilizer.
ULTRAVIST Injection is available in four strengths:
150 mgI/mL provides 311.7 mg/mL iopromide,
240 mgI/mL provides 498.72 mg/mL iopromide,
300 mgI/mL provides 623.4 mg/mL iopromide,
370 mgI/mL provides 768.86 mg/mL iopromide.
4. CONTRAINDICATIONS
•
Do not administer ULTRAVIST Injection intrathecally. Inadvertent intrathecal administration may cause death, convulsions, cerebral
hemorrhage, coma, paralysis, arachnoiditis, acute renal failure, cardiac arrest, seizures, rhabdomyolysis, hyperthermia, and brain
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
edema.
•
Preparatory dehydration (e.g. prolonged fasting and the administration of a laxative) before ULTRAVIST Injection is contraindicated
in pediatric patients because of risk of acute renal failure.
5. WARNINGS AND PRECAUTIONS
5.1 Anaphylactoid Reactions
Life-threatening or fatal, anaphylactoid reactions, may occur during or after ULTRAVIST administration. Manifestations include respiratory
arrest, laryngospasm, bronchospasm, angioedema, and shock. Increased risk is associated with a history of previous reaction to a contrast agent
(3-fold), a known sensitivity to iodine and known allergic disorders (i.e., bronchial asthma, hay fever and food allergies) or other
hypersensitivities (2-fold), [see Drug Interactions (7.1).] Exercise extreme caution when considering the use of iodinated contrast agents in
patients with these histories or disorders.
Emergency facilities and personnel trained in the treatment of anaphylactoid reactions should be available for at least 30 to 60 minutes after
ULTRAVIST administration.
5.2 Acute Renal Failure
Acute renal insufficiency or failure may occur following ULTRAVIST administration, particularly in patients with advanced vascular disease,
congestive heart disease, diabetes, multiple myeloma or other paraproteinacious diseases, patients on medications which alter renal function and
the elderly with age-related renal impairment. ULTRAVIST is cleared by glomerular filtration; patients with renal insufficiency have increased
systemic exposure to ULTRAVIST as compared to patients with normal renal function [see Use in Specific Populations (8.6)].
Exercise caution and use the lowest necessary dose of ULTRAVIST in patients with renal insufficiency. Adequately hydrate patients prior to and
following ULTRAVIST administration. Patients with congestive heart failure receiving concurrent diuretic therapy may have relative
intravascular volume depletion, which may affect the renal response to the contrast agent osmotic load. Observe such patients for several hours
following the procedure to detect delayed hemodynamic renal function disturbances.
5.3 Cardiovascular Reactions
The increase in the circulatory osmotic load may induce acute or delayed hemodynamic disturbances in patients with congestive heart failure,
severely impaired renal function, combined renal and hepatic disease, combined renal and cardiac disease, particularly when repetitive and/or
large doses are administered. [See Drug Interactions (7)]
Among patients who have had cardiovascular reactions, most deaths occurred from the start of injection to 10 minutes later; the main feature was
cardiac arrest with cardiovascular disease as the main underlying factor. Isolated reports of hypotensive collapse and shock have been published.
Based upon published reports, deaths from the administration of iodinated contrast agents range from 6.6 per 1 million (0.00066 percent) to 1 in
10,000 patients (0.01 percent). Observe patients with preexisting cardiovascular disease for several hours following ULTRAVIST administration.
5.4 Thromboembolic Complications
•
Angiography may be associated with local and distal organ damage, ischemia, thromboembolism and organ failure including stroke,
brachial plexus palsy, chest pain, myocardial infarction, sinus arrest, hepato-renal function abnormalities. For these reasons,
meticulous angiographic techniques are recommended, including close attention to guide wire and catheter manipulation, use of
manifold systems and/or three-way stopcocks, frequent catheter flushing with heparinized saline solutions and minimizing the length
of the procedure. In angiographic procedures, consider the possibility of dislodging plaques or damaging or perforating the vessel wall
with resultant pseudoaneurysms, hemorrhage at puncture site, dissection of coronary artery during catheter manipulations and contrast
agent injection. The physicochemical properties of the contrast agent, the dose and the speed of injection can influence the reactions.
Test injections to ensure proper catheter placement are suggested. Increased thrombosis and activation of the complement system has
also occurred. Specialized personnel, and adequate equipment and facilities for immediate resuscitation and cardioversion are
necessary. Monitor electrocardiograms and vital signs throughout the procedure.
•
Exercise care when performing venography in patients with suspected thrombosis, phlebitis, severe ischemic disease, local infection,
venous thrombosis or a totally obstructed venous system.
•
Clotting may occur when blood remains in contact with syringes containing iodinated contrast agents.
•
Avoid angiography whenever possible in patients with homocystinuria because of the risk of inducing thrombosis and embolism [see
Clinical Pharmacology (12.2)].
5.5 Reactions in Patients with Hyperthyroidism, Pheochromocytoma, or Sickle Cell Disease
Thyroid storm in patients with hyperthyroidism. Thyroid storm has occurred after the intravascular use of iodinated contrast agents in patients
with hyperthyroidism, or with an autonomously functioning thyroid nodule. Evaluate the risk in such patients before use of any iodinated contrast
agent.
Hypertensive crises in patients with pheochromocytoma. Administer iodinated contrast agents with extreme caution in patients with known or
suspected of having pheochromocytoma. Inject the minimum amount of contrast necessary. Assess the blood pressure throughout the procedure,
and have measures for treatment of a hypertensive crisis readily available.
Sickle cell disease. Contrast agents may promote sickling in individuals who are homozygous for sickle cell disease when administered intra
vascularly.
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5.6 Extravasation
Extravasation of ULTRAVIST Injection may cause tissue necrosis and/or compartment syndrome, particularly in patients with severe arterial or
venous disease.
5.7 Increased Radiation Exposure
The decision to use contrast enhancement is associated with risk and increased radiation exposure. Use contrast after a careful evaluation of
clinical, other radiologic data, and the results of non-contrast CT findings, taking into account the increased radiation dose and other risks.
5.8 Interference with Image Interpretation
As with other iodinated contrast agents, the use of ULTRAVIST Injection may obscure some lesions which were seen on non-contrast CT scans.
Calcified lesions are less likely to enhance. The enhancement of tumors after therapy may decrease. The opacification of the inferior vermis
following contrast agent administration has resulted in false-positive diagnosis. Cerebral infarctions of recent onset may be better visualized with
contrast enhancement. However, older infarctions may be obscured by the contrast agent.
In patients with normal blood-brain barriers and renal failure, iodinated contrast agents have been associated with blood-brain barrier disruption
and accumulation of contrast in the brain. Accumulation of contrast in the brain also occurs in patients where the blood-brain barrier is known or
suspected to be disrupted.
6. ADVERSE REACTIONS
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be
directly compared to rates in the clinical trials of another drug and may not reflect or predict the rates observed in practice.
The following table of incidence of reactions is based upon controlled clinical trials in which ULTRAVIST Injection was administered to 1142
patients. This listing includes all reported adverse reactions regardless of attribution.
Adverse reactions are listed by System Organ Class and in decreasing order of occurrence for rates greater than 1% in the ULTRAVIST group.
Table 3: ADVERSE REACTIONS REPORTED IN > 1% OF PATIENTS WHO RECEIVED
ULTRAVIST INJECTION IN CLINICAL TRIALS
System Organ Class
Adverse Reaction
Ultravist Injection
N= 1142 (%)
Nervous system disorders
Headache
46 (4)
Dysgeusia
15 (1.3)
Eye disorders
Abnormal Vision
12 (1.1)
Cardiac disorders
Chest pain
18 (1.6)
Vascular disorders
Vasodilatation
30 (2.6)
Gastrointestinal disorders
Nausea
42 (3.7)
Vomiting
22 (1.9)
Musculoskeletal and connective tissue disorders
Back pain
22 (1.9)
Renal and urinary disorders
Urinary urgency
21 (1.8)
General disorders and administration site
conditions
Injection site and infusion site
reactions (hemorrhage, hematoma,
pain, edema, erythema, rash)
41 (3.7)
Pain
13 (1.4)
One or more adverse reactions were recorded in 273 of 1142 (24%) patients during the clinical trials, coincident with the administration of
ULTRAVIST Injection or within the defined duration of the study follow-up period (24–72 hours). ULTRAVIST Injection is often associated
with sensations of warmth and/or pain.
Serious, life-threatening and fatal reactions have been associated with the administration of iodine-containing contrast media, including
ULTRAVIST Injection. In clinical trials 7/1142 patients given ULTRAVIST Injection died 5 days or later after drug administration. Also,
10/1142 patients given ULTRAVIST Injection had serious adverse events.
The following adverse reactions were observed in ≤1% of the subjects receiving ULTRAVIST Injection:
Cardiac disorders: atrio ventricular block (complete), bradycardia, ventricular extrasystole;
Gastrointestinal disorders: abdominal discomfort, abdominal pain, abdominal pain upper, constipation, diarrhea, dry mouth, dyspepsia,
gastrointestinal disorder, gastrointestinal pain, salivation increased, stomach discomfort, rectal tenesmus;
General disorders and administration site conditions: asthenia, chest discomfort, chills, excessive thirst, extravasation, feeling hot,
hyperhydrosis, malaise, edema peripheral, pyrexia;
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Immune system disorders: asthma, face edema;
Investigations: blood lactate dehydrogenase increased, blood urea increased, hemoglobin increased, white blood cell count increased;
Musculoskeletal and connective tissue disorders: arthralgia, musculoskeletal pain, myasthenia, neck pain, pain in extremity;
Nervous system disorders: agitation, confusion, convulsion, dizziness, hypertonia, hypesthesia, incoordination, neuropathy, somnolence, speech
disorder, tremor, paresthesia, visual field defect;
Psychiatric disorders: anxiety;
Renal and urinary disorders: dysuria, renal pain, urinary retention;
Respiratory, thoracic and mediastinal disorders: apnea, cough increased, dyspnea, hypoxia, pharyngeal edema, pharyngitis, pleural effusion,
pulmonary hypertension, respiratory disorder, sore throat;
Skin and subcutaneous tissue disorders: erythema, pruritus, rash, urticaria;
Vascular disorders: coronary artery thrombosis, flushing, hypertension, hypotension, peripheral vascular disorder, syncope, vascular anomaly.
6.2 Postmarketing Experience
The following adverse reactions have been identified during post approval use of ULTRAVIST Injection. Because these reactions are reported
voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to
drug exposure.
Adverse reactions reported in foreign postmarketing surveillance and other trials with the use of ULTRAVIST Injection include:
Cardiac disorders: cardiac arrest, ventricular fibrillation, atrial fibrillation, tachycardia, palpitations, congestive heart failure, myocardial
infarction, angina pectoris;
Ear and labyrinth disorders: vertigo, tinnitus;
Endocrine disorders: hyperthyroidism, thyrotoxic crisis, hypothyroidism;
Eye disorders: mydriasis, lacrimation disorder;
Gastrointestinal disorders: dysphagia, swelling of salivary glands;
Immune system disorders: anaphylactoid reaction (including fatal cases), respiratory arrest, anaphylactoid shock, angioedema, laryngeal edema,
laryngospasm, bronchospasm, hypersensitivity;
Nervous system disorders: cerebral ischemia/infarction, paralysis, paresis, transient cortical blindness, aphasia, coma, unconsciousness, amnesia,
hypotonia;
Renal and urinary disorders: renal failure, hematuria;
Respiratory, thoracic and mediastinal disorders: pulmonary edema, acute respiratory distress syndrome, asthma;
Skin and subcutaneous tissue disorders: Stevens-Johnson Syndrome, skin discoloration;
Vascular disorders: vasospasm
.
6.3 Pediatrics
The overall character, quality, and severity of adverse reactions in pediatric patients are generally similar to those reported in adult patients.
Additional adverse reactions reported in pediatric patients from foreign marketing surveillance or other information are: epistaxis, angioedema,
migraine, joint disorder (effusion), muscle cramps, mucous membrane disorder (mucosal swelling), conjunctivitis, hypoxia, fixed eruptions,
vertigo, diabetes insipidus, and brain edema.
7. DRUG INTERACTIONS
7.1 Drug-Drug Interactions
In patients taking biguanides (e.g. metformin), acute alterations in renal function after iodinated contrast agents may precipitate lactic acidosis.
Stop biguanides 48 hours before the contrast medium examination and withhold until 48 hours after the procedure. (See biguanide package
insert.)
Patients on beta-blockers may be unresponsive to the usual doses of epinephrine used to treat allergic reactions. Because of the risk of
hypersensitivity reactions, use caution when administering iodinated contrast agents to patients taking beta-blockers.
Interleukins are associated with an increased prevalence of delayed hypersensitivity reactions after iodinated contrast agent administration. These
reactions include fever, chills, nausea, vomiting, pruritus, rash, diarrhea, hypotension, edema, and oliguria.
Renal toxicity has been reported in a few patients with liver dysfunction who were given an oral cholecystographic agent followed by
intravascular contrast agents. Administration of any intravascular contrast agent should therefore be postponed in patients who have recently
received a cholecystographic contrast agent.
Do not mix other drugs with ULTRAVIST Injection [see How Supplied/Storage and Handling (16)].
7.2 Drug/Laboratory Test Interactions
Thyroid Function Tests:
The results of protein bound iodine and radioactive iodine uptake studies, which depend on iodine estimation, will not accurately reflect thyroid
function for at least 16 days following administration of iodinated contrast agents. However, thyroid function tests which do not depend on iodine
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estimations, e.g., T3 resin uptake and total or free thyroxine (T4) assays are not affected.
Laboratory Assay of Coagulation Parameters, Fibrinolysis and Complement System:
The effect of iopromide on coagulation factors in in vitro assays increased with the administered dose. Coagulation, fibrinolysis and complement
activation were evaluated with standard citrated human plasma in the following assays: thrombin time, thrombin coagulase time, calcium
thromboplastin time, partial thromboplastin time, plasminogen, thrombin, alpha-2 antiplasmin and factor XIIa activity. Thrombin inhibition was
almost complete. Data on reversibility are not available. The thrombin time increased from approximately 20 seconds at an iopromide
concentration of 10 mgI/mL, up to 100 seconds at an iopromide concentration of 70 mgI/mL.
The PTT increased from approximately 50 seconds at an iopromide concentration of 10 mgI/mL, up to approximately 100 seconds at an
iopromide concentration of 70 mgI/mL. A similar increase was noted in the thrombin coagulase time. Lesser effects were noted in the calcium
thromboplastin time. Coagulation time increased from 13.5 to 23 seconds at the highest iopromide concentration of 70 mgI/mL. The Hageman
factor split products decreased by about 20% over the range of 10 to 70 mgI/mL of iopromide. Plasminogen was relatively stable. There was no
evidence of activation of fibrinolysis. The complement alternate pathway was activated. Factor B conversion increased in a dose dependent
manner. The duration of these effects was not studied.
In vitro studies with human blood showed that iopromide had a slight effect on coagulation and fibrinolysis. No Factor XIIa formation could be
demonstrated. The complement alternate pathway also can be activated.
8. USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Teratogenic Effects: Pregnancy Category B
Reproduction studies performed with iopromide in rats and rabbits at doses up to 3.7 gI/kg (2.2 times the maximum recommended dose for a 50
kg human, or approximately 0.7 times the human dose following normalization of the data to body surface area estimates) have revealed no
evidence of direct harm to the fetus. Embryolethality was observed in rabbits that received 3.7 gI/kg, but this was considered to have been
secondary to maternal toxicity. Adequate and well-controlled studies in pregnant women have not been conducted. Because animal reproduction
studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
8.3 Nursing Mothers
It is not known whether ULTRAVIST Injection is excreted in human milk. However, many injectable contrast agents are excreted unchanged in
human milk. Although it has not been established that serious adverse reactions occur in nursing infants, caution should be exercised when
intravascular contrast agents are administered to nursing women because of potential adverse reaction, and consideration should be given to
temporarily discontinuing nursing.
8.4 Pediatric Use
The safety and efficacy of ULTRAVIST Injection have been established in the pediatric population over 2 years of age. Use of ULTRAVIST
Injection in these age groups is supported by evidence from adequate and well controlled studies of ULTRAVIST Injection in adults and
additional safety data obtained in literature and other reports in a total of 274 pediatric patients. Of these, there were 131 children (2-12 years), 57
adolescents, and 86 children of unreported or other ages. There were 148 females, 94 males and 32 in whom gender was not reported. The racial
distribution was: Caucasian 93 (33.9%), Black 1 (0.4%), Asian 6 (2.2%), and unknown 174 (63.5%). These patients were evaluated in intra
arterial coronary angiographic (n=60), intravenous contrast computerized tomography (CT) (n=87), excretory urography (n=99) and 28 other
procedures.
In these pediatric patients, a concentration of 300 mgI/mL was employed for intravenous contrast CT or excretory urography. A concentration of
370 mgI/mL was employed for intra-arterial and intracardiac administration in the radiographic evaluation of the heart cavities and major arteries.
Most pediatric patients received initial volumes of 1-2 mL/kg.
Optimal doses of ULTRAVIST Injection have not been established because different injection volumes, concentrations and injection rates were
not studied. The relationship of the volume of injection with respect to the size of the target vascular bed has not been established. The potential
need for dose adjustment on the basis of immature renal function has not been established. In the pediatric population, the pharmacokinetic
parameters have not been established.
Pediatric patients at higher risk of experiencing an adverse reaction during and after administration of any contrast agent include those with
asthma, a sensitivity to medication and/or allergens, cyanotic and acyanotic heart disease, congestive heart failure, or a serum creatinine greater
than 1.5 mg/dL. The injection rates in small vascular beds, and the relationship of the dose by volume or concentration in small pediatric patients
have not been established. Exercise caution in selecting the dose.
8.5 Geriatric Use
Middle-aged and elderly patients, without significantly impaired renal function, who received ULTRAVIST Injection in doses corresponding to
9–30 g iodine, had mean steady-state volumes of distribution that ranged between 30–40 L. Mean total and renal clearances were between 81–
125 mL/min and 70–115 mL/min respectively in these patients, and were similar to the values found in the young volunteers. The distribution
phase half-life in this patient population was 0.1 hour, the main elimination phase half-life was 2.3 hours, and the terminal elimination phase half-
life was 40 hours. The urinary excretion (97% of the dose) and fecal excretion (2%) was comparable to that observed in young healthy
volunteers, suggesting that, compared to the renal route, biliary and/or gastrointestinal excretion is not significant for iopromide.
8.6 Renal Impairment
In patients with renal impairment, opacification of the calyces and pelves by iopromide may be delayed due to slower renal excretion of
iopromide.
A pharmacokinetic study in patients with mild (n=2), moderate (n=6), and severe (n=3) renal impairment was conducted. The total clearance of
iopromide was decreased proportionately to the baseline decrease in creatinine clearance. The plasma AUC increased about 2- fold in patients
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with moderate renal impairment and 6-fold in patients with severe renal impairment compared to subjects with normal renal function. The
terminal half-life increased from 2.2 hrs for subjects with normal renal function to 11.6 hrs in patients with severe renal impairment. The peak
plasma concentration of iopromide was not influenced by the extent of renal impairment. Exercise caution and use the lowest necessary dose of
ULTRAVIST in patients with renal dysfunction [see Warnings and Precautions (5.2)].
10. OVERDOSAGE
The adverse effects of overdosage are life-threatening and affect mainly the pulmonary and cardiovascular systems. Treatment of an overdosage
is directed toward the support of all vital functions, and prompt institution of symptomatic therapy.
ULTRAVIST Injection binds negligibly to plasma or serum protein and can, therefore, be dialyzed.
11. DESCRIPTION
ULTRAVIST (iopromide) Injection is a nonionic, water soluble x-ray contrast agent for intravascular administration. The chemical name for
iopromide is 1,3-Benzenedicarboxam-ide,N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-5-[(methoxyacetyl)amino]-N-methyl-. Iopromide has a
molecular weight of 791.12 (iodine content 48.12%).
Iopromide has the following structural formula: Structural Formula
ULTRAVIST Injection is a nonionic, sterile, clear, colorless to slightly yellow, odorless, pyrogen-free aqueous solution of iopromide, containing
2.42 mg/mL tromethamine buffer and 0.1 mg/mL edetate calcium disodium stabilizer.
ULTRAVIST Injection is available in four strengths:
150 mgI/mL provides 311.7 mg/mL iopromide,
240 mgI/mL provides 498.72 mg/mL iopromide,
300 mgI/mL provides 623.4 mg/mL iopromide,
370 mgI/mL provides 768.86 mg/mL iopromide.
During the manufacture of ULTRAVIST Injection, sodium hydroxide or hydrochloric acid may be added for pH adjustment. ULTRAVIST
Injection has a pH of 7.4 (6.5 – 8) at 25± 2 °C, is sterilized by autoclaving and contains no preservatives.
The iodine concentrations (mgI/mL) available have the following physicochemical properties:
ULTRAVIST
INJECTION
ULTRAVIST
INJECTION
ULTRAVIST
INJECTION
ULTRAVIST
INJECTION
Property
150 mgI/mL
240 mgI/mL
300 mgI/mL
370 mgI/mL
Osmolality*(mOsmol/kg water) @37°C
328
483
607
774
Osmolarity*(mOsmol/L)
@ 37°C
278
368
428
496
Viscosity (cP)
@ 20°C
@ 37°C
2.3
1.5
4.9
2.8
9.2
4.9
22
10
Density (g/mL)
@ 20°C
@ 37°C
1.164
1.157
1.262
1.255
1.330
1.322
1.409
1.399
*Osmolality was measured by vapor-pressure osmometry. Osmolarity was calculated from the measured osmolal concentrations.
Solutions of ULTRAVIST Injection 150 mgI/mL, 240 mgI/mL, 300 mgI/mL and 370 mgI/mL have osmolalities from approximately 1.1 to 2.7
times that of plasma (285mOsmol/kg water).
12. CLINICAL PHARMACOLOGY
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12.1 Mechanism of Action
Iopromide is a nonionic, water soluble, tri-iodinated x-ray contrast agent for intravascular administration.
Intravascular injection of iopromide opacifies those vessels in the path of flow of the contrast agent, permitting radio-graphic visualization of the
internal structures until significant hemodilution occurs.
12.2 Pharmacodynamics
Following ULTRAVIST administration, the degree of contrast enhancement is directly related to the iodine content in the administered dose;
peak iodine plasma levels occur immediately following rapid intravenous injection. Iodine plasma levels fall rapidly within 5 to 10 minutes. This
can be accounted for by the dilution in the vascular and extravascular fluid compartments.
Intravascular Contrast: Contrast enhancement appears to be greatest immediately after bolus injections (15 seconds to 120 seconds). Thus,
greatest enhancement may be detected by a series of consecutive two-to-three second scans performed within 30 to 90 seconds after injection
(i.e., dynamic computed tomographic imaging).
ULTRAVIST Injection may be visualized in the renal parenchyma within 30–60 seconds following rapid intravenous injection. Opacification of
the calyces and pelves in patients with normal renal function becomes apparent within 1–3 minutes, with optimum contrast occurring within 5–15
minutes.
In contrast CT, some performance characteristics are different in the brain and body. In contrast CT of the body, iodinated contrast agents diffuse
rapidly from the vascular into the extravascular space. Following the administration of iodinated contrast agents, the increase in tissue density to
x-rays is related to blood flow, the concentration of the contrast agent, and the extraction of the contrast agent by various interstitial tissues.
Contrast enhancement is thus due to any relative differences in extravascular diffusion between adjacent tissues.
In the normal brain with an intact blood-brain barrier, contrast is generally due to the presence of iodinated contrast agent within the intravascular
space. The radiographic enhancement of vascular lesions, such as arteriovenous malformations and aneurysms, depends on the iodine content of
the circulating blood pool.
In tissues with a break in the blood-brain barrier, contrast agent accumulates within interstitial brain tissue. The time to maximum contrast
enhancement can vary from the time that peak blood iodine levels are reached to 1 hour after intravenous bolus administration. This delay
suggests that radiographic contrast enhancement is at least in part dependent on the accumulation of iodine containing medium within the lesion
and outside the blood pool. The mechanism by which this occurs is not clear.
For information on coagulation parameters, fibrinolysis and complement system see Drug Interactions (7.2).
12.3 Pharmacokinetics
Distribution
After intravenous administration to healthy young volunteers, plasma iopromide concentration time profile shows an initial distribution phase
with a half-life of 0.24 hour; a main elimination phase with a half-life of 2 hours; and a terminal elimination phase with a half-life of 6.2 hours.
The total volume of distribution at steady state is about 16 L suggesting distribution in to extracellular space. Plasma protein binding of
iopromide is 1%.
Iodinated contrast agents may cross the blood-brain barrier [see Warnings and Precautions (5.8)].
Elimination
The amounts excreted unchanged in urine represent 97% of the dose in young healthy subjects. Only 2% of the dose is recovered in the feces.
Similar recoveries in urine and feces are observed in middle-aged and elderly patients. This finding suggests that, compared to the renal route,
biliary and/or gastrointestinal excretion is not important for iopromide. During the slower terminal phase only 3% of the dose is eliminated; 97%
of the dose is disposed of during the earlier phases, the largest part of which occurs during the main elimination phase. The ratio of the renal
clearance of iopromide to the creatinine clearance is 0.82 suggesting that iopromide is mainly excreted by glomerular filtration. Additional
tubular reabsorption is possible. Pharmacokinetics of iopromide at intravenous doses up to 80 g iodine, are dose proportionate and first order.
The mean total and renal clearances are 107 mL/min and 104 mL/min, respectively.
Metabolism
Iopromide is not metabolized.
Specific Populations
A pharmacokinetic study was conducted in 11 patients with renal impairment [see Use in Specific Populations (8.6)].
13. NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term animal studies have not been performed with iopromide to evaluate carcinogenic potential or effects on fertility. Iopromide was not
genotoxic in a series of studies including the Ames test, an in vitro human lymphocytes analysis of chromosomal aberrations, an in vivo mouse
micro-nucleus assay, and in an in vivo mouse dominant lethal assay.
14. CLINICAL STUDIES
ULTRAVIST Injection was administered to 708 patients; 1 patient was less than 18 years of age, 347 patients were between 18 and 59 years of
age, and 360 patients were equal to or greater than 60 years of age; the mean age was 56.6 years (range 17 – 88). Of the 708 patients, 446 (63%)
were male and 262 (37%) were female. The racial distribution was: Caucasian 463 (65.4%), Black 95 (13.4%), Hispanic 36 (5.1%), Asian 11 (1.6
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%), and other or unknown 103 (14.5%). Efficacy assessment was based on the global evaluation of the quality of the radiographs by rating
visualization as either excellent, good, poor, or no image, and on the ability to make a diagnosis. Five (5) intra-arterial and three (3) intravenous
procedures were studied with 1 of 4 concentrations (370 mgI/mL, 300 mgI/mL, 240 mgI/mL, and 150 mgI/mL). These procedures were:
aortography/visceral angiography, coronary arteriography and left ventriculography, cerebral arteriography, peripheral arteriography, intra
arterial digital subtraction angiography (IA-DSA), contrast computed tomography (CT) of head and body, excretory urography, and peripheral
venography.
Cerebral arteriography was evaluated in two randomized, double-blind clinical trials of ULTRAVIST Injection 300 mgI/mL in 80 patients with
conditions such as altered cerebrovascular perfusion and/or permeability occurring in central nervous system diseases due to various CNS
disorders. Visualization ratings were good or excellent in 99% of the patients with ULTRAVIST Injection; a radiologic diagnosis was made in
the majority of the patients. Confirmation of the radiologic findings by other diagnostic methods was not obtained.
Coronary arteriography/left ventriculography was evaluated in two randomized, double-blind clinical trials and one unblinded, unrandomized
clinical trial of ULTRAVIST Injection 370 mgI/mL in 106 patients with conditions such as altered coronary artery perfusion due to metabolic
causes and in patients with conditions such as altered ventricular function. Visualization ratings were good or excellent in 99% or more of the
patients a radiologic diagnosis was made in the majority of the patients. A confirmation of the radiologic findings by other diagnostic methods
was not obtained.
Aortography/visceral angiography was evaluated in two randomized, double-blind clinical trials in 78 patients with conditions such as altered
aortic blood flow and/or visceral vascular disorders. Visualization ratings were good or excellent in the majority of the patients; a radiologic
diagnosis was made in 99% of the patients with ULTRAVIST Injection. A confirmation of radiologic findings by other diagnostic methods was
not obtained. The risks of renal arteriography could not be analyzed.
Contrast CT of head and body was evaluated in three randomized, double-blind clinical trials of ULTRAVIST Injection 300 mg/ml in 95 patients
with vascular disorders. Visualization ratings were good or excellent in 99% of the patients; a radiologic diagnosis was made in the majority of
the patients. A confirmation of contrast CT findings by other diagnostic methods was not obtained.
ULTRAVIST Injection was evaluated in a blinded reader trial for CT of the head and body. Among the 382 patients who were evaluated with
ULTRAVIST Injection 370 mgI/mL, visualization ratings were good or excellent in approximately 97% of patients.
Peripheral venography was evaluated in two randomized, double-blind clinical trials of ULTRAVIST Injection 240 mgI/mL in 63 patients with
disorders affecting venous drainage of the limbs. Visualization ratings were good or excellent in 100% of the patients; a radiologic diagnosis was
made in the majority of the patients. A confirmation of radiologic findings by other diagnostic methods was not obtained.
Similar studies were completed with comparable findings noted in intra-arterial digital subtraction angiography, peripheral arteriography and
excretory urography.
16. HOW SUPPLIED/STORAGE AND HANDLING
ULTRAVIST Injection is a sterile, clear, colorless to slightly yellow, odorless, pyrogen-free aqueous solution available in four strengths.
Glass Vials
NDC Number
ULTRAVIST Injection 150 mgI/mL
10 x 50 mL vials.............................................50419-340-05
ULTRAVIST Injection 240 mgI/mL
10 x 50 mL vials.............................................50419-342-05
10 x 100 mL vials...........................................50419-342-10
10 x 150 mL vials...........................................50419-342-15
ULTRAVIST Injection 300 mgI/mL
10 x 50 mL vials.............................................50419-344-05
10 x 75 mL fill/100 mL vials..........................50419-344-07
10 x 100 mL vials...........................................50419-344-10
10 x 125 mL fill/150 mL vials........................50419-344-12
10 x 150 mL vials...........................................50419-344-15
ULTRAVIST Injection 370 mgI/mL
10 x 50 mL vials.............................................50419-346-05
10 x 75 mL fill/100 mL vials..........................50419-346-07
10 x 100 mL vials...........................................50419-346-10
10 x 125 mL fill/150 mL vials........................50419-346-12
10 x 150 mL vials...........................................50419-346-15
10 x 200 mL fill/250 mL vials........................50419-346-20
Inspect contrast agents visually prior to use. Do not use if discolored, if particulate matter (including crystals) is present, or if containers are
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defective. As ULTRAVIST Injection is a highly concentrated solution, crystallization (milky-cloudy appearance and/or sediment at bottom, or
floating crystals) may occur.
As with all contrast agents, because of the potential for chemical incompatibility, do not mix or inject ULTRAVIST Injection in intravenous
administration lines containing other drugs, solutions or total nutritional admixtures.
Use sterile technique in all vascular injections involving contrast agents.
Inject intravascularly administered iodinated contrast agents at or close to body temperature.
If nondisposable equipment is used, take scrupulous care to prevent residual contamination with traces of cleansing agents.
Withdraw contrast agents from their containers under strict aseptic conditions using only sterile syringes and transfer devices. Use immediately
contrast agents which have been transferred into other delivery systems.
Store the preparation at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) and protected from light.
17. PATIENT COUNSELING INFORMATION
Instruct patients receiving ULTRAVIST Injection to inform their physician or health care provider of the following:
•
if they are pregnant [see Use in Specific Populations (8.1)]
•
if they are diabetic or if they have multiple myeloma, pheochromocytoma, homozygous sickle cell disease or thyroid disorder [see
Warnings and Precautions (5.2, 5.5)]
•
if they are allergic to any drugs or food, or if they have immune, autoimmune or immune deficiency disorders. Also, if they have had any
reaction to previous injections of dyes used for x-ray procedures [see Warnings and Precautions (5.1)]
•
all medications they are currently taking, including non-prescription (over-the-counter) drugs.
©2008, Bayer HealthCare Pharmaceuticals Inc, All rights reserved.
Mfd. for: Company logo
Mfd. in Berlin, Germany
Revised 12/09
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
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2025-02-12T13:47:02.913308
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020220s033lbl.pdf', 'application_number': 20220, 'submission_type': 'SUPPL ', 'submission_number': 33}
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HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
ULTRAVIST Injection safely and effectively. See full prescribing
information for ULTRAVIST Injection.
ULTRAVIST (iopromide) Injection, for intravenous or intra-arterial use
Initial U.S. Approval: 1995
WARNING: NOT FOR INTRATHECAL USE
Inadvertent intrathecal administration may cause death,
convulsions, cerebral hemorrhage, coma, paralysis,
arachnoiditis, acute renal failure, cardiac arrest, seizures,
rhabdomyolysis, hyperthermia, and brain edema.
----------------------------RECENT MAJOR CHANGES--------------------------
Warnings and Precautions (5)
05/2012
----------------------------INDICATIONS AND USAGE---------------------------
ULTRAVIST (iopromide) Injection is a radiographic contrast agent indicated
for:
Intra-arterial digital subtraction angiography (IA-DSA) (150 mg I/mL)
(1.1)
Cerebral arteriography and peripheral arteriography (300 mg I/mL) (1.1)
Coronary arteriography and left ventriculography, visceral angiography
and aortography (370 mg I/mL) (1.1)
Peripheral venography (240 mg I/mL) (1.2)
Excretory urography (300 mg I/mL) (1.2)
Contrast computed tomography (CT) imaging of head and body (300 mg
I/mL and 370 mg I/mL) (1.2)
----------------------DOSAGE AND ADMINISTRATION-----------------------
Carefully individualize the volume and concentration of ULTRAVIST
Injection to be used for a vascular procedure, according to the specific dosing
tables. Adjust the dose accounting for factors such as age, body weight, size of
the vessel and the rate of blood flow within the vessel. (2)
---------------------DOSAGE FORMS AND STRENGTHS----------------------
ULTRAVIST Injection is available in four strengths: 150 mg I/mL; 240 mg
I/mL; 300 mg I/mL; 370 mg I/mL. (3)
-------------------------------CONTRAINDICATIONS------------------------------
ULTRAVIST Injection is contraindicated for intrathecal use. (4)
Preparatory dehydration (for example, prolonged fasting and the
administration of a laxative before ULTRAVIST Injection) is
contraindicated in pediatric patients because of risk of renal failure. (4)
-----------------------WARNINGS AND PRECAUTIONS------------------------
Anaphylactoid Reactions: Life-threatening or fatal anaphylactoid
reactions may occur during or after ULTRAVIST administration,
particularly in patients with allergic disorders. (5.1)
Acute Renal Failure: Acute renal failure may occur following
ULTRAVIST administration, particularly in patients with renal
insufficiency, diabetes, multiple myeloma. Exercise caution and use the
lowest necessary dose of ULTRAVIST in patients with renal
dysfunction. (5.2)
Cardiovascular Reactions: Hemodynamic disturbances including shock
and cardiac arrest may occur during or shortly after administration of
ULTRAVIST.(5.3)
Thromboembolic Complications: Angiography may be associated with
local and distal organ damage, ischemia, thromboembolism and organ
failure. In angiographic procedures, consider the possibility of
dislodging plaques or damaging or perforating the vessel wall. The
physicochemical properties of the contrast agent, the dose and the speed
of injection can influence the reactions. (5.4)
------------------------------ADVERSE REACTIONS-------------------------------
Most common adverse reactions (>1%) are headache, nausea, injection site
and infusion site reactions, vasodilatation, vomiting, back pain, urinary
urgency, chest pain, pain, dysgeusia, and abnormal vision. (6)
To report SUSPECTED ADVERSE REACTIONS, contact Bayer
HealthCare Pharmaceuticals Inc. at 1-888-842-2937 or FDA at 1-800-
FDA-1088 or www.fda.gov/medwatch.
-----------------------USE IN SPECIFIC POPULATIONS------------------------
Adequate and well-controlled studies in pregnant women have not been
conducted. Because animal reproduction studies are not always
predictive of human response, this drug should be used during
pregnancy only if clearly needed. (8.1)
The safety and efficacy of ULTRAVIST Injection have been established
in the pediatric population over 2 years of age. (8.4)
See 17 for PATIENT COUNSELING INFORMATION.
Revised: 05/2012
______________________________________________________________________________________________________________________________________
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: NOT FOR INTRATHECAL USE
1 INDICATIONS AND USAGE.......................................................................2
1.1 Intra-Arterial Procedures*.......................................................................2
1.2 Intravenous Procedures* .........................................................................2
2 DOSAGE AND ADMINISTRATION ...........................................................2
2.1 Intra-Arterial Procedures.........................................................................2
2.2 Intravenous Procedures ........................................................................... 3
3
4
4
4
4
4
4
5
5
5
5
5
6
6
7
7
7
7
8
8
8
8
9
9
9
9
10
10
10
10
11
12
12
12
12
13
2.3 Pediatric Dosing ......................................................................................
3 DOSAGE FORMS AND STRENGTHS ........................................................
4 CONTRAINDICATIONS...............................................................................
5 WARNINGS AND PRECAUTIONS.............................................................
5.1 Anaphylactoid Reactions ........................................................................
5.2 Contrast Induced Acute Kidney Injury...................................................
5.3 Cardiovascular Reactions........................................................................
5.4 Thromboembolic Complications.............................................................
5.5 Reactions in Patients with Hyperthyroidism, Pheochromocytoma, or
Sickle Cell Disease........................................................................................
5.6 Extravasation...........................................................................................
5.7 Increased Radiation Exposure.................................................................
5.8 Interference with Image Interpretation ...................................................
6 ADVERSE REACTIONS...............................................................................
6.1 Clinical Trials Experience.......................................................................
6.2 Postmarketing Experience.......................................................................
6.3 Pediatrics .................................................................................................
7 DRUG INTERACTIONS...............................................................................
7.1 Drug-Drug Interactions...........................................................................
7.2 Drug-Laboratory Test Interactions.........................................................
8 USE IN SPECIFIC POPULATIONS.............................................................
8.1 Pregnancy................................................................................................
8.3 Nursing Mothers .....................................................................................
8.4 Pediatric Use...........................................................................................
8.5 Geriatric Use ...........................................................................................
8.6 Renal Impairment ...................................................................................
10 OVERDOSAGE ...........................................................................................
11 DESCRIPTION...........................................................................................
12 CLINICAL PHARMACOLOGY...............................................................
12.1 Mechanism of Action .........................................................................
12.2 Pharmacodynamics.............................................................................
12.3 Pharmacokinetics................................................................................
13 NONCLINICAL TOXICOLOGY..............................................................
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility ......................
14 CLINICAL STUDIES ................................................................................
16 HOW SUPPLIED/STORAGE AND HANDLING ...................................
17 PATIENT COUNSELING INFORMATION............................................
*Sections or subsections omitted from the full prescribing information are not
listed.
NDA 020220 ULTRAVIST INJ DD MMM 12
Reference ID: 3125107
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020220 ULTRAVIST INJ DD MMM 12
_______________________________________________________________________________________________________________________________________
FULL PRESCRIBING INFORMATION
WARNING: NOT FOR INTRATHECAL USE
Inadvertent intrathecal administration may cause death, convulsions, cerebral hemorrhage, coma, paralysis,
arachnoiditis, acute renal failure, cardiac arrest, seizures, rhabdomyolysis, hyperthermia, and brain edema.
[see Contraindications (4).]
1 INDICATIONS AND USAGE
ULTRAVIST
® Injection is an iodinated contrast agent indicated for:
1.1 Intra-Arterial Procedures*
150 mg I/mL for intra-arterial digital subtraction angiography (IA-DSA)
300 mg I/mL for cerebral arteriography and peripheral arteriography
370 mg I/mL for coronary arteriography and left ventriculography, visceral angiography, and aortography
1.2 Intravenous Procedures*
240 mg I/mL for peripheral venography
300 mg I/mL for excretory urography
300 mg I/mL and 370 mg I/mL for contrast Computed Tomography (CT) of the head and body (intrathoracic, intra-
abdominal and retroperitoneal regions) for the evaluation of neoplastic and non-neoplastic lesions. The usefulness of
contrast enhancement for the investigation of the retrobulbar space and of low grade or infiltrative glioma has not
been demonstrated.
*For information on the concentrations and doses for the Pediatric Population [see Dosage and Administration (2.3) and
Use in Specific Populations (8.4)].
2 DOSAGE AND ADMINISTRATION
Visually inspect ULTRAVIST for particulate matter and/or discoloration, whenever solution and container permit. Do
not administer ULTRAVIST if particulate matter and/or discoloration is observed.
Determine the volume and concentration of ULTRAVIST Injection to be used taking into account factors such as age,
body weight, size of the vessel and the rate of blood flow within the vessel; consider also extent of opacification
required, structure(s) or area to be examined, disease processes affecting the patient, and equipment and technique to
be employed. Specific dose adjustments for age, gender, weight and renal function have not been studied for
ULTRAVIST Injection. As with all iodinated contrast agents, lower doses may have less risk. The efficacy of
ULTRAVIST Injection below doses recommended has not been established.
The maximum recommended total dose of iodine in adults is 86 grams; a maximum recommended total dose of iodine
has not been established for pediatric patients.
Hydrate patients adequately prior to and following the administration of ULTRAVIST [see Warnings and
Precautions (5.2)].
Warming Ultravist to body temperature shortly before administration may help improve tolerability and ease of
injection [see How Supplied/Storage and Handling (16)].
2.1 Intra-Arterial Procedures
The volume and rate of injection of the contrast agent will vary depending on the injection site and the area being
examined. Inject contrast at rates approximately equal to the flow rate in the vessel being injected.
Cerebral Arteriography (300 mg I/mL), Coronary Arteriography and Left Ventriculography (370 mg I/mL),
Peripheral Arteriography (300 mg I/mL), Intra-arterial Digital Subtraction Angiography (IA-DSA) (150 mg I/mL):
see Table 1.
Reference ID: 3125107
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NDA 020220 ULTRAVIST INJ DD MMM 12
Aortography and Visceral Angiography (370 mg I/mL):
Use a volume and rate of contrast injection proportional to the blood flow and related to the vascular and pathological
characteristics of the specific vessels being studied. Do not exceed 225 mL as total dose for the procedure.
Table 1: Suggested Single Injection Doses for Adult Intra-Arterial Procedures
IA-DSA*
(150 mg
I/mL)
Cerebral
Arteriography
(300 mg I/mL)
Peripheral
Arteriography
(300 mg I/mL)
Coronary Arteriography
and
Left Ventriculography
(370 mg I/mL)
Carotid Arteries
Vertebral Arteries
Aortic Arch Injection (4 vessel study)
6–10 mL
4–8 mL
-
3–12 mL
4–12 mL
20–50 mL
-
-
-
-
-
-
Right Coronary Artery
Left Coronary Artery
Left Ventricle
-
-
-
-
-
-
-
-
-
3–14 mL
3–14 mL
30–60 mL
Aorta
Major Branches of the Abdominal
Aorta
20–50 mL
2–20 mL
-
-
-
-
-
-
Intra-Arterial Injection Sites
Subclavian or Femoral Artery
Aortic Bifurcation (distal runoff)
-
-
-
-
5–40 mL
25–50 mL
-
-
Maximum Total Dose
250 mL
150 mL
250 mL
225 mL
*IA-DSA = Intra-Arterial Digital Subtraction Angiography
2.2 Intravenous Procedures
Peripheral Venography (240 mg I/mL):
Inject the minimum volume necessary to visualize satisfactorily the structures under examination. Do not exceed 250
mL as total dose for the procedure.
Contrast Computed Tomography (CT) (300 mg I/mL and 370 mg I/mL) and Excretory Urography (300 mg I/mL): see
Table 2.
Table 2: Suggested ULTRAVIST Injection Dosing for Adult Intravenous Contrast Administration
Excretory Urography
(300 mg I/mL)
Contrast Computed Tomography
(300 mg I/mL)
Contrast Computed
Tomography (370 mg I/mL)
Excretory Urography
Approximately 300 mg
I/kg body wt. (Adults
with normal renal
function)
-
-
Head
-
50–200 mL
41–162 mL
Body
Bolus Injection
50–200 mL
41–162 mL
Rapid Infusion
100–200 mL
81–162 mL
Maximum Total Dose
100 mL (30 g iodine)
200 mL (60 g iodine)
162 mL (60 g iodine)
2.3 Pediatric Dosing
The recommended dose in children over 2 years of age for the following evaluations is:
Intra-arterial:
Cardiac chambers and related arteries (370 mg I/mL):
Reference ID: 3125107
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NDA 020220 ULTRAVIST INJ DD MMM 12
Inject 1 to 2 milliliters per kilogram (mL/kg). Do not exceed 4 mL/kg as total dose.
Intravenous:
Contrast Computerized Tomography or Excretory Urography (300 mg I/mL):
Inject 1 to 2 mL/kg. Do not exceed 3 mL/kg as total dose.
The safety and efficacy relationships of other doses, concentrations or procedures have not been established [see Use in
Specific Populations (8.4) and Clinical Pharmacology (12.3)].
3 DOSAGE FORMS AND STRENGTHS
ULTRAVIST Injection is a nonionic, sterile, clear, colorless to slightly yellow, odorless, pyrogen-free aqueous solution of
iopromide, containing 2.42 mg/mL tromethamine buffer and 0.1 mg/mL edetate calcium disodium stabilizer.
ULTRAVIST Injection is available in four strengths:
150 mg I/mL provides 311.7 mg/mL iopromide,
240 mg I/mL provides 498.72 mg/mL iopromide,
300 mg I/mL provides 623.4 mg/mL iopromide,
370 mg I/mL provides 768.86 mg/mL iopromide.
4 CONTRAINDICATIONS
Do not administer ULTRAVIST Injection intrathecally. Inadvertent intrathecal administration may cause death,
convulsions, cerebral hemorrhage, coma, paralysis, arachnoiditis, acute renal failure, cardiac arrest, seizures,
rhabdomyolysis, hyperthermia, and brain edema.
Preparatory dehydration (for example, prolonged fasting and the administration of a laxative) before ULTRAVIST
Injection is contraindicated in pediatric patients because of risk of acute renal failure.
5 WARNINGS AND PRECAUTIONS
5.1 Anaphylactoid Reactions
Life-threatening or fatal, anaphylactoid reactions, may occur during or after ULTRAVIST administration. Manifestations
include respiratory arrest, laryngospasm, bronchospasm, angioedema, and shock. Increased risk is associated with a
history of previous reaction to a contrast agent (3-fold), a known sensitivity to iodine and known allergic disorders (that is,
bronchial asthma, hay fever and food allergies) or other hypersensitivities (2-fold). Exercise extreme caution when
considering the use of iodinated contrast agents in patients with these histories or disorders.
Emergency facilities and personnel trained in the treatment of anaphylactoid reactions should be available for at least 30
to 60 minutes after ULTRAVIST administration.
5.2 Contrast Induced Acute Kidney Injury
Acute kidney injury, including renal failure,may occur after intravascular administration of ULTRAVIST. Risk factors
include: pre-existing renal insufficiency, dehydration, diabetes mellitus, congestive heart failure, advanced vascular
disease, elderly age, concomitant use of nephrotoxic or diuretic medications, multiple myeloma / paraproteinemia,
repetitive and/or large doses of ULTRAVIST.
Use the lowest necessary dose of ULTRAVIST in patients with renal impairment. Adequately hydrate patients prior to
and following ULTRAVIST administration.
5.3 Cardiovascular Reactions
ULTRAVIST increases the circulatory osmotic load and may induce acute or delayed hemodynamic disturbances in
patients with congestive heart failure, severely impaired renal function, combined renal and hepatic disease, combined
renal and cardiac disease, particularly when repetitive and/or large doses are administered [see Drug Interactions (7)].
Among patients who have had cardiovascular reactions, most deaths occurred from the start of injection to 10 minutes
later; the main feature was cardiac arrest with cardiovascular disease as the main underlying factor. Isolated reports of
hypotensive collapse and shock have been published.
Reference ID: 3125107
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NDA 020220 ULTRAVIST INJ DD MMM 12
The administration of ULTRAVIST may cause pulmonary edema in patients with heart failure. Based upon published
reports, deaths from the administration of iodinated contrast agents range from 6.6 per 1 million (0.00066 percent) to 1 in
10,000 patients (0.01 percent). Observe patients with preexisting cardiovascular disease for several hours following
ULTRAVIST administration.
5.4 Thromboembolic Complications
Angiography may be associated with local and distal organ damage, ischemia, thromboembolism and organ failure
including stroke, brachial plexus palsy, chest pain, myocardial infarction, sinus arrest, hepato-renal function
abnormalities. For these reasons, meticulous angiographic techniques are recommended, including close attention to
guide wire and catheter manipulation, use of manifold systems and/or three-way stopcocks, frequent catheter flushing
with heparinized saline solutions and minimizing the length of the procedure. In angiographic procedures, consider
the possibility of dislodging plaques or damaging or perforating the vessel wall with resultant pseudoaneurysms,
hemorrhage at puncture site, dissection of coronary artery during catheter manipulations and contrast agent injection.
The physicochemical properties of the contrast agent, the dose and the speed of injection can influence the reactions.
Test injections to ensure proper catheter placement are suggested. Increased thrombosis and activation of the
complement system has also occurred. Specialized personnel, and adequate equipment and facilities for immediate
resuscitation and cardioversion are necessary. Monitor electrocardiograms and vital signs throughout the procedure.
Exercise care when performing venography in patients with suspected thrombosis, phlebitis, severe ischemic disease,
local infection, venous thrombosis or a totally obstructed venous system.
Clotting may occur when blood remains in contact with syringes containing iodinated contrast agents.
Avoid angiography whenever possible in patients with homocystinuria because of the risk of inducing thrombosis and
embolism [see Clinical Pharmacology (12.2)].
5.5 Reactions in Patients with Hyperthyroidism, Pheochromocytoma, or Sickle Cell Disease
Thyroid storm in patients with hyperthyroidism. Thyroid storm has occurred after the intravascular use of iodinated
contrast agents in patients with hyperthyroidism, or with an autonomously functioning thyroid nodule. Evaluate the risk in
such patients before use of any iodinated contrast agent.
Hypertensive crises in patients with pheochromocytoma. Administer iodinated contrast agents with extreme caution in
patients with known or suspected pheochromocytoma. Inject the minimum amount of contrast necessary. Assess the blood
pressure throughout the procedure, and have measures for treatment of a hypertensive crisis readily available.
Sickle cell disease. Contrast agents may promote sickling in individuals who are homozygous for sickle cell disease when
administered intravascularly.
5.6 Extravasation
Extravasation of ULTRAVIST Injection may cause tissue necrosis and/or compartment syndrome, particularly in patients
with severe arterial or venous disease.
5.7 Increased Radiation Exposure
The decision to use contrast enhancement is associated with risk and increased radiation exposure. Use contrast after a
careful evaluation of clinical, other radiologic data, and the results of non-contrast CT findings, taking into account the
increased radiation dose and other risks.
5.8 Interference with Image Interpretation
As with other iodinated contrast agents, the use of ULTRAVIST Injection may obscure some lesions which were seen on
non-contrast CT scans. Calcified lesions are less likely to enhance. The enhancement of tumors after therapy may
decrease. The opacification of the inferior vermis following contrast agent administration has resulted in false-positive
diagnosis. Cerebral infarctions of recent onset may be better visualized with contrast enhancement. However, older
infarctions may be obscured by the contrast agent.
In patients with normal blood-brain barriers and renal failure, iodinated contrast agents have been associated with blood-
brain barrier disruption and accumulation of contrast in the brain. Accumulation of contrast in the brain also occurs in
patients where the blood-brain barrier is known or suspected to be disrupted.
Reference ID: 3125107
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NDA 020220 ULTRAVIST INJ DD MMM 12
6 ADVERSE REACTIONS
The most important adverse drug reactions in patients receiving ULTRAVIST are anaphylactoid shock, contrast induced
acute kidney injury, coma, cerebral infarction, stroke, brain edema, convulsion, arrhythmia, cardiac arrest, myocardial
ischemia, myocardial infarction, cardiac failure, bradycardia, cyanosis, hypotension, shock, dyspnea, pulmonary edema,
respiratory insufficiency and aspiration.
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials
of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect or predict the rates
observed in practice.
The following table of incidence of reactions is based upon controlled clinical trials in which ULTRAVIST Injection was
administered to 1142 patients. This listing includes all reported adverse reactions regardless of attribution.
Adverse reactions are listed by System Organ Class and in decreasing order of occurrence for rates greater than 1% in the
ULTRAVIST group: see Table 3.
Table 3: ADVERSE REACTIONS REPORTED IN > 1% OF PATIENTS WHO RECEIVED ULTRAVIST
INJECTION IN CLINICAL TRIALS
ULTRAVIST Injection
System Organ Class
Adverse Reaction
N=1142 (%)
Headache
46 (4)
Nervous system disorders
Dysgeusia
15 (1.3)
Eye disorders
Abnormal Vision
12 (1.1)
Cardiac disorders
Chest pain
18 (1.6)
Vascular disorders
Vasodilatation
30 (2.6)
Nausea
42 (3.7)
Gastrointestinal disorders
Vomiting
22 (1.9)
Musculoskeletal and connective tissue disorders
Back pain
22 (1.9)
Renal and urinary disorders
Urinary urgency
21 (1.8)
Injection site and infusion site
reactions (hemorrhage,
hematoma, pain, edema,
erythema, rash)
41 (3.7)
General disorders and administration site conditions
Pain
13 (1.4)
One or more adverse reactions were recorded in 273 of 1142 (24%) patients during the clinical trials, coincident with the
administration of ULTRAVIST Injection or within the defined duration of the study follow-up period (24–72 hours).
ULTRAVIST Injection is often associated with sensations of warmth and/or pain.
Serious, life-threatening and fatal reactions have been associated with the administration of iodine-containing contrast
media, including ULTRAVIST Injection. In clinical trials 7/1142 patients given ULTRAVIST Injection died 5 days or
later after drug administration. Also, 10/1142 patients given ULTRAVIST Injection had serious adverse events.
The following adverse reactions were observed in ≤ 1% of the subjects receiving ULTRAVIST Injection:
Cardiac disorders: atrioventricular block (complete), bradycardia, ventricular extrasystole;
Gastrointestinal disorders: abdominal discomfort, abdominal pain, abdominal pain upper, constipation, diarrhea, dry
mouth, dyspepsia, gastrointestinal disorder, gastrointestinal pain, salivation increased, stomach discomfort, rectal
tenesmus;
General disorders and administration site conditions: asthenia, chest discomfort, chills, excessive thirst, extravasation,
feeling hot, hyperhidrosis, malaise, edema peripheral, pyrexia;
Immune system disorders: asthma, face edema;
Investigations: blood lactate dehydrogenase increased, blood urea increased, hemoglobin increased, white blood cell
count increased;
Musculoskeletal and connective tissue disorders: arthralgia, musculoskeletal pain, myasthenia, neck pain, pain in
extremity;
Reference ID: 3125107
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NDA 020220 ULTRAVIST INJ DD MMM 12
Nervous system disorders: agitation, confusion, convulsion, dizziness, hypertonia, hypesthesia, incoordination,
neuropathy, somnolence, speech disorder, tremor, paresthesia, visual field defect;
Psychiatric disorders: anxiety;
Renal and urinary disorders: dysuria, renal pain, urinary retention;
Respiratory, thoracic and mediastinal disorders: apnea, cough increased, dyspnea, hypoxia, pharyngeal edema,
pharyngitis, pleural effusion, pulmonary hypertension, respiratory disorder, sore throat;
Skin and subcutaneous tissue disorders: erythema, pruritus, rash, urticaria;
Vascular disorders: coronary artery thrombosis, flushing, hypertension, hypotension, peripheral vascular disorder,
syncope, vascular anomaly.
6.2 Postmarketing Experience
The following adverse reactions have been identified during post approval use of ULTRAVIST Injection. Because these
reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their
frequency or establish a causal relationship to drug exposure.
Adverse reactions reported in foreign postmarketing surveillance and other trials with the use of ULTRAVIST Injection
include:
Cardiac disorders: cardiac arrest, ventricular fibrillation, atrial fibrillation, tachycardia, palpitations, congestive heart
failure, myocardial infarction, angina pectoris;
Ear and labyrinth disorders: vertigo, tinnitus;
Endocrine disorders: hyperthyroidism, thyrotoxic crisis, hypothyroidism;
Eye disorders: mydriasis, lacrimation disorder;
Gastrointestinal disorders: dysphagia, swelling of salivary glands;
Immune system disorders: anaphylactoid reaction (including fatal cases), respiratory arrest, anaphylactoid shock,
angioedema, laryngeal edema, laryngospasm, bronchospasm, hypersensitivity;
Musculoskeletal and connective tissue disorders: compartment syndrome in case of extravasation
Nervous system disorders: cerebral ischemia/infarction, paralysis, paresis, transient cortical blindness, aphasia, coma,
unconsciousness, amnesia, hypotonia, aggravation of myasthenia gravis symptoms
Renal and urinary disorders: renal failure, hematuria;
Respiratory, thoracic and mediastinal disorders: pulmonary edema, acute respiratory distress syndrome, asthma,
Skin and subcutaneous tissue disorders: Stevens-Johnson Syndrome, skin discoloration;
Vascular disorders: vasospasm.
6.3 Pediatrics
The overall character, quality, and severity of adverse reactions in pediatric patients are generally similar to those reported
in adult patients. Additional adverse reactions reported in pediatric patients from foreign marketing surveillance or other
information are: epistaxis, angioedema, migraine, joint disorder (effusion), muscle cramps, mucous membrane disorder
(mucosal swelling), conjunctivitis, hypoxia, fixed eruptions, vertigo, diabetes insipidus, and brain edema [see Use in
Specific Populations (8.4)].
7 DRUG INTERACTIONS
7.1 Drug-Drug Interactions
In patients with renal impairment, biguanides can cause lactic acidosis. ULTRAVIST appears to increase the
risk of biguanide induced lactic acidosis, possibly as a result of worsening renal function [see Warnings and
Precautions (5.2)].
Reference ID: 3125107
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NDA 020220 ULTRAVIST INJ DD MMM 12
Patients on beta-blockers may be unresponsive to the usual doses of epinephrine used to treat allergic reactions. Because
of the risk of hypersensitivity reactions, use caution when administering iodinated contrast agents to patients taking beta-
blockers.
Interleukins are associated with an increased prevalence of delayed hypersensitivity reactions after iodinated contrast
agent administration. These reactions include fever, chills, nausea, vomiting, pruritus, rash, diarrhea, hypotension, edema,
and oliguria.
Renal toxicity has been reported in a few patients with liver dysfunction who were given an oral cholecystographic agent
followed by intravascular contrast agents. Administration of any intravascular contrast agent should therefore be
postponed in patients who have recently received a cholecystographic contrast agent.
Do not mix other drugs with ULTRAVIST Injection [see How Supplied/Storage and Handling (16)].
7.2 Drug-Laboratory Test Interactions
Thyroid Function Tests:
The results of protein bound iodine and radioactive iodine uptake studies, which depend on iodine estimation, will not
accurately reflect thyroid function for at least 16 days following administration of iodinated contrast agents. However,
thyroid function tests which do not depend on iodine estimations, for example, T3 resin uptake and total or free thyroxine
(T4) assays are not affected.
Laboratory Assay of Coagulation Parameters, Fibrinolysis and Complement System:
The effect of iopromide on coagulation factors in in vitro assays increased with the administered dose. Coagulation,
fibrinolysis and complement activation were evaluated with standard citrated human plasma in the following assays:
thrombin time, thrombin coagulase time, calcium thromboplastin time, partial thromboplastin time, plasminogen,
thrombin, alpha-2 antiplasmin and factor XIIa activity. Thrombin inhibition was almost complete. Data on reversibility
are not available. The thrombin time increased from approximately 20 seconds at an iopromide concentration of 10 mg
I/mL, up to 100 seconds at an iopromide concentration of 70 mg I/mL.
The PTT increased from approximately 50 seconds at an iopromide concentration of 10 mg I/mL, up to approximately
100 seconds at an iopromide concentration of 70 mg I/mL. A similar increase was noted in the thrombin coagulase time.
Lesser effects were noted in the calcium thromboplastin time. Coagulation time increased from 13.5 to 23 seconds at the
highest iopromide concentration of 70 mg I/mL. The Hageman factor split products decreased by about 20% over the
range of 10 to 70 mg I/mL of iopromide. Plasminogen was relatively stable. There was no evidence of activation of
fibrinolysis. The complement alternate pathway was activated. Factor B conversion increased in a dose dependent
manner. The duration of these effects was not studied.
In vitro studies with human blood showed that iopromide had a slight effect on coagulation and fibrinolysis. No Factor
XIIa formation could be demonstrated. The complement alternate pathway also can be activated.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category B
Reproduction studies performed with iopromide in rats and rabbits at doses up to 3.7 g I/kg (2.2 times the maximum
recommended dose for a 50 kg human, or approximately 0.7 times the human dose following normalization of the data to
body surface area estimates) have revealed no evidence of direct harm to the fetus. Embryolethality was observed in
rabbits that received 3.7 g I/kg, but this was considered to have been secondary to maternal toxicity. Adequate and well-
controlled studies in pregnant women have not been conducted. Because animal reproduction studies are not always
predictive of human response, this drug should be used during pregnancy only if clearly needed.
8.3 Nursing Mothers
It is not known whether ULTRAVIST Injection is excreted in human milk. However, many injectable contrast agents are
excreted unchanged in human milk. Although it has not been established that serious adverse reactions occur in nursing
infants, caution should be exercised when intravascular contrast agents are administered to nursing women because of
potential adverse reaction, and consideration should be given to temporarily discontinuing nursing.
Reference ID: 3125107
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NDA 020220 ULTRAVIST INJ DD MMM 12
8.4 Pediatric Use
The safety and efficacy of ULTRAVIST Injection have been established in the pediatric population over 2 years of age.
Use of ULTRAVIST Injection in these age groups is supported by evidence from adequate and well controlled studies of
ULTRAVIST Injection in adults and additional safety data obtained in literature and other reports in a total of 274
pediatric patients. Of these, there were 131 children (2–12 years), 57 adolescents, and 86 children of unreported or other
ages. There were 148 females, 94 males and 32 in whom gender was not reported. The racial distribution was: Caucasian
93 (33.9%), Black 1 (0.4%), Asian 6 (2.2%), and unknown 174 (63.5%). These patients were evaluated in intra-arterial
coronary angiographic (n=60), intravenous contrast computerized tomography (CT) (n=87), excretory urography (n=99)
and 28 other procedures.
In these pediatric patients, a concentration of 300 mg I/mL was employed for intravenous contrast CT or excretory
urography. A concentration of 370 mg I/mL was employed for intra-arterial and intracardiac administration in the
radiographic evaluation of the heart cavities and major arteries. Most pediatric patients received initial volumes of 1–2
mL/kg.
Optimal doses of ULTRAVIST Injection have not been established because different injection volumes, concentrations
and injection rates were not studied. The relationship of the volume of injection with respect to the size of the target
vascular bed has not been established. The potential need for dose adjustment on the basis of immature renal function has
not been established. In the pediatric population, the pharmacokinetic parameters have not been established.
Pediatric patients at higher risk of experiencing an adverse reaction during and after administration of any contrast agent
include those with asthma, a sensitivity to medication and/or allergens, cyanotic and acyanotic heart disease, congestive
heart failure, or a serum creatinine greater than 1.5 mg/dL. The injection rates in small vascular beds, and the relationship
of the dose by volume or concentration in small pediatric patients have not been established. Exercise caution in selecting
the dose.
Safety and effectiveness in pediatric patients below the age of two have not been established.
8.5 Geriatric Use
Middle-aged and elderly patients, without significantly impaired renal function, who received ULTRAVIST Injection in
doses corresponding to 9–30 g iodine, had mean steady-state volumes of distribution that ranged between 30–40 L. Mean
total and renal clearances were between 81–125 mL/min and 70–115 mL/min respectively in these patients, and were
similar to the values found in the young volunteers. The distribution phase half-life in this patient population was 0.1
hour, the main elimination phase half-life was 2.3 hours, and the terminal elimination phase half-life was 40 hours. The
urinary excretion (97% of the dose) and fecal excretion (2%) was comparable to that observed in young healthy
volunteers, suggesting that, compared to the renal route, biliary and/or gastrointestinal excretion is not significant for
iopromide.
8.6 Renal Impairment
In patients with renal impairment, opacification of the calyces and pelves by iopromide may be delayed due to slower
renal excretion of iopromide.
A pharmacokinetic study in patients with mild (n=2), moderate (n=6), and severe (n=3) renal impairment was conducted.
The total clearance of iopromide was decreased proportionately to the baseline decrease in creatinine clearance. The
plasma AUC increased about 2-fold in patients with moderate renal impairment and 6-fold in patients with severe renal
impairment compared to subjects with normal renal function. The terminal half-life increased from 2.2 hrs for subjects
with normal renal function to 11.6 hrs in patients with severe renal impairment. The peak plasma concentration of
iopromide was not influenced by the extent of renal impairment. Exercise caution and use the lowest necessary dose of
ULTRAVIST in patients with renal dysfunction [see Warnings and Precautions (5.2)].
10 OVERDOSAGE
The adverse effects of overdosage are life-threatening and affect mainly the pulmonary and cardiovascular systems.
Treatment of an overdosage is directed toward the support of all vital functions, and prompt institution of symptomatic
therapy.
ULTRAVIST Injection binds negligibly to plasma or serum protein and can, therefore, be dialyzed.
Reference ID: 3125107
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For current labeling information, please visit https://www.fda.gov/drugsatfda
11 DESCRIPTION
ULTRAVIST
(iopromide) Injection is a nonionic, water soluble x-ray contrast agent for intravascular administration. The
chemical name for iopromide is N,N'-Bis(2,3-dihydroxypropyl)-2,4,6-triiodo-5-[(methoxyacetyl)amino]-N-methyl- 1,3-
benzenedicarboxamide. Iopromide has a molecular weight of 791.12 (iodine content 48.12%).
Iopromide has the following structural formula:
ULTRAVIST Injection is a nonionic sterile, clear, colorless to slightly yellow, odorless, pyrogen-free aqueous solution of
iopromide, containing 2.42 mg/mL tromethamine buffer and 0.1 mg/mL edetate calcium disodium stabilizer.
ULTRAVIST Injection is available in four strengths:
150 mg I/mL provides 311.7 mg/mL iopromide,
240 mg I/mL provides 498.72 mg/mL iopromide,
300 mg I/mL provides 623.4 mg/mL iopromide,
370 mg I/mL provides 768.86 mg/mL iopromide.
During the manufacture of ULTRAVIST Injection, sodium hydroxide or hydrochloric acid may be added for pH adjust-
ment. ULTRAVIST Injection has a pH of 7.4 (6.5–8) at 25± 2°C, is sterilized by autoclaving and contains no
preservatives.
The iodine concentrations (mg I/mL) available have the following physicochemical properties:
ULTRAVIST
INJECTION
ULTRAVIST
INJECTION
ULTRAVIST
INJECTION
ULTRAVIST
INJECTION
Property
150 mg I/mL
240 mg I/mL
300 mg I/mL
370 mg I/mL
Osmolality*(mOsmol/kg water) @ 37°C
328
483
607
774
Osmolarity*(mOsmol/L)
@ 37°C
278
368
428
496
Viscosity (cP)
@ 20°C
@ 37°C
2.3
1.5
4.9
2.8
9.2
4.9
22
10
Density (g/mL)
@ 20°C
@ 37°C
1.164
1.157
1.262
1.255
1.330
1.322
1.409
1.399
*Osmolality was measured by vapor-pressure osmometry. Osmolarity was calculated from the measured osmolal
concentrations.
Solutions of ULTRAVIST Injection 150 mg I/mL, 240 mg I/mL, 300 mg I/mL and 370 mg I/mL have osmolalities from
approximately 1.1 to 2.7 times that of plasma (285 mOsmol/kg water).
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Iopromide is a nonionic, water soluble, tri-iodinated x-ray contrast agent for intravascular administration.
Intravascular injection of iopromide opacifies those vessels in the path of flow of the contrast agent, permitting
radiographic visualization of the internal structures until significant hemodilution occurs.
12.2 Pharmacodynamics
Following ULTRAVIST administration, the degree of contrast enhancement is directly related to the iodine content in the
administered dose; peak iodine plasma levels occur immediately following rapid intravenous injection. Iodine plasma
NDA 020220 ULTRAVIST INJ DD MMM 12
Reference ID: 3125107
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NDA 020220 ULTRAVIST INJ DD MMM 12
levels fall rapidly within 5 to 10 minutes. This can be accounted for by the dilution in the vascular and extravascular fluid
compartments.
Intravascular Contrast: Contrast enhancement appears to be greatest immediately after bolus injections (15 seconds to 120
seconds). Thus, greatest enhancement may be detected by a series of consecutive two-to-three second scans performed
within 30 to 90 seconds after injection (that is, dynamic computed tomographic imaging).
ULTRAVIST Injection may be visualized in the renal parenchyma within 30–60 seconds following rapid intravenous
injection. Opacification of the calyces and pelves in patients with normal renal function becomes apparent within 1–3
minutes, with optimum contrast occurring within 5–15 minutes.
In contrast CT, some performance characteristics are different in the brain and body. In contrast CT of the body, iodinated
contrast agents diffuse rapidly from the vascular into the extravascular space. Following the administration of iodinated
contrast agents, the increase in tissue density to x-rays is related to blood flow, the concentration of the contrast agent, and
the extraction of the contrast agent by various interstitial tissues. Contrast enhancement is thus due to any relative
differences in extravascular diffusion between adjacent tissues.
In the normal brain with an intact blood-brain barrier, contrast is generally due to the presence of iodinated contrast agent
within the intravascular space. The radiographic enhancement of vascular lesions, such as arteriovenous malformations
and aneurysms, depends on the iodine content of the circulating blood pool.
In tissues with a break in the blood-brain barrier, contrast agent accumulates within interstitial brain tissue. The time to
maximum contrast enhancement can vary from the time that peak blood iodine levels are reached to 1 hour after
intravenous bolus administration. This delay suggests that radiographic contrast enhancement is at least in part dependent
on the accumulation of iodine containing medium within the lesion and outside the blood pool. The mechanism by which
this occurs is not clear.
For information on coagulation parameters, fibrinolysis and complement system [see Drug Interactions (7.2)].
12.3 Pharmacokinetics
Distribution
After intravenous administration to healthy young volunteers, plasma iopromide concentration time profile shows an
initial distribution phase with a half-life of 0.24 hour; a main elimination phase with a half-life of 2 hours; and a terminal
elimination phase with a half-life of 6.2 hours. The total volume of distribution at steady state is about 16 L suggesting
distribution in to extracellular space. Plasma protein binding of iopromide is 1%.
Iodinated contrast agents may cross the blood-brain barrier [see Warnings and Precautions (5.8)].
Metabolism
Iopromide is not metabolized.
Elimination
The amounts excreted unchanged in urine represent 97% of the dose in young healthy subjects. Only 2% of the dose is
recovered in the feces. Similar recoveries in urine and feces are observed in middle-aged and elderly patients. This finding
suggests that, compared to the renal route, biliary and/or gastrointestinal excretion is not important for iopromide. During
the slower terminal phase only 3% of the dose is eliminated; 97% of the dose is disposed of during the earlier phases, the
largest part of which occurs during the main elimination phase. The ratio of the renal clearance of iopromide to the
creatinine clearance is 0.82 suggesting that iopromide is mainly excreted by glomerular filtration. Additional tubular
reabsorption is possible. Pharmacokinetics of iopromide at intravenous doses up to 80 g iodine, are dose proportionate and
first order.
The mean total and renal clearances are 107 mL/min and 104 mL/min, respectively.
Specific Populations
A pharmacokinetic study was conducted in 11 patients with renal impairment [see Use in Specific Populations (8.6)].
Reference ID: 3125107
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020220 ULTRAVIST INJ DD MMM 12
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term animal studies have not been performed with iopromide to evaluate carcinogenic potential or effects on
fertility. Iopromide was not genotoxic in a series of studies including the Ames test, an in vitro human lymphocytes
analysis of chromosomal aberrations, an in vivo mouse micro-nucleus assay, and in an in vivo mouse dominant lethal
assay.
14 CLINICAL STUDIES
ULTRAVIST Injection was administered to 708 patients; 1 patient was less than 18 years of age, 347 patients were
between 18 and 59 years of age, and 360 patients were equal to or greater than 60 years of age; the mean age was 56.6
years (range 17–88). Of the 708 patients, 446 (63%) were male and 262 (37%) were female. The racial distribution was:
Caucasian 463 (65.4%), Black 95 (13.4%), Hispanic 36 (5.1%), Asian 11 (1.6 %), and other or unknown 103 (14.5%).
Efficacy assessment was based on the global evaluation of the quality of the radiographs by rating visualization as either
excellent, good, poor, or no image, and on the ability to make a diagnosis. Five (5) intra-arterial and three (3) intravenous
procedures were studied with 1 of 4 concentrations (370 mg I/mL, 300 mg I/mL, 240 mg I/mL, and 150 mg I/mL). These
procedures were: aortography/visceral angiography, coronary arteriography and left ventriculography, cerebral
arteriography, peripheral arteriography, intra-arterial digital subtraction angiography (IA-DSA), contrast computed
tomography (CT) of head and body, excretory urography, and peripheral venography.
Cerebral arteriography was evaluated in two randomized, double-blind clinical trials of ULTRAVIST Injection 300 mg
I/mL in 80 patients with conditions such as altered cerebrovascular perfusion and/or permeability occurring in central
nervous system diseases due to various CNS disorders. Visualization ratings were good or excellent in 99% of the patients
with ULTRAVIST Injection; a radiologic diagnosis was made in the majority of the patients. Confirmation of the
radiologic findings by other diagnostic methods was not obtained.
Coronary arteriography/left ventriculography was evaluated in two randomized, double-blind clinical trials and one
unblinded, unrandomized clinical trial of ULTRAVIST Injection 370 mg I/mL in 106 patients with conditions such as
altered coronary artery perfusion due to metabolic causes and in patients with conditions such as altered ventricular
function. Visualization ratings were good or excellent in 99% or more of the patients a radiologic diagnosis was made in
the majority of the patients. A confirmation of the radiologic findings by other diagnostic methods was not obtained.
Aortography/visceral angiography was evaluated in two randomized, double-blind clinical trials in 78 patients with
conditions such as altered aortic blood flow and/or visceral vascular disorders. Visualization ratings were good or
excellent in the majority of the patients; a radiologic diagnosis was made in 99% of the patients with ULTRAVIST
Injection. A confirmation of radiologic findings by other diagnostic methods was not obtained. The risks of renal
arteriography could not be analyzed.
Contrast CT of head and body was evaluated in three randomized, double-blind clinical trials of ULTRAVIST Injection
300 mg I/mL in 95 patients with vascular disorders. Visualization ratings were good or excellent in 99% of the patients; a
radiologic diagnosis was made in the majority of the patients. A confirmation of contrast CT findings by other diagnostic
methods was not obtained.
ULTRAVIST Injection was evaluated in a blinded reader trial for CT of the head and body. Among the 382 patients who
were evaluated with ULTRAVIST Injection 370 mg I/mL, visualization ratings were good or excellent in approximately
97% of patients.
Peripheral venography was evaluated in two randomized, double-blind clinical trials of ULTRAVIST Injection 240 mg
I/mL in 63 patients with disorders affecting venous drainage of the limbs. Visualization ratings were good or excellent in
100% of the patients; a radiologic diagnosis was made in the majority of the patients. A confirmation of radiologic
findings by other diagnostic methods was not obtained.
Similar studies were completed with comparable findings noted in intra-arterial digital subtraction angiography,
peripheral arteriography and excretory urography.
16 HOW SUPPLIED/STORAGE AND HANDLING
ULTRAVIST Injection is a sterile, clear, colorless to slightly yellow, odorless, pyrogen-free aqueous solution available in
four strengths.
Reference ID: 3125107
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020220 ULTRAVIST INJ DD MMM 12
Glass Vials
NDC Number
ULTRAVIST Injection 150 mg I/mL
10 x 50 mL vials
50419-340-05
ULTRAVIST Injection 240 mg I/mL
10 x 50 mL vials
50419-342-05
10 x 50 mL vials (RFID)
50419-342-41
10 x 100 mL vials
50419-342-10
10 x 100 mL vials (RFID)
50419-342-43
ULTRAVIST Injection 300 mg I/mL
10 x 50 mL vials
50419-344-05
10 x 50 mL vials (RFID)
50419-344-41
10 x 75 mL fill/100 mL vials
50419-344-07
10 x 100 mL vials
50419-344-10
10 x 100 mL vials (RFID)
50419-344-43
10 x 125 mL fill/150 mL vials
50419-344-12
10 x 150 mL vials
50419-344-15
ULTRAVIST Injection 370 mg I/mL
10 x 50 mL vials
50419-346-05
10 x 50 mL vials (RFID)
50419-346-41
10 x 75 mL fill/100 mL vials
50419-346-07
10 x 100 mL vials
50419-346-10
10 x 100 mL vials (RFID)
50419-346-43
10 x 125 mL fill/150 mL vials
50419-346-12
10 x 150 mL vials
50419-346-15
10 x 150 mL vials (RFID)
50419-346-45
10 x 200 mL fill/250 mL vials
50419-346-20
Inspect ULTRAVIST visually prior to use. Do not use if discolored, if particulate matter (including crystals) is present, or
if containers are defective. As ULTRAVIST Injection is a highly concentrated solution, crystallization (milky-cloudy
appearance and/or sediment at bottom, or floating crystals) may occur.
As with all contrast agents, because of the potential for chemical incompatibility, do not mix or inject ULTRAVIST
Injection in intravenous administration lines containing other drugs, solutions or total nutritional admixtures.
Administer ULTRAVIST at or close to body temperature.
If nondisposable equipment is used, take scrupulous care to prevent residual contamination with traces of cleansing
agents.
Withdraw ULTRAVIST from its container under strict aseptic conditions using only sterile syringes and transfer devices.
Use immediately contrast agents which have been transferred into other delivery systems.
Store ULTRAVIST at 25°C (77°F); excursions permitted to 15–30°C (59–86°F) and protected from light.
17 PATIENT COUNSELING INFORMATION
Instruct patients receiving ULTRAVIST Injection to inform their physician or healthcare provider of the following:
If they are pregnant [see Use in Specific Populations (8.1)]
Reference ID: 3125107
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For current labeling information, please visit https://www.fda.gov/drugsatfda
If they are diabetic or if they have multiple myeloma, pheochromocytoma, sickle cell disease or thyroid disorder [see
Warnings and Precautions (5.2, 5.5)]
If they are allergic to any drugs or food, or if they have immune, autoimmune or immune deficiency disorders. Also,
if they have had any reaction to previous injections of dyes used for x-ray procedures [see Warnings and Precautions
(5.1)]
All medications they are currently taking, including non-prescription (over-the-counter) drugs.
©2012, Bayer HealthCare Pharmaceuticals Inc. All rights reserved.
Mfd. for:
Mfd. in Germany
6703503
Revised 05/2012
NDA 020220 ULTRAVIST INJ DD MMM 12
Reference ID: 3125107
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:47:03.094840
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/020220s036lbl.pdf', 'application_number': 20220, 'submission_type': 'SUPPL ', 'submission_number': 36}
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NDA 20-221/S-024
Page 3
ETHYOL®
(amifostine) for Injection
Description
Clinical Pharmacology
Indications and Usage
Contraindications
Warnings
Precautions
Adverse Reactions
Overdosage
Dosage and Administration
How Supplied
Rx only
DESCRIPTION
ETHYOL (amifostine) is an organic thiophosphate cytoprotective agent known chemically as 2-[(3
aminopropyl)amino]ethanethiol dihydrogen phosphate (ester) and has the following structural formula:
H2N(CH2)3NH(CH2)2S-PO3H2
Amifostine is a white crystalline powder which is freely soluble in water. Its empirical formula is
C5H15N2O3PS and it has a molecular weight of 214.22.
ETHYOL is the trihydrate form of amifostine and is supplied as a sterile lyophilized powder requiring
reconstitution for intravenous infusion. Each single-use 10 mL vial contains 500 mg of amifostine on
the anhydrous basis.
CLINICAL PHARMACOLOGY
ETHYOL is a prodrug that is dephosphorylated by alkaline phosphatase in tissues to a
pharmacologically active free thiol metabolite. This metabolite is believed to be responsible for the
reduction of the cumulative renal toxicity of cisplatin and for the reduction of the toxic effects of
radiation on normal oral tissues. The ability of ETHYOL to differentially protect normal tissues is
attributed to the higher capillary alkaline phosphatase activity, higher pH and better vascularity of
normal tissues relative to tumor tissue, which results in a more rapid generation of the active thiol
metabolite as well as a higher rate constant for uptake into cells. The higher concentration of the thiol
metabolite in normal tissues is available to bind to, and thereby detoxify, reactive metabolites of
cisplatin. This thiol metabolite can also scavenge reactive oxygen species generated by exposure to
either cisplatin or radiation.
Pharmacokinetics: Clinical pharmacokinetic studies show that ETHYOL is rapidly cleared from the
plasma with a distribution half-life of < 1 minute and an elimination half-life of approximately 8
minutes. Less than 10% of ETHYOL remains in the plasma 6 minutes after drug administration.
ETHYOL is rapidly metabolized to an active free thiol metabolite. A disulfide metabolite is produced
subsequently and is less active than the free thiol. After a 10-second bolus dose of 150 mg/m2 of
ETHYOL, renal excretion of the parent drug and its two metabolites was low during the hour
following drug administration, averaging 0.69%, 2.64% and 2.22% of the administered dose for the
parent, thiol and disulfide, respectively. Measurable levels of the free thiol metabolite have been found
in bone marrow cells 5-8 minutes after intravenous infusion of ETHYOL. Pretreatment with
dexamethasone or metoclopramide has no effect on ETHYOL pharmacokinetics.
Clinical Studies
Chemotherapy for Ovarian Cancer . A randomized controlled trial compared six cycles of
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-221/S-024
Page 4
cyclophosphamide 1000 mg/m2, and cisplatin 100 mg/m2 with or without ETHYOL pretreatment at
910 mg/m2, in two successive cohorts of 121 patients with advanced ovarian cancer. In both cohorts,
after multiple cycles of chemotherapy, pretreatment with ETHYOL significantly reduced the
cumulative renal toxicity associated with cisplatin as assessed by the proportion of patients who had
≥40% decrease in creatinine clearance from pretreatment values, protracted elevations in serum
creatinine (>1.5 mg/dL), or severe hypomagnesemia. Subgroup analyses suggested that the effect of
ETHYOL was present in patients who had received nephrotoxic antibiotics, or who had preexisting
diabetes or hypertension (and thus may have been at increased risk for significant nephrotoxicity), as
well as in patients who lacked these risks. Selected analyses of the effects of ETHYOL in reducing the
cumulative renal toxicity of cisplatin in the randomized ovarian cancer study are provided in TABLES
1 and 2, below.
TABLE 1
Proportion of Patients with ≥40% Reduction in Calculated Creatinine Clearance*
ETHYOL+CP
CP
p-value
(2-sided)
All Patients
16/122 (13%)
36/120 (30%)
0.001
First Cohort
10/63
20/58
0.018
Second Cohort
6/59
16/62
0.026
*Creatinine clearance values were calculated using the Cockcroft-Gault formula, Nephron 1976;
16:31-41.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
TABLE 2
NCI Toxicity Grades of Serum Magnesium Levels
for Each Patient's Last Cycle of Therapy
NCI-CTC Grade:
0
1
2
3
4 p-value*
(mEq/L)
>1.4
≤1.4->1.1
≤1.1->0.8
≤0.8->0.5
≤0.5
All Patients
0.001
92
13
3
0
0
ETHYOL+CP
73
18
7
5
1
CP
First Cohort
0.017
49
10
3
0
0
ETHYOL+CP
35
8
6
3
1
CP
0.012
Second Cohort
ETHYOL+CP
43
3
0
0
0
CP
38
10
1
2
0
* Based on 2-sided Mantel-Haenszel Chi-Square statistic.
In the randomized ovarian cancer study, ETHYOL had no detectable effect on the antitumor efficacy
of cisplatin-cyclophosphamide chemotherapy. Objective response rates (including pathologically
confirmed complete remission rates), time to progression, and survival duration were all similar in the
ETHYOL and control study groups. The table below summarizes the principal efficacy findings of the
randomized ovarian cancer study.
TABLE 3
Comparison of Principal Efficacy Findings
ETHYOL +CP
CP
Complete pathologic tumor
21.3% 15.8%
response rate
Time to progression (months)
Median (± 95% CI)
15.8 (13.2, 25.1) 18.1 (12.5, 20.4)
Mean (± Std error)
19.8 (±1.04) 19.1 (±1.58)
Hazard ratio
.98 (.64, 1.4)
(95% Confidence Interval)
Survival (months)
Median (± 95% CI)
31.3 (28.3, 38.2) 31.8 (26.3, 39.8)
Mean (± Std error)
33.7 (±2.03) 34.3 (±2.04)
Hazard ratio
.97 (.69, 1.32)
(95% Confidence Interval)
NDA 20-221/S-024
Page 5
Radiotherapy for Head and Neck Cancer. A randomized controlled trial of standard fractionated
radiation (1.8 Gy - 2.0 Gy/day for 5 days/week for 5-7 weeks) with or without ETHYOL, administered
at 200 mg/m2 as a 3 minute i.v. infusion 15-30 minutes prior to each fraction of radiation, was
conducted in 315 patients with head and neck cancer. Patients were required to have at least 75% of
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-221/S-024
Page 6
both parotid glands in the radiation field. The incidence of Grade 2 or higher acute (90 days or less
from start of radiation) and late xerostomia (9-12 months following radiation) as assessed by RTOG
Acute and Late Morbidity Scoring Criteria, was significantly reduced in patients receiving ETHYOL
(TABLE 4).
TABLE 4
Incidence of Grade 2 or Higher Xerostomia
(RTOG criteria)
Acute
(≤90 days from
start of radiation)
Latea
(9-12 months
post radiation)
ETHYOL +RT
51% (75/148)
35% (36/103)
RT
78% (120/153)
57% (63/111)
p-value
p<0.0001
p=0.0016
aBased on the number of patients for whom actual data were available.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-221/S-024
Page 7
At one year following radiation, whole saliva collection following radiation showed that more patients
given ETHYOL produced >0.1 gm of saliva (72% vs. 49%). In addition, the median saliva production
at one year was higher in those patients who received ETHYOL (0.26 gm vs. 0.1 gm). Stimulated
saliva collections did not show a difference between treatment arms. These improvements in saliva
production were supported by the patients' subjective responses to a questionnaire regarding oral
dryness.
In the randomized head and neck cancer study, locoregional control, disease-free survival and overall
survival were all comparable in the two treatment groups after one year of follow-up (see TABLE 5).
TABLE 5
Comparison of Principal Efficacy Findings at 1 Year
Locoregional Control Ratea
Hazard Ratiob
95% Confidence Interval
Disease-Free Survival Ratea
Hazard Ratiob
95% Confidence Interval
Overall Survival Ratea
Hazard Ratiob
95% Confidence Interval
ETHYOL +RT
RT
76.1%
75.0%
1.013
(0.671, 1.530)
74.6%
70.4%
1.035
(0.702, 1.528)
89.4%
82.4%
1.585
(0.961, 2.613)
a1 year rates estimated using Kaplan-Meier method
bHazard ratio >1.0 is in favor of the ETHYOL + RT arm
INDICATIONS AND USAGE
ETHYOL (amifostine) is indicated to reduce the cumulative renal toxicity associated with
repeated administration of cisplatin in patients with advanced ovarian cancer.
ETHYOL is indicated to reduce the incidence of moderate to severe xerostomia in patients
undergoing post-operative radiation treatment for head and neck cancer, where the radiation
port includes a substantial portion of the parotid glands (see Clinical Studies).
For the approved indications, the clinical data do not suggest that the effectiveness of cisplatin based
chemotherapy regimens or radiation therapy is altered by ETHYOL. There are at present only limited
data on the effects of ETHYOL on the efficacy of chemotherapy or radiotherapy in other settings.
ETHYOL should not be administered to patients in other settings where chemotherapy can produce a
significant survival benefit or cure, or in patients receiving definitive radiotherapy, except in the
context of a clinical study (see WARNINGS).
CONTRAINDICATIONS
ETHYOL is contraindicated in patients with known hypersensitivity to aminothiol compounds.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-221/S-024
Page 8
WARNINGS
1. Effectiveness of the Cytotoxic Regimen
Limited data are currently available regarding the preservation of antitumor efficacy when ETHYOL is
administered prior to cisplatin therapy in settings other than advanced ovarian cancer. Although some
animal data suggest interference is possible, in most tumor models the antitumor effects of
chemotherapy are not altered by amifostine. ETHYOL should not be used in patients receiving
chemotherapy for other malignancies in which chemotherapy can produce a significant survival benefit
or cure (e.g., certain malignancies of germ cell origin), except in the context of a clinical study.
2. Effectiveness of Radiotherapy
ETHYOL should not be administered in patients receiving definitive radiotherapy, except in the
context of a clinical trial, since there are at present insufficient data to exclude a tumor-protective
effect in this setting. ETHYOL was studied only with standard fractionated radiotherapy and only
when ≥75% of both parotid glands were exposed to radiation. The effects of ETHYOL on the
incidence of xerostomia and on toxicity in the setting of combined chemotherapy and radiotherapy and
in the setting of accelerated and hyperfractionated therapy have not been systematically studied.
3. Hypotension
Patients who are hypotensive or in a state of dehydration should not receive ETHYOL. Patients
receiving ETHYOL at doses recommended for chemotherapy should have antihypertensive therapy
interrupted 24 hours preceding administration of ETHYOL. Patients receiving ETHYOL at doses
recommended for chemotherapy who are taking antihypertensive therapy that cannot be stopped for 24
hours preceding ETHYOL treatment, should not receive ETHYOL.
Prior to ETHYOL infusion patients should be adequately hydrated. During ETHYOL infusion patients
should be kept in a supine position. Blood pressure should be monitored every 5 minutes during the
infusion, and thereafter as clinically indicated. It is important that the duration of the 910 mg/m2
infusion not exceed 15 minutes, as administration of ETHYOL as a longer infusion is associated with a
higher incidence of side effects. For infusion durations less than 5 minutes, blood pressure should be
monitored at least before and immediately after the infusion, and thereafter as clinically indicated. If
hypotension occurs, patients should be placed in the Trendelenburg position and be given an infusion
of normal saline using a separate i.v. line. During and after ETHYOL infusion, care should be taken to
monitor the blood pressure of patients whose antihypertensive medication has been interrupted since
hypertension may be exacerbated by discontinuation of antihypertensive medication and other causes
such as i.v. hydration.
Guidelines for interrupting and restarting ETHYOL infusion if a decrease in systolic blood pressure
should occur are provided in the DOSAGE AND ADMINISTRATION section. Hypotension may
occur during or shortly after ETHYOL infusion, despite adequate hydration and positioning of the
patient (see ADVERSE REACTIONS and PRECAUTIONS). Hypotension has been reported to be
associated with dyspnea, apnea, hypoxia, and in rare cases seizures, unconsciousness, respiratory arrest
and renal failure.
4. Cutaneous Reactions
Serious cutaneous reactions have been associated with ETHYOL administration. Serious cutaneous
reactions have included erythema multiforme,
Stevens-Johnson syndrome, toxic epidermal necrolysis, toxoderma and exfoliative dermatitis. These
reactions have been reported more frequently when ETHYOL
is used as a radioprotectant (see ADVERSE REACTIONS). Some of these reactions have been fatal
or have required hospitalization and/or discontinuance of therapy. Patients should be carefully
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-221/S-024
Page 9
monitored prior to, during and after ETHYOL administration. Serious cutaneous reactions may
develop weeks after initiation of ETHYOL administration (see PRECAUTIONS).
5. Hypersensitivity
Allergic manifestations including anaphylaxis and severe cutaneous reactions have been associated
with ETHYOL administration.
Nausea and Vomiting
Antiemetic medication should be administered prior to and in conjunction with ETHYOL (see
DOSAGE AND ADMINISTRATlON). When ETHYOL is administered with highly emetogenic
chemotherapy, the fluid balance of the patient should be carefully monitored.
6. Hypocalcemia
Serum calcium levels should be monitored in patients at risk of hypocalcemia, such as those with
nephrotic syndrome or patients receiving multiple doses of ETHYOL (see ADVERSE REACTIONS).
If necessary, calcium supplements can be administered.
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NDA 20-221/S-024
Page 10
PRECAUTIONS
General
Patients should be adequately hydrated prior to the ETHYOL infusion and blood pressure should be
monitored (see DOSAGE AND ADMINISTRATION).
The safety of ETHYOL administration has not been established in elderly patients, or in patients with
preexisting cardiovascular or cerebrovascular conditions such as ischemic heart disease, arrhythmias,
congestive heart failure, or history of stroke or transient ischemic attacks. ETHYOL should be used
with particular care in these and other patients in whom the common ETHYOL adverse effects of
nausea/vomiting and hypotension may be more likely to have serious consequences.
Prior to chemotherapy, ETHYOL should be administered as a 15-minute infusion (see DOSAGE AND
ADMINISTRATION). Blood pressure should be monitored every 5 minutes during the infusion, and
thereafter as clinically indicated.
Prior to radiation therapy, ETHYOL should be administered as a 3-minute infusion (see DOSAGE
AND ADMINISTRATION). Blood pressure should be monitored at least before and immediately after
the infusion, and thereafter as clinically indicated.
Cutaneous Reactions
Cutaneous reactions may require permanent discontinuation of ETHYOL or urgent dermatologic
consultation and biopsy (see below).
Cutaneous evaluation of the patient prior to each ETHYOL administration should
be performed with particular attention paid to the development of the following:
-
Any rash involving the lips or involving mucosa not known to be due to
another etiology (e.g., radiation mucositis, herpes simplex, etc.)
-
Erythematous, edematous, or bullous lesions on the palms of the hands or soles
of the feet and/or other cutaneous reactions on the trunk (front, back, abdomen)
-
Cutaneous reactions with associated fever or other constitutional symptoms
Cutaneous reactions must be clearly differentiated from radiation-induced dermatitis and from
cutaneous reactions related to an alternate etiology. ETHYOL should
be permanently discontinued for serious or severe cutaneous reactions (see WARNINGS and
ADVERSE REACTIONS) or for cutaneous reactions associated
with fever or other constitutional symptoms not known to be due to another etiology. ETHYOL
should be withheld and dermatologic consultation and biopsy considered
for cutaneous reactions or mucosal lesions of unknown etiology appearing outside
of the injection site or radiation port and for erythematous, edematous or bullous lesions on the palms
of the hand or soles of the feet. Reinitiation of ETHYOL should be at the physician’s discretion based
on medical judgment and appropriate dermatologic evaluation.
Allergic Reactions
In case of severe acute allergic reactions ETHYOL should be immediately and permanently
discontinued. Epinephrine and other appropriate measures should be available for treatment of serious
allergic events such as anaphylaxis.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
_____________________________
_____________________________
NDA 20-221/S-024
Page 11
Drug Interactions
Special consideration should be given to the administration of ETHYOL in patients receiving
antihypertensive medications or other drugs that could cause or potentiate hypotension.
Carcinogenesis, Mutagenesis, Impairment of Fertility
No long term animal studies have been performed to evaluate the carcinogenic potential of ETHYOL.
ETHYOL was negative in the Ames test and in the mouse micronucleus test. The free thiol metabolite
was positive in the Ames test with S9 microsomal fraction in the TA1535 Salmonella typhimurium
strain and at the TK locus in the mouse L5178Y cell assay. The metabolite was negative in the mouse
micronucleus test and negative for clastogenicity in human lymphocytes.
Pregnancy
Pregnancy Category C. ETHYOL has been shown to be embryotoxic in rabbits at doses of 50 mg/kg,
approximately sixty percent of the recommended dose in humans on a body surface area basis. There
are no adequate and well-controlled studies in pregnant women. ETHYOL should be used during
pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nursing Mothers
No information is available on the excretion of ETHYOL or its metabolites into human milk. Because
many drugs are excreted in human milk and because of the potential for adverse reactions in nursing
infants, it is recommended that breast feeding be discontinued if the mother is treated with ETHYOL.
Pediatric Use
The safety and effectiveness in pediatric patients have not been established.
Geriatric Use
The clinical studies did not include sufficient number of subjects aged 65 and over to determine
whether they respond differently from younger subjects. Other reported clinical experience has not
identified differences in responses between elderly and younger patients. In general, dose selection for
an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or
cardiac function and of concomitant disease or other drug therapy in elderly patients.
ADVERSE REACTIONS
Controlled Trials
In the randomized study of patients with ovarian cancer given ETHYOL at a dose of 910 mg/m2 prior
to chemotherapy, transient hypotension was observed in 62% of patients treated. The mean time of
onset was 14 minutes into the 15-minute period of ETHYOL infusion, and the mean duration was 6
minutes. In some cases, the infusion had to be prematurely terminated due to a more pronounced drop
in systolic blood pressure. In general, the blood pressure returned to normal within 5-15 minutes.
Fewer than 3% of patients discontinued ETHYOL due to blood pressure reductions. In the randomized
study of patients with head and neck cancer given ETHYOL at a dose of 200 mg/m2 prior to
radiotherapy, hypotension was observed in 15% of patients treated. (see TABLE 6)
TABLE 6
Incidence of Common Adverse Events in Patients Receiving ETHYOL
Phase III Ovarian Cancer
Phase III Head and
Trial (WR-1)
Neck Cancer Trial (WR-38)
910 mg/m2
200 mg/m2
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NDA 20-221/S-024
Page 12
Nausea/Vomiting
≥Grade 3
All Grades
Hypotension
≥Grade 3a
All Grades
Per Patient
36/122 (30%)
117/122 (96%)
10/122 (8%)
75/122 (61%)
Per Infusion
53/592 (9%)
520/592 (88%)
159/592 (27%)
Per Patient
12/150 (8%)
80/150 (53%)
4/150 (3%)
22/150 (15%)
Per Infusion
13/4314 (<1%)
233/4314 (5%)
46/4314 (1%)
aAccording to protocol-defined criteria. WR-1: requiring interruption of infusion; WR-38: drop of
>20mm Hg.
In the randomized study of patients with head and neck cancer, 17% (26/150) discontinued ETHYOL
due to adverse events. All but one of these patients continued to receive radiation treatment until
completion.
Hypotension that requires interruption of the ETHYOL infusion should be treated with fluid infusion
and postural management of the patient (supine or Trendelenburg position). If the blood pressure
returns to normal within 5 minutes and the patient is asymptomatic, the infusion may be restarted, so
that the full dose of ETHYOL can
be administered. Short term, reversible loss of consciousness has been reported rarely.
Nausea and/or vomiting occur frequently after ETHYOL infusion and may be severe.
In the ovarian cancer randomized study, the incidence of severe nausea/vomiting on
day 1 of cyclophosphamide-cisplatin chemotherapy was 10% in patients who did not receive
ETHYOL, and 19% in patients who did receive ETHYOL. In the randomized study of patients with
head and neck cancer, the incidence of severe nausea/vomiting was 8% in patients who received
ETHYOL and 1% in patients who did not receive ETHYOL.
Decrease in serum calcium concentrations is a known pharmacological effect of ETHYOL. At the
recommended doses, clinically significant hypocalcemia
was reported in 1% of patients in the randomized head and neck cancer study (see WARNINGS), and
not reported in the ovarian cancer study.
Other effects, which have been described during, or following ETHYOL infusion are flushing/feeling
of warmth, chills/feeling of coldness, malaise, fever, rash, dizziness, somnolence, hiccups and
sneezing. These effects have not generally precluded the completion of therapy.
Clinical Trials and Pharmacovigilance Reports
Allergic reactions characterized by one or more of the following manifestations have been observed
during or after ETHYOL administration: hypotension, fever, chills/rigors, dyspnea, hypoxia, chest
tightness, cutaneous eruptions, pruritus, urticaria and laryngeal edema. Cutaneous eruptions have been
commonly reported during
clinical trials and were generally non-serious. Serious, sometimes fatal skin reactions including
erythema multiforme, and in rare cases, exfoliative dermatitis, Stevens-Johnson syndrome and toxic
epidermal necrolysis have also occurred. The reported incidence of serious skin reactions associated
with ETHYOL is higher in patients receiving ETHYOL as a radioprotectant than in patients receiving
This label may not be the latest approved by FDA.
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NDA 20-221/S-024
Page 13
ETHYOL as a chemoprotectant. Rare anaphylactoid reactions and cardiac arrest have also been
reported.
Hypotension, usually brief systolic and diastolic, has been associated with one or more of the
following adverse events: apnea, dyspnea, hypoxia, tachycardia, bradycardia, extrasystoles, chest pain,
myocardial ischemia and convulsion. Rare cases of renal failure, myocardial infarction, respiratory and
cardiac arrest have been observed
during or after hypotension. (See WARNINGS and PRECAUTIONS)
Rare cases of arrhythmias such as atrial fibrillation/flutter and supraventricular tachycardia have been
reported. These are sometimes associated with hypotension or allergic reactions.
Transient hypertension and exacerbations of preexisting hypertension have been observed rarely after
ETHYOL administration.
Seizures and syncope have been reported rarely. (See WARNINGS and PRECAUTIONS)
OVERDOSAGE
In clinical trials, the maximum single dose of ETHYOL was 1300 mg/m2. No information is available
on single doses higher than this in adults. In the setting of a clinical trial, pediatric patients have
received single ETHYOL doses of up to 2700 mg/m2. At the higher doses, anxiety and reversible
urinary retention occurred.
Administration of ETHYOL at 2 and 4 hours after the initial dose has not led to increased nausea and
vomiting or hypotension. The most likely symptom of overdosage is hypotension, which should be
managed by infusion of normal saline and other supportive measures, as clinically indicated.
DOSAGE AND ADMINISTRATION
For Reduction of Cumulative Renal Toxicity with Chemotherapy:
The recommended starting dose of ETHYOL is 910 mg/m2 administered once daily as a 15-minute i.v.
infusion, starting 30 minutes prior to chemotherapy.
The 15-minute infusion is better tolerated than more extended infusions. Further reductions in infusion
times for chemotherapy regimens have not been systematically investigated.
Patients should be adequately hydrated prior to ETHYOL infusion and kept in a supine position during
the infusion. Blood pressure should be monitored every 5 minutes during the infusion, and thereafter
as clinically indicated.
The infusion of ETHYOL should be interrupted if the systolic blood pressure decreases significantly
from the baseline value as listed in the guideline below:
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Baseline Systolic Blood Pressure (mm Hg)
<100
100-119 120-139 140-179
≥180
Decrease in systolic blood pressure
20
25
30
40
50
during infusion of ETHYOL (mm Hg)
If the blood pressure returns to normal within 5 minutes and the patient is asymptomatic, the infusion
NDA 20-221/S-024
Page 14
Guideline for Interrupting ETHYOL Infusion Due to Decrease
in Systolic Blood Pressure
may be restarted so that the full dose of ETHYOL may be administered. If the full dose of ETHYOL
cannot be administered, the dose of ETHYOL for subsequent chemotherapy cycles should be 740
mg/m2.
It is recommended that antiemetic medication, including dexamethasone 20 mg i.v. and a serotonin
5HT3 receptor antagonist, be administered prior to and in conjunction with ETHYOL. Additional
antiemetics may be required based on the chemotherapy drugs administered.
For Reduction of Moderate to Severe Xerostomia from Radiation of the Head and Neck:
The recommended dose of ETHYOL is 200 mg/m2 administered once daily as a 3-minute i.v. infusion,
starting 15-30 minutes prior to standard fraction radiation therapy (1.8-2.0 Gy).
Patients should be adequately hydrated prior to ETHYOL infusion. Blood pressure should be
monitored at least before and immediately after the infusion, and thereafter as clinically indicated.
It is recommended that antiemetic medication be administered prior to and in conjunction with
ETHYOL. Oral 5HT3 receptor antagonists, alone or in combination with other antiemetics, have been
used effectively in the radiotherapy setting.
Reconstitution
ETHYOL (amifostine) for Injection is supplied as a sterile lyophilized powder requiring reconstitution
for intravenous infusion. Each single-use vial contains 500 mg of amifostine on the anhydrous basis.
Prior to intravenous injection, ETHYOL is reconstituted with 9.7 mL of sterile 0.9% Sodium Chloride
Injection, USP. The reconstituted solution (500 mg amifostine/10 mL) is chemically stable for up to 5
hours at room temperature (approximately 25°C) or up to 24 hours under refrigeration (2°C to 8°C).
ETHYOL prepared in polyvinylchloride (PVC) bags at concentrations ranging from 5 mg/mL to 40
mg/mL is chemically stable for up to 5 hours when stored at room temperature (approximately 25°C)
or up to 24 hours when stored under refrigeration (2°C to 8°C).
CAUTION: Parenteral products should be inspected visually for particulate matter and discoloration
prior to administration whenever solution and container permit. Do not use if cloudiness or precipitate
is observed.
Incompatibilities
The compatibility of ETHYOL with solutions other than 0.9% Sodium Chloride for Injection, or
Sodium Chloride solutions with other additives, has not been examined. The use of other solutions is
not recommended.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-221/S-024
Page 15
HOW SUPPLIED
ETHYOL (amifostine) for Injection is supplied as a sterile lyophilized powder in 10 mL single-use
vials (NDC 58178-017-01). Each single-use vial contains 500 mg of amifostine on the anhydrous
basis. The vials are available packaged as follows:
3 pack - 3 vials per carton (NDC 58178-017-03)
Store the lyophilized dosage form at Controlled Room Temperature 20°-25°C (68°-77°F) [See USP].
U.S. Patents 5,424,471; 5,591,731; 5,994,409
Ethyol® is a registered trademark of MedImmune Oncology, Inc. logo
Manufactured by:
MedImmune Pharma B.V.
6545 CG Nijmegen
The Netherlands
Or:
Ben Venue, Inc.
Bedford, Ohio 44146
For product information, please call 1 877 633 4411
Revision Date 5/2007
RAL-ETH
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
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2025-02-12T13:47:03.190660
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/020221s024lbl.pdf', 'application_number': 20221, 'submission_type': 'SUPPL ', 'submission_number': 24}
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Colestid®
Flavored Colestid®
colestipol hydrochloride for oral suspension
DESCRIPTION
COLESTID Granules and FLAVORED COLESTID Granules contain colestipol
hydrochloride, which is a lipid lowering agent for oral use. Colestipol hydrochloride is an
insoluble, high molecular weight basic anion-exchange copolymer of diethylenetriamine
and 1-chloro-2, 3-epoxypropane, with approximately 1 out of 5 amine nitrogens
protonated (chloride form). It is a light yellow water-insoluble resin which is hygroscopic
and swells when suspended in water or aqueous fluids.
COLESTID is tasteless and odorless. Inactive ingredient: silicon dioxide. One dose (1
packet or 1 level teaspoon) of COLESTID contains 5 grams of colestipol hydrochloride.
FLAVORED COLESTID is orange flavored and light orange in color. One dose (1
packet or 1 level scoopful) of FLAVORED COLESTID is approximately 7.5 grams
which contains 5 grams of colestipol hydrochloride. This product also contains the
following inactive ingredients: aspartame, beta carotene, citric acid, flavor (natural and
artificial), glycerine, maltol, mannitol, and methylcellulose.
CLINICAL PHARMACOLOGY
Cholesterol is the major, and probably the sole precursor of bile acids. During normal
digestion, bile acids are secreted via the bile from the liver and gall bladder into the
intestines. Bile acids emulsify the fat and lipid materials present in food, thus facilitating
absorption. A major portion of the bile acids secreted is reabsorbed from the intestines
and returned via the portal circulation to the liver, thus completing the enterohepatic
cycle. Only very small amounts of bile acids are found in normal serum.
Colestipol hydrochloride binds bile acids in the intestine forming a complex that is
excreted in the feces. This nonsystemic action results in a partial removal of the bile acids
from the enterohepatic circulation, preventing their reabsorption. Since colestipol
hydrochloride is an anion exchange resin, the chloride anions of the resin can be replaced
by other anions, usually those with a greater affinity for the resin than chloride ion.
Colestipol hydrochloride is hydrophilic, but it is virtually water insoluble (99.75%) and it
is not hydrolyzed by digestive enzymes. The high molecular weight polymer in colestipol
hydrochloride apparently is not absorbed. In humans, less than 0.17% of a single 14C
labeled colestipol hydrochloride dose is excreted in the urine when given following 60
days of chronic dosing of 20 grams of colestipol hydrochloride per day.
The increased fecal loss of bile acids due to colestipol hydrochloride administration leads
to an increased oxidation of cholesterol to bile acids. This results in an increase in the
number of low-density lipoprotein (LDL) receptors, increased hepatic uptake of LDL and
a decrease in beta lipoprotein or low density lipoprotein serum levels, and a decrease in
Reference ID: 3511333
1
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For current labeling information, please visit https://www.fda.gov/drugsatfda
serum cholesterol levels. Although colestipol hydrochloride produces an increase in the
hepatic synthesis of cholesterol in man, serum cholesterol levels fall.
There is evidence to show that this fall in cholesterol is secondary to an increased rate of
clearance of cholesterol-rich lipoproteins (beta or low density lipoproteins) from the
plasma. Serum triglyceride levels may increase or remain unchanged in colestipol
hydrochloride treated patients.
The decline in serum cholesterol levels with colestipol hydrochloride treatment is usually
evident by one month. When colestipol hydrochloride is discontinued, serum cholesterol
levels usually return to baseline levels within one month. Periodic determinations of
serum cholesterol levels as outlined in the National Cholesterol Education Program
(NCEP) guidelines should be done to confirm a favorable initial and long-term response1 .
In a large, placebo-controlled, multiclinic study, the LRC-CPPT,2 hypercholesterolemic
subjects treated with cholestyramine, a bile-acid sequestrant with a mechanism of action
and an effect on serum cholesterol similar to that of colestipol hydrochloride, had
reductions in total and low-density lipoprotein cholesterol (LDL-C). Over the seven-year
study period the cholestyramine group experienced a 19% reduction (relative to the
incidence in the placebo group) in the combined rate of coronary heart disease death plus
non-fatal myocardial infarction (cumulative incidences of 7% cholestyramine and 8.6%,
placebo). The subjects included in the study were middle-aged men (age 35–59) with
serum cholesterol-levels above 265 mg/dL, LDL-C above 175 mg/dL on a moderate
cholesterol-lowering diet, and no history of heart disease. It is not clear to what extent
these findings can be extrapolated to other segments of the hypercholesterolemic
population not studied.
Treatment with colestipol hydrochloride results in a significant increase in lipoprotein
LpAI. Lipoprotein LpAI is one of the two major lipoprotein particles within the high-
density lipoprotein (HDL) density range3, and has been shown in cell culture to promote
cholesterol efflux or removal from cells4. Although the significance of this finding has
not been established in clinical studies, the elevation of the lipoprotein LpAI particle
within the HDL fraction is consistent with an antiatherogenic effect of colestipol
hydrochloride, even though little change is observed in HDL cholesterol.
In patients with heterozygous familial hypercholesterolemia who have not obtained an
optimal response to colestipol hydrochloride alone in maximal doses, the combination of
colestipol hydrochloride and nicotinic acid has been shown to further lower serum
cholesterol, triglyceride, and LDL cholesterol (LDL-C) values. Simultaneously, HDL
cholesterol (HDL-C) values increased significantly. In many such patients it is possible to
normalize serum lipid values.5–7
Preliminary evidence suggests that the cholesterol-lowering effects of lovastatin and the
bile acid sequestrant, colestipol hydrochloride, are additive.
Reference ID: 3511333
2
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
The effect of intensive lipid-lowering therapy on coronary atherosclerosis has been
assessed by arteriography in hyperlipidemic patients. In these randomized, controlled
clinical trials, patients were treated for two to four years by either conventional measures
(diet, placebo, or in some cases low-dose resin), or with intensive combination therapy
using diet and COLESTID Granules plus either nicotinic acid or lovastatin. When
compared to conventional measures, intensive lipid-lowering combination therapy
significantly reduced the frequency of progression and increased the frequency of
regression of coronary atherosclerotic lesions in patients with or at risk for coronary
artery disease.8–11
INDICATIONS AND USAGE
Since no drug is innocuous, strict attention should be paid to the indications and
contraindications, particularly when selecting drugs for chronic long-term use.
COLESTID Granules and FLAVORED COLESTID Granules are indicated as adjunctive
therapy to diet for the reduction of elevated serum total and low-density lipoprotein
(LDL) cholesterol in patients with primary hypercholesterolemia (elevated low density
lipoproteins [LDL] cholesterol) who do not respond adequately to diet. Generally,
COLESTID and FLAVORED COLESTID have no clinically significant effect on serum
triglycerides, but with its use triglyceride levels may be raised in some patients.
Therapy with lipid-altering agents should be a component of multiple risk factor
intervention in those individuals at significantly increased risk for atherosclerotic
vascular disease due to hypercholesterolemia. Treatment should begin and continue with
dietary therapy (see NCEP guidelines). A minimum of six months of intensive dietary
therapy and counseling should be carried out prior to initiation of drug therapy. Shorter
periods may be considered in patients with severe elevations of LDL-C or with definite
CHD.
According to the NCEP guidelines, the goal of treatment is to lower LDL-C, and LDL-C
is to be used to initiate and assess treatment response. Only if LDL-C levels are not
available, should the Total-C be used to monitor therapy. The NCEP treatment guidelines
are shown below.
LDL-Cholesterol
mg/dL (mmol/L)
Definite
Atherosclerotic
Disease*
Two or More
Other Risk
Factors**
Initiation
Level
Goal
No
No
Yes
No
Yes
Yes or No
≥190
(≥4.9)
≥160
(≥4.1)
≥130
(≥3.4)
<160
(<4.1)
<130
(<3.4)
≤100
(≤2.6)
* Coronary heart disease or peripheral vascular disease (including symptomatic carotid artery disease).
Reference ID: 3511333
3
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
** Other risk factors for coronary heart disease (CHD) include: age (males: ≥45 years; females: ≥55
years or premature menopause without estrogen replacement therapy); family history of premature
CHD; current cigarette smoking; hypertension; confirmed HDL-C <35 mg/dL (0.91 mmol/L); and
diabetes mellitus. Subtract one risk factor if HDL-C is ≥60 mg/dL (1.6 mmol/L).
CONTRAINDICATIONS
COLESTID Granules and FLAVORED COLESTID Granules are contraindicated in
those individuals who have shown hypersensitivity to any of its components.
WARNINGS
TO AVOID ACCIDENTAL INHALATION OR ESOPHAGEAL DISTRESS,
COLESTID GRANULES AND FLAVORED COLESTID GRANULES SHOULD NOT BE
TAKEN IN ITS DRY FORM. ALWAYS MIX COLESTID AND FLAVORED
COLESTID WITH WATER OR OTHER FLUIDS BEFORE INGESTING.
PHENYLKETONURICS: FLAVORED COLESTID CONTAINS 18.2 MG
PHENYLALANINE PER 7.5-GRAM DOSE.
PRECAUTIONS
Prior to initiating therapy with COLESTID Granules and FLAVORED COLESTID
Granules, secondary causes of hypercholesterolemia (e.g., poorly controlled diabetes
mellitus, hypothyroidism, nephrotic syndrome, dysproteinemias, obstructive liver disease,
other drug therapy, alcoholism), should be excluded, and a lipid profile performed to
assess Total cholesterol, HDL-C, and triglycerides (TG). For individuals with TG less
than 400 mg/dL (<4.5 mmol/L), LDL-C can be estimated using the following equation:
LDL-C = Total cholesterol - [ (Triglycerides / 5)+HDL-C]
For TG levels >400 mg/dL, this equation is less accurate and LDL-C concentrations
should be determined by ultracentrifugation. In hypertriglyceridemic patients, LDL-C
may be low or normal despite elevated Total-C. In such cases COLESTID and
FLAVORED COLESTID may not be indicated.
Because it sequesters bile acids, colestipol hydrochloride may interfere with normal fat
absorption and thus may reduce absorption of folic acid and fat soluble vitamins such as
A, D, and K.
Chronic use of colestipol hydrochloride may be associated with an increased bleeding
tendency due to hypoprothrombinemia from vitamin K deficiency. This will usually
respond promptly to parenteral vitamin K1 and recurrences can be prevented by oral
administration of vitamin K1.
Serum cholesterol and triglyceride levels should be determined periodically based on
NCEP guidelines to confirm a favorable initial and adequate long-term response.
COLESTID and FLAVORED COLESTID may produce or severely worsen pre-existing
constipation. The dosage should be increased gradually in patients to minimize the risk of
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developing fecal impaction. In patients with pre-existing constipation, the starting dose
should be 1 packet or 1 scoop once daily for 5–7 days, increasing to twice daily with
monitoring of constipation and of serum lipoproteins, at least twice, 4–6 weeks apart.
Increased fluid and fiber intake should be encouraged to alleviate constipation and a stool
softener may occasionally be indicated. If the initial dose is well tolerated, the dose may
be increased as needed by one dose/day (at monthly intervals) with periodic monitoring
of serum lipoproteins. If constipation worsens or the desired therapeutic response is not
achieved at one to six doses/day, combination therapy or alternate therapy should be
considered. Particular effort should be made to avoid constipation in patients with
symptomatic coronary artery disease. Constipation associated with COLESTID and
FLAVORED COLESTID may aggravate hemorrhoids.
While there have been no reports of hypothyroidism induced in individuals with normal
thyroid function, the theoretical possibility exists, particularly in patients with limited
thyroid reserve.
Since colestipol hydrochloride is a chloride form of an anion exchange resin, there is a
possibility that prolonged use may lead to the development of hyperchloremic acidosis.
Carcinogenesis, mutagenesis and impairment of fertility
In studies conducted in rats in which cholestyramine resin (a bile acid sequestering agent
similar to colestipol hydrochloride) was used as a tool to investigate the role of various
intestinal factors, such as fat, bile salts and microbial flora, in the development of
intestinal tumors induced by potent carcinogens, the incidence of such tumors was
observed to be greater in cholestyramine resin treated rats than in control rats.
The relevance of this laboratory observation from studies in rats with cholestyramine
resin to the clinical use of colestipol hydrochloride is not known. In the LRC-CPPT study
referred to above, the total incidence of fatal and non-fatal neoplasms was similar in both
treatment groups. When the many different categories of tumors are examined, various
alimentary system cancers were somewhat more prevalent in the cholestyramine group.
The small numbers and the multiple categories prevent conclusions from being drawn.
Further follow-up of the LRC-CPPT participants by the sponsors of that study is planned
for cause-specific mortality and cancer morbidity.
When colestipol hydrochloride was administered in the diet to rats for 18 months, there
was no evidence of any drug related intestinal tumor formation. In the Ames assay,
colestipol hydrochloride was not mutagenic.
Use in Pregnancy
Since colestipol hydrochloride is essentially not absorbed systemically (less than 0.17%
of the dose), it is not expected to cause fetal harm when administered during pregnancy in
recommended dosages. There are no adequate and well controlled studies in pregnant
women, and the known interference with absorption of fat soluble vitamins may be
detrimental even in the presence of supplementation. The use of COLESTID or
FLAVORED COLESTID in pregnancy or by women of childbearing potential requires
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that the potential benefits of drug therapy be weighed against possible hazards to the
mother or child.
Nursing Mother
Caution should be exercised when COLESTID or FLAVORED COLESTID is
administered to a nursing mother. The possible lack of proper vitamin absorption
described in the “pregnancy” section may have an effect on nursing infants.
Pediatric Use
Safety and effectiveness in the pediatric population have not been established.
Drug Interactions
Since colestipol hydrochloride is an anion exchange resin, it may have a strong affinity
for anions other than the bile acids. In vitro studies have indicated that colestipol
hydrochloride binds a number of drugs. Therefore, COLESTID and FLAVORED
COLESTID resin may delay or reduce the absorption of concomitant oral medication.
The interval between the administration of COLESTID and FLAVORED COLESTID
and any other medication should be as long as possible. Patients should take other drugs
at least one hour before or four hours after COLESTID and FLAVORED COLESTID to
avoid impeding their absorption.
Repeated doses of colestipol hydrochloride given prior to a single dose of propranolol in
human trials have been reported to decrease propranolol absorption. However, in a
follow-up study in normal subjects, single dose administration of colestipol
hydrochloride and propranolol and twice-a-day administration for 5 days of both agents
did not effect the extent of propranolol absorption, but had a small yet statistically
significant effect on its rate of absorption; the time to reach maximum concentration was
delayed 30 minutes. Effects on the absorption of other beta-blockers have not been
determined. Therefore, patients on propranolol should be observed when COLESTID or
FLAVORED COLESTID is either added or deleted from a therapeutic regimen.
Studies in humans show that the absorption of chlorothiazide as reflected in urinary
excretion is markedly decreased even when administered one hour before colestipol
hydrochloride. The absorption of tetracycline, furosemide, penicillin G,
hydrochlorothiazide, and gemfibrozil was significantly decreased when given
simultaneously with colestipol hydrochloride; these drugs were not tested to determine
the effect of administration one hour before colestipol hydrochloride.
No depressant effect on blood levels in humans was noted when colestipol hydrochloride
was administered with any of the following drugs: aspirin, clindamycin, clofibrate,
methyldopa, nicotinic acid (niacin), tolbutamide, phenytoin or warfarin. Particular
caution should be observed with digitalis preparations since there are conflicting results
for the effect of colestipol hydrochloride on the availability of digoxin and digitoxin. The
potential for binding of these drugs if given concomitantly is present. Discontinuing
colestipol hydrochloride could pose a hazard to health if a potentially toxic drug that is
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significantly bound to the resin has been titrated to a maintenance level while the patient
was taking colestipol hydrochloride.
Bile acid binding resins may also interfere with the absorption of oral phosphate
supplements and hydrocortisone.
A study has shown that cholestyramine binds bile acids and reduces mycophenolic acid
exposure. As colestipol also binds bile acids, colestipol may reduce mycophenolic acid
exposure and potentially reduce efficacy of mycophenolate mofetil.
ADVERSE REACTIONS
Gastrointestinal
The most common adverse reactions are confined to the gastrointestinal tract. To achieve
minimal GI disturbance with an optimal LDL-cholesterol lowering effect, a gradual
increase of dosage starting with one dose/day is recommended. Constipation is the major
single complaint and at times is severe. Most instances of constipation are mild, transient,
and controlled with standard treatment. Increased fluid intake and inclusion of additional
dietary fiber should be the first step; a stool softener may be added if needed. Some
patients require decreased dosage or discontinuation of therapy. Hemorrhoids may be
aggravated.
Other, less frequent gastrointestinal complaints consist of abdominal discomfort
(abdominal pain and cramping), intestinal gas, (bloating and flatulence), indigestion and
heartburn, diarrhea and loose stools, and nausea and vomiting. Bleeding hemorrhoids and
blood in the stool have been infrequently reported. Peptic ulceration, cholecystitis, and
cholelithiasis have been rarely reported in patients receiving colestipol hydrochloride
granules, and are not necessarily drug related.
Transient and modest elevations of aspartate aminotransferase (AST, SGOT), alanine
aminotransferase (ALT, SGPT) and alkaline phosphatase were observed on one or more
occasions in various patients treated with colestipol hydrochloride.
The following non-gastrointestinal adverse reactions have been reported with generally
equal frequency in patients receiving COLESTID Granules, FLAVORED COLESTID
Granules, or placebo in clinical studies:
Cardiovascular
Chest pain, angina, and tachycardia have been infrequently reported.
Hypersensitivity
Rash has been infrequently reported. Urticaria and dermatitis have been rarely noted in
patients receiving colestipol hydrochloride granules.
Musculoskeletal
Musculoskeletal pain, aches and pains in the extremities, joint pains, arthritis, and
backache have been reported.
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Neurologic
Headache, migraine headache and sinus headache have been reported. Other infrequently
reported complaints include dizziness, light-headedness, and insomnia.
Miscellaneous
Anorexia, fatigue, weakness, shortness of breath, and swelling of the hands or feet, have
been infrequently reported.
OVERDOSAGE
Overdosage of COLESTID Granules or FLAVORED COLESTID Granules has not been
reported. Should overdosage occur, however, the chief potential harm would be
obstruction of the gastrointestinal tract. The location of such potential obstruction, the
degree of obstruction and the presence or absence of normal gut motility would
determine treatment.
DOSAGE AND ADMINISTRATION
One dose (1 packet or 1 level teaspoon) of COLESTID Granules contains 5 grams of
colestipol hydrochloride. One dose (1 packet or 1 level scoopful) of FLAVORED
COLESTID Granules is approximately 7.5 grams which contains 5 grams of colestipol
hydrochloride. The recommended daily adult dose is one to six packets or level scoopfuls
given once or in divided doses. Treatment should be started with one dose once or twice
daily with an increment of one dose/day at one- or two-month intervals. Appropriate use
of lipid profiles as per NCEP guidelines including LDL-cholesterol and triglycerides is
advised so that optimal, but not excessive doses are used to obtain the desired therapeutic
effect on LDL-cholesterol level. If the desired therapeutic effect is not obtained at one to
six doses/day with good compliance and acceptable side effects, combined therapy or
alternate treatment should be considered.
To avoid accidental inhalation or esophageal distress, COLESTID and FLAVORED
COLESTID should not be taken in its dry form. COLESTID and FLAVORED
COLESTID should always be mixed with water or other fluids before ingesting. Patients
should take other drugs at least one hour before or four hours after COLESTID or
FLAVORED COLESTID to minimize possible interference with their absorption. (See
PRECAUTIONS, Drug Interactions.)
Before COLESTID or FLAVORED COLESTID Administration
1. Define the type of hyperlipoproteinemia, as described in NCEP guidelines.
2. Institute a trial of diet and weight reduction.
3. Establish baseline serum total and LDL-cholesterol and triglyceride levels.
During COLESTID or FLAVORED COLESTID Administration
1. The patient should be carefully monitored clinically, including serum cholesterol
and triglyceride levels. Periodic determinations of serum cholesterol levels as
outlined in the NCEP guidelines should be done to confirm a favorable initial and
longer-term response.
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2. Failure of total or LDL-cholesterol to fall within the desired range should lead one
to first examine dietary and drug compliance. If these are deemed acceptable,
combined therapy or alternate treatment should be considered.
3. Significant rise in triglyceride level should be considered as indication for dose
reduction, drug discontinuation, or combined or alternate therapy.
Mixing and Administration Guide
COLESTID and FLAVORED COLESTID should always be mixed in a liquid such as
water or the beverage of your choice. It may also be taken in soups or with cereals or
pulpy fruits. COLESTID or FLAVORED COLESTID should never be taken in its dry
form.
FLAVORED COLESTID is an orange-flavored product. Although it may be mixed with
a variety of liquids or foods, the selection should be based on patient preference.
With Beverages
1. Add the prescribed amount of COLESTID or FLAVORED COLESTID to a
glassful (three ounces or more) of water or the beverage of your choice. A heavy
or pulpy juice may minimize complaints relative to consistency.
2. Stir the mixture until the medication is completely mixed. (COLESTID and
FLAVORED COLESTID will not dissolve in the liquid.) COLESTID and
FLAVORED COLESTID may also be mixed with carbonated beverages, slowly
stirred in a large glass; however, this mixture may be associated with GI
complaints.
Rinse the glass with a small amount of additional beverage to make sure all the
medication is taken.
With cereals, soups, and fruits
COLESTID and FLAVORED COLESTID may be taken mixed with milk in hot or
regular breakfast cereals, or even mixed in soups that have a high fluid content. It may
also be added to fruits that are pulpy such as crushed pineapple, pears, peaches, or fruit
cocktail.
HOW SUPPLIED
COLESTID Granules are available as follows:
Cartons of 30 foil packets — NDC 0009-0260-01
Cartons of 90 foil packets — NDC 0009-0260-04
Bottles of 300 grams with scoop — NDC 0009-0260-17
Bottles of 500 grams with scoop — NDC 0009-0260-02
Each packet or level scoop supplies 5 grams of COLESTID.
FLAVORED COLESTID Granules are available as follows:
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Cartons of 60 foil packets — NDC 0009-0370-03
Bottles of 450 grams (equivalent to approximately 60 doses) with scoop — NDC 0009
0370-05
Each packet or each level scoopful supplies approximately 7.5 grams of FLAVORED
COLESTID containing 5 grams of colestipol hydrochloride.
Store at controlled room temperature 20° to 25° C (68° to 77° F) [see USP].
REFERENCES
1. Summary of the Second Report of the National Cholesterol Education Program
(NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood
Cholesterol in Adults (Adult Treatment Panel II). JAMA 269(23):3015–3023,
1993.
2. Lipid Metabolism-Atherogenesis Branch, National Heart, Lung, and Blood
Institute, Bethesda, MD: The Lipid Research Clinics Coronary Primary
Prevention Trial Results. I. Reduction in Incidence of Coronary Heart Disease.
JAMA 251:351–364, 1984.
3. Parra HJ, et al. Differential electroimmunoassay of human LpA-I lipoprotein
particles on ready-to-use plates. Clin. Chem. 36(8):1431–1435, 1990.
4. Barbaras R, et al. Cholesterol efflux from cultured adipose cells is mediated by
LpAI particles but not by LpAI:AII particles. Biochem. Biophys. Res. Comm.
142(1):63–69, 1987.
5. Kane JP, et al. Normalization of low-density-lipoprotein levels in heterozygous
familial hypercholesterolemia with a combined drug regimen. N Engl. J. Med.
304:251–258, 1981.
6. Illingworth DR, et al. Colestipol plus nicotinic acid in treatment of heterozygous
familial hypercholesterolemia. Lancet 1:296–298, 1981.
7. Kuo PT, et al. Familial type II hyperlipoproteinemia with coronary heart disease:
Effect of diet-colestipol-nicotinic acid treatment. Chest 79:286–291, 1981.
8. Blankenhorn DH, et al. Beneficial Effects of Combined Colestipol-Niacin
Therapy on Coronary Atherosclerosis and Coronary Venous Bypass Grafts. JAMA
257(23):3233–3240, 1987.
9. Cashin-Hemphill L, et al. Beneficial Effects of Colestipol-Niacin on Coronary
Atherosclerosis: A 4-Year Follow-up. JAMA 264:3013–3017, 1990.
Reference ID: 3511333
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For current labeling information, please visit https://www.fda.gov/drugsatfda
10. Brown G, et al. Regression of Coronary Artery Disease as a Result of Intensive
Lipid-Lowering Therapy in Men with High Levels of Apolipoprotein B. N Engl,
J. Med 323:1289–1298, 1990.
11. Kane JP, et al. Regression of Coronary Atherosclerosis During Treatment of
Familial Hypercholesterolemia with Combined Drug Regimens. JAMA 264:3007–
3012, 1990.
Rx only company logo
LAB-0054-2.x
Revised May 2014
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Colestid®
micronized colestipol hydrochloride tablets
DESCRIPTION
The active ingredient in COLESTID Tablets is micronized colestipol hydrochloride,
which is a lipid lowering agent for oral use. Colestipol is an insoluble, high molecular
weight basic anion-exchange copolymer of diethylenetriamine and 1-chloro-2, 3
epoxypropane, with approximately 1 out of 5 amine nitrogens protonated (chloride form).
It is a light yellow water-insoluble resin which is hygroscopic and swells when suspended
in water or aqueous fluids.
Each COLESTID Tablet contains one gram of micronized colestipol hydrochloride.
COLESTID Tablets are light yellow in color and are tasteless and odorless. Inactive
ingredients: cellulose acetate phthalate, glyceryl triacetate, carnauba wax, hypromellose,
magnesium stearate, povidone, silicon dioxide. COLESTID Tablets contain no calories.
CLINICAL PHARMACOLOGY
Cholesterol is the major, and probably the sole precursor of bile acids. During normal
digestion, bile acids are secreted via the bile from the liver and gall bladder into the
intestines. Bile acids emulsify the fat and lipid materials present in food, thus facilitating
absorption. A major portion of the bile acids secreted is reabsorbed from the intestines
and returned via the portal circulation to the liver, thus completing the enterohepatic
cycle. Only very small amounts of bile acids are found in normal serum.
Colestipol hydrochloride binds bile acids in the intestine forming a complex that is
excreted in the feces. This nonsystemic action results in a partial removal of the bile acids
from the enterohepatic circulation, preventing their reabsorption. Since colestipol
hydrochloride is an anion exchange resin, the chloride anions of the resin can be replaced
by other anions, usually those with a greater affinity for the resin than the chloride ion.
Colestipol hydrochloride is hydrophilic, but it is virtually water insoluble (99.75%) and it
is not hydrolyzed by digestive enzymes. The high molecular weight polymer in colestipol
hydrochloride apparently is not absorbed. In humans, less than 0.17% of a single 14C
labeled colestipol hydrochloride dose is excreted in the urine when given following 60
days of dosing of 20 grams of colestipol hydrochloride per day.
The increased fecal loss of bile acids due to colestipol hydrochloride administration leads
to an increased oxidation of cholesterol to bile acids. This results in an increase in the
number of low-density lipoprotein (LDL) receptors, increased hepatic uptake of LDL and
a decrease in beta lipoprotein or LDL serum levels, and a decrease in serum cholesterol
levels. Although colestipol hydrochloride produces an increase in the hepatic synthesis of
cholesterol in man, serum cholesterol levels fall.
There is evidence to show that this fall in cholesterol is secondary to an increased rate of
clearance of cholesterol-rich lipoproteins (beta or low-density lipoproteins) from the
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plasma. Serum triglyceride levels may increase or remain unchanged in colestipol
hydrochloride treated patients.
The decline in serum cholesterol levels with colestipol hydrochloride treatment is usually
evident by one month. When colestipol hydrochloride is discontinued, serum cholesterol
levels usually return to baseline levels within one month. Periodic determinations of
serum cholesterol levels as outlined in the National Cholesterol Education Program
(NCEP) guidelines, should be done to confirm a favorable initial and long-term
1
response.
In a large, placebo-controlled, multiclinic study, the LRC-CPPT2, hypercholesterolemic
subjects treated with cholestyramine, a bile-acid sequestrant with a mechanism of action
and an effect on serum cholesterol similar to that of colestipol hydrochloride, had
reductions in total and LDL-C. Over the 7-year study period the cholestyramine group
experienced a 19% reduction (relative to the incidence in the placebo group) in the
combined rate of coronary heart disease (CHD) death plus nonfatal myocardial infarction
(cumulative incidences of 7% cholestyramine and 8.6% placebo). The subjects included
in the study were middle-aged men (aged 35–59) with serum cholesterol levels above 265
mg/dL, LDL-C above 175 mg/dL on a moderate cholesterol-lowering diet, and no history
of heart disease. It is not clear to what extent these findings can be extrapolated to other
segments of the hypercholesterolemic population not studied.
Treatment with colestipol results in a significant increase in lipoprotein LpAI.
Lipoprotein LpAI is one of the two major lipoprotein particles within the high-density
lipoprotein (HDL) density range3, and has been shown in cell culture to promote
cholesterol efflux or removal from cells4. Although the significance of this finding has
not been established in clinical studies, the elevation of the lipoprotein LpAI particle
within the HDL fraction is consistent with an antiatherogenic effect of colestipol
hydrochloride, even though little change is observed in HDL cholesterol (HDL-C).
In patients with heterozygous familial hypercholesterolemia who have not obtained an
optimal response to colestipol hydrochloride alone in maximal doses, the combination of
colestipol hydrochloride and nicotinic acid has been shown to further lower serum
cholesterol, triglyceride, and LDL-cholesterol (LDL-C) values. Simultaneously, HDL-C
values increased significantly. In many such patients it is possible to normalize serum
lipid values.5–7
Preliminary evidence suggests that the cholesterol-lowering effects of lovastatin and the
bile acid sequestrant, colestipol hydrochloride, are additive.
The effect of intensive lipid-lowering therapy on coronary atherosclerosis has been
assessed by arteriography in hyperlipidemic patients. In these randomized, controlled
clinical trials, patients were treated for two to four years by either conventional measures
(diet, placebo, or in some cases low-dose resin), or with intensive combination therapy
using diet and COLESTID Granules plus either nicotinic acid or lovastatin. When
compared to conventional measures, intensive lipid-lowering combination therapy
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significantly reduced the frequency of progression and increased the frequency of
regression of coronary atherosclerotic lesions in patients with or at risk for coronary
artery disease.8–11
INDICATIONS AND USAGE
Since no drug is innocuous, strict attention should be paid to the indications and
contraindications, particularly when selecting drugs for chronic long-term use.
COLESTID Tablets are indicated as adjunctive therapy to diet for the reduction of
elevated serum total and LDL-C in patients with primary hypercholesterolemia (elevated
LDL-C) who do not respond adequately to diet. Generally, COLESTID Tablets have no
clinically significant effect on serum triglycerides, but with their use, triglyceride levels
may be raised in some patients.
Therapy with lipid-altering agents should be a component of multiple risk factor
intervention in those individuals at significantly increased risk for atherosclerotic
vascular disease due to hypercholesterolemia. Treatment should begin and continue with
dietary therapy (see NCEP guidelines). A minimum of six months of intensive dietary
therapy and counseling should be carried out prior to initiation of drug therapy. Shorter
periods may be considered in patients with severe elevations of LDL-C or with definite
CHD.
According to the NCEP guidelines, the goal of treatment is to lower LDL-C, and LDL-C
is to be used to initiate and assess treatment response. Only if LDL-C levels are not
available, should the Total-C be used to monitor therapy. The NCEP treatment guidelines
are shown below.
LDL-Cholesterol
mg/dL (mmol/L)
Definite
Two or More
Initiation
Goal
Atherosclerotic
Other Risk
Level
Disease*
Factors**
No
No
≥190
<160
(≥4.9)
(<4.1)
No
Yes
≥160
<130
(≥4.1)
(<3.4)
Yes
Yes or No
≥130
≤100
(≥3.4)
(≤2.6)
* Coronary heart disease or peripheral vascular disease (including symptomatic carotid artery disease).
** Other risk factors for coronary heart disease (CHD) include: age (males: ≥45 years; female: ≥55 years
or premature menopause without estrogen replacement therapy); family history of premature CHD;
current cigarette smoking; hypertension; confirmed HDL-C <35 mg/dL (0.91 mmol/L); and diabetes
mellitus. Subtract one risk factor if HDL-C is ≥60 mg/dL (1.6 mmol/L).
CONTRAINDICATIONS
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COLESTID Tablets are contraindicated in those individuals who have shown
hypersensitivity to any of their components.
PRECAUTIONS
Prior to initiating therapy with COLESTID Tablets, secondary causes of
hypercholesterolemia (e.g., poorly controlled diabetes mellitus, hypothyroidism,
nephrotic syndrome, dysproteinemias, obstructive liver disease, other drug therapy,
alcoholism), should be excluded, and a lipid profile performed to assess total cholesterol,
HDL-C, and triglycerides (TG). For individuals with TG less than 400 mg/dL (<4.5
mmol/L), LDL-C can be estimated using the following equation:
LDL-C = Total cholesterol – [(Triglycerides/5) + HDL-C]
For TG levels >400 mg/dL, this equation is less accurate and LDL-C concentrations
should be determined by ultracentrifugation. In hypertriglyceridemic patients, LDL-C
may be low or normal despite elevated Total-C. In such cases COLESTID Tablets may
not be indicated.
Because it sequesters bile acids, colestipol hydrochloride may interfere with normal fat
absorption and, thus, may reduce absorption of folic acid and fat soluble vitamins such as
A, D, and K.
Chronic use of colestipol hydrochloride may be associated with an increased bleeding
tendency due to hypoprothrombinemia from vitamin K deficiency. This will usually
respond promptly to parenteral vitamin K1 and recurrences can be prevented by oral
administration of vitamin K1.
Serum cholesterol and triglyceride levels should be determined periodically based on
NCEP guidelines to confirm a favorable initial and adequate long-term response.
COLESTID Tablets may produce or severely worsen pre-existing constipation. The
dosage should be increased gradually in patients to minimize the risk of developing fecal
impaction. In patients with pre-existing constipation, the starting dose should be 2 grams
once or twice a day. Increased fluid and fiber intake should be encouraged to alleviate
constipation and a stool softener may occasionally be indicated. If the initial dose is well
tolerated, the dose may be increased as needed by a further 2 to 4 grams/day (at monthly
intervals) with periodic monitoring of serum lipoproteins. If constipation worsens or the
desired therapeutic response is not achieved at 2 to 16 grams/day, combination therapy or
alternate therapy should be considered. Particular effort should be made to avoid
constipation in patients with symptomatic coronary artery disease. Constipation
associated with COLESTID Tablets may aggravate hemorrhoids.
While there have been no reports of hypothyroidism induced in individuals with normal
thyroid function, the theoretical possibility exists, particularly in patients with limited
thyroid reserve.
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Since colestipol hydrochloride is a chloride form of an anion exchange resin, there is a
possibility that prolonged use may lead to the development of hyperchloremia acidosis.
Carcinogenesis, Mutagenesis and Impairment of Fertility
In studies conducted in rats in which cholestyramine resin (a bile acid sequestering agent
similar to colestipol hydrochloride) was used as a tool to investigate the role of various
intestinal factors, such as fat, bile salts, and microbial flora, in the development of
intestinal tumors induced by potent carcinogens, the incidence of such tumors was
observed to be greater in cholestyramine resin treated rats than in control rats.
The relevance of this laboratory observation from studies in rats with cholestyramine
resin to the clinical use of COLESTID Tablets is not known. In the LRC-CPPT study
referred to above, the total incidence of fatal and nonfatal neoplasms was similar in both
treatment groups. When the many different categories of tumors are examined, various
alimentary system cancers were somewhat more prevalent in the cholestyramine group.
The small numbers and the multiple categories prevent conclusions from being drawn.
Further follow-up of the LRC-CPPT participants by the sponsors of that study is planned
for cause-specific mortality and cancer morbidity. When colestipol hydrochloride was
administered in the diet to rats for 18 months, there was no evidence of any drug related
intestinal tumor formation. In the Ames assay, colestipol hydrochloride was not
mutagenic.
Use in Pregnancy
Since colestipol hydrochloride is essentially not absorbed systemically (less than 0.17%
of the dose), it is not expected to cause fetal harm when administered during pregnancy in
recommended dosages. There are no adequate and well-controlled studies in pregnant
women, and the known interference with absorption of fat-soluble vitamins may be
detrimental even in the presence of supplementation. The use of COLESTID tablets in
pregnancy or by women of childbearing potential requires that the potential benefits of
drug therapy be weighed against possible hazards to the mother or child.
Nursing Mothers: Caution should be exercised when COLESTID Tablets are
administered to a nursing mother. The possible lack of proper vitamin absorption
described in the “Pregnancy” section may have an effect on nursing infants.
Pediatric Use
Safety and effectiveness in the pediatric population have not been established.
Information for Patients
COLESTID Tablets may be larger than pills you have taken before. If you have had
swallowing problems or choking with food, liquids or other tablets or capsules in the
past, you should discuss this with your doctor before taking COLESTID Tablets.
It is important that you take COLESTID Tablets correctly:
1. Always take one tablet at a time and swallow promptly.
2. Swallow each tablet whole. Do not cut, crush, or chew the tablets.
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3. COLESTID Tablets must be taken with water or another liquid that you prefer.
Swallowing the tablets will be easier if you drink plenty of liquid as you swallow
each tablet.
Difficulty swallowing and temporary obstruction of the esophagus (the tube between
your mouth and stomach) have been rarely reported in patients taking COLESTID
Tablets. If a tablet does get stuck after you swallow it, you may notice pressure or
discomfort. If this happens to you, you should contact your doctor. Do not take
COLESTID Tablets again without your doctor’s advice.
If you are taking other medications, you should take them at least one hour before or four
hours after taking COLESTID Tablets.
Drug Interactions
Since colestipol hydrochloride is an anion exchange resin, it may have a strong affinity
for anions other than the bile acids. In vitro studies have indicated that colestipol
hydrochloride binds a number of drugs. Therefore, COLESTID Tablets may delay or
reduce the absorption of concomitant oral medication. The interval between the
administration of COLESTID Tablets and any other medication should be as long as
possible. Patients should take other drugs at least one hour before or four hours after
COLESTID Tablets to avoid impeding their absorption.
Repeated doses of colestipol hydrochloride given prior to a single dose of propranolol in
human trials have been reported to decrease propranolol absorption. However, in a
follow-up study in normal subjects, single-dose administration of colestipol
hydrochloride and propranolol and twice-a-day administration for 5 days of both agents
did not affect the extent of propranolol absorption, but had a small yet statistically
significant effect on its rate of absorption; the time to reach maximum concentration was
delayed approximately 30 minutes. Effects on the absorption of other beta-blockers have
not been determined. Therefore, patients on propranolol should be observed when
COLESTID Tablets are either added or deleted from a therapeutic regimen.
Studies in humans show that the absorption of chlorothiazide as reflected in urinary
excretion is markedly decreased even when administered one hour before colestipol
hydrochloride. The absorption of tetracycline, furosemide, penicillin G,
hydrochlorothiazide, and gemfibrozil was significantly decreased when given
simultaneously with colestipol hydrochloride; these drugs were not tested to determine
the effect of administration one hour before colestipol hydrochloride.
No depressant effect on blood levels in humans was noted when colestipol hydrochloride
was administered with any of the following drugs: aspirin, clindamycin, clofibrate,
methyldopa, nicotinic acid (niacin), tolbutamide, phenytoin or warfarin. Particular
caution should be observed with digitalis preparations since there are conflicting results
for the effect of colestipol hydrochloride on the availability of digoxin and digitoxin. The
potential for binding of these drugs if given concomitantly is present. Discontinuing
colestipol hydrochloride could pose a hazard to health if a potentially toxic drug that is
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significantly bound to the resin has been titrated to a maintenance level while the patient
was taking colestipol hydrochloride.
Bile acid binding resins may also interfere with the absorption of oral phosphate
supplements and hydrocortisone.
A study has shown that cholestyramine binds bile acids and reduces mycophenolic acid
exposure. As colestipol also binds bile acids, colestipol may reduce mycophenolic acid
exposure and potentially reduce efficacy of mycophenolate mofetil.
ADVERSE REACTIONS
Gastrointestinal
The most common adverse reactions are confined to the gastrointestinal tract. To achieve
minimal GI disturbance with an optimal LDL-C lowering effect, a gradual increase of
dosage starting with 2 grams, once or twice daily is recommended. Constipation is the
major single complaint and at times is severe. Most instances of constipation are mild,
transient, and controlled with standard treatment. Increased fluid intake and inclusion of
additional dietary fiber should be the first step; a stool softener may be added if needed.
Some patients require decreased dosage or discontinuation of therapy. Hemorrhoids may
be aggravated.
Other, less frequent gastrointestinal complaints consist of abdominal discomfort
(abdominal pain and cramping), intestinal gas (bloating and flatulence), indigestion and
heartburn, diarrhea and loose stools, and nausea and vomiting. Bleeding hemorrhoids and
blood in the stool have been infrequently reported. Peptic ulceration, cholecystitis, and
cholelithiasis have been rarely reported in patients receiving colestipol hydrochloride
granules, and are not necessarily drug related.
Difficulty swallowing and transient esophageal obstruction have been rarely reported in
patients taking COLESTID Tablets.
Transient and modest elevations of aspartate aminotransferase (AST, SGOT), alanine
aminotransferase (ALT, SGPT) and alkaline phosphatase were observed on one or more
occasions in various patients treated with colestipol hydrochloride.
The following nongastrointestinal adverse reactions have been reported with generally
equal frequency in patients receiving COLESTID Tablets, colestipol granules, or placebo
in clinical studies:
Cardiovascular
Chest pain, angina, and tachycardia have been infrequently reported.
Hypersensitivity
Rash has been infrequently reported. Urticaria and dermatitis have been rarely noted in
patients receiving colestipol hydrochloride granules.
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Musculoskeletal
Musculoskeletal pain, aches and pains in the extremities, joint pain and arthritis, and
backache have been reported.
Neurologic
Headache, migraine headache, and sinus headache have been reported. Other infrequently
reported complaints include dizziness, light-headedness, and insomnia.
Miscellaneous
Anorexia, fatigue, weakness, shortness of breath, and swelling of the hands or feet, have
been infrequently reported.
OVERDOSAGE
Overdosage of COLESTID Tablets has not been reported. Should overdosage occur,
however, the chief potential harm would be obstruction of the gastrointestinal tract. The
location of such potential obstruction, the degree of obstruction and the presence or
absence of normal gut motility would determine treatment.
DOSAGE AND ADMINISTRATION
For adults, COLESTID Tablets are recommended in doses of 2 to 16 grams/day given
once or in divided doses. The starting dose should be 2 grams once or twice daily.
Dosage increases of 2 grams, once or twice daily should occur at 1- or 2-month intervals.
Appropriate use of lipid profiles as per NCEP guidelines including LDL-C and
triglycerides, is advised so that optimal but not excessive doses are used to obtain the
desired therapeutic effect on LDL-C level. If the desired therapeutic effect is not obtained
at a dose of 2 to 16 grams/day with good compliance and acceptable side effects,
combined therapy or alternate treatment should be considered.
COLESTID Tablets must be taken one at a time and be promptly swallowed whole, using
plenty of water or other appropriate liquid. Do not cut, crush, or chew the tablets. Patients
should take other drugs at least one hour before or four hours after COLESTID Tablets to
minimize possible interference with their absorption. (See Drug Interactions.)
Before Administration of COLESTID Tablets
1. Define the type of hyperlipoproteinemia, as described in NCEP guidelines.
2. Institute a trial of diet and weight reduction.
3. Establish baseline serum total and LDL-C and triglyceride levels.
During Administration of COLESTID Tablets
1. The patient should be carefully monitored clinically, including serum cholesterol
and triglyceride levels. Periodic determinations of serum cholesterol levels as
outlined in the NCEP guidelines should be done to confirm a favorable initial and
long-term response.
2. Failure of total or LDL-C to fall within the desired range should lead one to first
examine dietary and drug compliance. If these are deemed acceptable, combined
therapy or alternate treatment should be considered.
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3. Significant rise in triglyceride level should be considered as indication for dose
reduction, drug discontinuation, or combined or alternate therapy.
HOW SUPPLIED
COLESTID Tablets are yellow, elliptical, imprinted U, and are supplied as follows:
Bottles of 120
NDC 0009-0450-03
Bottles of 500
NDC 0009-0450-04
Each tablet contains 1 gram of colestipol hydrochloride.
Store at controlled room temperature 20° to 25°C (68° to 77°F) [see USP].
REFERENCES
1. Summary of the Second Report of the National Cholesterol Education Program
(NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood
Cholesterol in Adults (Adult Treatment Panel II). JAMA 1993; 269(23):3015–
3023.
2. Lipid Metabolism-Atherogenesis Branch, National Heart, Lung, and Blood
Institute, Bethesda, MD: The Lipid Research Clinics Coronary Primary
Prevention Trial Results. I. Reduction in Incidence of Coronary Heart Disease.
JAMA 1984; 251:351–364.
3. Parra HJ, et al. Differential electroimmunoassay of human LpA-I lipoprotein
particles on ready-to-use plates. Clin. Chem. 1990; 36(8):1431–1435.
4. Barbaras R, et al. Cholesterol efflux from cultured adipose cells is mediated by
LpAI particles but not by LpAI:AII particles. Biochem. Biophys. Res. Comm.
1987; 142(1):63–69.
5. Kane JP, et al. Normalization of low-density-lipoprotein levels in heterozygous
familial hypercholesterolemia with a combined drug regimen. N Engl. J. Med.
1981; 304:251–258.
6. Illingworth DR, et al. Colestipol plus nicotinic acid in treatment of heterozygous
familial hypercholesterolemia. Lancet 1981; 1:296–298.
7. Kuo PT, et al. Familial type II hyperlipoproteinemia with coronary heart disease:
Effect of diet-colestipol-nicotinic acid treatment. Chest 1981; 79:286–291.
8. Blankenhorn DH, et al. Beneficial Effects of Combined Colestipol-Niacin
Therapy on Coronary Atherosclerosis and Coronary Venous Bypass Grafts. JAMA
1987; 257(23):3233–3240.
9. Cashin-Hemphill L, et al. Beneficial Effects of Colestipol-Niacin on Coronary
Atherosclerosis: A 4-Year Follow-up. JAMA 1990; 264:3013–3017.
10. Brown G. et al. Regression of Coronary Artery Disease as a Result of Intensive
Lipid-Lowering Therapy in Men with High Levels of Apolipoprotein B. N. Engl.
J. Med. 1990; 323:1289–1298.
11. Kane JP, et al. Regression of Coronary Atherosclerosis During Treatment of
Familial Hypercholesterolemia with Combined Drug Regimens. JAMA 1990;
264:3007–3012.
Rx only
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company logo
LAB-0053-3.x
Revised Month 2013
Reference ID: 3511333
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______________________________________________________________________________________________________________________________________
HIGHLIGHTS OF PRESCRIBING INFORMATION
•
Preparatory dehydration (for example, prolonged fasting and the
administration of a laxative before ULTRAVIST Injection) is
These highlights do not include all the information needed to use
contraindicated in pediatric patients because of risk of renal failure. (4)
ULTRAVIST Injection safely and effectively. See full prescribing
information for ULTRAVIST Injection.
-----------------------WARNINGS AND PRECAUTIONS-----------------------
ULTRAVIST (iopromide) Injection, for intravenous or intra-arterial use
Initial U.S. Approval: 1995
WARNING: NOT FOR INTRATHECAL USE
See ful prescribing information for complete boxed warning.
Inadvertent intrathecal administration may cause death,
convulsions, cerebral hemorrhage, coma, paralysis,
arachnoiditis, acute renal failure, cardiac arrest, seizures,
rhabdomyolysis, hyperthermia, and brain edema.
----------------------------INDICATIONS AND USAGE--------------------------
ULTRAVIST (iopromide) Injection is a radiographic contrast agent indicated
for:
•
Intra-arterial digital subtraction angiography (IA-DSA) (150 mg I/mL)
(1.1)
•
Cerebral arteriography and peripheral arteriography (300 mg I/mL) (1.1)
•
Coronary arteriography and left ventriculography, visceral angiography
and aortography (370 mg I/mL) (1.1)
•
Peripheral venography (240 mg I/mL) (1.2)
•
Excretory urography (300 mg I/mL) (1.2)
•
Contrast computed tomography (CT) imaging of head and body (300 mg
I/mL and 370 mg I/mL) (1.2)
----------------------DOSAGE AND ADMINISTRATION----------------------
Carefully individualize the volume and concentration of ULTRAVIST
Injection to be used for a vascular procedure, according to the specific dosing
tables. Adjust the dose accounting for factors such as age, body weight, size of
the vessel and the rate of blood flow within the vessel. (2)
---------------------DOSAGE FORMS AND STRENGTHS---------------------
ULTRAVIST Injection is available in four strengths: 150 mg I/mL; 240 mg
I/mL; 300 mg I/mL; 370 mg I/mL. (3)
-------------------------------CONTRAINDICATIONS-----------------------------
•
ULTRAVIST Injection is contraindicated for intrathecal use. (4)
•
Anaphylactoid Reactions: Life-threatening or fatal anaphylactoid
reactions may occur during or after ULTRAVIST administration,
particularly in patients with allergic disorders. (5.1)
•
Acute Renal Failure: Acute renal failure may occur following
ULTRAVIST administration, particularly in patients with renal
insufficiency, diabetes, multiple myeloma. Exercise caution and use the
lowest necessary dose of ULTRAVIST in patients with renal
dysfunction. (5.2)
•
Cardiovascular Reactions: Hemodynamic disturbances including shock
and cardiac arrest may occur during or shortly after administration of
ULTRAVIST.(5.3)
•
Thromboembolic Complications: Angiography may be associated with
local and distal organ damage, ischemia, thromboembolism and organ
failure. In angiographic procedures, consider the possibility of
dislodging plaques or damaging or perforating the vessel wall. The
physicochemical properties of the contrast agent, the dose and the speed
of injection can influence the reactions. (5.4)
------------------------------ADVERSE REACTIONS------------------------------
Most common adverse reactions (>1%) are headache, nausea, injection site
and infusion site reactions, vasodilatation, vomiting, back pain, urinary
urgency, chest pain, pain, dysgeusia, and abnormal vision. (6)
To report SUSPECTED ADVERSE REACTIONS, contact Bayer
HealthCare Pharmaceuticals Inc. at 1-888-842-2937 or FDA at 1-800
FDA-1088 or www.fda.gov/medwatch.
-----------------------USE IN SPECIFIC POPULATIONS-----------------------
•
Adequate and well-controlled studies in pregnant women have not been
conducted. Because animal reproduction studies are not always
predictive of human response, this drug should be used during
pregnancy only if clearly needed. (8.1)
•
The safety and efficacy of ULTRAVIST Injection have been established
in the pediatric population over 2 years of age. (8.4)
See 17 for PATIENT COUNSELING INFORMATION.
Revised: 3/2015
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: NOT FOR INTRATHECAL USE
1 INDICATIONS AND USAGE
1.1 Intra-Arterial Procedures*
1.2 Intravenous Procedures*
2 DOSAGE AND ADMINISTRATION
2.1 Intra-Arterial Procedures
2.2 Intravenous Procedures
2.3 Pediatric Dosing
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Anaphylactoid Reactions
5.2 Contrast Induced Acute Kidney Injury
5.3 Cardiovascular Reactions
5.4 Thromboembolic Complications
5.5 Reactions in Patients with Hyperthyroidism, Pheochromocytoma, or
Sickle Cell Disease
5.6 Extravasation
5.7 Increased Radiation Exposure
5.8 Interference with Image Interpretation
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
6.2 Postmarketing Experience
6.3 Pediatrics
7 DRUG INTERACTIONS
7.1 Drug-Drug Interactions
7.2 Drug-Laboratory Test Interactions
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Renal Impairment
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information are not
listed.
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_______________________________________________________________________________________________________________________________________
FULL PRESCRIBING INFORMATION
WARNING: NOT FOR INTRATHECAL USE
Inadvertent intrathecal administration may cause death, convulsions, cerebral hemorrhage, coma, paralysis,
arachnoiditis, acute renal failure, cardiac arrest, seizures, rhabdomyolysis, hyperthermia, and brain edema.
[see Contraindications (4).]
1 INDICATIONS AND USAGE
ULTRAVIST
® Injection is an iodinated contrast agent indicated for:
1.1 Intra-Arterial Procedures*
• 150 mg I/mL for intra-arterial digital subtraction angiography (IA-DSA)
• 300 mg I/mL for cerebral arteriography and peripheral arteriography
• 370 mg I/mL for coronary arteriography and left ventriculography, visceral angiography, and aortography
1.2 Intravenous Procedures*
• 240 mg I/mL for peripheral venography
• 300 mg I/mL for excretory urography
• 300 mg I/mL and 370 mg I/mL for contrast Computed Tomography (CT) of the head and body (intrathoracic, intra
abdominal and retroperitoneal regions) for the evaluation of neoplastic and non-neoplastic lesions. The usefulness of
contrast enhancement for the investigation of the retrobulbar space and of low grade or infiltrative glioma has not
been demonstrated.
*For information on the concentrations and doses for the Pediatric Population [see Dosage and Administration (2.3) and
Use in Specific Populations (8.4)].
2 DOSAGE AND ADMINISTRATION
• Visually inspect ULTRAVIST for particulate matter and/or discoloration, whenever solution and container permit. Do
not administer ULTRAVIST if particulate matter and/or discoloration is observed.
• Determine the volume and concentration of ULTRAVIST Injection to be used taking into account factors such as age,
body weight, size of the vessel and the rate of blood flow within the vessel; consider also extent of opacification
required, structure(s) or area to be examined, disease processes affecting the patient, and equipment and technique to
be employed. Specific dose adjustments for age, gender, weight and renal function have not been studied for
ULTRAVIST Injection. As with all iodinated contrast agents, lower doses may have less risk. The efficacy of
ULTRAVIST Injection below doses recommended has not been established.
• The maximum recommended total dose of iodine in adults is 86 grams; a maximum recommended total dose of iodine
has not been established for pediatric patients.
• Hydrate patients adequately prior to and following the administration of ULTRAVIST [see Warnings and
Precautions (5.2)].
• Warming ULTRAVIST to body temperature shortly before administration may help improve tolerability and ease of
injection [see How Supplied/Storage and Handling (16)].
2.1 Intra-Arterial Procedures
The volume and rate of injection of the contrast agent will vary depending on the injection site and the area being
examined. Inject contrast at rates approximately equal to the flow rate in the vessel being injected.
• Cerebral Arteriography (300 mg I/mL), Coronary Arteriography and Left Ventriculography (370 mg I/mL),
Peripheral Arteriography (300 mg I/mL), Intra-arterial Digital Subtraction Angiography (IA-DSA) (150 mg I/mL):
see Table 1.
• Aortography and Visceral Angiography (370 mg I/mL):
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Use a volume and rate of contrast injection proportional to the blood flow and related to the vascular and pathological
characteristics of the specific vessels being studied. Do not exceed 225 mL as total dose for the procedure.
Table 1: Suggested Single Injection Doses for Adult Intra-Arterial Procedures
IA-DSA*
(150 mg
I/mL)
Cerebral
Arteriography
(300 mg I/mL)
Peripheral
Arteriography
(300 mg I/mL)
Coronary Arteriography
and
Left Ventriculography
(370 mg I/mL)
Intra-Arterial Injection Sites
Carotid Arteries
Vertebral Arteries
Aortic Arch Injection (4 vessel study)
6–10 mL
4–8 mL
-
3–12 mL
4–12 mL
20–50 mL
-
-
-
-
-
-
Right Coronary Artery
Left Coronary Artery
Left Ventricle
-
-
-
-
-
-
-
-
-
3–14 mL
3–14 mL
30–60 mL
Aorta
Major Branches of the Abdominal
Aorta
20–50 mL
2–20 mL
-
-
-
-
-
-
Subclavian or Femoral Artery
Aortic Bifurcation (distal runoff)
-
-
-
-
5–40 mL
25–50 mL
-
-
Maximum Total Dose
250 mL
150 mL
250 mL
225 mL
*IA-DSA = Intra-Arterial Digital Subtraction Angiography
2.2 Intravenous Procedures
• Peripheral Venography (240 mg I/mL):
Inject the minimum volume necessary to visualize satisfactorily the structures under examination. Do not exceed 250
mL as total dose for the procedure.
• Contrast Computed Tomography (CT) (300 mg I/mL and 370 mg I/mL) and Excretory Urography (300 mg I/mL): see
Table 2.
Table 2: Suggested ULTRAVIST Injection Dosing for Adult Intravenous Contrast Administration
Excretory Urography
(300 mg I/mL)
Contrast Computed Tomography
(300 mg I/mL)
Contrast Computed
Tomography (370 mg I/mL)
Excretory Urography
Approximately 300 mg
I/kg body wt. (Adults
with normal renal
function)
-
-
Head
-
50–200 mL
41–162 mL
Body
Bolus Injection
Rapid Infusion
50–200 mL
100–200 mL
41–162 mL
81–162 mL
Maximum Total Dose
100 mL (30 g iodine)
200 mL (60 g iodine)
162 mL (60 g iodine)
2.3 Pediatric Dosing
The recommended dose in children over 2 years of age for the following evaluations is:
• Intra-arterial:
Cardiac chambers and related arteries (370 mg I/mL):
Inject 1 to 2 milliliters per kilogram (mL/kg). Do not exceed 4 mL/kg as total dose.
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• Intravenous:
Contrast Computerized Tomography or Excretory Urography (300 mg I/mL):
Inject 1 to 2 mL/kg. Do not exceed 3 mL/kg as total dose.
The safety and efficacy relationships of other doses, concentrations or procedures have not been established [see Use in
Specific Populations (8.4) and Clinical Pharmacology (12.3)].
3 DOSAGE FORMS AND STRENGTHS
ULTRAVIST Injection is a nonionic, sterile, clear, colorless to slightly yellow, odorless, pyrogen-free aqueous solution of
iopromide, containing 2.42 mg/mL tromethamine buffer and 0.1 mg/mL edetate calcium disodium stabilizer.
ULTRAVIST Injection is available in four strengths:
150 mg I/mL provides 311.7 mg/mL iopromide,
240 mg I/mL provides 498.72 mg/mL iopromide,
300 mg I/mL provides 623.4 mg/mL iopromide,
370 mg I/mL provides 768.86 mg/mL iopromide.
4 CONTRAINDICATIONS
• Do not administer ULTRAVIST Injection intrathecally. Inadvertent intrathecal administration may cause death,
convulsions, cerebral hemorrhage, coma, paralysis, arachnoiditis, acute renal failure, cardiac arrest, seizures,
rhabdomyolysis, hyperthermia, and brain edema.
• Preparatory dehydration (for example, prolonged fasting and the administration of a laxative) before ULTRAVIST
Injection is contraindicated in pediatric patients because of risk of acute renal failure.
5 WARNINGS AND PRECAUTIONS
5.1 Anaphylactoid Reactions
Life-threatening or fatal, anaphylactoid reactions, may occur during or after ULTRAVIST administration. Manifestations
include respiratory arrest, laryngospasm, bronchospasm, angioedema, and shock. Increased risk is associated with a
history of previous reaction to a contrast agent (3-fold), a known sensitivity to iodine and known allergic disorders (that is,
bronchial asthma, hay fever and food allergies) or other hypersensitivities (2-fold). Exercise extreme caution when
considering the use of iodinated contrast agents in patients with these histories or disorders.
Emergency facilities and personnel trained in the treatment of anaphylactoid reactions should be available for at least 30
to 60 minutes after ULTRAVIST administration.
5.2 Contrast Induced Acute Kidney Injury
Acute kidney injury, including renal failure, may occur after intravascular administration of ULTRAVIST. Risk factors
include: pre-existing renal insufficiency, dehydration, diabetes mellitus, congestive heart failure, advanced vascular
disease, elderly age, concomitant use of nephrotoxic or diuretic medications, multiple myeloma / paraproteinemia,
repetitive and/or large doses of ULTRAVIST.
Use the lowest necessary dose of ULTRAVIST in patients with renal impairment. Adequately hydrate patients prior to
and following ULTRAVIST administration.
5.3 Cardiovascular Reactions
ULTRAVIST increases the circulatory osmotic load and may induce acute or delayed hemodynamic disturbances in
patients with congestive heart failure, severely impaired renal function, combined renal and hepatic disease, combined
renal and cardiac disease, particularly when repetitive and/or large doses are administered [see Drug Interactions (7)].
Among patients who have had cardiovascular reactions, most deaths occurred from the start of injection to 10 minutes
later; the main feature was cardiac arrest with cardiovascular disease as the main underlying factor. Isolated reports of
hypotensive collapse and shock have been published.
The administration of ULTRAVIST may cause pulmonary edema in patients with heart failure. Based upon published
reports, deaths from the administration of iodinated contrast agents range from 6.6 per 1 million (0.00066 percent) to 1 in
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10,000 patients (0.01 percent). Observe patients with preexisting cardiovascular disease for several hours following
ULTRAVIST administration.
5.4 Thromboembolic Complications
• Angiography may be associated with local and distal organ damage, ischemia, thromboembolism and organ failure
including stroke, brachial plexus palsy, chest pain, myocardial infarction, sinus arrest, hepato-renal function
abnormalities. For these reasons, meticulous angiographic techniques are recommended, including close attention to
guide wire and catheter manipulation, use of manifold systems and/or three-way stopcocks, frequent catheter flushing
with heparinized saline solutions and minimizing the length of the procedure. In angiographic procedures, consider
the possibility of dislodging plaques or damaging or perforating the vessel wall with resultant pseudoaneurysms,
hemorrhage at puncture site, dissection of coronary artery during catheter manipulations and contrast agent injection.
The physicochemical properties of the contrast agent, the dose and the speed of injection can influence the reactions.
Test injections to ensure proper catheter placement are suggested. Increased thrombosis and activation of the
complement system has also occurred. Specialized personnel, and adequate equipment and facilities for immediate
resuscitation and cardioversion are necessary. Monitor electrocardiograms and vital signs throughout the procedure.
• Exercise care when performing venography in patients with suspected thrombosis, phlebitis, severe ischemic disease,
local infection, venous thrombosis or a totally obstructed venous system.
• Clotting may occur when blood remains in contact with syringes containing iodinated contrast agents.
• Avoid angiography whenever possible in patients with homocystinuria because of the risk of inducing thrombosis and
embolism [see Clinical Pharmacology (12.2)].
5.5 Reactions in Patients with Hyperthyroidism, Pheochromocytoma, or Sickle Cell Disease
Thyroid storm in patients with hyperthyroidism. Thyroid storm has occurred after the intravascular use of iodinated
contrast agents in patients with hyperthyroidism, or with an autonomously functioning thyroid nodule. Evaluate the risk in
such patients before use of any iodinated contrast agent.
Hypertensive crises in patients with pheochromocytoma. Administer iodinated contrast agents with extreme caution in
patients with known or suspected pheochromocytoma. Inject the minimum amount of contrast necessary. Assess the blood
pressure throughout the procedure, and have measures for treatment of a hypertensive crisis readily available.
Sickle cell disease. Contrast agents may promote sickling in individuals who are homozygous for sickle cell disease when
administered intravascularly.
5.6 Extravasation
Extravasation of ULTRAVIST Injection may cause tissue necrosis and/or compartment syndrome, particularly in patients
with severe arterial or venous disease.
5.7 Increased Radiation Exposure
The decision to use contrast enhancement is associated with risk and increased radiation exposure. Use contrast after a
careful evaluation of clinical, other radiologic data, and the results of non-contrast CT findings, taking into account the
increased radiation dose and other risks.
5.8 Interference with Image Interpretation
As with other iodinated contrast agents, the use of ULTRAVIST Injection may obscure some lesions which were seen on
non-contrast CT scans. Calcified lesions are less likely to enhance. The enhancement of tumors after therapy may
decrease. The opacification of the inferior vermis following contrast agent administration has resulted in false-positive
diagnosis. Cerebral infarctions of recent onset may be better visualized with contrast enhancement. However, older
infarctions may be obscured by the contrast agent.
In patients with normal blood-brain barriers and renal failure, iodinated contrast agents have been associated with blood-
brain barrier disruption and accumulation of contrast in the brain. Accumulation of contrast in the brain also occurs in
patients where the blood-brain barrier is known or suspected to be disrupted.
Reference ID: 3788196
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6 ADVERSE REACTIONS
The most important adverse drug reactions in patients receiving ULTRAVIST are anaphylactoid shock, contrast induced
acute kidney injury, coma, cerebral infarction, stroke, brain edema, convulsion, arrhythmia, cardiac arrest, myocardial
ischemia, myocardial infarction, cardiac failure, bradycardia, cyanosis, hypotension, shock, dyspnea, pulmonary edema,
respiratory insufficiency and aspiration.
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials
of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect or predict the rates
observed in practice.
The following table of incidence of reactions is based upon controlled clinical trials in which ULTRAVIST Injection was
administered to 1142 patients. This listing includes all reported adverse reactions regardless of attribution.
Adverse reactions are listed by System Organ Class and in decreasing order of occurrence for rates greater than 1% in the
ULTRAVIST group: see Table 3.
Table 3: ADVERSE REACTIONS REPORTED IN > 1% OF PATIENTS WHO RECEIVED ULTRAVIST
INJECTION IN CLINICAL TRIALS
System Organ Class
Adverse Reaction
ULTRAVIST Injection
N=1142 (%)
Nervous system disorders
Headache
46 (4)
Dysgeusia
15 (1.3)
Eye disorders
Abnormal Vision
12 (1.1)
Cardiac disorders
Chest pain
18 (1.6)
Vascular disorders
Vasodilatation
30 (2.6)
Gastrointestinal disorders
Nausea
42 (3.7)
Vomiting
22 (1.9)
Musculoskeletal and connective tissue disorders
Back pain
22 (1.9)
Renal and urinary disorders
Urinary urgency
21 (1.8)
General disorders and administration site conditions
Injection site and infusion site
reactions (hemorrhage,
hematoma, pain, edema,
erythema, rash)
41 (3.7)
Pain
13 (1.4)
One or more adverse reactions were recorded in 273 of 1142 (24%) patients during the clinical trials, coincident with the
administration of ULTRAVIST Injection or within the defined duration of the study follow-up period (24–72 hours).
ULTRAVIST Injection is often associated with sensations of warmth and/or pain.
Serious, life-threatening and fatal reactions have been associated with the administration of iodine-containing contrast
media, including ULTRAVIST Injection. In clinical trials 7/1142 patients given ULTRAVIST Injection died 5 days or
later after drug administration. Also, 10/1142 patients given ULTRAVIST Injection had serious adverse events.
The following adverse reactions were observed in ≤ 1% of the subjects receiving ULTRAVIST Injection:
Cardiac disorders: atrioventricular block (complete), bradycardia, ventricular extrasystole
Gastrointestinal disorders: abdominal discomfort, abdominal pain, abdominal pain upper, constipation, diarrhea, dry
mouth, dyspepsia, gastrointestinal disorder, gastrointestinal pain, salivation increased, stomach discomfort, rectal
tenesmus
General disorders and administration site conditions: asthenia, chest discomfort, chills, excessive thirst, extravasation,
feeling hot, hyperhidrosis, malaise, edema peripheral, pyrexia
Immune system disorders: asthma, face edema
Investigations: blood lactate dehydrogenase increased, blood urea increased, hemoglobin increased, white blood cell
count increased
Musculoskeletal and connective tissue disorders: arthralgia, musculoskeletal pain, myasthenia, neck pain, pain in
extremity
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Nervous system disorders: agitation, confusion, convulsion, dizziness, hypertonia, hypesthesia, incoordination,
neuropathy, somnolence, speech disorder, tremor, paresthesia, visual field defect
Psychiatric disorders: anxiety
Renal and urinary disorders: dysuria, renal pain, urinary retention
Respiratory, thoracic and mediastinal disorders: apnea, cough increased, dyspnea, hypoxia, pharyngeal edema,
pharyngitis, pleural effusion, pulmonary hypertension, respiratory disorder, sore throat
Skin and subcutaneous tissue disorders: erythema, pruritus, rash, urticaria
Vascular disorders: coronary artery thrombosis, flushing, hypertension, hypotension, peripheral vascular disorder,
syncope, vascular anomaly
6.2 Postmarketing Experience
The following adverse reactions have been identified during post approval use of ULTRAVIST Injection. Because these
reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their
frequency or establish a causal relationship to drug exposure.
Adverse reactions reported in foreign postmarketing surveillance and other trials with the use of ULTRAVIST Injection
include:
Cardiac disorders: cardiac arrest, ventricular fibrillation, atrial fibrillation, tachycardia, palpitations, congestive heart
failure, myocardial infarction, angina pectoris
Ear and labyrinth disorders: vertigo, tinnitus
Endocrine disorders: hyperthyroidism, thyrotoxic crisis, hypothyroidism; Thyroid function tests indicative of
hypothyroidism or transient thyroid suppression have been uncommonly reported following iodinated contrast
administration to adult and pediatric patients, including infants. Some patients were treated for hypothyroidism.
Eye disorders: mydriasis, lacrimation disorder
Gastrointestinal disorders: dysphagia, swelling of salivary glands
Immune system disorders: anaphylactoid reaction (including fatal cases), respiratory arrest, anaphylactoid shock,
angioedema, laryngeal edema, laryngospasm, bronchospasm, hypersensitivity
Musculoskeletal and connective tissue disorders: compartment syndrome in case of extravasation
Nervous system disorders: cerebral ischemia/infarction, paralysis, paresis, transient cortical blindness, aphasia, coma,
unconsciousness, amnesia, hypotonia, aggravation of myasthenia gravis symptoms
Renal and urinary disorders: renal failure, hematuria
Respiratory, thoracic and mediastinal disorders: pulmonary edema, acute respiratory distress syndrome, asthma
Skin and subcutaneous tissue disorders: Stevens-Johnson Syndrome, skin discoloration
Vascular disorders: vasospasm
6.3 Pediatrics
The overall character, quality, and severity of adverse reactions in pediatric patients are generally similar to those reported
in adult patients. Additional adverse reactions reported in pediatric patients from foreign marketing surveillance or other
information are: epistaxis, angioedema, migraine, joint disorder (effusion), muscle cramps, mucous membrane disorder
(mucosal swelling), conjunctivitis, hypoxia, fixed eruptions, vertigo, diabetes insipidus, and brain edema [see Use in
Specific Populations (8.4)].
7 DRUG INTERACTIONS
7.1 Drug-Drug Interactions
In patients with renal impairment, biguanides can cause lactic acidosis. ULTRAVIST appears to increase the risk of
biguanide induced lactic acidosis, possibly as a result of worsening renal function [see Warnings and Precautions (5.2)].
Reference ID: 3788196
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Patients on beta-blockers may be unresponsive to the usual doses of epinephrine used to treat allergic reactions. Because
of the risk of hypersensitivity reactions, use caution when administering iodinated contrast agents to patients taking beta-
blockers.
Interleukins are associated with an increased prevalence of delayed hypersensitivity reactions after iodinated contrast
agent administration. These reactions include fever, chills, nausea, vomiting, pruritus, rash, diarrhea, hypotension, edema,
and oliguria.
Renal toxicity has been reported in a few patients with liver dysfunction who were given an oral cholecystographic agent
followed by intravascular contrast agents. Administration of any intravascular contrast agent should therefore be
postponed in patients who have recently received a cholecystographic contrast agent.
Do not mix other drugs with ULTRAVIST Injection [see How Supplied/Storage and Handling (16)].
7.2 Drug-Laboratory Test Interactions
Thyroid Function Tests:
The results of protein bound iodine and radioactive iodine uptake studies, which depend on iodine estimation, will not
accurately reflect thyroid function for at least 16 days following administration of iodinated contrast agents. However,
thyroid function tests which do not depend on iodine estimations, for example, T3 resin uptake and total or free thyroxine
(T4) assays are not affected.
Laboratory Assay of Coagulation Parameters, Fibrinolysis and Complement System:
The effect of iopromide on coagulation factors in in vitro assays increased with the administered dose. Coagulation,
fibrinolysis and complement activation were evaluated with standard citrated human plasma in the following assays:
thrombin time, thrombin coagulase time, calcium thromboplastin time, partial thromboplastin time, plasminogen,
thrombin, alpha-2 antiplasmin and factor XIIa activity. Thrombin inhibition was almost complete. Data on reversibility
are not available. The thrombin time increased from approximately 20 seconds at an iopromide concentration of 10 mg
I/mL, up to 100 seconds at an iopromide concentration of 70 mg I/mL.
The PTT increased from approximately 50 seconds at an iopromide concentration of 10 mg I/mL, up to approximately
100 seconds at an iopromide concentration of 70 mg I/mL. A similar increase was noted in the thrombin coagulase time.
Lesser effects were noted in the calcium thromboplastin time. Coagulation time increased from 13.5 to 23 seconds at the
highest iopromide concentration of 70 mg I/mL. The Hageman factor split products decreased by about 20% over the
range of 10 to 70 mg I/mL of iopromide. Plasminogen was relatively stable. There was no evidence of activation of
fibrinolysis. The complement alternate pathway was activated. Factor B conversion increased in a dose dependent
manner. The duration of these effects was not studied.
In vitro studies with human blood showed that iopromide had a slight effect on coagulation and fibrinolysis. No Factor
XIIa formation could be demonstrated. The complement alternate pathway also can be activated.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category B
Reproduction studies performed with iopromide in rats and rabbits at doses up to 3.7 g I/kg (2.2 times the maximum
recommended dose for a 50 kg human, or approximately 0.7 times the human dose following normalization of the data to
body surface area estimates) have revealed no evidence of direct harm to the fetus. Embryolethality was observed in
rabbits that received 3.7 g I/kg, but this was considered to have been secondary to maternal toxicity. Adequate and well-
controlled studies in pregnant women have not been conducted. Because animal reproduction studies are not always
predictive of human response, this drug should be used during pregnancy only if clearly needed.
8.3 Nursing Mothers
It is not known whether ULTRAVIST Injection is excreted in human milk. However, many injectable contrast agents are
excreted unchanged in human milk. Although it has not been established that serious adverse reactions occur in nursing
infants, caution should be exercised when intravascular contrast agents are administered to nursing women because of
potential adverse reaction, and consideration should be given to temporarily discontinuing nursing.
Reference ID: 3788196
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8.4 Pediatric Use
The safety and efficacy of ULTRAVIST Injection have been established in the pediatric population over 2 years of age.
Use of ULTRAVIST Injection in these age groups is supported by evidence from adequate and well controlled studies of
ULTRAVIST Injection in adults and additional safety data obtained in literature and other reports in a total of 274
pediatric patients. Of these, there were 131 children (2–12 years), 57 adolescents, and 86 children of unreported or other
ages. There were 148 females, 94 males and 32 in whom gender was not reported. The racial distribution was: Caucasian
93 (33.9%), Black 1 (0.4%), Asian 6 (2.2%), and unknown 174 (63.5%). These patients were evaluated in intra-arterial
coronary angiographic (n=60), intravenous contrast computerized tomography (CT) (n=87), excretory urography (n=99)
and 28 other procedures.
In these pediatric patients, a concentration of 300 mg I/mL was employed for intravenous contrast CT or excretory
urography. A concentration of 370 mg I/mL was employed for intra-arterial and intracardiac administration in the
radiographic evaluation of the heart cavities and major arteries. Most pediatric patients received initial volumes of 1–2
mL/kg.
Optimal doses of ULTRAVIST Injection have not been established because different injection volumes, concentrations
and injection rates were not studied. The relationship of the volume of injection with respect to the size of the target
vascular bed has not been established. The potential need for dose adjustment on the basis of immature renal function has
not been established. In the pediatric population, the pharmacokinetic parameters have not been established.
Pediatric patients at higher risk of experiencing an adverse reaction during and after administration of any contrast agent
include those with asthma, a sensitivity to medication and/or allergens, cyanotic and acyanotic heart disease, congestive
heart failure, or a serum creatinine greater than 1.5 mg/dL. The injection rates in small vascular beds, and the relationship
of the dose by volume or concentration in small pediatric patients have not been established. Exercise caution in selecting
the dose.
Safety and effectiveness in pediatric patients below the age of two have not been established.
8.5 Geriatric Use
Middle-aged and elderly patients, without significantly impaired renal function, who received ULTRAVIST Injection in
doses corresponding to 9–30 g iodine, had mean steady-state volumes of distribution that ranged between 30–40 L. Mean
total and renal clearances were between 81–125 mL/min and 70–115 mL/min respectively in these patients, and were
similar to the values found in the young volunteers. The distribution phase half-life in this patient population was 0.1
hour, the main elimination phase half-life was 2.3 hours, and the terminal elimination phase half-life was 40 hours. The
urinary excretion (97% of the dose) and fecal excretion (2%) was comparable to that observed in young healthy
volunteers, suggesting that, compared to the renal route, biliary and/or gastrointestinal excretion is not significant for
iopromide.
8.6 Renal Impairment
In patients with renal impairment, opacification of the calyces and pelves by iopromide may be delayed due to slower
renal excretion of iopromide.
A pharmacokinetic study in patients with mild (n=2), moderate (n=6), and severe (n=3) renal impairment was conducted.
The total clearance of iopromide was decreased proportionately to the baseline decrease in creatinine clearance. The
plasma AUC increased about 2-fold in patients with moderate renal impairment and 6-fold in patients with severe renal
impairment compared to subjects with normal renal function. The terminal half-life increased from 2.2 hrs for subjects
with normal renal function to 11.6 hrs in patients with severe renal impairment. The peak plasma concentration of
iopromide was not influenced by the extent of renal impairment. Exercise caution and use the lowest necessary dose of
ULTRAVIST in patients with renal dysfunction [see Warnings and Precautions (5.2)].
10 OVERDOSAGE
The adverse effects of overdosage are life-threatening and affect mainly the pulmonary and cardiovascular systems.
Treatment of an overdosage is directed toward the support of all vital functions, and prompt institution of symptomatic
therapy.
ULTRAVIST Injection binds negligibly to plasma or serum protein and can, therefore, be dialyzed.
Reference ID: 3788196
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11 DESCRIPTION
ULTRAVIST (iopromide) Injection is a nonionic, water soluble x-ray contrast agent for intravascular administration. The
chemical name for iopromide is N,N'-Bis(2,3-dihydroxypropyl)-2,4,6-triiodo-5-[(methoxyacetyl)amino]-N-methyl- 1,3
benzenedicarboxamide. Iopromide has a molecular weight of 791.12 (iodine content 48.12%).
Iopromide has the following structural formula: structural formula
ULTRAVIST Injection is a nonionic sterile, clear, colorless to slightly yellow, odorless, pyrogen-free aqueous solution of
iopromide, containing 2.42 mg/mL tromethamine buffer and 0.1 mg/mL edetate calcium disodium stabilizer.
ULTRAVIST Injection is available in four strengths:
150 mg I/mL provides 311.7 mg/mL iopromide
240 mg I/mL provides 498.72 mg/mL iopromide
300 mg I/mL provides 623.4 mg/mL iopromide
370 mg I/mL provides 768.86 mg/mL iopromide
During the manufacture of ULTRAVIST Injection, sodium hydroxide or hydrochloric acid may be added for pH adjust
ment. ULTRAVIST Injection has a pH of 7.4 (6.5–8) at 25± 2°C, is sterilized by autoclaving and contains no
preservatives.
The iodine concentrations (mg I/mL) available have the following physicochemical properties:
ULTRAVIST
INJECTION
ULTRAVIST
INJECTION
ULTRAVIST
INJECTION
ULTRAVIST
INJECTION
Property
150 mg I/mL
240 mg I/mL
300 mg I/mL
370 mg I/mL
Osmolality*(mOsmol/kg water)
@ 37°C
328
483
607
774
Osmolarity*(mOsmol/L)
@ 37°C
278
368
428
496
Viscosity (cP)
@ 20°C
@ 37°C
2.3
1.5
4.9
2.8
9.2
4.9
22
10
Density (g/mL)
@ 20°C
@ 37°C
1.164
1.157
1.262
1.255
1.330
1.322
1.409
1.399
*Osmolality was measured by vapor-pressure osmometry. Osmolarity was calculated from the measured osmolal
concentrations.
Solutions of ULTRAVIST Injection 150 mg I/mL, 240 mg I/mL, 300 mg I/mL and 370 mg I/mL have osmolalities from
approximately 1.1 to 2.7 times that of plasma (285 mOsmol/kg water).
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Iopromide is a nonionic, water soluble, tri-iodinated x-ray contrast agent for intravascular administration.
Intravascular injection of iopromide opacifies those vessels in the path of flow of the contrast agent, permitting
radiographic visualization of the internal structures until significant hemodilution occurs.
12.2 Pharmacodynamics
Following ULTRAVIST administration, the degree of contrast enhancement is directly related to the iodine content in the
administered dose; peak iodine plasma levels occur immediately following rapid intravenous injection. Iodine plasma
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levels fall rapidly within 5 to 10 minutes. This can be accounted for by the dilution in the vascular and extravascular fluid
compartments.
Intravascular Contrast: Contrast enhancement appears to be greatest immediately after bolus injections (15 seconds to 120
seconds). Thus, greatest enhancement may be detected by a series of consecutive two-to-three second scans performed
within 30 to 90 seconds after injection (that is, dynamic computed tomographic imaging).
ULTRAVIST Injection may be visualized in the renal parenchyma within 30–60 seconds following rapid intravenous
injection. Opacification of the calyces and pelves in patients with normal renal function becomes apparent within 1–3
minutes, with optimum contrast occurring within 5–15 minutes.
In contrast CT, some performance characteristics are different in the brain and body. In contrast CT of the body, iodinated
contrast agents diffuse rapidly from the vascular into the extravascular space. Following the administration of iodinated
contrast agents, the increase in tissue density to x-rays is related to blood flow, the concentration of the contrast agent, and
the extraction of the contrast agent by various interstitial tissues. Contrast enhancement is thus due to any relative
differences in extravascular diffusion between adjacent tissues.
In the normal brain with an intact blood-brain barrier, contrast is generally due to the presence of iodinated contrast agent
within the intravascular space. The radiographic enhancement of vascular lesions, such as arteriovenous malformations
and aneurysms, depends on the iodine content of the circulating blood pool.
In tissues with a break in the blood-brain barrier, contrast agent accumulates within interstitial brain tissue. The time to
maximum contrast enhancement can vary from the time that peak blood iodine levels are reached to 1 hour after
intravenous bolus administration. This delay suggests that radiographic contrast enhancement is at least in part dependent
on the accumulation of iodine containing medium within the lesion and outside the blood pool. The mechanism by which
this occurs is not clear.
For information on coagulation parameters, fibrinolysis and complement system [see Drug Interactions (7.2)].
12.3 Pharmacokinetics
Distribution
After intravenous administration to healthy young volunteers, plasma iopromide concentration time profile shows an
initial distribution phase with a half-life of 0.24 hour; a main elimination phase with a half-life of 2 hours; and a terminal
elimination phase with a half-life of 6.2 hours. The total volume of distribution at steady state is about 16 L suggesting
distribution in to extracellular space. Plasma protein binding of iopromide is 1%.
Iodinated contrast agents may cross the blood-brain barrier [see Warnings and Precautions (5.8)].
Metabolism
Iopromide is not metabolized.
Elimination
The amounts excreted unchanged in urine represent 97% of the dose in young healthy subjects. Only 2% of the dose is
recovered in the feces. Similar recoveries in urine and feces are observed in middle-aged and elderly patients. This finding
suggests that, compared to the renal route, biliary and/or gastrointestinal excretion is not important for iopromide. During
the slower terminal phase only 3% of the dose is eliminated; 97% of the dose is disposed of during the earlier phases, the
largest part of which occurs during the main elimination phase. The ratio of the renal clearance of iopromide to the
creatinine clearance is 0.82 suggesting that iopromide is mainly excreted by glomerular filtration. Additional tubular
reabsorption is possible. Pharmacokinetics of iopromide at intravenous doses up to 80 g iodine, are dose proportionate and
first order.
The mean total and renal clearances are 107 mL/min and 104 mL/min, respectively.
Specific Populations
A pharmacokinetic study was conducted in 11 patients with renal impairment [see Use in Specific Populations (8.6)].
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term animal studies have not been performed with iopromide to evaluate carcinogenic potential or effects on
fertility. Iopromide was not genotoxic in a series of studies including the Ames test, an in vitro human lymphocytes
Reference ID: 3788196
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analysis of chromosomal aberrations, an in vivo mouse micro-nucleus assay, and in an in vivo mouse dominant lethal
assay.
14 CLINICAL STUDIES
ULTRAVIST Injection was administered to 708 patients; 1 patient was less than 18 years of age, 347 patients were
between 18 and 59 years of age, and 360 patients were equal to or greater than 60 years of age; the mean age was 56.6
years (range 17–88). Of the 708 patients, 446 (63%) were male and 262 (37%) were female. The racial distribution was:
Caucasian 463 (65.4%), Black 95 (13.4%), Hispanic 36 (5.1%), Asian 11 (1.6 %), and other or unknown 103 (14.5%).
Efficacy assessment was based on the global evaluation of the quality of the radiographs by rating visualization as either
excellent, good, poor, or no image, and on the ability to make a diagnosis. Five (5) intra-arterial and three (3) intravenous
procedures were studied with 1 of 4 concentrations (370 mg I/mL, 300 mg I/mL, 240 mg I/mL, and 150 mg I/mL). These
procedures were: aortography/visceral angiography, coronary arteriography and left ventriculography, cerebral
arteriography, peripheral arteriography, intra-arterial digital subtraction angiography (IA-DSA), contrast computed
tomography (CT) of head and body, excretory urography, and peripheral venography.
Cerebral arteriography was evaluated in two randomized, double-blind clinical trials of ULTRAVIST Injection 300 mg
I/mL in 80 patients with conditions such as altered cerebrovascular perfusion and/or permeability occurring in central
nervous system diseases due to various CNS disorders. Visualization ratings were good or excellent in 99% of the patients
with ULTRAVIST Injection; a radiologic diagnosis was made in the majority of the patients. Confirmation of the
radiologic findings by other diagnostic methods was not obtained.
Coronary arteriography/left ventriculography was evaluated in two randomized, double-blind clinical trials and one
unblinded, unrandomized clinical trial of ULTRAVIST Injection 370 mg I/mL in 106 patients with conditions such as
altered coronary artery perfusion due to metabolic causes and in patients with conditions such as altered ventricular
function. Visualization ratings were good or excellent in 99% or more of the patients a radiologic diagnosis was made in
the majority of the patients. A confirmation of the radiologic findings by other diagnostic methods was not obtained.
Aortography/visceral angiography was evaluated in two randomized, double-blind clinical trials in 78 patients with
conditions such as altered aortic blood flow and/or visceral vascular disorders. Visualization ratings were good or
excellent in the majority of the patients; a radiologic diagnosis was made in 99% of the patients with ULTRAVIST
Injection. A confirmation of radiologic findings by other diagnostic methods was not obtained. The risks of renal
arteriography could not be analyzed.
Contrast CT of head and body was evaluated in three randomized, double-blind clinical trials of ULTRAVIST Injection
300 mg I/mL in 95 patients with vascular disorders. Visualization ratings were good or excellent in 99% of the patients; a
radiologic diagnosis was made in the majority of the patients. A confirmation of contrast CT findings by other diagnostic
methods was not obtained.
ULTRAVIST Injection was evaluated in a blinded reader trial for CT of the head and body. Among the 382 patients who
were evaluated with ULTRAVIST Injection 370 mg I/mL, visualization ratings were good or excellent in approximately
97% of patients.
Peripheral venography was evaluated in two randomized, double-blind clinical trials of ULTRAVIST Injection 240 mg
I/mL in 63 patients with disorders affecting venous drainage of the limbs. Visualization ratings were good or excellent in
100% of the patients; a radiologic diagnosis was made in the majority of the patients. A confirmation of radiologic
findings by other diagnostic methods was not obtained.
Similar studies were completed with comparable findings noted in intra-arterial digital subtraction angiography,
peripheral arteriography and excretory urography.
16 HOW SUPPLIED/STORAGE AND HANDLING
ULTRAVIST Injection is a sterile, clear, colorless to slightly yellow, odorless, pyrogen-free aqueous solution available in
four strengths.
Glass Vials
NDC Number
ULTRAVIST Injection 150 mg I/mL
10 x 50 mL vials
50419-340-05
Reference ID: 3788196
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For current labeling information, please visit https://www.fda.gov/drugsatfda
ULTRAVIST Injection 240 mg I/mL
10 x 50 mL vials
50419-342-05
10 x 50 mL vials (RFID)
50419-342-41
10 x 100 mL vials
50419-342-10
10 x 100 mL vials (RFID)
50419-342-43
ULTRAVIST Injection 300 mg I/mL
10 x 50 mL vials
50419-344-05
10 x 50 mL vials (RFID)
50419-344-41
10 x 75 mL fill/100 mL vials
50419-344-07
10 x 100 mL vials
50419-344-10
10 x 100 mL vials (RFID)
50419-344-43
10 x 125 mL fill/150 mL vials
50419-344-12
10 x 150 mL vials
50419-344-15
ULTRAVIST Injection 370 mg I/mL
10 x 50 mL vials
50419-346-05
10 x 50 mL vials (RFID)
50419-346-41
10 x 75 mL fill/100 mL vials
50419-346-07
10 x 100 mL vials
50419-346-10
10 x 100 mL vials (RFID)
50419-346-43
10 x 125 mL fill/150 mL vials
50419-346-12
10 x 150 mL vials
50419-346-15
10 x 150 mL vials (RFID)
50419-346-45
10 x 200 mL fill/250 mL vials
50419-346-20
Inspect ULTRAVIST visually prior to use. Do not use if discolored, if particulate matter (including crystals) is present, or
if containers are defective. As ULTRAVIST Injection is a highly concentrated solution, crystallization (milky-cloudy
appearance and/or sediment at bottom, or floating crystals) may occur.
As with all contrast agents, because of the potential for chemical incompatibility, do not mix or inject ULTRAVIST
Injection in intravenous administration lines containing other drugs, solutions or total nutritional admixtures.
Administer ULTRAVIST at or close to body temperature.
If nondisposable equipment is used, take scrupulous care to prevent residual contamination with traces of cleansing
agents.
Withdraw ULTRAVIST from its container under strict aseptic conditions using only sterile syringes and transfer devices.
Use immediately contrast agents which have been transferred into other delivery systems.
Store ULTRAVIST at 25°C (77°F); excursions permitted to 15–30°C (59–86°F) and protected from light.
17 PATIENT COUNSELING INFORMATION
Instruct patients receiving ULTRAVIST Injection to inform their physician or healthcare provider of the following:
• If they are pregnant [see Use in Specific Populations (8.1)]
• If they are diabetic or if they have multiple myeloma, pheochromocytoma, sickle cell disease or thyroid disorder [see
Warnings and Precautions (5.2, 5.5)]
Reference ID: 3788196
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• If they are allergic to any drugs or food, or if they have immune, autoimmune or immune deficiency disorders. Also,
if they have had any reaction to previous injections of dyes used for x-ray procedures [see Warnings and Precautions
(5.1)]
• All medications they are currently taking, including non-prescription (over-the-counter) drugs
©2015, Bayer HealthCare Pharmaceuticals Inc. All rights reserved.
Manufactured for: company logo
Bayer HealthCare Pharmaceuticals Inc.
Whippany, NJ 07981
Manufactured in Germany
Reference ID: 3788196
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_______________________________________________________________________________________________________________________________________
HIGHLIGHTS OF PRESCRIBING INFORMATION
administration of a laxative before ULTRAVIST Injection) is
contraindicated in pediatric patients because of risk of renal failure. (4)
These highlights do not include all the information needed to use
ULTRAVIST Injection safely and effectively. See full prescribing
-----------------------WARNINGS AND PRECAUTIONS-----------------------
information for ULTRAVIST Injection.
ULTRAVIST (iopromide) Injection, for intravenous or intra-arterial use
Initial U.S. Approval: 1995
PHARMACY BULK PACKAGE
NOT FOR DIRECT INFUSION
WARNING: NOT FOR INTRATHECAL USE
See ful prescribing information for complete boxed warning.
Inadvertent intrathecal administration may cause death,
convulsions, cerebral hemorrhage, coma, paralysis,
arachnoiditis, acute renal failure, cardiac arrest, seizures,
rhabdomyolysis, hyperthermia, and brain edema.
----------------------------INDICATIONS AND USAGE--------------------------
ULTRAVIST (iopromide) Injection is a radiographic contrast agent indicated
for:
•
Cerebral arteriography and peripheral arteriography (300 mg I/mL) (1.1)
•
Coronary arteriography and left ventriculography, visceral angiography
and aortography (370 mg I/mL) (1.1)
•
Peripheral venography (240 mg I/mL) (1.2)
•
Excretory urography (300 mg I/mL) (1.2)
•
Contrast computed tomography (CT) imaging of head and body (300 mg
I/mL and 370 mg I/mL) (1.2)
----------------------DOSAGE AND ADMINISTRATION----------------------
Carefully individualize the volume and concentration of ULTRAVIST
Injection to be used for a vascular procedure, according to the specific dosing
tables. Adjust the dose accounting for factors such as age, body weight, size of
the vessel and the rate of blood flow within the vessel. (2)
---------------------DOSAGE FORMS AND STRENGTHS---------------------
ULTRAVIST Injection PHARMACY BULK PACKAGE is available in three
strengths: 240 mg I/mL; 300 mg I/mL; 370 mg I/mL. (3)
-------------------------------CONTRAINDICATIONS-----------------------------
•
ULTRAVIST Injection is contraindicated for intrathecal use. (4)
•
Preparatory dehydration (for example, prolonged fasting and the
•
Anaphylactoid Reactions: Life-threatening or fatal anaphylactoid
reactions may occur during or after ULTRAVIST administration,
particularly in patients with allergic disorders. (5.1)
•
Acute Renal Failure: Acute renal failure may occur following
ULTRAVIST administration, particularly in patients with renal
insufficiency, diabetes, multiple myeloma. Exercise caution and use the
lowest necessary dose of ULTRAVIST in patients with renal
dysfunction. (5.2)
•
Cardiovascular Reactions: Hemodynamic disturbances including shock
and cardiac arrest may occur during or shortly after administration of
ULTRAVIST.(5.3)
•
Thromboembolic Complications: Angiography may be associated with
local and distal organ damage, ischemia, thromboembolism and organ
failure. In angiographic procedures, consider the possibility of
dislodging plaques or damaging or perforating the vessel wall. The
physicochemical properties of the contrast agent, the dose and the speed
of injection can influence the reactions. (5.4)
------------------------------ADVERSE REACTIONS------------------------------
Most common adverse reactions (>1%) are headache, nausea, , injection site
and infusion site reactions, vasodilatation, vomiting, back pain, urinary
urgency, chest pain, pain, dysgeusia and abnormal vision. (6)
To report SUSPECTED ADVERSE REACTIONS, contact Bayer
HealthCare Pharmaceuticals Inc. at 1-888-842-2937 or FDA at 1-800
FDA-1088 or www.fda.gov/medwatch
-----------------------USE IN SPECIFIC POPULATIONS-----------------------
•
Adequate and well-controlled studies in pregnant women have not been
conducted. Because animal reproduction studies are not always
predictive of human response, this drug should be used during
pregnancy only if clearly needed. (8.1)
•
The safety and efficacy of ULTRAVIST Injection have been established
in the pediatric population over 2 years of age. (8.4)
See 17 for PATIENT COUNSELING INFORMATION
Revised: 3/2015
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: NOT FOR INTRATHECAL USE
1 INDICATIONS AND USAGE
1.1 Intra-Arterial Procedures*
1.2 Intravenous Procedures*
2 DOSAGE AND ADMINISTRATION
2.1 Intra-Arterial Procedures
2.2 Intravenous Procedures
2.3 Pediatric Dosing
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Anaphylactoid Reactions
5.2 Contrast Induced Acute Kidney Injury
5.3 Cardiovascular Reactions
5.4 Thromboembolic Complications
5.5 Reactions in Patients with Hyperthyroidism, Pheochromocytoma, or
Sickle Cell Disease
5.6 Extravasation
5.7 Increased Radiation Exposure
5.8 Interference with Image Interpretation
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
6.2 Postmarketing Experience
6.3 Pediatrics
7 DRUG INTERACTIONS
7.1 Drug-Drug Interactions
7.2 Drug-Laboratory Test Interactions
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Renal Impairment
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information are not
listed.
Reference ID: 3788196
1
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For current labeling information, please visit https://www.fda.gov/drugsatfda
_______________________________________________________________________________________________________________________________________
FULL PRESCRIBING INFORMATION
WARNING: NOT FOR INTRATHECAL USE
Inadvertent intrathecal administration may cause death, convulsions, cerebral hemorrhage, coma, paralysis,
arachnoiditis, acute renal failure, cardiac arrest, seizures, rhabdomyolysis, hyperthermia, and brain edema.
[See Contraindications (4).]
1 INDICATIONS AND USAGE
ULTRAVIST
® Injection is an iodinated contrast agent indicated for:
1.1 Intra-Arterial Procedures*
• 300 mg I/mL for cerebral arteriography and peripheral arteriography
• 370 mg I/mL for coronary arteriography and left ventriculography, visceral angiography, and aortography
1.2 Intravenous Procedures*
• 240 mg I/mL for peripheral venography
• 300 mg I/mL for excretory urography
• 300 mg I/mL and 370 mg I/mL for contrast Computed Tomography (CT) of the head and body (intrathoracic, intra
abdominal and retroperitoneal regions) for the evaluation of neoplastic and non-neoplastic lesions. The usefulness of
contrast enhancement for the investigation of the retrobulbar space and of low grade or infiltrative glioma has not
been demonstrated.
*For information on the concentrations and doses for the Pediatric Population [see Dosage and Administration (2.3) and
Use in Specific Populations (8.4)].
2 DOSAGE AND ADMINISTRATION
• Visually inspect ULTRAVIST for particulate matter and/or discoloration, whenever solution and container permit. Do
not administer ULTRAVIST if particulate matter and/or discoloration is observed.
• Determine the volume and concentration of ULTRAVIST Injection to be used taking into account factors such as age,
body weight, size of the vessel and the rate of blood flow within the vessel; consider also extent of opacification
required, structure(s) or area to be examined, disease processes affecting the patient, and equipment and technique to
be employed. Specific dose adjustments for age, gender, weight and renal function have not been studied for
ULTRAVIST Injection. As with all iodinated contrast agents, lower doses may have less risk. The efficacy of
ULTRAVIST Injection below doses recommended has not been established.
• The maximum recommended total dose of iodine in adults is 86 grams; a maximum recommended total dose of iodine
has not been established for pediatric patients.
• Hydrate patients adequately prior to and following the administration of ULTRAVIST. [See Warnings and
Precautions (5.2).]
2.1 Intra-Arterial Procedures
The volume and rate of injection of the contrast agent will vary depending on the injection site and the area being
examined. Inject contrast at rates approximately equal to the flow rate in the vessel being injected.
• Cerebral Arteriography (300 mg I/mL), Coronary Arteriography and Left Ventriculography (370 mg I/mL),
Peripheral Arteriography (300 mg I/mL): see Table 1.
• Aortography and Visceral Angiography (370 mg I/mL):
Use a volume and rate of contrast injection proportional to the blood flow and related to the vascular and pathological
characteristics of the specific vessels being studied. Do not exceed 225 mL as total dose for the procedure.
Reference ID: 3788196
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 1: Suggested Single Injection Doses for Adult Intra-Arterial Procedures
Cerebral Arteriography
(300 mg I/mL)
Peripheral Arteriography
(300 mg I/mL)
Coronary Arteriography
and Left Ventriculography
(370 mg I/mL)
Intra-Arterial Injection Sites
Carotid Arteries
Vertebral Arteries
Aortic Arch Injection (4 vessel study)
3–12 mL
4–12 mL
20–50 mL
-
-
-
-
-
-
Right Coronary Artery
Left Coronary Artery
Left Ventricle
-
-
-
-
-
-
3–14 mL
3–14 mL
30–60 mL
Subclavian or Femoral Artery
Aortic Bifurcation (distal runoff)
-
-
5–40 mL
25–50 mL
-
-
Maximum Total Dose
150 mL
250 mL
225 mL
2.2 Intravenous Procedures
• Peripheral Venography (240 mg I/mL):
Inject the minimum volume necessary to visualize satisfactorily the structures under examination. Do not exceed
250 mL as total dose for the procedure.
• Contrast Computed Tomography (CT) (300 mg I/mL and 370 mg I/mL) and Excretory Urography (300 mg I/mL): see
Table 2.
Table 2: Suggested ULTRAVIST Injection Dosing for Adult Intravenous Contrast Administration
Excretory Urography
(300 mg I/mL)
Contrast Computed
Tomography (300 mg I/mL)
Contrast Computed
Tomography (370 mg I/mL)
Excretory Urography
Approximately
300 mg I/kg body wt.
(Adults with normal
renal function)
-
-
Head
-
50–200 mL
41–162 mL
Body
Bolus Injection
Rapid Infusion
50–200 mL
100–200 mL
41–162 mL
81–162 mL
Maximum Total Dose
100 mL
200 mL (60 g iodine)
162 mL (60 g iodine)
2.3 Pediatric Dosing
The recommended dose in children over 2 years of age for the following evaluations is:
• Intra-arterial:
Cardiac chambers and related arteries (370 mg I/mL):
Inject 1 to 2 milliliters per kilogram (mL/kg). Do not exceed 4 mL/kg as total dose.
• Intravenous:
Contrast Computerized Tomography or Excretory Urography (300 mg I/mL):
Inject 1 to 2 mL/kg. Do not exceed 3 mL/kg as total dose.
The safety and efficacy relationships of other doses, concentrations or procedures have not been established [see Use in
Specific Populations (8.4) and Clinical Pharmacology (12.3)].
Reference ID: 3788196
3
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For current labeling information, please visit https://www.fda.gov/drugsatfda
3 DOSAGE FORMS AND STRENGTHS
ULTRAVIST Injection is a nonionic, sterile, clear, colorless to slightly yellow, odorless, pyrogen-free aqueous solution of
iopromide, containing 2.42 mg/mL tromethamine buffer and 0.1 mg/mL edetate calcium disodium stabilizer.
ULTRAVIST Injection PHARMACY BULK PACKAGE is available in three strengths:
240 mg I/mL provides 498.72 mg/mL iopromide
300 mg I/mL provides 623.4 mg/mL iopromide
370 mg I/mL provides 768.86 mg/mL iopromide
4 CONTRAINDICATIONS
• Do not administer ULTRAVIST Injection intrathecally. Inadvertent intrathecal administration may cause death,
convulsions, cerebral hemorrhage, coma, paralysis, arachnoiditis, acute renal failure, cardiac arrest, seizures,
rhabdomyolysis, hyperthermia, and brain edema.
• Preparatory dehydration (for example, prolonged fasting and the administration of a laxative) before ULTRAVIST
Injection is contraindicated in pediatric patients because of risk of acute renal failure.
5 WARNINGS AND PRECAUTIONS
5.1 Anaphylactoid Reactions
Life-threatening or fatal, anaphylactoid reactions, may occur during or after ULTRAVIST administration. Manifestations
include respiratory arrest, laryngospasm, bronchospasm, angioedema, and shock. Increased risk is associated with a
history of previous reaction to a contrast agent (3-fold), a known sensitivity to iodine and known allergic disorders (that is,
bronchial asthma, hay fever and food allergies) or other hypersensitivities (2-fold). Exercise extreme caution when
considering the use of iodinated contrast agents in patients with these histories or disorders.
Emergency facilities and personnel trained in the treatment of anaphylactoid reactions should be available for at least 30
to 60 minutes after ULTRAVIST administration.
5.2 Contrast Induced Acute Kidney Injury
Acute kidney injury, including renal failure, may occur after intravascular administration of ULTRAVIST. Risk factors
include: pre-existing renal insufficiency, dehydration, diabetes mellitus, congestive heart failure, advanced vascular
disease, elderly age, concomitant use of nephrotoxic or diuretic medications, multiple myeloma / paraproteinemia,
repetitive and/or large doses of ULTRAVIST.
Use the lowest necessary dose of ULTRAVIST in patients with renal impairment. Adequately hydrate patients prior to
and following ULTRAVIST administration. Patients with congestive heart failure receiving concurrent diuretic therapy
may have relative intravascular volume depletion, which may affect the renal response to the contrast agent osmotic load.
Observe such patients for several hours following the procedure to detect delayed hemodynamic renal function
disturbances.
5.3 Cardiovascular Reactions
ULTRAVIST increases the circulatory osmotic load and may induce acute or delayed hemodynamic disturbances in
patients with congestive heart failure, severely impaired renal function, combined renal and hepatic disease, combined
renal and cardiac disease, particularly when repetitive and/or large doses are administered [see Drug Interactions (7)].
Among patients who have had cardiovascular reactions, most deaths occurred from the start of injection to 10 minutes
later; the main feature was cardiac arrest with cardiovascular disease as the main underlying factor. Isolated reports of
hypotensive collapse and shock have been published.
The administration of ULTRAVIST may cause pulmonary edema in patients with heart failure. Based upon published
reports, deaths from the administration of iodinated contrast agents range from 6.6 per 1 million (0.00066 percent) to 1 in
10,000 patients (0.01 percent). Observe patients with preexisting cardiovascular disease for several hours following
ULTRAVIST administration.
Reference ID: 3788196
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For current labeling information, please visit https://www.fda.gov/drugsatfda
5.4 Thromboembolic Complications
• Angiography may be associated with local and distal organ damage, ischemia, thromboembolism and organ failure
including stroke, brachial plexus palsy, chest pain, myocardial infarction, sinus arrest, hepato-renal function
abnormalities. For these reasons, meticulous angiographic techniques are recommended, including close attention to
guide wire and catheter manipulation, use of manifold systems and/or three-way stopcocks, frequent catheter flushing
with heparinized saline solutions and minimizing the length of the procedure. In angiographic procedures, consider
the possibility of dislodging plaques or damaging or perforating the vessel wall with resultant pseudoaneurysms,
hemorrhage at puncture site, dissection of coronary artery during catheter manipulations and contrast agent injection.
The physicochemical properties of the contrast agent, the dose and the speed of injection can influence the reactions.
Test injections to ensure proper catheter placement are suggested. Increased thrombosis and activation of the
complement system has also occurred. Specialized personnel, and adequate equipment and facilities for immediate
resuscitation and cardioversion are necessary. Monitor electrocardiograms and vital signs throughout the procedure.
• Exercise care when performing venography in patients with suspected thrombosis, phlebitis, severe ischemic disease,
local infection, venous thrombosis or a totally obstructed venous system.
• Clotting may occur when blood remains in contact with syringes containing iodinated contrast agents.
• Avoid angiography whenever possible in patients with homocystinuria because of the risk of inducing thrombosis and
embolism [see Clinical Pharmacology (12.2)].
5.5 Reactions in Patients with Hyperthyroidism, Pheochromocytoma, or Sickle Cell Disease
Thyroid storm in patients with hyperthyroidism. Thyroid storm has occurred after the intravascular use of iodinated
contrast agents in patients with hyperthyroidism, or with an autonomously functioning thyroid nodule. Evaluate the risk in
such patients before use of any iodinated contrast agent.
Hypertensive crises in patients with pheochromocytoma. Administer iodinated contrast agents with extreme caution in
patients with known or suspected of having pheochromocytoma. Inject the minimum amount of contrast necessary. Assess
the blood pressure throughout the procedure, and have measures for treatment of a hypertensive crisis readily available.
Sickle cell disease. Contrast agents may promote sickling in individuals who are homozygous for sickle cell disease when
administered intravascularly.
5.6 Extravasation
Extravasation of ULTRAVIST Injection may cause tissue necrosis and/or compartment syndrome, particularly in patients
with severe arterial or venous disease.
5.7 Increased Radiation Exposure
The decision to use contrast enhancement is associated with risk and increased radiation exposure. Use contrast after a
careful evaluation of clinical, other radiologic data, and the results of non-contrast CT findings, taking into account the
increased radiation dose and other risks.
5.8 Interference with Image Interpretation
As with other iodinated contrast agents, the use of ULTRAVIST Injection may obscure some lesions which were seen on
non-contrast CT scans. Calcified lesions are less likely to enhance. The enhancement of tumors after therapy may
decrease. The opacification of the inferior vermis following contrast agent administration has resulted in false-positive
diagnosis. Cerebral infarctions of recent onset may be better visualized with contrast enhancement. However, older
infarctions may be obscured by the contrast agent.
In patients with normal blood-brain barriers and renal failure, iodinated contrast agents have been associated with blood-
brain barrier disruption and accumulation of contrast in the brain. Accumulation of contrast in the brain also occurs in
patients where the blood-brain barrier is known or suspected to be disrupted.
Reference ID: 3788196
5
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For current labeling information, please visit https://www.fda.gov/drugsatfda
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials
of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect or predict the rates
observed in practice.
The following table of incidence of reactions is based upon controlled clinical trials in which ULTRAVIST Injection was
administered to 1142 patients. This listing includes all reported adverse reactions regardless of attribution.
Adverse reactions are listed by System Organ Class and in decreasing order of occurrence for rates greater than 1% in the
ULTRAVIST group: see Table 3.
Table 3: ADVERSE REACTIONS REPORTED IN > 1% OF PATIENTS WHO RECEIVED
ULTRAVIST INJECTION IN CLINICAL TRIALS
System Organ Class
Adverse Reaction
ULTRAVIST Injection
N=1142 (%)
Nervous system disorders
Headache
46 (4)
Dysgeusia
15 (1.3)
Eye disorders
Abnormal Vision
12 (1.1)
Cardiac disorders
Chest pain
18 (1.6)
Vascular disorders
Vasodilatation
30 (2.6)
Gastrointestinal disorders
Nausea
42 (3.7)
Vomiting
22 (1.9)
Musculoskeletal and connective
tissue disorders
Back pain
22 (1.9)
Renal and urinary disorders
Urinary urgency
21 (1.8)
General disorders and administration
site conditions
Injection site and infusion site
reactions (hemorrhage,
hematoma, pain, edema,
erythema, rash)
41 (3.7)
Pain
13 (1.4)
One or more adverse reactions were recorded in 273 of 1142 (24%) patients during the clinical trials, coincident with the
administration of ULTRAVIST Injection or within the defined duration of the study follow-up period (24–72 hours).
ULTRAVIST Injection is often associated with sensations of warmth and/or pain.
Serious, life-threatening and fatal reactions have been associated with the administration of iodine-containing contrast
media, including ULTRAVIST Injection. In clinical trials 7/1142 patients given ULTRAVIST Injection died 5 days or
later after drug administration. Also, 10/1142 patients given ULTRAVIST Injection had serious adverse events.
The following adverse reactions were observed in ≤1% of the subjects receiving ULTRAVIST Injection:
Cardiac disorders: atrioventricular block (complete), bradycardia, ventricular extrasystole
Gastrointestinal disorders: abdominal discomfort, abdominal pain, abdominal pain upper, constipation, diarrhea, dry
mouth, dyspepsia, gastrointestinal disorder, gastrointestinal pain, salivation increased, stomach discomfort, rectal
tenesmus
General disorders and administration site conditions: asthenia, chest discomfort, chills, excessive thirst, extravasation,
feeling hot, hyperhidrosis, malaise, edema peripheral, pyrexia
Immune system disorders: asthma, face edema
Investigations: blood lactate dehydrogenase increased, blood urea increased, hemoglobin increased, white blood cell count
increased
Musculoskeletal and connective tissue disorders: arthralgia, musculoskeletal pain, myasthenia, neck pain, pain in
extremity
Reference ID: 3788196
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Nervous system disorders: agitation, confusion, convulsion, dizziness, hypertonia, hypesthesia, incoordination,
neuropathy, somnolence, speech disorder, tremor, paresthesia, visual field defect
Psychiatric disorders: anxiety
Renal and urinary disorders: dysuria, renal pain, urinary retention
Respiratory, thoracic and mediastinal disorders: apnea, cough increased, dyspnea, hypoxia, pharyngeal edema,
pharyngitis, pleural effusion, pulmonary hypertension, respiratory disorder, sore throat
Skin and subcutaneous tissue disorders: erythema, pruritus, rash, urticaria
Vascular disorders: coronary artery thrombosis, flushing, hypertension, hypotension, peripheral vascular disorder,
syncope, vascular anomaly
6.2 Postmarketing Experience
The following adverse reactions have been identified during post approval use of ULTRAVIST Injection. Because these
reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their
frequency or establish a causal relationship to drug exposure.
Adverse reactions reported in foreign postmarketing surveillance and other trials with the use of ULTRAVIST Injection
include:
Cardiac disorders: cardiac arrest, ventricular fibrillation, atrial fibrillation, tachycardia, palpitations, congestive heart
failure, myocardial infarction, angina pectoris
Ear and labyrinth disorders: vertigo, tinnitus
Endocrine disorders: hyperthyroidism, thyrotoxic crisis, hypothyroidism; Thyroid function tests indicative of
hypothyroidism or transient thyroid suppression have been uncommonly reported following iodinated contrast
administration to adult and pediatric patients, including infants. Some patients were treated for hypothyroidism.
Eye disorders: mydriasis, lacrimation disorder
Gastrointestinal disorders: dysphagia, swelling of salivary glands
Immune system disorders: anaphylactoid reaction (including fatal cases), respiratory arrest, anaphylactoid shock,
angioedema, laryngeal edema, laryngospasm, bronchospasm, hypersensitivity
Musculoskeleal and connective tissue disorders: compartment syndrome in case of extravasation
Nervous system disorders: cerebral ischemia/infarction, paralysis, paresis, transient cortical blindness, aphasia, coma,
unconsciousness, amnesia, hypotonia, aggravation of myasthenia gravis symptoms
Renal and urinary disorders: renal failure, hematuria
Respiratory, thoracic and mediastinal disorders: pulmonary edema, acute respiratory distress syndrome, asthma
Skin and subcutaneous tissue disorders: Stevens-Johnson Syndrome, skin discoloration
Vascular disorders: vasospasm
6.3 Pediatrics
The overall character, quality, and severity of adverse reactions in pediatric patients are generally similar to those reported
in adult patients. Additional adverse reactions reported in pediatric patients from foreign marketing surveillance or other
information are: epistaxis, angioedema, migraine, joint disorder (effusion), muscle cramps, mucous membrane disorder
(mucosal swelling), conjunctivitis, hypoxia, fixed eruptions, vertigo, diabetes insipidus, and brain edema. [See Use in
Specific Populations (8.4).]
7 DRUG INTERACTIONS
7.1 Drug-Drug Interactions
In patients with renal impairment, biguanides can cause lactic acidosis. ULTRAVIST appears to increase the risk of
biguanide induced lactic acidosis, possibly as a result of worsening renal function [see Warnings and Precautions (5.2)].
Reference ID: 3788196
7
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Patients on beta-blockers may be unresponsive to the usual doses of epinephrine used to treat allergic reactions. Because
of the risk of hypersensitivity reactions, use caution when administering iodinated contrast agents to patients taking beta-
blockers.
Interleukins are associated with an increased prevalence of delayed hypersensitivity reactions after iodinated contrast
agent administration. These reactions include fever, chills, nausea, vomiting, pruritus, rash, diarrhea, hypotension, edema,
and oliguria.
Renal toxicity has been reported in a few patients with liver dysfunction who were given an oral cholecystographic agent
followed by intravascular contrast agents. Administration of any intravascular contrast agent should therefore be
postponed in patients who have recently received a cholecystographic contrast agent.
Do not mix other drugs with ULTRAVIST Injection [see How Supplied/Storage and Handling (16)].
7.2 Drug-Laboratory Test Interactions
Thyroid Function Tests:
The results of protein bound iodine and radioactive iodine uptake studies, which depend on iodine estimation, will not
accurately reflect thyroid function for at least 16 days following administration of iodinated contrast agents. However,
thyroid function tests which do not depend on iodine estimations, for example, T3 resin uptake and total or free thyroxine
(T4) assays are not affected.
Laboratory Assay of Coagulation Parameters, Fibrinolysis and Complement System:
The effect of iopromide on coagulation factors in in vitro assays increased with the administered dose. Coagulation,
fibrinolysis and complement activation were evaluated with standard citrated human plasma in the following assays:
thrombin time, thrombin coagulase time, calcium thromboplastin time, partial thromboplastin time, plasminogen,
thrombin, alpha-2 antiplasmin and factor XIIa activity. Thrombin inhibition was almost complete. Data on reversibility
are not available. The thrombin time increased from approximately 20 seconds at an iopromide concentration of 10 mg
I/mL, up to 100 seconds at an iopromide concentration of 70 mg I/mL.
The PTT increased from approximately 50 seconds at an iopromide concentration of 10 mg I/mL, up to approximately
100 seconds at an iopromide concentration of 70 mg I/mL. A similar increase was noted in the thrombin coagulase time.
Lesser effects were noted in the calcium thromboplastin time. Coagulation time increased from 13.5 to 23 seconds at the
highest iopromide concentration of 70 mg I/mL. The Hageman factor split products decreased by about 20% over the
range of 10 to 70 mg I/mL of iopromide. Plasminogen was relatively stable. There was no evidence of activation of
fibrinolysis. The complement alternate pathway was activated. Factor B conversion increased in a dose dependent
manner. The duration of these effects was not studied.
In vitro studies with human blood showed that iopromide had a slight effect on coagulation and fibrinolysis. No Factor
XIIa formation could be demonstrated. The complement alternate pathway also can be activated.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category B
Reproduction studies performed with iopromide in rats and rabbits at doses up to 3.7 g I/kg (2.2 times the maximum
recommended dose for a 50 kg human, or approximately 0.7 times the human dose following normalization of the data to
body surface area estimates) have revealed no evidence of direct harm to the fetus. Embryolethality was observed in
rabbits that received 3.7 g I/kg, but this was considered to have been secondary to maternal toxicity. Adequate and well-
controlled studies in pregnant women have not been conducted. Because animal reproduction studies are not always
predictive of human response, this drug should be used during pregnancy only if clearly needed.
8.3 Nursing Mothers
It is not known whether ULTRAVIST Injection is excreted in human milk. However, many injectable contrast agents are
excreted unchanged in human milk. Although it has not been established that serious adverse reactions occur in nursing
infants, caution should be exercised when intravascular contrast agents are administered to nursing women because of
potential adverse reaction, and consideration should be given to temporarily discontinuing nursing.
Reference ID: 3788196
8
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
8.4 Pediatric Use
The safety and efficacy of ULTRAVIST Injection have been established in the pediatric population over 2 years of age.
Use of ULTRAVIST Injection in these age groups is supported by evidence from adequate and well controlled studies of
ULTRAVIST Injection in adults and additional safety data obtained in literature and other reports in a total of 274
pediatric patients. Of these, there were 131 children (2–12 years), 57 adolescents, and 86 children of unreported or other
ages. There were 148 females, 94 males and 32 in whom gender was not reported. The racial distribution was: Caucasian
93 (33.9%), Black 1 (0.4%), Asian 6 (2.2%), and unknown 174 (63.5%). These patients were evaluated in intra-arterial
coronary angiographic (n=60), intravenous contrast computerized tomography (CT) (n=87), excretory urography (n=99)
and 28 other procedures.
In these pediatric patients, a concentration of 300 mg I/mL was employed for intravenous contrast CT or excretory
urography. A concentration of 370 mg I/mL was employed for intra-arterial and intracardiac administration in the
radiographic evaluation of the heart cavities and major arteries. Most pediatric patients received initial volumes of 1–2
mL/kg.
Optimal doses of ULTRAVIST Injection have not been established because different injection volumes, concentrations
and injection rates were not studied. The relationship of the volume of injection with respect to the size of the target
vascular bed has not been established. The potential need for dose adjustment on the basis of immature renal function has
not been established. In the pediatric population, the pharmacokinetic parameters have not been established.
Pediatric patients at higher risk of experiencing an adverse reaction during and after administration of any contrast agent
include those with asthma, a sensitivity to medication and/or allergens, cyanotic and acyanotic heart disease, congestive
heart failure, or a serum creatinine greater than 1.5 mg/dL. The injection rates in small vascular beds, and the relationship
of the dose by volume or concentration in small pediatric patients have not been established. Exercise caution in selecting
the dose.
Safety and effectiveness in pediatric patients below the age of two have not been established.
8.5 Geriatric Use
Middle-aged and elderly patients, without significantly impaired renal function, who received ULTRAVIST Injection in
doses corresponding to 9–30 g iodine, had mean steady-state volumes of distribution that ranged between 30–40 L. Mean
total and renal clearances were between 81–125 mL/min and 70–115 mL/min respectively in these patients, and were
similar to the values found in the young volunteers. The distribution phase half-life in this patient population was 0.1
hour, the main elimination phase half-life was 2.3 hours, and the terminal elimination phase half-life was 40 hours. The
urinary excretion (97% of the dose) and fecal excretion (2%) was comparable to that observed in young healthy
volunteers, suggesting that, compared to the renal route, biliary and/or gastrointestinal excretion is not significant for
iopromide.
8.6 Renal Impairment
In patients with renal impairment, opacification of the calyces and pelves by iopromide may be delayed due to slower
renal excretion of iopromide.
A pharmacokinetic study in patients with mild (n=2), moderate (n=6), and severe (n=3) renal impairment was conducted.
The total clearance of iopromide was decreased proportionately to the baseline decrease in creatinine clearance. The
plasma AUC increased about 2-fold in patients with moderate renal impairment and 6-fold in patients with severe renal
impairment compared to subjects with normal renal function. The terminal half-life increased from 2.2 hrs for subjects
with normal renal function to 11.6 hrs in patients with severe renal impairment. The peak plasma concentration of
iopromide was not influenced by the extent of renal impairment. Exercise caution and use the lowest necessary dose of
ULTRAVIST in patients with renal dysfunction [see Warnings and Precautions (5.2)].
10 OVERDOSAGE
The adverse effects of overdosage are life-threatening and affect mainly the pulmonary and cardiovascular systems.
Treatment of an overdosage is directed toward the support of all vital functions, and prompt institution of symptomatic
therapy.
ULTRAVIST Injection binds negligibly to plasma or serum protein and can, therefore, be dialyzed.
Reference ID: 3788196
9
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For current labeling information, please visit https://www.fda.gov/drugsatfda
11 DESCRIPTION
ULTRAVIST (iopromide) Injection is a nonionic, water soluble x-ray contrast agent for intravascular administration. Each
bottle is to be used as a Pharmacy Bulk Package for dispensing multiple single dose preparations utilizing a suitable
transfer device. The chemical name for iopromide is N,N'-Bis(2,3-dihydroxypropyl) –2,4,6–triiodo–5–
[(methoxyacetyl)amino] –N-methyl–1,3-benzenedicarboxamide. Iopromide has a molecular weight of 791.12 (iodine
content 48.12%).
Iopromide has the following structural formula: structural formula
ULTRAVIST Injection is a nonionic sterile, clear, colorless to slightly yellow, odorless, pyrogen-free aqueous solution of
iopromide, containing 2.42 mg/mL tromethamine buffer and 0.1 mg/mL edetate calcium disodium stabilizer.
ULTRAVIST Injection Pharmacy Bulk Package is available in three strengths:
240 mg I/mL provides 498.72 mg/mL iopromide
300 mg I/mL provides 623.4 mg/mL iopromide
370 mg I/mL provides 768.86 mg/mL iopromide
During the manufacture of ULTRAVIST Injection, sodium hydroxide or hydrochloric acid may be added for pH
adjustment. ULTRAVIST Injection has a pH of 7.4 (6.5–8) at 25± 2°C, is sterilized by autoclaving and contains no
preservatives.
The iodine concentrations (mg I/mL) available have the following physicochemical properties:
ULTRAVIST
INJECTION
ULTRAVIST
INJECTION
ULTRAVIST
INJECTION
Property
240 mg I/mL
300 mg I/mL
370 mg I/mL
Osmolality*(mOsmol/kg water)
@ 37°C
483
607
774
Osmolarity*(mOsmol/L)
@ 37°C
368
428
496
Viscosity (cP)
@ 20°C
@ 37°C
4.9
2.8
9.2
4.9
22
10
Density (g/mL)
@ 20°C
@ 37°C
1.262
1.255
1.330
1.322
1.409
1.399
*Osmolality was measured by vapor-pressure osmometry. Osmolarity was calculated from the measured osmolal
concentrations.
Solutions of ULTRAVIST Injection 240 mg I/mL, 300 mg I/mL and 370 mg I/mL have osmolalities from approximately
1.1 to 2.7 times that of plasma (285 mOsmol/kg water).
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Iopromide is a nonionic, water soluble, tri-iodinated x-ray contrast agent for intravascular administration.
Intravascular injection of iopromide opacifies those vessels in the path of flow of the contrast agent, permitting
radiographic visualization of the internal structures until significant hemodilution occurs.
Reference ID: 3788196
10
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For current labeling information, please visit https://www.fda.gov/drugsatfda
12.2 Pharmacodynamics
Following ULTRAVIST administration, the degree of contrast enhancement is directly related to the iodine content in the
administered dose; peak iodine plasma levels occur immediately following rapid intravenous injection. Iodine plasma
levels fall rapidly within 5 to 10 minutes. This can be accounted for by the dilution in the vascular and extravascular fluid
compartments.
Intravascular Contrast: Contrast enhancement appears to be greatest immediately after bolus injections (15 seconds to 120
seconds). Thus, greatest enhancement may be detected by a series of consecutive two-to-three second scans performed
within 30 to 90 seconds after injection (that is, dynamic computed tomographic imaging).
ULTRAVIST Injection may be visualized in the renal parenchyma within 30–60 seconds following rapid intravenous
injection. Opacification of the calyces and pelves in patients with normal renal function becomes apparent within 1–3
minutes, with optimum contrast occurring within 5–15 minutes.
In contrast CT, some performance characteristics are different in the brain and body. In contrast CT of the body, iodinated
contrast agents diffuse rapidly from the vascular into the extravascular space. Following the administration of iodinated
contrast agents, the increase in tissue density to x-rays is related to blood flow, the concentration of the contrast agent, and
the extraction of the contrast agent by various interstitial tissues. Contrast enhancement is thus due to any relative
differences in extravascular diffusion between adjacent tissues.
In the normal brain with an intact blood-brain barrier, contrast is generally due to the presence of iodinated contrast agent
within the intravascular space. The radiographic enhancement of vascular lesions, such as arteriovenous malformations
and aneurysms, depends on the iodine content of the circulating blood pool.
In tissues with a break in the blood-brain barrier, contrast agent accumulates within interstitial brain tissue. The time to
maximum contrast enhancement can vary from the time that peak blood iodine levels are reached to 1 hour after
intravenous bolus administration. This delay suggests that radiographic contrast enhancement is at least in part dependent
on the accumulation of iodine containing medium within the lesion and outside the blood pool. The mechanism by which
this occurs is not clear.
For information on coagulation parameters, fibrinolysis and complement system [see Drug Interactions (7.2)].
12.3 Pharmacokinetics
Distribution
After intravenous administration to healthy young volunteers, plasma iopromide concentration time profile shows an
initial distribution phase with a half-life of 0.24 hour; a main elimination phase with a half-life of 2 hours; and a terminal
elimination phase with a half-life of 6.2 hours. The total volume of distribution at steady state is about 16 L suggesting
distribution in to extracellular space. Plasma protein binding of iopromide is 1%.
Iodinated contrast agents may cross the blood-brain barrier [see Warnings and Precautions (5.8)].
Metabolism
Iopromide is not metabolized.
Elimination
The amounts excreted unchanged in urine represent 97% of the dose in young healthy subjects. Only 2% of the dose is
recovered in the feces. Similar recoveries in urine and feces are observed in middle-aged and elderly patients. This finding
suggests that, compared to the renal route, biliary and/or gastrointestinal excretion is not important for iopromide. During
the slower terminal phase only 3% of the dose is eliminated; 97% of the dose is disposed of during the earlier phases, the
largest part of which occurs during the main elimination phase. The ratio of the renal clearance of iopromide to the
creatinine clearance is 0.82 suggesting that iopromide is mainly excreted by glomerular filtration. Additional tubular
reabsorption is possible. Pharmacokinetics of iopromide at intravenous doses up to 80 g iodine, are dose proportionate and
first order.
The mean total and renal clearances are 107 mL/min and 104 mL/min, respectively.
Specific Populations
A pharmacokinetic study was conducted in 11 patients with renal impairment [see Use in Specific Populations (8.6)].
Reference ID: 3788196
11
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term animal studies have not been performed with iopromide to evaluate carcinogenic potential or effects on
fertility. Iopromide was not genotoxic in a series of studies including the Ames test, an in vitro human lymphocytes
analysis of chromosomal aberrations, an in vivo mouse micro-nucleus assay, and in an in vivo mouse dominant lethal
assay.
14 CLINICAL STUDIES
ULTRAVIST Injection was administered to 708 patients; 1 patient was less than 18 years of age, 347 patients were
between 18 and 59 years of age, and 360 patients were equal to or greater than 60 years of age; the mean age was 56.6
years (range 17–88). Of the 708 patients, 446 (63%) were male and 262 (37%) were female. The racial distribution was:
Caucasian 463 (65.4%), Black 95 (13.4%), Hispanic 36 (5.1%), Asian 11 (1.6 %), and other or unknown 103 (14.5%).
Efficacy assessment was based on the global evaluation of the quality of the radiographs by rating visualization as either
excellent, good, poor, or no image, and on the ability to make a diagnosis. Five (5) intra-arterial and three (3) intravenous
procedures were studied with 1 of 4 concentrations (370 mg I/mL, 300 mg I/mL, 240 mg I/mL, and 150 mg I/mL). These
procedures were: aortography/visceral angiography, coronary arteriography and left ventriculography, cerebral
arteriography, peripheral arteriography, intra-arterial digital subtraction angiography (IA-DSA), contrast computed
tomography (CT) of head and body, excretory urography, and peripheral venography.
Cerebral arteriography was evaluated in two randomized, double-blind clinical trials of ULTRAVIST Injection 300 mg
I/mL in 80 patients with conditions such as altered cerebrovascular perfusion and/or permeability occurring in central
nervous system diseases due to various CNS disorders. Visualization ratings were good or excellent in 99% of the patients
with ULTRAVIST Injection; a radiologic diagnosis was made in the majority of the patients. Confirmation of the
radiologic findings by other diagnostic methods was not obtained.
Coronary arteriography/left ventriculography was evaluated in two randomized, double-blind clinical trials and one
unblinded, unrandomized clinical trial of ULTRAVIST Injection 370 mg I/mL in 106 patients with conditions such as
altered coronary artery perfusion due to metabolic causes and in patients with conditions such as altered ventricular
function. Visualization ratings were good or excellent in 99% or more of the patients a radiologic diagnosis was made in
the majority of the patients. A confirmation of the radiologic findings by other diagnostic methods was not obtained.
Aortography/visceral angiography was evaluated in two randomized, double-blind clinical trials in 78 patients with
conditions such as altered aortic blood flow and/or visceral vascular disorders. Visualization ratings were good or
excellent in the majority of the patients; a radiologic diagnosis was made in 99% of the patients with ULTRAVIST
Injection. A confirmation of radiologic findings by other diagnostic methods was not obtained. The risks of renal
arteriography could not be analyzed.
Contrast CT of head and body was evaluated in three randomized, double-blind clinical trials of ULTRAVIST Injection
300 mg I/mL in 95 patients with vascular disorders. Visualization ratings were good or excellent in 99% of the patients; a
radiologic diagnosis was made in the majority of the patients. A confirmation of contrast CT findings by other diagnostic
methods was not obtained.
ULTRAVIST Injection was evaluated in a blinded reader trial for CT of the head and body. Among the 382 patients who
were evaluated with ULTRAVIST Injection 370 mg I/mL, visualization ratings were good or excellent in approximately
97% of patients.
Peripheral venography was evaluated in two randomized, double-blind clinical trials of ULTRAVIST Injection 240 mg
I/mL in 63 patients with disorders affecting venous drainage of the limbs. Visualization ratings were good or excellent in
100% of the patients; a radiologic diagnosis was made in the majority of the patients. A confirmation of radiologic
findings by other diagnostic methods was not obtained.
Similar studies were completed with comparable findings noted in intra-arterial digital subtraction angiography,
peripheral arteriography and excretory urography.
Reference ID: 3788196
12
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
16 HOW SUPPLIED/STORAGE AND HANDLING
ULTRAVIST Injection is a sterile, clear, colorless to slightly yellow, odorless, pyrogen-free aqueous solution available in
three strengths.
ULTRAVIST Injection 240 mg I/mL Pharmacy Bulk Package
10 x 200 mL fill/250 mL bottles
50419-342-21
ULTRAVIST Injection 300 mg I/mL Pharmacy Bulk Package
10 x 200 mL fill/250 mL bottles
50419-344-21
8 x 500 mL bottles
50419-344-58
8 x 500 mL bottles (RFID)
50419-344-48
ULTRAVIST Injection 370 mg I/mL Pharmacy Bulk Package
10 x 250 mL bottles
50419-346-25
8 x 500 mL bottles
50419-346-58
8 x 500 mL bottles (RFID)
50419-346-48
Inspect ULTRAVIST visually prior to use. Do not use if discolored, if particulate matter (including crystals) is present, or
if containers are defective. As ULTRAVIST Injection is a highly concentrated solution, crystallization (milky-cloudy
appearance and/or sediment at bottom, or floating crystals) may occur.
As with all contrast agents, because of the potential for chemical incompatibility, do not mix or inject ULTRAVIST
Injection in intravenous administration lines containing other drugs, solutions or total nutritional admixtures.
Administer ULTRAVIST at or close to body temperature.
If nondisposable equipment is used, take scrupulous care to prevent residual contamination with traces of cleansing
agents.
Withdraw ULTRAVIST from its container under strict aseptic conditions using only sterile syringes and transfer devices.
Use immediately contrast agents which have been transferred into other delivery systems.
Store ULTRAVIST at 25°C (77°F); excursions permitted to 15–30°C (59–86°F) and protected from light.
Directions for Proper Use of ULTRAVIST Injection PHARMACY BULK PACKAGE
1. Perform the transfer of ULTRAVIST Injection from the PHARMACY BULK PACKAGE in a suitable work area,
such as a laminar flow hood, utilizing aseptic technique.
2. Penetrate the container closure only one time, utilizing a suitable transfer device.
3. After initial puncture use the contents of the PHARMACY BULK PACKAGE within 10 hours.
4. Discard any unused ULTRAVIST Injection 10 hours after the initial puncture of the bulk package.
17 PATIENT COUNSELING INFORMATION
Instruct patients receiving ULTRAVIST Injection to inform their physician or healthcare provider of the following:
• If they are pregnant [see Use in Specific Populations (8.1)]
• If they are diabetic or if they have multiple myeloma, pheochromocytoma, sickle cell disease or thyroid disorder [see
Warnings and Precautions (5.2, 5.5)]
• If they are allergic to any drugs or food, or if they have immune, autoimmune or immune deficiency disorders. Also,
if they have had any reaction to previous injections of dyes used for x-ray procedures [see Warnings and Precautions
(5.1)]
• All medications they are currently taking, including non-prescription (over-the-counter) drugs.
©2015, Bayer HealthCare Pharmaceuticals Inc. All rights reserved.
Reference ID: 3788196
13
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Manufactured for: company logo
Bayer HealthCare Pharmaceuticals Inc.
Whippany, NJ 07981
Manufactured in Germany
Reference ID: 3788196
14
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For current labeling information, please visit https://www.fda.gov/drugsatfda
|
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020220s041,021425s024lbl.pdf', 'application_number': 20220, 'submission_type': 'SUPPL ', 'submission_number': 41}
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12,334
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This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
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---------------------------------------------------------------------------------------------------------
This is a representation of an electronic record t at was signed
electronically and this page is the manifestation of the electronic
signature.
---------------------------------------------------------------------------------------------------------
/s/
----------------------------------------------------
THERESA M MICHELE
03/24/2016
Reference ID: 3907595
(b)
(4)
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For current labeling information, please visit https://www.fda.gov/drugsatfda
|
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2025-02-12T13:47:03.830153
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/020231Orig1s075lbl.pdf', 'application_number': 20231, 'submission_type': 'SUPPL ', 'submission_number': 75}
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12,336
|
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
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This label may not be the latest approved by FDA.
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This label may not be the latest approved by FDA.
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This label may not be the latest approved by FDA.
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This label may not be the latest approved by FDA.
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This label may not be the latest approved by FDA.
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This label may not be the latest approved by FDA.
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custom-source
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2025-02-12T13:47:04.155014
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/1996/020234lbl.pdf', 'application_number': 20234, 'submission_type': 'ORIG ', 'submission_number': 1}
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Fioricet® with Codeine C-III
(Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate) Capsules
Rx only
184178-3
WARNING: HEPATOTOXICITY AND DEATH RELATED TO ULTRA-RAPID
METABOLISM
OF CODEINE TO MORPHINE
•
Fioricet with Codeine contains butalbital, acetaminophen, caffeine, and codeine phosphate. Acetaminophen
has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of
the cases of liver injury are associated with the use of acetaminophen at doses that exceed 4000 milligrams per
day, and often involve more than one acetaminophen-containing product.
•
Respiratory depression and death have occurred in children who received codeine following tonsillectomy
and/or adenoidectomy and had evidence of being ultra-rapid metabolizers of codeine due to a CYP2D6
polymorphism.
DESCRIPTION
Fioricet with Codeine (Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate) is supplied in capsule form for oral
administration.
Each capsule contains the following active ingredients:
butalbital, USP………….............
50 mg
acetaminophen, USP………......
325 mg
caffeine, USP……………..........
40 mg
codeine phosphate, USP…........
30 mg
Butalbital (5-allyl-5-isobutylbarbituric acid) is a short- to intermediate-acting barbiturate. It has the following structural
formula: structural formula
C11H16N2O3
molecular weight 224.26
Acetaminophen (4´-hydroxyacetanilide) is a non-opiate, non-salicylate analgesic and antipyretic. It has the following structural
formula: structural formula
C8H9NO2
molecular weight 151.16
Reference ID: 3306513
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Caffeine (1,3,7-trimethylxanthine) is a central nervous system stimulant. It has the following structural formula: structural formula
C8H10N4O2
molecular weight 194.19
Codeine phosphate (7,8-Didehydro-4,5α-epoxy-3-methoxy-17-methylmorphinan-6α-ol phosphate (1:1) (salt) hemihydrate) is
a narcotic analgesic and antitussive. It has the following structural formula: structural formula
C18H24NO7P
anhydrous molecular weight 397.37
Inactive Ingredients: colloidal silicon dioxide, magnesium stearate, pregelatinized starch. Gelatin capsules contain black iron
oxide, D&C Red No. 33, FD&C Blue No. 1, gelatin, red iron oxide, and titanium dioxide. The capsules are printed with edible
inks containing D&C Red No. 7 Calcium Lake, FD&C Blue No. 1 Aluminum Lake, and titanium dioxide.
CLINICAL PHARMACOLOGY
Fioricet with Codeine is a combination drug product intended as a treatment for tension headache.
Fioricet (Butalbital, Acetaminophen, and Caffeine Tablets, USP) consists of a fixed combination of butalbital 50 mg,
acetaminophen 325 mg and caffeine 40 mg. The role each component plays in the relief of the complex of symptoms known as
tension headache is incompletely understood.
Pharmacokinetics
The behavior of the individual components is described below.
Butalbital
Butalbital is well absorbed from the gastrointestinal tract and is expected to distribute to most tissues in the body. Barbiturates
in general may appear in breast milk and readily cross the placental barrier. They are bound to plasma and tissue proteins to a
varying degree and binding increases directly as a function of lipid solubility.
Elimination of butalbital is primarily via the kidney (59%-88% of the dose) as unchanged drug or metabolites. The plasma
half-life is about 35 hours. Urinary excretion products include parent drug (about 3.6% of the dose),
5-isobutyl-5-(2,3-dihydroxypropyl) barbituric acid (about 24% of the dose), 5-allyl-5(3-hydroxy-2-methyl-1-propyl) barbituric
acid (about 4.8% of the dose), products with the barbituric acid ring hydrolyzed with excretion of urea (about 14% of the dose),
as well as unidentified materials. Of the material excreted in the urine, 32% is conjugated.
Reference ID: 3306513
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
The in vitro plasma protein binding of butalbital is 45% over the concentration range of 0.5-20 mcg/mL. This falls within the
range of plasma protein binding (20%-45%) reported with other barbiturates such as phenobarbital, pentobarbital, and
secobarbital sodium. The plasma-to-blood concentration ratio was almost unity indicating that there is no preferential
distribution of butalbital into either plasma or blood cells.
See OVERDOSAGE for toxicity information.
Acetaminophen
Acetaminophen is rapidly absorbed from the gastrointestinal tract and is distributed throughout most body tissues. The plasma
half-life is 1.25-3 hours, but may be increased by liver damage and following overdosage. Elimination of acetaminophen is
principally by liver metabolism (conjugation) and subsequent renal excretion of metabolites. Approximately 85% of an oral
dose appears in the urine within 24 hours of administration, most as the glucuronide conjugate, with small amounts of other
conjugates and unchanged drug.
See OVERDOSAGE for toxicity information.
Caffeine
Like most xanthines, caffeine is rapidly absorbed and distributed in all body tissues and fluids, including the CNS, fetal tissues,
and breast milk.
Caffeine is cleared through metabolism and excretion in the urine. The plasma half-life is about 3 hours. Hepatic
biotransformation prior to excretion results in about equal amounts of 1-methylxanthine and 1-methyluric acid. Of the 70% of
the dose that is recovered in the urine, only 3% is unchanged drug.
See OVERDOSAGE for toxicity information.
Codeine
Codeine is readily absorbed from the gastrointestinal tract. It is rapidly distributed from the intravascular spaces to the various
body tissues, with preferential uptake by parenchymatous organs such as the liver, spleen and kidney. Codeine crosses the
blood-brain barrier, and is found in fetal tissue and breast milk. The plasma concentration does not correlate with brain
concentration or relief of pain; however, codeine is not bound to plasma proteins and does not accumulate in body tissues.
The plasma half-life is about 2.9 hours. The elimination of codeine is primarily via the kidneys, and about 90% of an oral dose
is excreted by the kidneys within 24 hours of dosing. The urinary secretion products consist of free and glucuronide conjugated
codeine (about 70%), free and conjugated norcodeine (about 10%), free and conjugated morphine (about 10%), normorphine
(about 4%), and hydrocodone (1%). The remainder of the dose is excreted in the feces.
At therapeutic doses, the analgesic effect reaches a peak within 2 hours and persists between 4 and 6 hours.
See OVERDOSAGE for toxicity information.
INDICATIONS
Fioricet with Codeine is indicated for the relief of the symptom complex of tension (or muscle contraction) headache.
Evidence supporting the efficacy and safety of Fioricet with Codeine in the treatment of multiple recurrent headaches is
unavailable. Caution in this regard is required because codeine and butalbital are habit-forming and potentially abusable.
CONTRAINDICATIONS
Fioricet with Codeine is contraindicated under the following conditions:
− Postoperative pain management in children who have undergone tonsillectomy and/or adenoidectomy.
− Hypersensitivity or intolerance to acetaminophen, caffeine, butalbital, or codeine.
− Patients with porphyria.
WARNINGS
Hepatotoxicity
Fioricet with Codeine contains butalbital, acetaminophen, caffeine, and codeine phosphate. Acetaminophen has been
associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are
Reference ID: 3306513
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For current labeling information, please visit https://www.fda.gov/drugsatfda
associated with the use of acetaminophen at doses that exceed 4000 milligrams per day, and often involve more than one
acetaminophen-containing product. The excessive intake of acetaminophen may be intentional to cause self-harm or
unintentional as patients attempt to obtain more pain relief or unknowingly take other acetaminophen-containing products.
The risk of acute liver failure is higher in individuals with underlying liver disease and in individuals who ingest alcohol while
taking acetaminophen.
Instruct patients to look for acetaminophen or APAP on package labels and not to use more than one product that contains
acetaminophen. Instruct patients to seek medical attention immediately upon ingestion of more than 4000 milligrams of
acetaminophen per day, even if they feel well.
Death Related to Ultra-Rapid Metabolism of Codeine to Morphine
Respiratory depression and death have occurred in children who received codeine in the postoperative period following
tonsillectomy and/or adenoidectomy and had evidence of being ultra-rapid metabolizers of codeine (i.e., multiple copies of the
gene for cytochrome P450 isoenzyme 2D6 or high morphine concentrations). Deaths have also occurred in nursing infants who
were exposed to high levels of morphine in breast milk because their mothers were ultra-rapid metabolizers of codeine.
Some individuals may be ultra-rapid metabolizers because of a specific CYP2D6 genotype (gene duplications denoted as
*1/*1xN or *1/*2xN). The prevalence of this CYP2D6 phenotype varies widely and has been estimated at 0.5 to 1% in Chinese
and Japanese, 0.5 to 1% in Hispanics, 1 to 10% in Caucasians, 3% in African Americans, and 16 to 28% in North Africans,
Ethiopians, and Arabs. Data are not available for other ethnic groups. These individuals convert codeine into its active
metabolite, morphine, more rapidly and completely than other people. This rapid conversion results in higher than expected
serum morphine levels. Even at labeled dosage regimens, individuals who are ultra-rapid metabolizers may have
life-threatening or fatal respiratory depression or experience signs of overdose (such as extreme sleepiness, confusion, or
shallow breathing).
Children with obstructive sleep apnea who are treated with codeine for post-tonsillectomy and/or adenoidectomy pain may be
particularly sensitive to the respiratory depressant effects of codeine that has been rapidly metabolized to morphine. Fioricet
with Codeine is contraindicated for postoperative pain management in all pediatric patients undergoing tonsillectomy and/or
adenoidectomy [see Contraindications].
When prescribing Fioricet with Codeine, healthcare providers should choose the lowest effective dose for the shortest period of
time and inform patients and caregivers about these risks and the signs of morphine overdose.
Hypersensitivity/Anaphylaxis
There have been post-marketing reports of hypersensitivity and anaphylaxis associated with the use of acetaminophen. Clinical
signs included swelling of the face, mouth, and throat, respiratory distress, urticaria, rash, pruritus, and vomiting. There were
infrequent reports of life-threatening anaphylaxis requiring emergency medical attention. Instruct patients to discontinue
Fioricet with Codeine immediately and seek medical care if they experience these symptoms. Do not prescribe Fioricet with
Codeine for patients with acetaminophen allergy.
In the presence of head injury or other intracranial lesions, the respiratory depressant effects of codeine and other narcotics may
be markedly enhanced, as well as their capacity for elevating cerebrospinal fluid pressure. Narcotics also produce other CNS
depressant effects, such as drowsiness, that may further obscure the clinical course of the patients with head injuries.
Codeine or other narcotics may obscure signs on which to judge the diagnosis or clinical course of patients with acute
abdominal conditions.
Butalbital and codeine are both habit-forming and potentially abusable. Consequently, the extended use of Fioricet with
Codeine is not recommended.
PRECAUTIONS
General
Fioricet with Codeine should be prescribed with caution in certain special-risk patients such as the elderly or debilitated, and
those with severe impairment of renal or hepatic function, head injuries, elevated intracranial pressure, acute abdominal
conditions, hypothyroidism, urethral stricture, Addison’s disease, or prostatic hypertrophy.
Reference ID: 3306513
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Information for Patients/Caregivers
• Do not take Fioricet with Codeine if you are allergic to any of its ingredients.
• If you develop signs of allergy such as a rash or difficulty breathing, stop taking Fioricet with Codeine and contact your
healthcare provider immediately.
• Do not take more than 4000 milligrams of acetaminophen per day. Call your doctor if you took more than the
recommended dose.
• Fioricet with Codeine may impair mental and/or physical abilities required for the performance of potentially hazardous
tasks such as driving a car or operating machinery. Such tasks should be avoided while taking Fioricet with Codeine.
• Alcohol and other CNS depressants may produce an additive CNS depression, when taken with Fioricet with Codeine,
and should be avoided.
• Codeine and butalbital may be habit-forming. Patients should take the drug only for as long as it is prescribed, in the
amounts prescribed, and no more frequently than prescribed.
• For information on use in geriatric patients, see PRECAUTIONS, Geriatric Use.
• Advise patients that some people have a genetic variation that results in codeine changing into morphine more rapidly
and completely than other people. Most people are unaware of whether they are an ultra-rapid codeine metabolizer or
not. These higher-than-normal levels of morphine in the blood may lead to life-threatening or fatal respiratory depression
or signs of overdose such as extreme sleepiness, confusion, or shallow breathing. Children with this genetic variation
who were prescribed codeine after tonsillectomy and/or adenoidectomy for obstructive sleep apnea may be at greatest
risk based on reports of several deaths in this population due to respiratory depression. Fioricet with Codeine is
contraindicated in children who undergo tonsillectomy and/or adenoidectomy. Advise caregivers of children receiving
Fioricet with Codeine for other reasons to monitor for signs of respiratory depression.
• Nursing mothers taking codeine can also have higher morphine levels in their breast milk if they are ultra-rapid
metabolizers. These higher levels of morphine in breast milk may lead to life-threatening or fatal side effects in nursing
babies. Instruct nursing mothers to watch for signs of morphine toxicity in their infants including increased sleepiness
(more than usual), difficulty breastfeeding, breathing difficulties, or limpness. Instruct nursing mothers to talk to the
baby's doctor immediately if they notice these signs and, if they cannot reach the doctor right away, to take the baby to an
emergency room or call 911 (or local emergency services).
Laboratory Tests
In patients with severe hepatic or renal disease, effects of therapy should be monitored with serial liver and/or renal function
tests.
Drug Interactions
The CNS effects of butalbital may be enhanced by monoamine oxidase (MAO) inhibitors.
Fioricet with Codeine may enhance the effects of:
− Other narcotic analgesics, alcohol, general anesthetics, tranquilizers such as chlordiazepoxide, sedative-hypnotics, or other
CNS depressants, causing increased CNS depression.
Drug/Laboratory Test Interactions
Acetaminophen
Acetaminophen may produce false-positive test results for urinary 5-hydroxyindoleacetic acid.
Codeine
Codeine may increase serum amylase levels.
Carcinogenesis, Mutagenesis, Impairment of Fertility
No adequate studies have been conducted in animals to determine whether acetaminophen, codeine and butalbital have a
potential for carcinogenesis or mutagenesis. No adequate studies have been conducted in animals to determine whether
acetaminophen and butalbital have a potential for impairment of fertility.
Reference ID: 3306513
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Pregnancy
Teratogenic Effects
Pregnancy Category C: Animal reproduction studies have not been conducted with Fioricet with Codeine. It is also not known
whether Fioricet with Codeine can cause fetal harm when administered to a pregnant woman or can affect reproduction
capacity. Fioricet with Codeine should be given to a pregnant woman only when clearly needed.
Nonteratogenic Effects
Withdrawal seizures were reported in a two-day-old male infant whose mother had taken a butalbital-containing drug during
the last 2 months of pregnancy. Butalbital was found in the infant’s serum. The infant was given phenobarbital 5 mg/kg, which
was tapered without further seizure or other withdrawal symptoms.
Labor and Delivery
Use of codeine during labor may lead to respiratory depression in the neonate.
Nursing Mothers
Codeine is secreted into human milk. In women with normal codeine metabolism (normal CYP2D6 activity), the amount of
codeine secreted into human milk is low and dose-dependent. Despite the common use of codeine products to manage
postpartum pain, reports of adverse events in infants are rare. However, some women are ultra-rapid metabolizers of codeine.
These women achieve higher-than-expected serum levels of codeine's active metabolite, morphine, leading to
higher-than-expected levels of morphine in breast milk and potentially dangerously high serum morphine levels in their
breastfed infants. Therefore, maternal use of codeine can potentially lead to serious adverse reactions, including death, in
nursing infants.
The risk of infant exposure to codeine and morphine through breast milk should be weighed against the benefits of
breastfeeding for both the mother and baby. Caution should be exercised when codeine is administered to a nursing woman. If
a codeine-containing product is selected, the lowest dose should be prescribed for the shortest period of time to achieve the
desired clinical effect. Mothers using codeine should be informed about when to seek immediate medical care and how to
identify the signs and symptoms of neonatal toxicity, such as drowsiness or sedation, difficulty breastfeeding, breathing
difficulties, and decreased tone, in their baby. Nursing mothers who are ultra-rapid metabolizers may also experience overdose
symptoms such as extreme sleepiness, confusion or shallow breathing. Prescribers should closely monitor mother-infant pairs
and notify treating pediatricians about the use of codeine during breastfeeding. (See Warnings – Death Related to Ultra-rapid
Metabolism of Codeine to Morphine)
Barbiturates, acetaminophen, and caffeine are also excreted in breast milk in small amounts. Because of potential for serious
adverse reactions in nursing infants from Fioricet with Codeine, a decision should be made whether to discontinue nursing or to
discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Respiratory depression and death have occurred in children with obstructive sleep apnea who received codeine in the
post-operative period following tonsillectomy and/or adenoidectomy and had evidence of being ultra-rapid metabolizers of
codeine (i.e., multiple copies of the gene for cytochrome P450 isoenzyme 2D6 or high morphine concentrations). These
children may be particularly sensitive to the respiratory depressant effects of codeine that has been rapidly metabolized to
morphine. Fioricet with Codeine is contraindicated for post-operative pain management in all pediatric patients undergoing
tonsillectomy and/or adenoidectomy.[see Contraindications]
Geriatric Use
Clinical studies of Fioricet with Codeine did not include sufficient numbers of subjects aged 65 and over to determine whether
they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses
between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at
the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of
concomitant disease or other drug therapy.
Reference ID: 3306513
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Butalbital is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in
patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be
taken in dose selection, and it may be useful to monitor renal function.
ADVERSE REACTIONS
Frequently Observed
The most frequently reported adverse reactions are drowsiness, lightheadedness, dizziness, sedation, shortness of breath,
nausea, vomiting, abdominal pain, and intoxicated feeling.
Infrequently Observed
All adverse events tabulated below are classified as infrequent.
Central Nervous: headache, shaky feeling, tingling, agitation, fainting, fatigue, heavy eyelids, high energy, hot spells,
numbness, sluggishness, seizure. Mental confusion, excitement or depression can also occur due to intolerance, particularly in
elderly or debilitated patients, or due to overdosage of butalbital.
Autonomic Nervous: dry mouth, hyperhidrosis.
Gastrointestinal: difficulty swallowing, heartburn, flatulence, constipation.
Cardiovascular: tachycardia.
Musculoskeletal: leg pain, muscle fatigue.
Genitourinary: diuresis.
Miscellaneous: pruritus, fever, earache, nasal congestion, tinnitus, euphoria, allergic reactions.
The following adverse reactions have been voluntarily reported as temporally associated with Fiorinal® with Codeine,
a related product containing aspirin, butalbital, caffeine, and codeine.
Central Nervous: abuse, addiction, anxiety, disorientation, hallucination, hyperactivity, insomnia, libido decrease,
nervousness, neuropathy, psychosis, sexual activity increase, slurred speech, twitching, unconsciousness, vertigo.
Autonomic Nervous: epistaxis, flushing, miosis, salivation.
Gastrointestinal: anorexia, appetite increased, diarrhea, esophagitis, gastroenteritis, gastrointestinal spasms, hiccup, mouth
burning, pyloric ulcer.
Cardiovascular: chest pain, hypotensive reaction, palpitations, syncope.
Skin: erythema, erythema multiforme, exfoliative dermatitis, hives, rash, toxic epidermal necrolysis.
Urinary: kidney impairment, urinary difficulty.
Miscellaneous: allergic reaction, anaphylactic shock, cholangiocarcinoma, drug interaction with erythromycin (stomach
upset), edema.
The following adverse drug events may be borne in mind as potential effects of the components of Fioricet with
Codeine. Potential effects of high dosage are listed in the OVERDOSAGE section.
Acetaminophen: allergic reactions, rash, thrombocytopenia, agranulocytosis.
Caffeine: cardiac stimulation, irritability, tremor, dependence, nephrotoxicity, hyperglycemia.
Codeine: nausea, vomiting, drowsiness, lightheadedness, constipation, pruritus.
Several cases of dermatological reactions, including toxic epidermal necrolysis and erythema multiforme, have been reported
for Fioricet® (Butalbital, Acetaminophen, and Caffeine Tablets, USP).
DRUG ABUSE AND DEPENDENCE
Controlled Substance
Reference ID: 3306513
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Fioricet with Codeine is controlled by the Drug Enforcement Administration and is classified under Schedule III.
Abuse and Dependence
Butalbital
Barbiturates may be habit-forming: Tolerance, psychological dependence, and physical dependence may occur especially
following prolonged use of high doses of barbiturates. The average daily dose for the barbiturate addict is usually about 1,500
mg. As tolerance to barbiturates develops, the amount needed to maintain the same level of intoxication increases; tolerance to
a fatal dosage, however, does not increase more than two-fold. As this occurs, the margin between an intoxication dosage and
fatal dosage becomes smaller. The lethal dose of a barbiturate is far less if alcohol is also ingested. Major withdrawal symptoms
(convulsions and delirium) may occur within 16 hours and last up to 5 days after abrupt cessation of these drugs. Intensity of
withdrawal symptoms gradually declines over a period of approximately 15 days. Treatment of barbiturate dependence consists
of cautious and gradual withdrawal of the drug. Barbiturate-dependent patients can be withdrawn by using a number of
different withdrawal regimens. One method involves initiating treatment at the patient’s regular dosage level and gradually
decreasing the daily dosage as tolerated by the patient.
Codeine
Codeine can produce drug dependence of the morphine type and, therefore, has the potential for being abused. Psychological
dependence, physical dependence, and tolerance may develop upon repeated administration and it should be prescribed and
administered with the same degree of caution appropriate to the use of other oral narcotic medications.
OVERDOSAGE
Following an acute overdosage of Fioricet with Codeine, toxicity may result from the barbiturate, the codeine, or the
acetaminophen. Toxicity due to the caffeine is less likely, due to the relatively small amounts in this formulation.
Signs and Symptoms
Toxicity from barbiturate poisoning include drowsiness, confusion, and coma; respiratory depression; hypotension; and
hypovolemic shock. Toxicity from codeine poisoning includes the opioid triad of: pinpoint pupils, depression of respiration,
and loss of consciousness. Convulsions may occur.
In acetaminophen overdosage: dose-dependent, potentially fatal hepatic necrosis is the most serious adverse effect. Renal
tubular necrosis, hypoglycemic coma, and coagulation defects may also occur. Early symptoms following a potentially
hepatotoxic overdose may include: nausea, vomiting, diaphoresis, and general malaise. Clinical and laboratory evidence of
hepatic toxicity may not be apparent until 48-72 hours post-ingestion.
Acute caffeine poisoning may cause insomnia, restlessness, tremor, and delirium, tachycardia, and extrasystoles.
Treatment
A single or multiple drug overdose with Fioricet with Codeine is a potentially lethal polydrug overdose, and consultation with
a regional poison control center is recommended. Immediate treatment includes support of cardiorespiratory function and
measures to reduce drug absorption. Oxygen, intravenous fluids, vasopressors, and other supportive measures should be
employed as indicated. Assisted or controlled ventilation should also be considered. For respiratory depression due to
overdosage or unusual sensitivity to codeine, parenteral naloxone is a specific and effective antagonist.
Gastric decontamination with activated charcoal should be administered just prior to N-acetylcysteine (NAC) to decrease
systemic absorption if acetaminophen ingestion is known or suspected to have occurred within a few hours of presentation.
Serum acetaminophen levels should be obtained immediately if the patient presents 4 hours or more after ingestion to assess
potential risk of hepatotoxicity; acetaminophen levels drawn less than 4 hours post-ingestion may be misleading. To obtain the
best possible outcome, NAC should be administered as soon as possible where impending or evolving liver injury is suspected.
Intravenous NAC may be administered when circumstances preclude oral administration.
Vigorous supportive therapy is required in severe intoxication. Procedures to limit the continuing absorption of the drug must
be readily performed since the hepatic injury is dose dependent and occurs early in the course of intoxication.
DOSAGE AND ADMINISTRATION
One or 2 capsules every 4 hours. Total daily dosage should not exceed 6 capsules.
Reference ID: 3306513
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Extended and repeated use of this product is not recommended because of the potential for physical dependence.
HOW SUPPLIED
Fioricet® with Codeine Capsules
Dark blue, opaque cap with a light grey, opaque body. Cap is imprinted twice with “FIORICET’’ and “CODEINE” in light
blue. Body is imprinted twice with four-head profile “
” in red.
Bottles of 100 are supplied with child-resistant closures. (NDC 52544-958-01)
Store and Dispense
Below 30°C (86°F); tight container.
Rx only
Keep out of reach of children.
For all medical inquiries contact:
WATSON
Medical Communications
Parsippany, NJ 07054
800-272-5525
Distributed By:
Watson Pharma, Inc.
Parsippany, NJ 07054 USA
Revised: May 2013
184178-3
Reference ID: 3306513
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020232s035lbl.pdf', 'application_number': 20232, 'submission_type': 'SUPPL ', 'submission_number': 35}
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Tegretol®
carbamazepine USP
Chewable Tablets of 100 mg - red-speckled, pink
Tablets of 200 mg – pink
Suspension of 100 mg/5 mL
Tegretol®-XR
(carbamazepine extended-release tablets)
100 mg, 200 mg, 400 mg
Rx only
Prescribing Information
WARNING
APLASTIC ANEMIA AND AGRANULOCYTOSIS HAVE BEEN REPORTED IN ASSOCIATION
WITH THE USE OF TEGRETOL. DATA FROM A POPULATION-BASED CASE CONTROL
STUDY DEMONSTRATE THAT THE RISK OF DEVELOPING THESE REACTIONS IS 5-8
TIMES GREATER THAN IN THE GENERAL POPULATION. HOWEVER, THE OVERALL RISK
OF THESE REACTIONS IN THE UNTREATED GENERAL POPULATION IS LOW,
APPROXIMATELY SIX PATIENTS PER ONE MILLION POPULATION PER YEAR FOR
AGRANULOCYTOSIS AND TWO PATIENTS PER ONE MILLION POPULATION PER YEAR
FOR APLASTIC ANEMIA.
ALTHOUGH REPORTS OF TRANSIENT OR PERSISTENT DECREASED PLATELET OR
WHITE BLOOD CELL COUNTS ARE NOT UNCOMMON IN ASSOCIATION WITH THE USE
OF TEGRETOL, DATA ARE NOT AVAILABLE TO ESTIMATE ACCURATELY THEIR
INCIDENCE OR OUTCOME. HOWEVER, THE VAST MAJORITY OF THE CASES OF
LEUKOPENIA HAVE NOT PROGRESSED TO THE MORE SERIOUS CONDITIONS OF
APLASTIC ANEMIA OR AGRANULOCYTOSIS.
BECAUSE OF THE VERY LOW INCIDENCE OF AGRANULOCYTOSIS AND APLASTIC
ANEMIA, THE VAST MAJORITY OF MINOR HEMATOLOGIC CHANGES OBSERVED IN
MONITORING OF PATIENTS ON TEGRETOL ARE UNLIKELY TO SIGNAL THE
OCCURRENCE OF EITHER ABNORMALITY. NONETHELESS, COMPLETE PRETREATMENT
HEMATOLOGICAL TESTING SHOULD BE OBTAINED AS A BASELINE. IF A PATIENT IN
THE COURSE OF TREATMENT EXHIBITS LOW OR DECREASED WHITE BLOOD CELL OR
PLATELET
COUNTS,
THE
PATIENT
SHOULD
BE
MONITORED
CLOSELY.
DISCONTINUATION OF THE DRUG SHOULD BE CONSIDERED IF ANY EVIDENCE OF
SIGNIFICANT BONE MARROW DEPRESSION DEVELOPS.
Before prescribing Tegretol, the physician should be thoroughly familiar with the details of
this prescribing information, particularly regarding use with other drugs, especially those which
accentuate toxicity potential.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 4
DESCRIPTION
Tegretol, carbamazepine USP, is an anticonvulsant and specific analgesic for trigeminal neuralgia,
available for oral administration as chewable tablets of 100 mg, tablets of 200 mg, XR tablets of 100,
200, and 400 mg, and as a suspension of 100 mg/5 mL (teaspoon). Its chemical name is 5H-dibenz[b,f
]azepine-5-carboxamide, and its structural formula is
Carbamazepine USP is a white to off-white powder, practically insoluble in water and soluble in
alcohol and in acetone. Its molecular weight is 236.27.
Inactive Ingredients. Tablets: Colloidal silicon dioxide, D&C Red No. 30 Aluminum Lake
(chewable tablets only), FD&C Red No. 40 (200-mg tablets only), flavoring (chewable tablets only),
gelatin, glycerin, magnesium stearate, sodium starch glycolate (chewable tablets only), starch, stearic
acid, and sucrose (chewable tablets only). Suspension: Citric acid, FD&C Yellow No. 6, flavoring,
polymer, potassium sorbate, propylene glycol, purified water, sorbitol, sucrose, and xanthan gum.
Tegretol-XR tablets: cellulose compounds, dextrates, iron oxides, magnesium stearate, mannitol,
polyethylene glycol, sodium lauryl sulfate, titanium dioxide (200-mg tablets only).
CLINICAL PHARMACOLOGY
In controlled clinical trials, Tegretol has been shown to be effective in the treatment of psychomotor
and grand mal seizures, as well as trigeminal neuralgia.
Mechanism of Action
Tegretol has demonstrated anticonvulsant properties in rats and mice with electrically and chemically
induced seizures. It appears to act by reducing polysynaptic responses and blocking the post-tetanic
potentiation. Tegretol greatly reduces or abolishes pain induced by stimulation of the infraorbital nerve
in cats and rats. It depresses thalamic potential and bulbar and polysynaptic reflexes, including the
linguomandibular reflex in cats. Tegretol is chemically unrelated to other anticonvulsants or other
drugs used to control the pain of trigeminal neuralgia. The mechanism of action remains unknown.
The principal metabolite of Tegretol, carbamazepine-10,11-epoxide, has anticonvulsant activity as
demonstrated in several in vivo animal models of seizures. Though clinical activity for the epoxide
has been postulated, the significance of its activity with respect to the safety and efficacy of Tegretol
has not been established.
Pharmacokinetics
In clinical studies, Tegretol suspension, conventional tablets, and XR tablets delivered equivalent
amounts of drug to the systemic circulation. However, the suspension was absorbed somewhat faster,
and the XR tablet slightly slower, than the conventional tablet. The bioavailability of the XR tablet was
89% compared to suspension. Following a b.i.d. dosage regimen, the suspension provides higher peak
levels and lower trough levels than those obtained from the conventional tablet for the same dosage
regimen. On the other hand, following a t.i.d. dosage regimen, Tegretol suspension affords steady-state
plasma levels comparable to Tegretol tablets given b.i.d. when administered at the same total mg daily
dose. Following a b.i.d. dosage regimen, Tegretol-XR tablets afford steady-state plasma levels
This label may not be the latest approved by FDA.
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Page 5
comparable to conventional Tegretol tablets given q.i.d., when administered at the same total mg daily
dose. Tegretol in blood is 76% bound to plasma proteins. Plasma levels of Tegretol are variable and
may range from 0.5-25 µg/mL, with no apparent relationship to the daily intake of the drug. Usual
adult therapeutic levels are between 4 and 12 µg/mL. In polytherapy, the concentration of Tegretol
and concomitant drugs may be increased or decreased during therapy, and drug effects may be altered
(see PRECAUTIONS, Drug Interactions). Following chronic oral administration of suspension,
plasma levels peak at approximately 1.5 hours compared to 4-5 hours after administration of
conventional Tegretol tablets, and 3-12 hours after administration of Tegretol-XR tablets. The
CSF/serum ratio is 0.22, similar to the 24% unbound Tegretol in serum. Because Tegretol induces its
own metabolism, the half-life is also variable. Autoinduction is completed after 3-5 weeks of a fixed
dosing regimen. Initial half-life values range from 25-65 hours, decreasing to 12-17 hours on repeated
doses. Tegretol is metabolized in the liver. Cytochrome P450 3A4 was identified as the major isoform
responsible for the formation of carbamazepine-10,11-epoxide from Tegretol. After oral administration
of 14C-carbamazepine, 72% of the administered radioactivity was found in the urine and 28% in the
feces. This urinary radioactivity was composed largely of hydroxylated and conjugated metabolites,
with only 3% of unchanged Tegretol.
The pharmacokinetic parameters of Tegretol disposition are similar in children and in adults.
However, there is a poor correlation between plasma concentrations of carbamazepine and Tegretol
dose in children. Carbamazepine is more rapidly metabolized to carbamazepine-10,11-epoxide (a
metabolite shown to be equipotent to carbamazepine as an anticonvulsant in animal screens) in the
younger age groups than in adults. In children below the age of 15, there is an inverse relationship
between CBZ-E/CBZ ratio and increasing age (in one report from 0.44 in children below the age of 1
year to 0.18 in children between 10-15 years of age).
The effects of race and gender on carbamazepine pharmacokinetics have not been systematically
evaluated.
INDICATIONS AND USAGE
Epilepsy
Tegretol is indicated for use as an anticonvulsant drug. Evidence supporting efficacy of Tegretol as an
anticonvulsant was derived from active drug-controlled studies that enrolled patients with the
following seizure types:
1. Partial seizures with complex symptomatology (psychomotor, temporal lobe). Patients with these
seizures appear to show greater improvement than those with other types.
2. Generalized tonic-clonic seizures (grand mal).
3. Mixed seizure patterns which include the above, or other partial or generalized seizures. Absence
seizures (petit mal) do not appear to be controlled by Tegretol (see PRECAUTIONS, General).
Trigeminal Neuralgia
Tegretol is indicated in the treatment of the pain associated with true trigeminal neuralgia.
Beneficial results have also been reported in glossopharyngeal neuralgia.
This drug is not a simple analgesic and should not be used for the relief of trivial aches or pains.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 6
CONTRAINDICATIONS
Tegretol should not be used in patients with a history of previous bone marrow depression,
hypersensitivity to the drug, or known sensitivity to any of the tricyclic compounds, such as
amitriptyline, desipramine, imipramine, protriptyline, nortriptyline, etc. Likewise, on theoretical
grounds its use with monoamine oxidase inhibitors is not recommended. Before administration of
Tegretol, MAO inhibitors should be discontinued for a minimum of 14 days, or longer if the clinical
situation permits.
Co-administration of carbamazepine and nefazodone may result in insufficient plasma concentrations
of nefazodone and its active metabolite to achieve a therapeutic effect. Co-administration of
carbamazepine with nefazodone is contraindicated.
WARNINGS
Patients with a history of adverse hematologic reaction to any drug may be particularly at risk.
Severe dermatologic reactions, including toxic epidermal necrolysis (Lyell’s syndrome) and
Stevens-Johnson syndrome, have been reported with Tegretol. These reactions have been extremely
rare. However, a few fatalities have been reported.
Tegretol has shown mild anticholinergic activity; therefore, patients with increased intraocular
pressure should be closely observed during therapy.
Because of the relationship of the drug to other tricyclic compounds, the possibility of activation of
a latent psychosis and, in elderly patients, of confusion or agitation should be borne in mind.
The use of Tegretol should be avoided in patients with a history of hepatic porphyria (e.g., acute
intermittent porphyria, variegate porphyria, porphyria cutanea tarda). Acute attacks have been reported
in such patients receiving Tegretol therapy. Carbamazepine administration has also been demonstrated
to increase porphyrin precursors in rodents, a presumed mechanism for the induction of acute attacks
of porphyria.
As with all antiepileptic drugs, Tegretol should be withdrawn gradually to minimize the potential
of increased seizure frequency.
Usage in Pregnancy
Carbamazepine can cause fetal harm when administered to a pregnant woman.
Epidemiological data suggest that there may be an association between the use of carbamazepine
during pregnancy and congenital malformations, including spina bifida. There have also been reports
that associate carbamazepine with developmental disorders and congenital anomalies (e.g., craniofacial
defects, cardiovascular malformations and anomalies involving various body systems). Developmental
delays based on neurobehavioral assessments have been reported. In treating or counseling women of
childbearing potential, the prescribing physician will wish to weigh the benefits of therapy against the
risks. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug,
the patient should be apprised of the potential hazard to the fetus.
Retrospective case reviews suggest that, compared with monotherapy, there may be a higher
prevalence of teratogenic effects associated with the use of anticonvulsants in combination therapy.
Therefore, if therapy is to be continued, monotherapy may be preferable for pregnant women.
In humans, transplacental passage of carbamazepine is rapid (30-60 minutes), and the drug is
accumulated in the fetal tissues, with higher levels found in liver and kidney than in brain and lung.
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Carbamazepine has been shown to have adverse effects in reproduction studies in rats when given
orally in dosages 10-25 times the maximum human daily dosage (MHDD) of 1200 mg on a mg/kg
basis or 1.5-4 times the MHDD on a mg/m2 basis. In rat teratology studies, 2 of 135 offspring showed
kinked ribs at 250 mg/kg and 4 of 119 offspring at 650 mg/kg showed other anomalies (cleft palate, 1;
talipes, 1; anophthalmos, 2). In reproduction studies in rats, nursing offspring demonstrated a lack of
weight gain and an unkempt appearance at a maternal dosage level of 200 mg/kg.
Antiepileptic drugs should not be discontinued abruptly in patients in whom the drug is
administered to prevent major seizures because of the strong possibility of precipitating status
epilepticus with attendant hypoxia and threat to life. In individual cases where the severity and
frequency of the seizure disorder are such that removal of medication does not pose a serious threat to
the patient, discontinuation of the drug may be considered prior to and during pregnancy, although it
cannot be said with any confidence that even minor seizures do not pose some hazard to the
developing embryo or fetus.
Tests to detect defects using currently accepted procedures should be considered a part of routine
prenatal care in childbearing women receiving carbamazepine.
There have been a few cases of neonatal seizures and/or respiratory depression associated with
maternal Tegretol and other concomitant anticonvulsant drug use. A few cases of neonatal vomiting,
diarrhea, and/or decreased feeding have also been reported in association with maternal Tegretol use.
These symptoms may represent a neonatal withdrawal syndrome.
PRECAUTIONS
General
Before initiating therapy, a detailed history and physical examination should be made.
Tegretol should be used with caution in patients with a mixed seizure disorder that includes
atypical absence seizures, since in these patients Tegretol has been associated with increased frequency
of generalized convulsions (see INDICATIONS AND USAGE).
Therapy should be prescribed only after critical benefit-to-risk appraisal in patients with a history
of cardiac conduction disturbance, including second and third degree AV heart block; cardiac, hepatic,
or renal damage; adverse hematologic or hypersensitivity reaction to other drugs, including reactions to
other anticonvulsants; or interrupted courses of therapy with Tegretol.
AV heart block, including second and third degree block, have been reported following, Tegretol
treatment. This occurred generally, but not solely, in patients with underling EKG abnormalities or risk
factors for conduction disturbances.
Hepatic effects, ranging from slight elevations in liver enzymes to rare cases of hepatic failure have
been reported (see ADVERSE REACTIONS and PRECAUTIONS, Laboratory Tests). In some cases,
hepatic effects may progress despite discontinuation of the drug.
Multi-organ hypersensitivity reactions occurring days to weeks or months after initiating treatment
have been reported in rare cases (see ADVERSE REACTIONS, Other and PRECAUTIONS,
Information for Patients).
Discontinuation of carbamazepine should be considered if any evidence of hypersensitivity
develops.
Hypersensitivity reactions to carbamazepine have been reported in patients who previously
experienced this reaction to anticonvulsants including phenytoin and phenobarbital. A history of
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Page 8
hypersensitivity reactions should be obtained for a patient and the immediate family members. If
positive, caution should be used in prescribing carbamazepine.
Since a given dose of Tegretol suspension will produce higher peak levels than the same dose
given as the tablet, it is recommended that patients given the suspension be started on lower doses and
increased slowly to avoid unwanted side effects (see DOSAGE AND ADMINISTRATION).
Information for Patients
Patients should be made aware of the early toxic signs and symptoms of a potential hematologic
problem, as well as dermatologic, hypersensitivity or hepatic reactions. These symptoms may include,
but are not limited to, fever, sore throat, rash, ulcers in the mouth, easy bruising, lymphadenopathy and
petechial or purpuric hemorrhage, and in the case of liver reactions, anorexia, nausea/vomiting, or
jaundice. The patient should be advised that, because these signs and symptoms may signal a serious
reaction, that they must report any occurrence immediately to a physician. In addition, the patient
should be advised that these signs and symptoms should be reported even if mild or when occurring
after extended use.
Tegretol may interact with some drugs. Therefore, patients should be advised to report to their doctors
the use of any other prescription or non-prescription medications or herbal products.
Caution should be exercised if alcohol is taken in combination with Tegretol therapy, due to a possible
additive sedative effect.
Since dizziness and drowsiness may occur, patients should be cautioned about the hazards of
operating machinery or automobiles or engaging in other potentially dangerous tasks.
Laboratory Tests
Complete pretreatment blood counts, including platelets and possibly reticulocytes and serum iron,
should be obtained as a baseline. If a patient in the course of treatment exhibits low or decreased white
blood cell or platelet counts, the patient should be monitored closely. Discontinuation of the drug
should be considered if any evidence of significant bone marrow depression develops.
Baseline and periodic evaluations of liver function, particularly in patients with a history of liver
disease, must be performed during treatment with this drug since liver damage may occur (see
PRECAUTIONS, General and ADVERSE REACTIONS). Carbamazepine should be discontinued,
based on clinical judgment, if indicated by newly occurring or worsening clinical or laboratory
evidence of liver dysfunction or hepatic damage, or in the case of active liver disease.
Baseline and periodic eye examinations, including slit-lamp, funduscopy, and tonometry, are
recommended since many phenothiazines and related drugs have been shown to cause eye changes.
Baseline and periodic complete urinalysis and BUN determinations are recommended for patients
treated with this agent because of observed renal dysfunction.
Monitoring of blood levels (see CLINICAL PHARMACOLOGY) has increased the efficacy and
safety of anticonvulsants. This monitoring may be particularly useful in cases of dramatic increase in
seizure frequency and for verification of compliance. In addition, measurement of drug serum levels
may aid in determining the cause of toxicity when more than one medication is being used.
Thyroid function tests have been reported to show decreased values with Tegretol administered
alone.
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Hyponatremia has been reported in association with Tegretol use, either alone or in combination
with other drugs.
Interference with some pregnancy tests has been reported.
Drug Interactions
There has been a report of a patient who passed an orange rubbery precipitate in his stool the day after
ingesting Tegretol suspension immediately followed by Thorazine® solution. Subsequent testing has
shown that mixing Tegretol suspension and chlorpromazine solution (both generic and brand name) as
well as Tegretol suspension and liquid Mellaril® resulted in the occurrence of this precipitate. Because
the extent to which this occurs with other liquid medications is not known, Tegretol suspension should
not be administered simultaneously with other liquid medicinal agents or diluents. (see Dosage and
Administration).
Clinically meaningful drug interactions have occurred with concomitant medications and include,
but are not limited to, the following:
Agents That May Affect Tegretol Plasma Levels
CYP 3A4 inhibitors inhibit Tegretol metabolism and can thus increase plasma carbamazepine levels.
Drugs that have been shown, or would be expected, to increase plasma carbamazepine levels include
cimetidine, danazol, diltiazem, macrolides, erythromycin, troleandomycin, clarithromycin,
fluoxetine, fluvoxamine, nefazodone, loratadine, terfenadine, isoniazid, niacinamide,
nicotinamide,
propoxyphene,
azoles
(e.g.,
ketaconazole,
itraconazole,
fluconazole),
acetazolamide, verapamil, grapefruit juice, protease inhibitors, valproate.*
CYP 3A4 inducers can increase the rate of Tegretol metabolism. Drugs that have been shown, or that
would be expected, to decrease plasma carbamazepine levels include
cisplatin, doxorubicin HCl, felbamate,† rifampin, phenobarbital, phenytoin, primidone,
methsuximide, theophylline.
When carbamazepine is given with drugs that can increase or decrease carbamazepine levels, close
monitoring of carbamazepine levels is indicated and dosage adjustment may be required.
*increased levels of the active 10,11-epoxide
†decreased levels of carbamazepine and increased levels of the 10,11-epoxide
Effect of Tegretol on Plasma Levels of Concomitant Agents
Increased levels: clomipramine HCl, phenytoin, primidone
Tegretol induces hepatic CYP activity. Tegretol causes, or would be expected to cause, decreased
levels of the following:
acetaminophen, alprazolam, dihydropyridine calcium channel blockers (e.g., felodipine),
cyclosporine, corticosteroids (e.g., prednisolone, dexamethasone), clonazepam, clozapine,
dicumarol, doxycycline, ethosuximide, haloperidol, itraconazole, lamotrigine, levothyroxine,
methadone, methsuximide, midazolam, olanzapine, oral and other hormonal contraceptives,
oxcarbazepine, phensuximide, phenytoin, praziquantel, protease inhibitors, risperidone,
theophylline, tiagabine, topiramate, tramadol, tricyclic antidepressants (e.g., imipramine,
amitriptyline, nortriptyline), valproate, warfarin,ziprasidone, zonisamide.
In concomitant use with Tegretol, dosage adjustment of the above agents may be necessary.
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Co-administration of carbamazepine with nefazodone results in insufficient plasma concentrations of
nefazodone and its active metabolite to achieve a therapeutic effect. Co-administration of
carbamazepine with nefazodone is contraindicated. (See CONTRAINDICATIONS).
Concomitant administration of carbamazepine and lithium may increase the risk of neurotoxic side
effects.
Alterations of thyroid function have been reported in combination therapy with other
anticonvulsant medications.
Concomitant use of Tegretol with hormonal contraceptive products (e.g., oral, and levonorgestrel
subdermal implant contraceptives) may render the contraceptives less effective because the plasma
concentrations of the hormones may be decreased. Breakthrough bleeding and unintended pregnancies
have been reported. Alternative or back-up methods of contraception should be considered.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carbamazepine, when administered to Sprague-Dawley rats for two years in the diet at doses of 25, 75,
and 250 mg/kg/day, resulted in a dose-related increase in the incidence of hepatocellular tumors in
females and of benign interstitial cell adenomas in the testes of males.
Carbamazepine must, therefore, be considered to be carcinogenic in Sprague-Dawley rats.
Bacterial and mammalian mutagenicity studies using carbamazepine produced negative results. The
significance of these findings relative to the use of carbamazepine in humans is, at present, unknown.
Usage in Pregnancy
Pregnancy Category D (see WARNINGS).
Labor and Delivery
The effect of Tegretol on human labor and delivery is unknown.
Nursing Mothers
Tegretol and its epoxide metabolite are transferred to breast milk. The ratio of the concentration in
breast milk to that in maternal plasma is about 0.4 for Tegretol and about 0.5 for the epoxide. The
estimated doses given to the newborn during breast feeding are in the range of 2-5 mg daily for
Tegretol and 1-2 mg daily for the epoxide.
Because of the potential for serious adverse reactions in nursing infants from carbamazepine, a
decision should be made whether to discontinue nursing or to discontinue the drug, taking into account
the importance of the drug to the mother.
Pediatric Use
Substantial evidence of Tegretol’s effectiveness for use in the management of children with epilepsy
(see Indications for specific seizure types) is derived from clinical investigations performed in adults
and from studies in several in vitro systems which support the conclusion that (1) the pathogenetic
mechanisms underlying seizure propagation are essentially identical in adults and children, and (2) the
mechanism of action of carbamazepine in treating seizures is essentially identical in adults and
children.
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Taken as a whole, this information supports a conclusion that the generally accepted therapeutic
range of total carbamazepine in plasma (i.e., 4-12 mcg/mL) is the same in children and adults.
The evidence assembled was primarily obtained from short-term use of carbamazepine. The safety
of carbamazepine in children has been systematically studied up to 6 months. No longer-term data
from clinical trials is available.
Geriatric Use
No systematic studies in geriatric patients have been conducted.
ADVERSE REACTIONS
If adverse reactions are of such severity that the drug must be discontinued, the physician must be
aware that abrupt discontinuation of any anticonvulsant drug in a responsive epileptic patient may lead
to seizures or even status epilepticus with its life-threatening hazards.
The most severe adverse reactions have been observed in the hemopoietic system (see boxed
WARNING), the skin, liver, and the cardiovascular system.
The most frequently observed adverse reactions, particularly during the initial phases of therapy,
are dizziness, drowsiness, unsteadiness, nausea, and vomiting. To minimize the possibility of such
reactions, therapy should be initiated at the low dosage recommended.
The following additional adverse reactions have been reported:
Hemopoietic System: Aplastic anemia, agranulocytosis, pancytopenia, bone marrow depression,
thrombocytopenia, leukopenia, leukocytosis, eosinophilia, acute intermittent porphyria.
Skin: Pruritic and erythematous rashes, urticaria, toxic epidermal necrolysis (Lyell’s syndrome) (see
WARNINGS), Stevens-Johnson syndrome (see WARNINGS), photosensitivity reactions, alterations
in skin pigmentation, exfoliative dermatitis, erythema multiforme and nodosum, purpura, aggravation
of disseminated lupus erythematosus, alopecia, and diaphoresis. In certain cases, discontinuation of
therapy may be necessary. Isolated cases of hirsutism have been reported, but a causal relationship is
not clear.
Cardiovascular System: Congestive heart failure, edema, aggravation of hypertension, hypotension,
syncope and collapse, aggravation of coronary artery disease, arrhythmias and AV block,
thrombophlebitis, thromboembolism, and adenopathy or lymphadenopathy.
Some of these cardiovascular complications have resulted in fatalities. Myocardial infarction has
been associated with other tricyclic compounds.
Liver: Abnormalities in liver function tests, cholestatic and hepatocellular jaundice, hepatitis; very
rare cases of hepatic failure.
Pancreatic: Pancreatitis.
Respiratory System: Pulmonary hypersensitivity characterized by fever, dyspnea, pneumonitis, or
pneumonia.
Genitourinary System: Urinary frequency, acute urinary retention, oliguria with elevated blood
pressure, azotemia, renal failure, and impotence. Albuminuria, glycosuria, elevated BUN, and
microscopic deposits in the urine have also been reported.
Testicular atrophy occurred in rats receiving Tegretol orally from 4-52 weeks at dosage levels of
50-400 mg/kg/day. Additionally, rats receiving Tegretol in the diet for 2 years at dosage levels of 25,
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75, and 250 mg/kg/day had a dose-related incidence of testicular atrophy and aspermatogenesis. In
dogs, it produced a brownish discoloration, presumably a metabolite, in the urinary bladder at dosage
levels of 50 mg/kg and higher. Relevance of these findings to humans is unknown.
Nervous System: Dizziness, drowsiness, disturbances of coordination, confusion, headache, fatigue,
blurred vision, visual hallucinations, transient diplopia, oculomotor disturbances, nystagmus, speech
disturbances, abnormal involuntary movements, peripheral neuritis and paresthesias, depression with
agitation, talkativeness, tinnitus, and hyperacusis.
There have been reports of associated paralysis and other symptoms of cerebral arterial
insufficiency, but the exact relationship of these reactions to the drug has not been established.
Isolated cases of neuroleptic malignant syndrome have been reported with concomitant use of
psychotropic drugs.
Digestive System: Nausea, vomiting, gastric distress and abdominal pain, diarrhea, constipation,
anorexia, and dryness of the mouth and pharynx, including glossitis and stomatitis.
Eyes: Scattered punctate cortical lens opacities, as well as conjunctivitis, have been reported. Although
a direct causal relationship has not been established, many phenothiazines and related drugs have been
shown to cause eye changes.
Musculoskeletal System: Aching joints and muscles, and leg cramps.
Metabolism: Fever and chills. Inappropriate antidiuretic hormone (ADH) secretion syndrome has
been reported. Cases of frank water intoxication, with decreased serum sodium (hyponatremia) and
confusion, have been reported in association with Tegretol use (see PRECAUTIONS, Laboratory
Tests). Decreased levels of plasma calcium have been reported.
Other: Multi-organ hypersensitivity reactions occurring days to weeks or months after initiating
treatment have been reported in rare cases. Signs or symptoms may include, but are not limited to
fever, skin rashes, vasculitis, lymphadenopathy, disorders mimicking lymphoma, arthralgia,
leukopenia, eosinophilia, hepato-splenomegaly and abnormal liver function tests. These signs and
symptoms may occur in various combinations and not necessarily concurrently. Signs and symptoms
may initially be mild. Various organs, including but not limited to, liver, skin, immune system, lungs,
kidneys, pancreas, myocardium, and colon may be affected (see PRECAUTIONS, General and
PRECAUTIONS, Information for Patients).
Isolated cases of a lupus erythematosus-like syndrome have been reported. There have been
occasional reports of elevated levels of cholesterol, HDL cholesterol, and triglycerides in patients
taking anticonvulsants.
A case of aseptic meningitis, accompanied by myoclonus and peripheral eosinophilia, has been
reported in a patient taking carbamazepine in combination with other medications. The patient was
successfully dechallenged, and the meningitis reappeared upon rechallenge with carbamazepine.
DRUG ABUSE AND DEPENDENCE
No evidence of abuse potential has been associated with Tegretol, nor is there evidence of
psychological or physical dependence in humans.
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OVERDOSAGE
Acute Toxicity
Lowest known lethal dose: adults, 3.2 g (a 24-year-old woman died of a cardiac arrest and a 24-year-
old man died of pneumonia and hypoxic encephalopathy); children, 4 g (a 14-year-old girl died of a
cardiac arrest), 1.6 g (a 3-year-old girl died of aspiration pneumonia).
Oral LD50 in animals (mg/kg): mice, 1100-3750; rats, 3850-4025; rabbits, 1500-2680; guinea pigs,
920.
Signs and Symptoms
The first signs and symptoms appear after 1-3 hours. Neuromuscular disturbances are the most
prominent. Cardiovascular disorders are generally milder, and severe cardiac complications occur only
when very high doses (> 60 g) have been ingested.
Respiration: Irregular breathing, respiratory depression.
Cardiovascular System: Tachycardia, hypotension or hypertension, shock, conduction disorders.
Nervous System and Muscles: Impairment of consciousness ranging in severity to deep coma.
Convulsions, especially in small children. Motor restlessness, muscular twitching, tremor, athetoid
movements, opisthotonos, ataxia, drowsiness, dizziness, mydriasis, nystagmus, adiadochokinesia,
ballism, psychomotor disturbances, dysmetria. Initial hyperreflexia, followed by hyporeflexia.
Gastrointestinal Tract: Nausea, vomiting.
Kidneys and Bladder: Anuria or oliguria, urinary retention.
Laboratory Findings: Isolated instances of overdosage have included leukocytosis, reduced leukocyte
count, glycosuria, and acetonuria. EEG may show dysrhythmias.
Combined Poisoning: When alcohol, tricyclic antidepressants, barbiturates, or hydantoins are taken at
the same time, the signs and symptoms of acute poisoning with Tegretol may be aggravated or
modified.
Treatment
The prognosis in cases of severe poisoning is critically dependent upon prompt elimination of the drug,
which may be achieved by inducing vomiting, irrigating the stomach, and by taking appropriate steps
to diminish absorption. If these measures cannot be implemented without risk on the spot, the patient
should be transferred at once to a hospital, while ensuring that vital functions are safeguarded. There is
no specific antidote.
Elimination of the Drug: Induction of vomiting.
Gastric lavage. Even when more than 4 hours have elapsed following ingestion of the drug, the
stomach should be repeatedly irrigated, especially if the patient has also consumed alcohol.
Measures to Reduce Absorption: Activated charcoal, laxatives.
Measures to Accelerate Elimination: Forced diuresis.
Dialysis is indicated only in severe poisoning associated with renal failure. Replacement
transfusion is indicated in severe poisoning in small children.
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Respiratory Depression: Keep the airways free; resort, if necessary, to endotracheal intubation,
artificial respiration, and administration of oxygen.
Hypotension, Shock: Keep the patient’s legs raised and administer a plasma expander. If blood
pressure fails to rise despite measures taken to increase plasma volume, use of vasoactive substances
should be considered.
Convulsions: Diazepam or barbiturates.
Warning: Diazepam or barbiturates may aggravate respiratory depression (especially in children),
hypotension, and coma. However, barbiturates should not be used if drugs that inhibit monoamine
oxidase have also been taken by the patient either in overdosage or in recent therapy (within 1 week).
Surveillance: Respiration, cardiac function (ECG monitoring), blood pressure, body temperature,
pupillary reflexes, and kidney and bladder function should be monitored for several days.
Treatment of Blood Count Abnormalities: If evidence of significant bone marrow depression
develops, the following recommendations are suggested: (1) stop the drug, (2) perform daily CBC,
platelet, and reticulocyte counts, (3) do a bone marrow aspiration and trephine biopsy immediately and
repeat with sufficient frequency to monitor recovery.
Special periodic studies might be helpful as follows: (1) white cell and platelet antibodies, (2)
59Fe-ferrokinetic studies, (3) peripheral blood cell typing, (4) cytogenetic studies on marrow and
peripheral blood, (5) bone marrow culture studies for colony-forming units, (6) hemoglobin
electrophoresis for A2 and F hemoglobin, and (7) serum folic acid and B12 levels.
A fully developed aplastic anemia will require appropriate, intensive monitoring and therapy, for
which specialized consultation should be sought.
DOSAGE AND ADMINISTRATION (SEE TABLE BELOW)
Tegretol suspension in combination with liquid chlorpromazine or thioridazine results in
precipitate formation, and, in the case of chlorpromazine, there has been a report of a patient passing
an orange rubbery precipitate in the stool following coadministration of the two drugs. (See Drug
Interactions). Because the extent to which this occurs with other liquid medications is not known,
Tegretol suspension should not be administered simultaneously with other liquid medications or
diluents.
Monitoring of blood levels has increased the efficacy and safety of anticonvulsants (see
PRECAUTIONS, Laboratory Tests). Dosage should be adjusted to the needs of the individual patient.
A low initial daily dosage with a gradual increase is advised. As soon as adequate control is achieved,
the dosage may be reduced very gradually to the minimum effective level. Medication should be taken
with meals.
Since a given dose of Tegretol suspension will produce higher peak levels than the same dose
given as the tablet, it is recommended to start with low doses (children 6-12 years: 1/2 teaspoon q.i.d.)
and to increase slowly to avoid unwanted side effects.
Conversion of patients from oral Tegretol tablets to Tegretol suspension: Patients should be
converted by administering the same number of mg per day in smaller, more frequent doses (i.e., b.i.d.
tablets to t.i.d. suspension).
Tegretol-XR is an extended-release formulation for twice-a-day administration. When converting
patients from Tegretol conventional tablets to Tegretol-XR, the same total daily mg dose of
Tegretol-XR should be administered. Tegretol-XR tablets must be swallowed whole and never
crushed or chewed. Tegretol-XR tablets should be inspected for chips or cracks. Damaged tablets, or
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Page 15
tablets without a release portal, should not be consumed. Tegretol-XR tablet coating is not absorbed
and is excreted in the feces; these coatings may be noticeable in the stool.
Epilepsy (see INDICATIONS AND USAGE)
Adults and children over 12 years of age - Initial: Either 200 mg b.i.d. for tablets and XR tablets, or
1 teaspoon q.i.d. for suspension (400 mg/day). Increase at weekly intervals by adding up to 200
mg/day using a b.i.d. regimen of Tegretol-XR or a t.i.d. or q.i.d. regimen of the other formulations until
the optimal response is obtained. Dosage generally should not exceed 1000 mg daily in children 12-15
years of age, and 1200 mg daily in patients above 15 years of age. Doses up to 1600 mg daily have
been used in adults in rare instances. Maintenance: Adjust dosage to the minimum effective level,
usually 800-1200 mg daily.
Children 6-12 years of age - Initial: Either 100 mg b.i.d. for tablets or XR tablets, or 1/2 teaspoon
q.i.d. for suspension (200 mg/day). Increase at weekly intervals by adding up to 100 mg/day using a
b.i.d. regimen of Tegretol-XR or a t.i.d. or q.i.d. regimen of the other formulations until the optimal
response is obtained. Dosage generally should not exceed 1000 mg daily. Maintenance: Adjust
dosage to the minimum effective level, usually 400-800 mg daily.
Children under 6 years of age - Initial: 10-20 mg/kg/day b.i.d. or t.i.d. as tablets, or q.i.d. as
suspension. Increase weekly to achieve optimal clinical response administered t.i.d. or q.i.d.
Maintenance: Ordinarily, optimal clinical response is achieved at daily doses below 35 mg/kg. If
satisfactory clinical response has not been achieved, plasma levels should be measured to determine
whether or not they are in the therapeutic range. No recommendation regarding the safety of
carbamazepine for use at doses above 35 mg/kg/24 hours can be made.
Combination Therapy: Tegretol may be used alone or with other anticonvulsants. When added to
existing anticonvulsant therapy, the drug should be added gradually while the other anticonvulsants are
maintained or gradually decreased, except phenytoin, which may have to be increased (see
PRECAUTIONS, Drug Interactions, and Pregnancy Category D).
Trigeminal Neuralgia (see INDICATIONS AND USAGE)
Initial: On the first day, either 100 mg b.i.d. for tablets or XR tablets, or 1/2 teaspoon q.i.d. for
suspension, for a total daily dose of 200 mg. This daily dose may be increased by up to 200 mg/day
using increments of 100 mg every 12 hours for tablets or XR tablets, or 50 mg (1/2 teaspoon) q.i.d. for
suspension, only as needed to achieve freedom from pain. Do not exceed 1200 mg daily.
Maintenance: Control of pain can be maintained in most patients with 400-800 mg daily. However,
some patients may be maintained on as little as 200 mg daily, while others may require as much as
1200 mg daily. At least once every 3 months throughout the treatment period, attempts should be made
to reduce the dose to the minimum effective level or even to discontinue the drug.
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Dosage Information
Initial Dose
Subsequent Dose
Maximum Daily Dose
Indication
Tablet*
XR
†
Suspension
Tablet*
XR
†
Suspension
Tablet*
XR
†
Suspension
Epilepsy
Under 6 yr
10-20 mg/kg/day
b.i.d. or t.i.d.
10-20 mg/kg/day
q.i.d.
Increase
weekly to
achieve
optimal clinical
response,
t.i.d. or q.i.d.
Increase weekly
to achieve
optimal clinical
response, t.i.d. or
q.i.d.
35 mg/kg/24 hr
(see Dosage and
Administration
section above)
35 mg/kg/24 hr
(see Dosage and
Administration
section above)
6-12 yr
100 mg b.i.d.
(200 mg/day)
100 mg b.i.d.
(200 mg/day)
½ tsp q.i.d.
(200 mg/day)
Add up to 100
mg/day at
weekly
intervals, t.i.d.
or q.i.d.
Add
100 mg/day
at weekly
intervals,
b.i.d.
Add up to 1 tsp
(100 mg)/day at
weekly intervals,
t.i.d. or q.i.d.
1000 mg/24 hr
Over 12 yr
200 mg b.i.d.
(400 mg/day)
200 mg b.i.d.
(400 mg/day)
1 tsp q.i.d.
(400 mg/day)
Add up to 200
mg/day at
weekly
intervals, t.i.d.
or q.i.d.
Add up to
200 mg/day
at weekly
intervals,
b.i.d.
Add up to 2 tsp
(200 mg)/day at
weekly intervals,
t.i.d. or q.i.d.
1000 mg/24 hr (12-15 yr)
1200 mg/24 hr (>15 yr)
1600 mg/24 hr (adults, in rare instances)
Trigeminal
Neuralgia
100 mg b.i.d.
(200 mg/day)
100 mg b.i.d.
(200 mg/day)
½ tsp q.i.d.
(200 mg/day)
Add up to 200
mg/day in
increments of
100 mg every
12 hr
Add up to
200 mg/day
in increments
of 100 mg
every 12 hr
Add up to 2 tsp
(200 mg)/day
in increments of
50 mg
(½ tsp) q.i.d.
1200 mg/24 hr
*Tablet = Chewable or conventional tablets
†XR = Tegretol
®-XR extended-release tablets
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
-------- ------- -- --------------------------------- ------------- -------
------ -- ------ --- -------- -
----- - ---- -- ---- - ---- --- --- -- - ---
----- - - --- ------------- ---
HOW SUPPLIED
Chewable Tablets 100 mg - round, red-speckled, pink, single-scored (imprinted Tegretol on one side
and 52 twice on the scored side)
Bottles of 100.........................................................................................NDC 0083-0052-30
Unit Dose (blister pack)
Box of 100 (strips of 10)..................................................................NDC 0083-0052-32
Do not store above 30°C (86°F). Protect from light and moisture.
Dispense in tight, light-resistant container (USP).
Meets USP Dissolution Test 1.
Tablets 200 mg - capsule-shaped, pink, single-scored (imprinted Tegretol on one side and 27 twice on
the partially scored side)
Bottles of 100.........................................................................................NDC 0083-0027-30
Bottles of 1000.......................................................................................NDC 0083-0027-40
Unit Dose (blister pack)
Box of 100 (strips of 10)..................................................................NDC 0083-0027-32
Do not store above 30°C (86°F). Protect from moisture. Dispense in tight container (USP).
Meets USP Dissolution Test 2.
XR Tablets 100 mg - round, yellow, coated (imprinted T on one side and 100 mg on the other), release
portal on one side
Bottles of 100.........................................................................................NDC 0083-0061-30
XR Tablets 200 mg - round, pink, coated (imprinted T on one side and 200 mg on the other), release
portal on one side
Bottles of 100.........................................................................................NDC 0083-0062-30
XR Tablets 400 mg - round, brown, coated (imprinted T on one side and 400 mg on the other), release
portal on one side
Bottles of 100.........................................................................................NDC 0083-0060-30
Store at controlled room temperature 15°C-30°C (59°F-86°F). Protect from moisture. Dispense in
tight, container (USP).
Suspension 100 mg/5 mL (teaspoon) - yellow-orange, citrus-vanilla flavored
Bottles of 450 mL..................................................................................NDC 0083-0019-76
Shake well before using.
Do not store above 30°C (86°F). Dispense in tight, light resistant container (USP).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 16-608/SLR-096; NDA 18-281/S-044;
NDA18-927/S-035; NDA 20-234/S-025
Page 2
Tegretol Chewable Tablets Manufactured by:
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936
Tegretol Tablets Manufactured by:
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936
Tegretol Suspension Manufactured by:
Patheon Inc.
Whitby Operations
Whitby Ontario, Canada
L1N 5Z5
Tegretol XR Tablets Manufactured by:
Novartis Pharma GmbH
D-79664 Wehr, Germany
Distributed by:
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936
REV: July 2007
© 2007Novartis
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
---------------------------------------------------------------------------------------------------------------------
This is a representation of an electronic record that was signed electronically and
this page is the manifestation of the electronic signature.
---------------------------------------------------------------------------------------------------------------------
/s/
---------------------
Russell Katz
8/16/2007 05:01:49 PM
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:47:04.741016
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/016608s096,018281s044,018927s035,020234s025REVISED_LABEL.pdf', 'application_number': 20234, 'submission_type': 'SUPPL ', 'submission_number': 25}
|
12,338
|
NDA 016608/S-097
NDA 018281/S-045
NDA 018927/S-038
NDA 020234/S-026
FDA Approved Labeling Text dated 8/28/2015
Page 1
Tegretol®
carbamazepine USP
Chewable Tablets of 100 mg - red-speckled, pink
Tablets of 200 mg – pink
Suspension of 100 mg/5 mL
Tegretol®-XR
(carbamazepine extended-release tablets)
100 mg, 200 mg, 400 mg
Rx only
Prescribing Information
WARNINGS
SERIOUS DERMATOLOGIC REACTIONS AND HLA-B*1502 ALLELE
SERIOUS AND SOMETIMES FATAL DERMATOLOGIC REACTIONS, INCLUDING TOXIC
EPIDERMAL NECROLYSIS (TEN) AND STEVENS-JOHNSON SYNDROME (SJS), HAVE BEEN
REPORTED DURING TREATMENT WITH TEGRETOL. THESE REACTIONS ARE ESTIMATED TO
OCCUR IN 1 TO 6 PER 10,000 NEW USERS IN COUNTRIES WITH MAINLY CAUCASIAN
POPULATIONS, BUT THE RISK IN SOME ASIAN COUNTRIES IS ESTIMATED TO BE ABOUT 10
TIMES HIGHER. STUDIES IN PATIENTS OF CHINESE ANCESTRY HAVE FOUND A STRONG
ASSOCIATION BETWEEN THE RISK OF DEVELOPING SJS/TEN AND THE PRESENCE OF
HLA-B*1502, AN INHERITED ALLELIC VARIANT OF THE HLA-B GENE. HLA-B*1502 IS FOUND
ALMOST EXCLUSIVELY IN PATIENTS WITH ANCESTRY ACROSS BROAD AREAS OF ASIA.
PATIENTS WITH ANCESTRY IN GENETICALLY AT-RISK POPULATIONS SHOULD BE SCREENED
FOR THE PRESENCE OF HLA-B*1502 PRIOR TO INITIATING TREATMENT WITH TEGRETOL.
PATIENTS TESTING POSITIVE FOR THE ALLELE SHOULD NOT BE TREATED WITH TEGRETOL
UNLESS THE BENEFIT CLEARLY OUTWEIGHS THE RISK (SEE WARNINGS AND PRECAUTIONS,
LABORATORY TESTS).
APLASTIC ANEMIA AND AGRANULOCYTOSIS
APLASTIC ANEMIA AND AGRANULOCYTOSIS HAVE BEEN REPORTED IN ASSOCIATION WITH
THE USE OF TEGRETOL. DATA FROM A POPULATION-BASED CASE CONTROL STUDY
DEMONSTRATE THAT THE RISK OF DEVELOPING THESE REACTIONS IS 5 TO 8 TIMES GREATER
THAN IN THE GENERAL POPULATION. HOWEVER, THE OVERALL RISK OF THESE REACTIONS
IN THE UNTREATED GENERAL POPULATION IS LOW, APPROXIMATELY SIX PATIENTS PER ONE
MILLION POPULATION PER YEAR FOR AGRANULOCYTOSIS AND TWO PATIENTS PER ONE
MILLION POPULATION PER YEAR FOR APLASTIC ANEMIA.
ALTHOUGH REPORTS OF TRANSIENT OR PERSISTENT DECREASED PLATELET OR WHITE
BLOOD CELL COUNTS ARE NOT UNCOMMON IN ASSOCIATION WITH THE USE OF TEGRETOL,
Reference ID: 3812964
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For current labeling information, please visit https://www.fda.gov/drugsatfda
DATA ARE NOT AVAILABLE TO ESTIMATE ACCURATELY THEIR INCIDENCE OR OUTCOME.
HOWEVER, THE VAST MAJORITY OF THE CASES OF LEUKOPENIA HAVE NOT PROGRESSED TO
THE MORE SERIOUS CONDITIONS OF APLASTIC ANEMIA OR AGRANULOCYTOSIS.
BECAUSE OF THE VERY LOW INCIDENCE OF AGRANULOCYTOSIS AND APLASTIC ANEMIA,
THE VAST MAJORITY OF MINOR HEMATOLOGIC CHANGES OBSERVED IN MONITORING OF
PATIENTS ON TEGRETOL ARE UNLIKELY TO SIGNAL THE OCCURRENCE OF EITHER
ABNORMALITY. NONETHELESS, COMPLETE PRETREATMENT HEMATOLOGICAL TESTING
SHOULD BE OBTAINED AS A BASELINE. IF A PATIENT IN THE COURSE OF TREATMENT
EXHIBITS LOW OR DECREASED WHITE BLOOD CELL OR PLATELET COUNTS, THE PATIENT
SHOULD BE MONITORED CLOSELY. DISCONTINUATION OF THE DRUG SHOULD BE
CONSIDERED IF ANY EVIDENCE OF SIGNIFICANT BONE MARROW DEPRESSION DEVELOPS.
Before prescribing Tegretol, the physician should be thoroughly familiar with the details of this
prescribing information, particularly regarding use with other drugs, especially those which accentuate
toxicity potential.
DESCRIPTION
Tegretol, carbamazepine USP, is an anticonvulsant and specific analgesic for trigeminal neuralgia, available for
oral administration as chewable tablets of 100 mg, tablets of 200 mg, XR tablets of 100, 200, and 400 mg, and
as a suspension of 100 mg/5 mL (teaspoon). Its chemical name is 5H-dibenz[b,f ]azepine-5-carboxamide, and
its structural formula is: structural formula
Carbamazepine USP is a white to off-white powder, practically insoluble in water and soluble in alcohol and in
acetone. Its molecular weight is 236.27.
Inactive Ingredients Tablets: Colloidal silicon dioxide, D&C Red No. 30 Aluminum Lake (chewable tablets
only), FD&C Red No. 40 (200 mg tablets only), flavoring (chewable tablets only), gelatin, glycerin, magnesium
stearate, sodium starch glycolate (chewable tablets only), starch, stearic acid, and sucrose (chewable tablets
only). Suspension: Citric acid, FD&C Yellow No. 6, flavoring, polymer, potassium sorbate, propylene glycol,
purified water, sorbitol, sucrose, and xanthan gum. Tegretol-XR tablets: cellulose compounds, dextrates, iron
oxides, magnesium stearate, mannitol, polyethylene glycol, sodium lauryl sulfate, titanium dioxide (200 mg
tablets only).
CLINICAL PHARMACOLOGY
In controlled clinical trials, Tegretol has been shown to be effective in the treatment of psychomotor and grand
mal seizures, as well as trigeminal neuralgia.
Mechanism of Action
Tegretol has demonstrated anticonvulsant properties in rats and mice with electrically and chemically induced
seizures. It appears to act by reducing polysynaptic responses and blocking the post-tetanic potentiation.
Tegretol greatly reduces or abolishes pain induced by stimulation of the infraorbital nerve in cats and rats. It
depresses thalamic potential and bulbar and polysynaptic reflexes, including the linguomandibular reflex in
cats. Tegretol is chemically unrelated to other anticonvulsants or other drugs used to control the pain of
trigeminal neuralgia. The mechanism of action remains unknown.
The principal metabolite of Tegretol, carbamazepine-10,11-epoxide, has anticonvulsant activity as
demonstrated in several in vivo animal models of seizures. Though clinical activity for the epoxide has been
Reference ID: 3812964
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For current labeling information, please visit https://www.fda.gov/drugsatfda
postulated, the significance of its activity with respect to the safety and efficacy of Tegretol has not been
established.
Pharmacokinetics
In clinical studies, Tegretol suspension, conventional tablets, and XR tablets delivered equivalent amounts of
drug to the systemic circulation. However, the suspension was absorbed somewhat faster, and the XR tablet
slightly slower, than the conventional tablet. The bioavailability of the XR tablet was 89% compared to
suspension. Following a b.i.d. dosage regimen, the suspension provides higher peak levels and lower trough
levels than those obtained from the conventional tablet for the same dosage regimen. On the other hand,
following a t.i.d. dosage regimen, Tegretol suspension affords steady-state plasma levels comparable to
Tegretol tablets given b.i.d. when administered at the same total mg daily dose. Following a b.i.d. dosage
regimen, Tegretol-XR tablets afford steady-state plasma levels comparable to conventional Tegretol tablets
given q.i.d., when administered at the same total mg daily dose. Tegretol in blood is 76% bound to plasma
proteins. Plasma levels of Tegretol are variable and may range from 0.5 to 25 mcg/mL, with no apparent
relationship to the daily intake of the drug. Usual adult therapeutic levels are between 4 and 12 mcg/mL. In
polytherapy, the concentration of Tegretol and concomitant drugs may be increased or decreased during
therapy, and drug effects may be altered (see PRECAUTIONS, Drug Interactions). Following chronic oral
administration of suspension, plasma levels peak at approximately 1.5 hours compared to 4 to 5 hours after
administration of conventional Tegretol tablets, and 3 to 12 hours after administration of Tegretol-XR tablets.
The CSF/serum ratio is 0.22, similar to the 24% unbound Tegretol in serum. Because Tegretol induces its own
metabolism, the half-life is also variable. Autoinduction is completed after 3 to 5 weeks of a fixed dosing
regimen. Initial half-life values range from 25 to 65 hours, decreasing to 12 to 17 hours on repeated doses.
Tegretol is metabolized in the liver. Cytochrome P450 3A4 was identified as the major isoform responsible for
the formation of carbamazepine-10,11-epoxide from Tegretol. Human microsomal epoxide hydrolase has been
identified as the enzyme responsible for the formation of the 10,11-transdiol derivative from carbamazepine
10,11 epoxide. After oral administration of 14C-carbamazepine, 72% of the administered radioactivity was
found in the urine and 28% in the feces. This urinary radioactivity was composed largely of hydroxylated and
conjugated metabolites, with only 3% of unchanged Tegretol.
The pharmacokinetic parameters of Tegretol disposition are similar in children and in adults. However, there is
a poor correlation between plasma concentrations of carbamazepine and Tegretol dose in children.
Carbamazepine is more rapidly metabolized to carbamazepine-10,11-epoxide (a metabolite shown to be
equipotent to carbamazepine as an anticonvulsant in animal screens) in the younger age groups than in adults. In
children below the age of 15, there is an inverse relationship between CBZ-E/CBZ ratio and increasing age (in
one report from 0.44 in children below the age of 1 year to 0.18 in children between 10 to 15 years of age).
The effects of race and gender on carbamazepine pharmacokinetics have not been systematically evaluated.
INDICATIONS AND USAGE
Epilepsy
Tegretol is indicated for use as an anticonvulsant drug. Evidence supporting efficacy of Tegretol as an
anticonvulsant was derived from active drug-controlled studies that enrolled patients with the following seizure
types:
1. Partial seizures with complex symptomatology (psychomotor, temporal lobe). Patients with these seizures
appear to show greater improvement than those with other types.
2. Generalized tonic-clonic seizures (grand mal).
3. Mixed seizure patterns which include the above, or other partial or generalized seizures. Absence seizures
(petit mal) do not appear to be controlled by Tegretol (see PRECAUTIONS, General).
Reference ID: 3812964
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Trigeminal Neuralgia
Tegretol is indicated in the treatment of the pain associated with true trigeminal neuralgia.
Beneficial results have also been reported in glossopharyngeal neuralgia.
This drug is not a simple analgesic and should not be used for the relief of trivial aches or pains.
CONTRAINDICATIONS
Tegretol should not be used in patients with a history of previous bone marrow depression, hypersensitivity to
the drug, or known sensitivity to any of the tricyclic compounds, such as amitriptyline, desipramine,
imipramine, protriptyline, nortriptyline, etc. Likewise, on theoretical grounds its use with monoamine oxidase
(MAO) inhibitors is not recommended. Before administration of Tegretol, MAO inhibitors should be
discontinued for a minimum of 14 days, or longer if the clinical situation permits.
Coadministration of carbamazepine and nefazodone may result in insufficient plasma concentrations of
nefazodone and its active metabolite to achieve a therapeutic effect. Coadministration of carbamazepine with
nefazodone is contraindicated.
WARNINGS
Serious Dermatologic Reactions
Serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN) and
Stevens-Johnson syndrome (SJS), have been reported with Tegretol treatment. The risk of these events is
estimated to be about 1 to 6 per 10,000 new users in countries with mainly Caucasian populations. However, the
risk in some Asian countries is estimated to be about 10 times higher. Tegretol should be discontinued at the
first sign of a rash, unless the rash is clearly not drug-related. If signs or symptoms suggest SJS/TEN, use of this
drug should not be resumed and alternative therapy should be considered.
SJS/TEN and HLA-B*1502 Allele
Retrospective case-control studies have found that in patients of Chinese ancestry there is a strong association
between the risk of developing SJS/TEN with carbamazepine treatment and the presence of an inherited variant
of the HLA-B gene, HLA-B*1502. The occurrence of higher rates of these reactions in countries with higher
frequencies of this allele suggests that the risk may be increased in allele-positive individuals of any ethnicity.
Across Asian populations, notable variation exists in the prevalence of HLA-B*1502. Greater than 15% of the
population is reported positive in Hong Kong, Thailand, Malaysia, and parts of the Philippines, compared to
about 10% in Taiwan and 4% in North China. South Asians, including Indians, appear to have intermediate
prevalence of HLA-B*1502, averaging 2% to 4%, but higher in some groups. HLA-B*1502 is present in less
than 1% of the population in Japan and Korea.
HLA-B*1502 is largely absent in individuals not of Asian origin (e.g., Caucasians, African-Americans,
Hispanics, and Native Americans).
Prior to initiating Tegretol therapy, testing for HLA-B*1502 should be performed in patients with
ancestry in populations in which HLA-B*1502 may be present. In deciding which patients to screen, the
rates provided above for the prevalence of HLA-B*1502 may offer a rough guide, keeping in mind the
limitations of these figures due to wide variability in rates even within ethnic groups, the difficulty in
ascertaining ethnic ancestry, and the likelihood of mixed ancestry. Tegretol should not be used in patients
positive for HLA-B*1502 unless the benefits clearly outweigh the risks. Tested patients who are found to be
negative for the allele are thought to have a low risk of SJS/TEN (see BOXED WARNING and
PRECAUTIONS, Laboratory Tests).
Over 90% of Tegretol treated patients who will experience SJS/TEN have this reaction within the first few
months of treatment. This information may be taken into consideration in determining the need for screening of
genetically at-risk patients currently on Tegretol.
Reference ID: 3812964
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For current labeling information, please visit https://www.fda.gov/drugsatfda
The HLA-B*1502 allele has not been found to predict risk of less severe adverse cutaneous reactions from
Tegretol such as maculopapular eruption (MPE) or to predict Drug Reaction with Eosinophilia and Systemic
Symptoms (DRESS).
Limited evidence suggests that HLA-B*1502 may be a risk factor for the development of SJS/TEN in patients
of Chinese ancestry taking other antiepileptic drugs associated with SJS/TEN, including phenytoin.
Consideration should be given to avoiding use of other drugs associated with SJS/TEN in HLA-B*1502
positive patients, when alternative therapies are otherwise equally acceptable.
Hypersensitivity Reactions and HLA-A*3101 Allele
Retrospective case-control studies in patients of European, Korean, and Japanese ancestry have found a
moderate association between the risk of developing hypersensitivity reactions and the presence of HLA
A*3101, an inherited allelic variant of the HLA-A gene, in patients using carbamazepine. These
hypersensitivity reactions include SJS/TEN, maculopapular eruptions, and Drug Reaction with Eosinophilia and
Systemic Symptoms (see DRESS/Multiorgan hypersensitivity below).
HLA-A*3101 is expected to be carried by more than 15% of patients of Japanese, Native American, Southern
Indian (for example, Tamil Nadu) and some Arabic ancestry; up to about 10% in patients of Han Chinese,
Korean, European, Latin American, and other Indian ancestry; and up to about 5% in African-Americans and
patients of Thai, Taiwanese, and Chinese (Hong Kong) ancestry.
The risks and benefits of Tegretol therapy should be weighed before considering Tegretol in patients known to
be positive for HLA-A*3101.
Application of HLA genotyping as a screening tool has important limitations and must never substitute for
appropriate clinical vigilance and patient management. Many HLA-B*1502-positive and HLA-A*3101-positive
patients treated with Tegretol will not develop SJS/TEN or other hypersensitivity reactions, and these reactions
can still occur infrequently in HLA-B*1502-negative and HLA-A*3101-negative patients of any ethnicity. The
role of other possible factors in the development of, and morbidity from, SJS/TEN and other hypersensitivity
reactions, such as antiepileptic drug (AED) dose, compliance, concomitant medications, comorbidities, and the
level of dermatologic monitoring, have not been studied.
Aplastic Anemia and Agranulocytosis
Aplastic anemia and agranulocytosis have been reported in association with the use of TEGRETOL (see
BOXED WARNING). Patients with a history of adverse hematologic reaction to any drug may be particularly
at risk of bone marrow depression.
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan
Hypersensitivity
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as multiorgan
hypersensitivity, has occurred with Tegretol. Some of these events have been fatal or life-threatening. DRESS
typically, although not exclusively, presents with fever, rash, and/or lymphadenopathy, in association with other
organ system involvement, such as hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis
sometimes resembling an acute viral infection. Eosinophilia is often present. This disorder is variable in its
expression, and other organ systems not noted here may be involved. It is important to note that early
manifestations of hypersensitivity (e.g., fever, lymphadenopathy) may be present even though rash is not
evident. If such signs or symptoms are present, the patient should be evaluated immediately. Tegretol should be
discontinued if an alternative etiology for the signs or symptoms cannot be established.
Hypersensitivity
Hypersensitivity reactions to carbamazepine have been reported in patients who previously experienced this
reaction to anticonvulsants including phenytoin, primidone, and phenobarbital. If such history is present,
benefits and risks should be carefully considered and, if carbamazepine is initiated, the signs and symptoms of
hypersensitivity should be carefully monitored.
Reference ID: 3812964
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Patients should be informed that about a third of patients who have had hypersensitivity reactions to
carbamazepine also experience hypersensitivity reactions with oxcarbazepine (Trileptal®).
Suicidal Behavior and Ideation
Antiepileptic drugs (AEDs), including Tegretol, increase the risk of suicidal thoughts or behavior in patients
taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for
the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood
or behavior.
Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs
showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk
1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these
trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or
ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated
patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530
patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated
patients, but the number is too small to allow any conclusion about drug effect on suicide.
The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting
drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in
the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could
not be assessed.
The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The
finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests
that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5 to 100
years) in the clinical trials analyzed. Table 1 shows absolute and relative risk by indication for all evaluated
AEDs.
Table 1 Risk by Indication for Antiepileptic Drugs in the Pooled Analysis
Indication
Placebo Patients
with Events Per
1,000 Patients
Drug Patients
with Events Per
1,000 Patients
Relative Risk:
Incidence of
Events in Drug
Patients/Incidence
in Placebo
Patients
Risk Difference:
Additional Drug
Patients with
Events Per 1,000
Patients
Epilepsy
1.0
3.4
3.5
2.4
Psychiatric
5.7
8.5
1.5
2.9
Other
1.0
1.8
1.9
0.9
Total
2.4
4.3
1.8
1.9
The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials
for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric
indications.
Anyone considering prescribing Tegretol or any other AED must balance the risk of suicidal thoughts or
behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are
themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior.
Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the
emergence of these symptoms in any given patient may be related to the illness being treated.
Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and
behavior and should be advised of the need to be alert for the emergence or worsening of the signs and
Reference ID: 3812964
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For current labeling information, please visit https://www.fda.gov/drugsatfda
symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts,
behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare
providers.
General
Tegretol has shown mild anticholinergic activity that may be associated with increased intraocular pressure;
therefore, patients with increased intraocular pressure should be closely observed during therapy.
Because of the relationship of the drug to other tricyclic compounds, the possibility of activation of a latent
psychosis and, in elderly patients, of confusion or agitation should be borne in mind.
The use of Tegretol should be avoided in patients with a history of hepatic porphyria (e.g., acute intermittent
porphyria, variegate porphyria, porphyria cutanea tarda). Acute attacks have been reported in such patients
receiving Tegretol therapy. Carbamazepine administration has also been demonstrated to increase porphyrin
precursors in rodents, a presumed mechanism for the induction of acute attacks of porphyria.
As with all antiepileptic drugs, Tegretol should be withdrawn gradually to minimize the potential of increased
seizure frequency.
Hyponatremia can occur as a result of treatment with Tegretol. In many cases, the hyponatremia appears to be
caused by the syndrome of inappropriate antidiuretic hormone secretion (SIADH). The risk of developing
SIADH with Tegretol treatment appears to be dose-related. Elderly patients and patients treated with diuretics
are at greater risk of developing hyponatremia. Consider discontinuing Tegretol in patients with symptomatic
hyponatremia. Signs and symptoms of hyponatremia include headache, new or increased seizure frequency,
difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which can lead to falls.
Consider discontinuing Tegretol in patients with symptomatic hyponatremia.
Usage in Pregnancy
Carbamazepine can cause fetal harm when administered to a pregnant woman.
Epidemiological data suggest that there may be an association between the use of carbamazepine during
pregnancy and congenital malformations, including spina bifida. There have also been reports that associate
carbamazepine with developmental disorders and congenital anomalies (e.g., craniofacial defects,
cardiovascular malformations, and anomalies involving various body systems). Developmental delays based on
neurobehavioral assessments have been reported. When treating or counseling women of childbearing potential,
the prescribing physician will wish to weigh the benefits of therapy against the risks. If this drug is used during
pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the
potential hazard to the fetus.
Retrospective case reviews suggest that, compared with monotherapy, there may be a higher prevalence of
teratogenic effects associated with the use of anticonvulsants in combination therapy. Therefore, if therapy is to
be continued, monotherapy may be preferable for pregnant women.
In humans, transplacental passage of carbamazepine is rapid (30 to 60 minutes), and the drug is accumulated in
the fetal tissues, with higher levels found in liver and kidney than in brain and lung.
Carbamazepine has been shown to have adverse effects in reproduction studies in rats when given orally in
dosages 10 to 25 times the maximum human daily dosage (MHDD) of 1200 mg on a mg/kg basis or 1.5 to
4 times the MHDD on a mg/m2 basis. In rat teratology studies, 2 of 135 offspring showed kinked ribs at 250
mg/kg and 4 of 119 offspring at 650 mg/kg showed other anomalies (cleft palate, 1; talipes, 1; anophthalmos,
2). In reproduction studies in rats, nursing offspring demonstrated a lack of weight gain and an unkempt
appearance at a maternal dosage level of 200 mg/kg.
Antiepileptic drugs should not be discontinued abruptly in patients in whom the drug is administered to prevent
major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and
threat to life. In individual cases where the severity and frequency of the seizure disorder are such that removal
of medication does not pose a serious threat to the patient, discontinuation of the drug may be considered prior
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to and during pregnancy, although it cannot be said with any confidence that even minor seizures do not pose
some hazard to the developing embryo or fetus.
Tests to detect defects using currently accepted procedures should be considered a part of routine prenatal care
in childbearing women receiving carbamazepine.
There have been a few cases of neonatal seizures and/or respiratory depression associated with maternal
Tegretol and other concomitant anticonvulsant drug use. A few cases of neonatal vomiting, diarrhea, and/or
decreased feeding have also been reported in association with maternal Tegretol use. These symptoms may
represent a neonatal withdrawal syndrome.
To provide information regarding the effects of in utero exposure to Tegretol, physicians are advised to
recommend that pregnant patients taking Tegretol enroll in the North American Antiepileptic Drug (NAAED)
Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by
patients themselves. Information on the registry can also be found at the website
http://www.aedpregnancyregistry.org/.
PRECAUTIONS
General
Before initiating therapy, a detailed history and physical examination should be made.
Tegretol should be used with caution in patients with a mixed seizure disorder that includes atypical absence
seizures, since in these patients Tegretol has been associated with increased frequency of generalized
convulsions (see INDICATIONS AND USAGE).
Therapy should be prescribed only after critical benefit-to-risk appraisal in patients with a history of cardiac
conduction disturbance, including second- and third-degree AV heart block; cardiac, hepatic, or renal damage;
adverse hematologic or hypersensitivity reaction to other drugs, including reactions to other anticonvulsants; or
interrupted courses of therapy with Tegretol.
AV heart block, including second- and third-degree block, have been reported following Tegretol treatment.
This occurred generally, but not solely, in patients with underlying EKG abnormalities or risk factors for
conduction disturbances.
Hepatic effects, ranging from slight elevations in liver enzymes to rare cases of hepatic failure have been
reported (see ADVERSE REACTIONS and PRECAUTIONS, Laboratory Tests). In some cases, hepatic effects
may progress despite discontinuation of the drug. In addition rare instances of vanishing bile duct syndrome
have been reported. This syndrome consists of a cholestatic process with a variable clinical course ranging from
fulminant to indolent, involving the destruction and disappearance of the intrahepatic bile ducts. Some, but not
all, cases are associated with features that overlap with other immunoallergenic syndromes such as multiorgan
hypersensitivity (DRESS syndrome) and serious dermatologic reactions. As an example there has been a report
of vanishing bile duct syndrome associated with Stevens-Johnson syndrome and in another case an association
with fever and eosinophilia.
Since a given dose of Tegretol suspension will produce higher peak levels than the same dose given as the
tablet, it is recommended that patients given the suspension be started on lower doses and increased slowly to
avoid unwanted side effects (see DOSAGE AND ADMINISTRATION).
Tegretol suspension contains sorbitol and, therefore, should not be administered to patients with rare hereditary
problems of fructose intolerance.
Information for Patients
Patients should be informed of the availability of a Medication Guide and they should be instructed to read the
Medication Guide before taking Tegretol.
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Patients should be made aware of the early toxic signs and symptoms of a potential hematologic problem, as
well as dermatologic, hypersensitivity or hepatic reactions. These symptoms may include, but are not limited to,
fever, sore throat, rash, ulcers in the mouth, easy bruising, lymphadenopathy and petechial or purpuric
hemorrhage, and in the case of liver reactions, anorexia, nausea/vomiting, or jaundice. The patient should be
advised that, because these signs and symptoms may signal a serious reaction, that they must report any
occurrence immediately to a physician. In addition, the patient should be advised that these signs and symptoms
should be reported even if mild or when occurring after extended use.
Patients should be advised that serious skin reactions have been reported in association with Tegretol. In the
event a skin reaction should occur while taking Tegretol, patients should consult with their physician
immediately (see WARNINGS).
Patients, their caregivers, and families should be counseled that AEDs, including Tegretol, may increase the risk
of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening
of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts,
behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare
providers.
Tegretol may interact with some drugs. Therefore, patients should be advised to report to their doctors the use
of any other prescription or nonprescription medications or herbal products.
Caution should be exercised if alcohol is taken in combination with Tegretol therapy, due to a possible additive
sedative effect.
Since dizziness and drowsiness may occur, patients should be cautioned about the hazards of operating
machinery or automobiles or engaging in other potentially dangerous tasks.
Patients should be encouraged to enroll in the NAAED Pregnancy Registry if they become pregnant. This
registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients
can call the toll free number 1-888-233-2334 (see WARNINGS, Usage in Pregnancy subsection).
Laboratory Tests
For genetically at-risk patients (see WARNINGS), high-resolution ‘HLA-B*1502 typing’ is recommended. The
test is positive if either one or two HLA-B*1502 alleles are detected and negative if no HLA-B*1502 alleles are
detected.
Complete pretreatment blood counts, including platelets and possibly reticulocytes and serum iron, should be
obtained as a baseline. If a patient in the course of treatment exhibits low or decreased white blood cell or
platelet counts, the patient should be monitored closely. Discontinuation of the drug should be considered if any
evidence of significant bone marrow depression develops.
Baseline and periodic evaluations of liver function, particularly in patients with a history of liver disease, must
be performed during treatment with this drug since liver damage may occur (see PRECAUTIONS, General and
ADVERSE REACTIONS). Carbamazepine should be discontinued, based on clinical judgment, if indicated by
newly occurring or worsening clinical or laboratory evidence of liver dysfunction or hepatic damage, or in the
case of active liver disease.
Baseline and periodic eye examinations, including slit-lamp, funduscopy, and tonometry, are recommended
since many phenothiazines and related drugs have been shown to cause eye changes.
Baseline and periodic complete urinalysis and BUN determinations are recommended for patients treated with
this agent because of observed renal dysfunction.
Monitoring of blood levels (see CLINICAL PHARMACOLOGY) has increased the efficacy and safety of
anticonvulsants. This monitoring may be particularly useful in cases of dramatic increase in seizure frequency
and for verification of compliance. In addition, measurement of drug serum levels may aid in determining the
cause of toxicity when more than one medication is being used.
Thyroid function tests have been reported to show decreased values with Tegretol administered alone.
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Interference with some pregnancy tests has been reported.
Drug Interactions
There has been a report of a patient who passed an orange rubbery precipitate in his stool the day after ingesting
Tegretol suspension immediately followed by Thorazine®* solution. Subsequent testing has shown that mixing
Tegretol suspension and chlorpromazine solution (both generic and brand name) as well as Tegretol suspension
and liquid Mellaril®, resulted in the occurrence of this precipitate. Because the extent to which this occurs with
other liquid medications is not known, Tegretol suspension should not be administered simultaneously with
other liquid medicinal agents or diluents (see DOSAGE AND ADMINISTRATION).
Clinically meaningful drug interactions have occurred with concomitant medications and include (but are not
limited to) the following:
Agents That May Affect Tegretol Plasma Levels
When carbamazepine is given with drugs that can increase or decrease carbamazepine levels, close monitoring
of carbamazepine levels is indicated and dosage adjustment may be required.
Agents That Increase Carbamazepine Levels
CYP3A4 inhibitors inhibit Tegretol metabolism and can thus increase plasma carbamazepine levels. Drugs that
have been shown, or would be expected, to increase plasma carbamazepine levels include aprepitant,
cimetidine, ciprofloxacin, danazol, diltiazem, macrolides, erythromycin, troleandomycin, clarithromycin,
fluoxetine, fluvoxamine, trazodone, olanzapine, loratadine, terfenadine, omeprazole, oxybutynin, dantrolene,
isoniazid, niacinamide, nicotinamide, ibuprofen, propoxyphene, azoles (e.g., ketaconazole, itraconazole,
fluconazole, voriconazole), acetazolamide, verapamil, ticlopidine, grapefruit juice, and protease inhibitors.
Human microsomal epoxide hydrolase has been identified as the enzyme responsible for the formation of the
10,11-transdiol derivative from carbamazepine-10,11 epoxide. Coadministration of inhibitors of human
microsomal epoxide hydrolase may result in increased carbamazepine-10,11 epoxide plasma concentrations.
Accordingly, the dosage of Tegretol should be adjusted and/or the plasma levels monitored when used
concomitantly with loxapine, quetiapine, or valproic acid.
Agents That Decrease Carbamazepine Levels
CYP3A4 inducers can increase the rate of Tegretol metabolism. Drugs that have been shown, or that would be
expected, to decrease plasma carbamazepine levels include cisplatin, doxorubicin HCl, felbamate, fosphenytoin,
rifampin, phenobarbital, phenytoin, primidone, methsuximide, theophylline, aminophylline.
Effect of Tegretol on Plasma Levels of Concomitant Agents
Decreased Levels of Concomitant Medications
Tegretol is a potent inducer of hepatic 3A4 and is also known to be an inducer of CYP1A2, 2B6, 2C9/19 and
may therefore reduce plasma concentrations of co-medications mainly metabolized by CYP 1A2, 2B6, 2C9/19
and 3A4, through induction of their metabolism. When used concomitantly with Tegretol, monitoring of
concentrations or dosage adjustment of these agents may be necessary:
• When carbamazepine is added to aripiprazole, the aripiprazole dose should be doubled. Additional dose
increases should be based on clinical evaluation. If carbamazepine is later withdrawn, the aripiprazole
dose should be reduced.
• When carbamazepine is used with tacrolimus, monitoring of tacrolimus blood concentrations and
appropriate dosage adjustments are recommended.
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• The use of concomitant strong CYP3A4 inducers such as carbamazepine should be avoided with
temsirolimus. If patients must be coadministered carbamazepine with temsirolimus, an adjustment of
temsirolimus dosage should be considered.
• The use of carbamazepine with lapatinib should generally be avoided. If carbamazepine is started in a
patient already taking lapatinib, the dose of lapatinib should be gradually titrated up. If carbamazepine
is discontinued, the lapatinib dose should be reduced.
• Concomitant use of carbamazepine with nefazodone results in plasma concentrations of nefazodone and
its active metabolite insufficient to achieve a therapeutic effect. Coadministration of carbamazepine with
nefazodone is contraindicated (see CONTRAINDICATIONS).
• Monitor concentrations of valproate when Tegretol is introduced or withdrawn in patients using valproic
acid.
In addition, Tegretol causes, or would be expected to cause, decreased levels of the following drugs, for which
monitoring of concentrations or dosage adjustment may be necessary: acetaminophen, albendazole, alprazolam,
aprepitant, buprenorphone, bupropion, citalopram, clonazepam, clozapine, corticosteroids (e.g., prednisolone,
dexamethasone), cyclosporine, dicumarol, dihydropyridine calcium channel blockers (e.g., felodipine),
doxycycline, ethosuximide, everolimus, haloperidol, imatinib, itraconazole, lamotrigine, levothyroxine,
methadone, methsuximide, mianserin, midazolam, olanzapine, oral and other hormonal contraceptives,
oxcarbazepine, paliperidone, phensuximide, phenytoin, praziquantel, protease inhibitors, risperidone, sertraline,
sirolimus, tadalafil, theophylline, tiagabine, topiramate, tramadol, trazodone, tricyclic antidepressants (e.g.,
imipramine, amitriptyline, nortriptyline), valproate, warfarin, ziprasidone, zonisamide.
Other Drug Interactions
• Cyclophosphamide is an inactive prodrug and is converted to its active metabolite in part by CYP3A.
The rate of metabolism and the leukopenic activity of cyclophosphamide are reportedly increased by
chronic coadministration of CYP3A4 inducers. There is a potential for increased cyclophosphamide
toxicity when coadministered with carbamazepine.
• Concomitant administration of carbamazepine and lithium may increase the risk of neurotoxic side
effects.
• Concomitant use of carbamazepine and isoniazid has been reported to increase isoniazid-induced
hepatotoxicity.
• Alterations of thyroid function have been reported in combination therapy with other anticonvulsant
medications.
• Concomitant use of Tegretol with hormonal contraceptive products (e.g., oral, and levonorgestrel
subdermal implant contraceptives) may render the contraceptives less effective because the plasma
concentrations of the hormones may be decreased. Breakthrough bleeding and unintended pregnancies
have been reported. Alternative or back-up methods of contraception should be considered.
• Resistance to the neuromuscular blocking action of the nondepolarizing neuromuscular blocking agents
pancuronium, vecuronium, rocuronium and cisatracurium has occurred in patients chronically
administered carbamazepine. Whether or not carbamazepine has the same effect on other non-
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depolarizing agents is unknown. Patients should be monitored closely for more rapid recovery from
neuromuscular blockade than expected, and infusion rate requirements may be higher.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carbamazepine, when administered to Sprague-Dawley rats for two years in the diet at doses of 25, 75, and
250 mg/kg/day, resulted in a dose-related increase in the incidence of hepatocellular tumors in females and of
benign interstitial cell adenomas in the testes of males.
Carbamazepine must, therefore, be considered to be carcinogenic in Sprague-Dawley rats. Bacterial and
mammalian mutagenicity studies using carbamazepine produced negative results. The significance of these
findings relative to the use of carbamazepine in humans is, at present, unknown.
Usage in Pregnancy
Pregnancy Category D (see WARNINGS).
Labor and Delivery
The effect of Tegretol on human labor and delivery is unknown.
Nursing Mothers
Tegretol and its epoxide metabolite are transferred to breast milk. The ratio of the concentration in breast milk
to that in maternal plasma is about 0.4 for Tegretol and about 0.5 for the epoxide. The estimated doses given to
the newborn during breastfeeding are in the range of 2 to 5 mg daily for Tegretol and 1 to 2 mg daily for the
epoxide.
Because of the potential for serious adverse reactions in nursing infants from carbamazepine, a decision should
be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the
drug to the mother.
Pediatric Use
Substantial evidence of Tegretol’s effectiveness for use in the management of children with epilepsy (see
INDICATIONS AND USAGE for specific seizure types) is derived from clinical investigations performed in
adults and from studies in several in vitro systems which support the conclusion that (1) the pathogenetic
mechanisms underlying seizure propagation are essentially identical in adults and children, and (2) the
mechanism of action of carbamazepine in treating seizures is essentially identical in adults and children.
Taken as a whole, this information supports a conclusion that the generally accepted therapeutic range of total
carbamazepine in plasma (i.e. 4 to 12 mcg/mL) is the same in children and adults.
The evidence assembled was primarily obtained from short-term use of carbamazepine. The safety of
carbamazepine in children has been systematically studied up to 6 months. No longer-term data from clinical
trials is available.
Geriatric Use
No systematic studies in geriatric patients have been conducted.
ADVERSE REACTIONS
If adverse reactions are of such severity that the drug must be discontinued, the physician must be aware that
abrupt discontinuation of any anticonvulsant drug in a responsive epileptic patient may lead to seizures or even
status epilepticus with its life-threatening hazards.
The most severe adverse reactions have been observed in the hemopoietic system and skin (see BOXED
WARNING), the liver, and the cardiovascular system.
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The most frequently observed adverse reactions, particularly during the initial phases of therapy, are dizziness,
drowsiness, unsteadiness, nausea, and vomiting. To minimize the possibility of such reactions, therapy should
be initiated at the lowest dosage recommended.
The following additional adverse reactions have been reported:
Hemopoietic System: Aplastic anemia, agranulocytosis, pancytopenia, bone marrow depression,
thrombocytopenia, leukopenia, leukocytosis, eosinophilia, acute intermittent porphyria, variegate porphyria,
porphyria cutanea tarda.
Skin: Toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) (see BOXED WARNING),
Acute Generalized Exanthematous Pustulosis (AGEP), pruritic and erythematous rashes, urticaria,
photosensitivity reactions, alterations in skin pigmentation, exfoliative dermatitis, erythema multiforme and
nodosum, purpura, aggravation of disseminated lupus erythematosus, alopecia, diaphoresis, onychomadesis and
hirsutism. In certain cases, discontinuation of therapy may be necessary.
Cardiovascular System: Congestive heart failure, edema, aggravation of hypertension, hypotension, syncope
and collapse, aggravation of coronary artery disease, arrhythmias and AV block, thrombophlebitis,
thromboembolism (e.g., pulmonary embolism), and adenopathy or lymphadenopathy.
Some of these cardiovascular complications have resulted in fatalities. Myocardial infarction has been
associated with other tricyclic compounds.
Liver: Abnormalities in liver function tests, cholestatic and hepatocellular jaundice, hepatitis, very rare cases of
hepatic failure.
Pancreatic: Pancreatitis.
Respiratory System: Pulmonary hypersensitivity characterized by fever, dyspnea, pneumonitis, or pneumonia.
Genitourinary System: Urinary frequency, acute urinary retention, oliguria with elevated blood pressure,
azotemia, renal failure, and impotence. Albuminuria, glycosuria, elevated BUN, and microscopic deposits in the
urine have also been reported. There have been rare reports of impaired male fertility and/or abnormal
spermatogenesis.
Testicular atrophy occurred in rats receiving Tegretol orally from 4 to 52 weeks at dosage levels of 50 to 400
mg/kg/day. Additionally, rats receiving Tegretol in the diet for 2 years at dosage levels of 25, 75, and 250
mg/kg/day had a dose-related incidence of testicular atrophy and aspermatogenesis. In dogs, it produced a
brownish discoloration, presumably a metabolite, in the urinary bladder at dosage levels of 50 mg/kg and
higher. Relevance of these findings to humans is unknown.
Nervous System: Dizziness, drowsiness, disturbances of coordination, confusion, headache, fatigue, blurred
vision, visual hallucinations, transient diplopia, oculomotor disturbances, nystagmus, speech disturbances,
abnormal involuntary movements, peripheral neuritis and paresthesias, depression with agitation, talkativeness,
tinnitus, hyperacusis, neuroleptic malignant syndrome.
There have been reports of associated paralysis and other symptoms of cerebral arterial insufficiency, but the
exact relationship of these reactions to the drug has not been established.
Isolated cases of neuroleptic malignant syndrome have been reported both with and without concomitant use of
psychotropic drugs.
Digestive System: Nausea, vomiting, gastric distress and abdominal pain, diarrhea, constipation, anorexia, and
dryness of the mouth and pharynx, including glossitis and stomatitis.
Eyes: Scattered punctate cortical lens opacities, increased intraocular pressure (see WARNINGS, General) as
well as conjunctivitis, have been reported. Although a direct causal relationship has not been established, many
phenothiazines and related drugs have been shown to cause eye changes.
Musculoskeletal System: Aching joints and muscles, and leg cramps.
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Metabolism: Fever and chills. Hyponatremia (seeWARNINGS,General). Decreased levels of plasma calcium
have been reported. Osteoporosis has been reported.
Isolated cases of a lupus erythematosus-like syndrome have been reported. There have been occasional reports
of elevated levels of cholesterol, HDL cholesterol, and triglycerides in patients taking anticonvulsants.
A case of aseptic meningitis, accompanied by myoclonus and peripheral eosinophilia, has been reported in a
patient taking carbamazepine in combination with other medications. The patient was successfully
dechallenged, and the meningitis reappeared upon rechallenge with carbamazepine.
DRUG ABUSE AND DEPENDENCE
No evidence of abuse potential has been associated with Tegretol, nor is there evidence of psychological or
physical dependence in humans.
OVERDOSAGE
Acute Toxicity
Lowest known lethal dose: adults, 3.2 g (a 24-year-old woman died of a cardiac arrest and a 24-year-old man
died of pneumonia and hypoxic encephalopathy); children, 4 g (a 14-year-old girl died of a cardiac arrest), 1.6 g
(a 3-year-old girl died of aspiration pneumonia).
Oral LD50 in animals (mg/kg): mice, 1100 to 3750; rats, 3850 to 4025; rabbits, 1500 to 2680; guinea pigs, 920.
Signs and Symptoms
The first signs and symptoms appear after 1 to 3 hours. Neuromuscular disturbances are the most prominent.
Cardiovascular disorders are generally milder, and severe cardiac complications occur only when very high
doses (greater than 60 g) have been ingested.
Respiration: Irregular breathing, respiratory depression.
Cardiovascular System: Tachycardia, hypotension or hypertension, shock, conduction disorders.
Nervous System and Muscles: Impairment of consciousness ranging in severity to deep coma. Convulsions,
especially in small children. Motor restlessness, muscular twitching, tremor, athetoid movements, opisthotonos,
ataxia, drowsiness, dizziness, mydriasis, nystagmus, adiadochokinesia, ballism, psychomotor disturbances,
dysmetria. Initial hyperreflexia, followed by hyporeflexia.
Gastrointestinal Tract: Nausea, vomiting.
Kidneys and Bladder: Anuria or oliguria, urinary retention.
Laboratory Findings: Isolated instances of overdosage have included leukocytosis, reduced leukocyte count,
glycosuria, and acetonuria. EEG may show dysrhythmias.
Combined Poisoning: When alcohol, tricyclic antidepressants, barbiturates, or hydantoins are taken at the same
time, the signs and symptoms of acute poisoning with Tegretol may be aggravated or modified.
Treatment
The prognosis in cases of severe poisoning is critically dependent upon prompt elimination of the drug, which
may be achieved by inducing vomiting, irrigating the stomach, and by taking appropriate steps to diminish
absorption. If these measures cannot be implemented without risk on the spot, the patient should be transferred
at once to a hospital, while ensuring that vital functions are safeguarded. There is no specific antidote.
Elimination of the Drug: Induction of vomiting.
Gastric lavage. Even when more than 4 hours have elapsed following ingestion of the drug, the stomach should
be repeatedly irrigated, especially if the patient has also consumed alcohol.
Measures to Reduce Absorption: Activated charcoal, laxatives.
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Measures to Accelerate Elimination: Forced diuresis.
Dialysis is indicated only in severe poisoning associated with renal failure. Replacement transfusion is indicated
in severe poisoning in small children.
Respiratory Depression: Keep the airways free; resort, if necessary, to endotracheal intubation, artificial
respiration, and administration of oxygen.
Hypotension, Shock: Keep the patient’s legs raised and administer a plasma expander. If blood pressure fails to
rise despite measures taken to increase plasma volume, use of vasoactive substances should be considered.
Convulsions: Diazepam or barbiturates.
Warning: Diazepam or barbiturates may aggravate respiratory depression (especially in children), hypotension,
and coma. However, barbiturates should not be used if drugs that inhibit monoamine oxidase have also been
taken by the patient either in overdosage or in recent therapy (within 1 week).
Surveillance: Respiration, cardiac function (ECG monitoring), blood pressure, body temperature, pupillary
reflexes, and kidney and bladder function should be monitored for several days.
Treatment of Blood Count Abnormalities: If evidence of significant bone marrow depression develops, the
following recommendations are suggested: (1) stop the drug, (2) perform daily CBC, platelet, and reticulocyte
counts, (3) do a bone marrow aspiration and trephine biopsy immediately and repeat with sufficient frequency
to monitor recovery.
Special periodic studies might be helpful as follows: (1) white cell and platelet antibodies, (2) 59Fe-ferrokinetic
studies, (3) peripheral blood cell typing, (4) cytogenetic studies on marrow and peripheral blood, (5) bone
marrow culture studies for colony-forming units, (6) hemoglobin electrophoresis for A2 and F hemoglobin, and
(7) serum folic acid and B12 levels.
A fully developed aplastic anemia will require appropriate, intensive monitoring and therapy, for which
specialized consultation should be sought.
DOSAGE AND ADMINISTRATION (SEE TABLE BELOW)
Tegretol suspension in combination with liquid chlorpromazine or thioridazine results in precipitate formation,
and, in the case of chlorpromazine, there has been a report of a patient passing an orange rubbery precipitate in
the stool following coadministration of the two drugs (see PRECAUTIONS, Drug Interactions). Because the
extent to which this occurs with other liquid medications is not known, Tegretol suspension should not be
administered simultaneously with other liquid medications or diluents.
Monitoring of blood levels has increased the efficacy and safety of anticonvulsants (see PRECAUTIONS,
Laboratory Tests). Dosage should be adjusted to the needs of the individual patient. A low initial daily dosage
with a gradual increase is advised. As soon as adequate control is achieved, the dosage may be reduced very
gradually to the minimum effective level. Medication should be taken with meals.
Since a given dose of Tegretol suspension will produce higher peak levels than the same dose given as the
tablet, it is recommended to start with low doses (children 6 to 12 years: ½ teaspoon q.i.d.) and to increase
slowly to avoid unwanted side effects.
Conversion of patients from oral Tegretol tablets to Tegretol suspension: Patients should be converted by
administering the same number of mg per day in smaller, more frequent doses (i.e., b.i.d. tablets to t.i.d.
suspension).
Tegretol-XR is an extended-release formulation for twice-a-day administration. When converting patients from
Tegretol conventional tablets to Tegretol-XR, the same total daily mg dose of Tegretol-XR should be
administered. Tegretol-XR tablets must be swallowed whole and never crushed or chewed. Tegretol-XR
tablets should be inspected for chips or cracks. Damaged tablets, or tablets without a release portal, should not
be consumed. Tegretol-XR tablet coating is not absorbed and is excreted in the feces; these coatings may be
noticeable in the stool.
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Epilepsy (SEE INDICATIONS AND USAGE)
Adults and children over 12 years of age-Initial: Either 200 mg b.i.d. for tablets and XR tablets, or 1 teaspoon
q.i.d. for suspension (400 mg/day). Increase at weekly intervals by adding up to 200 mg/day using a b.i.d.
regimen of Tegretol-XR or a t.i.d. or q.i.d. regimen of the other formulations until the optimal response is
obtained. Dosage generally should not exceed 1000 mg daily in children 12 to 15 years of age, and 1200 mg
daily in patients above 15 years of age. Doses up to 1600 mg daily have been used in adults in rare instances.
Maintenance: Adjust dosage to the minimum effective level, usually 800 to 1200 mg daily.
Children 6 to 12 years of age-Initial: Either 100 mg b.i.d. for tablets or XR tablets, or ½ teaspoon q.i.d. for
suspension (200 mg/day). Increase at weekly intervals by adding up to 100 mg/day using a b.i.d. regimen of
Tegretol-XR or a t.i.d. or q.i.d. regimen of the other formulations until the optimal response is obtained. Dosage
generally should not exceed 1000 mg daily. Maintenance: Adjust dosage to the minimum effective level,
usually 400 to 800 mg daily.
Children under 6 years of age-Initial: 10 to 20 mg/kg/day b.i.d. or t.i.d. as tablets, or q.i.d. as suspension.
Increase weekly to achieve optimal clinical response administered t.i.d. or q.i.d. Maintenance: Ordinarily,
optimal clinical response is achieved at daily doses below 35 mg/kg. If satisfactory clinical response has not
been achieved, plasma levels should be measured to determine whether or not they are in the therapeutic range.
No recommendation regarding the safety of carbamazepine for use at doses above 35 mg/kg/24 hours can be
made.
Combination Therapy: Tegretol may be used alone or with other anticonvulsants. When added to existing
anticonvulsant therapy, the drug should be added gradually while the other anticonvulsants are maintained or
gradually decreased, except phenytoin, which may have to be increased (see PRECAUTIONS, Drug
Interactions, and Pregnancy Category D).
Trigeminal Neuralgia (SEE INDICATIONS AND USAGE)
Initial: On the first day, either 100 mg b.i.d. for tablets or XR tablets, or ½ teaspoon q.i.d. for suspension, for a
total daily dose of 200 mg. This daily dose may be increased by up to 200 mg/day using increments of 100 mg
every 12 hours for tablets or XR tablets, or 50 mg (½ teaspoon) q.i.d. for suspension, only as needed to achieve
freedom from pain. Do not exceed 1200 mg daily. Maintenance: Control of pain can be maintained in most
patients with 400 to 800 mg daily. However, some patients may be maintained on as little as 200 mg daily,
while others may require as much as 1200 mg daily. At least once every 3 months throughout the treatment
period, attempts should be made to reduce the dose to the minimum effective level or even to discontinue the
drug.
Reference ID: 3812964
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Dosage Information
Initial Dose
Subsequent Dose
Maximum Daily Dose
Indication
Tablet*
XR†
Suspension
Tablet*
XR†
Suspension
Tablet*
XR†
Suspension
Epilepsy
Under 6 yr
10-20 mg/kg/day
b.i.d. or t.i.d.
10-20 mg/kg/day
q.i.d.
Increase weekly
to achieve
optimal clinical
response, t.i.d.
or q.i.d.
Increase
weekly to
achieve optimal
clinical
response, t.i.d.
or q.i.d.
35 mg/kg/24 hr
(see Dosage
and
Administration
section above)
35 mg/kg/24 hr
(see Dosage
and
Administration
section above)
6-12 yr
100 mg b.i.d.
(200 mg/day)
100 mg b.i.d.
(200 mg/day)
½ tsp q.i.d.
(200 mg/day)
Add up to
100 mg/day at
weekly intervals,
t.i.d. or q.i.d.
Add
100 mg/day
at weekly
intervals,
b.i.d.
Add up to 1 tsp
(100 mg)/day at
weekly
intervals, t.i.d.
or q.i.d.
1000 mg/24 hr
Over 12 yr
200 mg b.i.d.
200 mg b.i.d.
1 tsp q.i.d.
Add up to
Add up to
Add up to 2 tsp
1000 mg/24 hr (12-15 yr)
(400 mg/day)
(400 mg/day)
(400 mg/day)
200 mg/day at
200 mg/day
(200 mg)/day at
1200 mg/24 hr (>15 yr)
weekly intervals,
t.i.d. or q.i.d.
at weekly
intervals,
b.i.d.
weekly
intervals, t.i.d.
or q.i.d.
1600 mg/24 hr (adults, in rare instances)
Trigeminal
100 mg b.i.d.
100 mg b.i.d.
½ tsp q.i.d.
Add up to
Add up to
Add up to 2 tsp
1200 mg/24 hr
Neuralgia
(200 mg/day)
(200 mg/day)
(200 mg/day)
200 mg/day in
increments of
100 mg every
12 hr
200 mg/day
in increments
of 100 mg
every 12 hr
(200 mg)/day
in increments
of 50 mg
(½ tsp) q.i.d.
*Tablet = Chewable or conventional tablets
†XR = Tegretol-XR extended-release tablets
Reference ID: 3812964
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
HOW SUPPLIED
Chewable Tablets 100 mg - round, red-speckled, pink, single-scored (imprinted Tegretol on one
side and 52 twice on the scored side)
Bottles of 100 ............................................................................................................................ NDC 0078-0492-05
Unit Dose (blister pack)
Box of 100 (strips of 10) ........................................................................................................... NDC 0078-0492-35
Do not store above 30°C (86°F). Protect from light and moisture.
Dispense in tight, light-resistant container (USP).
Meets USP Dissolution Test 1.
Tablets 200 mg - capsule-shaped, pink, single-scored (imprinted Tegretol on one side and
27 twice on the partially scored side)
Bottles of 100 ............................................................................................................................ NDC 0078-0509-05
Do not store above 30°C (86°F). Protect from moisture.
Dispense in tight container (USP).
Meets USP Dissolution Test 2.
XR Tablets 100 mg - round, yellow, coated (imprinted T on one side and 100 mg on the other),
release portal on one side
Bottles of 100 ............................................................................................................................ NDC 0078-0510-05
XR Tablets 200 mg - round, pink, coated (imprinted T on one side and 200 mg on the other),
release portal on one side
Bottles of 100 ............................................................................................................................ NDC 0078-0511-05
XR Tablets 400 mg - round, brown, coated (imprinted T on one side and 400 mg on the other),
release portal on one side
Bottles of 100 ............................................................................................................................ NDC 0078-0512-05
Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) Protect from
moisture.
Dispense in tight container (USP).
Suspension 100 mg/5 mL (teaspoon) – yellow-orange, citrus-vanilla flavored
Bottles of 450 mL ..................................................................................................................... NDC 0078-0508-83
Shake well before using.
Do not store above 30°C (86°F). Dispense in tight, light-resistant container (USP).
*Thorazine® is a registered trademark of GlaxoSmithKline.
September 2015
Reference ID: 3812964
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEDICATION GUIDE
TEGRETOL® and TEGRETOL®-XR (Teg-ret-ol)
(carbamazepine)
Tablets, Suspension, Chewable Tablets, Extended-Release Tablets
Read this Medication Guide before you start taking Tegretol or Tegretol–XR (TEGRETOL) and
each time you get a refill. There may be new information. This information does not take the
place of talking to your healthcare provider about your medical condition or treatment.
What is the most important information I should know about TEGRETOL?
Do not stop taking TEGRETOL without first talking to your healthcare provider.
Stopping TEGRETOL suddenly can cause serious problems.
TEGRETOL can cause serious side effects, including:
1. TEGRETOL may cause rare but serious skin rashes that may lead to death.
These serious skin reactions are more likely to happen when you begin taking
TEGRETOL within the first four months of treatment but may occur at later
times. These reactions can happen in anyone, but are more likely in people of
Asian descent. If you are of Asian descent, you may need a genetic blood test
before you take TEGRETOL to see if you are at a higher risk for serious skin
reactions with this medicine. Symptoms may include:
• skin rash
• hives
• sores in your mouth
• blistering or peeling of the skin
2. TEGRETOL may cause rare but serious blood problems. Symptoms may
include:
• fever, sore throat, or other infections that come and go or do not go away
• easy bruising
• red or purple spots on your body
• bleeding gums or nose bleeds
• severe fatigue or weakness
3. Like other antiepileptic drugs, TEGRETOL may cause suicidal thoughts or
actions in a very small number of people, about 1 in 500.
Call your healthcare provider right away if you have any of these symptoms,
especially if they are new, worse, or worry you:
• thoughts about suicide or dying
• attempts to commit suicide
Reference ID: 3812964
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• new or worse depression
• new or worse anxiety
• feeling agitated or restless
• panic attacks
• trouble sleeping (insomnia)
• new or worse irritability
• acting aggressive, being angry, or violent
• acting on dangerous impulses
• an extreme increase in activity and talking (mania)
• other unusual changes in behavior or mood
How can I watch for early symptoms of suicidal thoughts and actions?
•
Pay attention to any changes, especially sudden changes, in mood, behaviors,
thoughts, or feelings.
•
Keep all follow-up visits with your healthcare provider as scheduled.
Call your healthcare provider between visits as needed, especially if you are worried
about symptoms.
Do not stop TEGRETOL without first talking to a healthcare provider.
Stopping TEGRETOL suddenly can cause serious problems. You should talk to your
healthcare provider before stopping.
Suicidal thoughts or actions can be caused by things other than medicines. If you have
suicidal thoughts or actions, your healthcare provider may check for other causes.
What is TEGRETOL?
TEGRETOL is a prescription medicine used to treat:
• certain types of seizures (partial, tonic-clonic, mixed)
• certain types of nerve pain (trigeminal and glossopharyngeal neuralgia)
TEGRETOL is not a regular pain medicine and should not be used for aches or pains.
Who should not take TEGRETOL?
Do not take TEGRETOL if you:
• have a history of bone marrow depression.
• are allergic to carbamazepine or any of the ingredients in TEGRETOL. See the end of this
Medication Guide for a complete list of ingredients in TEGRETOL.
• take nefazodone.
Reference ID: 3812964
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• are allergic to medicines called tricyclic antidepressants (TCAs). Ask your healthcare
provider or pharmacist for a list of these medicines if you are not sure.
• have taken a medicine called a Monoamine Oxidase Inhibitor (MAOI) in the last 14 days.
Ask your healthcare provider or pharmacist for a list of these medicines if you are not sure.
What should I tell my healthcare provider before taking TEGRETOL?
Before you take TEGRETOL, tell your healthcare provider if you:
• have or have had suicidal thoughts or actions, depression, or mood problems
• have or ever had heart problems
• have or ever had blood problems
• have or ever had liver problems
• have or ever had kidney problems
• have or ever had allergic reactions to medicines
• have or ever had increased pressure in your eye
• have any other medical conditions
• drink grapefruit juice or eat grapefruit
• use birth control. TEGRETOL may make your birth control less effective. Tell your
healthcare provider if your menstrual bleeding changes while you take birth control and
TEGRETOL.
• are pregnant or plan to become pregnant. TEGRETOL may harm your unborn baby.
Tell your healthcare provider right away if you become pregnant while taking
TEGRETOL. You and your healthcare provider should decide if you should take
TEGRETOL while you are pregnant.
▪ If you become pregnant while taking TEGRETOL, talk to your healthcare provider
about registering with the North American Antiepileptic Drug (NAAED) Pregnancy
Registry. The purpose of this registry is to collect information about the safety of
antiepileptic medicine during pregnancy. You can enroll in this registry by calling 1-888
233-2334.
• are breastfeeding or plan to breastfeed. TEGRETOL passes into breast milk. You and
your healthcare provider should discuss whether you should take TEGRETOL or
breastfeed; you should not do both.
Reference ID: 3812964
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Tell your healthcare provider about all the medicines you take, including prescription and
non-prescription medicines, vitamins, and herbal supplements.
Taking TEGRETOL with certain other medicines may cause side effects or affect how well they
work. Do not start or stop other medicines without talking to your healthcare provider.
Know the medicines you take. Keep a list of them and show it to your healthcare provider and
pharmacist when you get a new medicine.
How should I take TEGRETOL?
• Do not stop taking TEGRETOL without first talking to your healthcare provider. Stopping
TEGRETOL suddenly can cause serious problems. Stopping seizure medicine suddenly in a
patient who has epilepsy may cause seizures that will not stop (status epilepticus).
• Take TEGRETOL exactly as prescribed. Your healthcare provider will tell you how much
TEGRETOL to take.
• Your healthcare provider may change your dose. Do not change your dose of TEGRETOL
without talking to your healthcare provider.
• Take TEGRETOL with food.
• TEGRETOL-XR Tablets:
• Do not crush, chew, or break TEGRETOL-XR tablets.
• Tell your healthcare provider if you can not swallow TEGRETOL-XR whole.
• TEGRETOL Suspension:
• Shake the bottle well each time before use.
• Do not take TEGRETOL suspension at the same time you take other liquid medicines.
• If you take too much TEGRETOL, call your healthcare provider or local Poison Control
Center right away.
What should I avoid while taking TEGRETOL?
• Do not drink alcohol or take other drugs that make you sleepy or dizzy while taking
TEGRETOL until you talk to your healthcare provider. TEGRETOL taken with alcohol
or drugs that cause sleepiness or dizziness may make your sleepiness or dizziness worse.
• Do not drive, operate heavy machinery, or do other dangerous activities until you know
how TEGRETOL affects you. TEGRETOL may slow your thinking and motor skills.
What are the possible side effects of TEGRETOL?
See “What is the most important information I should know about TEGRETOL?”
TEGRETOL may cause other serious side effects. These include:
Reference ID: 3812964
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• Irregular heartbeat - symptoms include:
o Fast, slow, or pounding heartbeat
o Shortness of breath
o Feeling lightheaded
o Fainting
• Liver problems - symptoms include:
o yellowing of your skin or the whites of your eyes
o dark urine
o pain on the right side of your stomach area (abdominal pain)
o easy bruising
o loss of appetite
o nausea or vomiting
Get medical help right away if you have any of the symptoms listed above or listed in
“What is the most important information I should know about TEGRETOL?”
The most common side effects of TEGRETOL include:
• dizziness
• drowsiness
• problems with walking and coordination (unsteadiness)
• nausea
• vomiting
These are not all the possible side effects of TEGRETOL. For more information, ask your
healthcare provider or pharmacist.
Tell your healthcare provider if you have any side effect that bothers you or that does not go
away.
Call your doctor for medical advice about side effects. You may report side effects to FDA
at 1-800-FDA-1088.
How should I store TEGRETOL?
Reference ID: 3812964
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
•
Do not store TEGRETOL Tablets above 30°C (86°F).
• Keep TEGRETOL Tablets dry.
• Do not store TEGRETOL Chewable Tablets above 30°C (86°F).
• Keep TEGRETOL Chewable Tablets out of the light.
• Keep TEGRETOL Chewable Tablets dry.
• Store TEGRETOL-XR Tablets at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F
to 86°F).
• Keep TEGRETOL-XR Tablets dry.
• Do not store TEGRETOL Suspension above 30°C (86°F).
• Shake well before using.
• Keep TEGRETOL Suspension in a tight, light-resistant container.
Keep TEGRETOL and all medicines out of the reach of children.
General Information about TEGRETOL
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide.
Do not use TEGRETOL for a condition for which it was not prescribed. Do not give
TEGRETOL to other people, even if they have the same symptoms that you have. It may harm
them.
This Medication Guide summarizes the most important information about TEGRETOL. If you
would like more information, talk with your healthcare provider. You can ask your pharmacist or
healthcare provider for the full prescribing information about TEGRETOL that is written for
health professionals.
For more information, go to www.pharma.us.novartis.com or call 1-888-669-6682.
What are the ingredients in TEGRETOL?
Active ingredient: carbamazepine
Inactive ingredients:
• TEGRETOL Tablets: colloidal silicon dioxide, D&C Red No. 30 Aluminum Lake
(chewable tablets only), FD&C Red No. 40 (200 mg tablets only), flavoring (chewable
tablets only), gelatin, glycerin, magnesium stearate, sodium starch glycolate (chewable
tablets only), starch, stearic acid, and sucrose (chewable tablets only).
• TEGRETOL Suspension: Citric acid, FD&C Yellow No. 6, flavoring, polymer,
potassium sorbate, propylene glycol, purified water, sorbitol, sucrose, and xanthan gum.
Reference ID: 3812964
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• TEGRETOL-XR Tablets: cellulose compounds, dextrates, iron oxides, magnesium
stearate, mannitol, polyethylene glycol, sodium lauryl sulfate, titanium dioxide (200 mg
tablets only).
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Distributed by:
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936
© Novartis
September 2015
Reference ID: 3812964
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:47:06.609250
|
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Labels for NDA 20231
Supplement S-072
Reference ID: 3523812
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Total Adv Clean Between Paste 5.8oz Carton For FDA approval
Date: 05/09/2014
Part# Front: P9888149
Morristown, TN
Version# 1
4 of 15
Reference ID: 3523812
(b) (4)
(b) (4)
(b) (4)
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Total Clean Between Paste 5.8oz Tube For FDA approval
Date: 05/13/2014
Version# 1
Part# Front: P9894796
Morristown, TN
6 of 15
Reference ID: 3523812
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(b) (4)
(b) (4)
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Total Adv Clean Between Gel 5.8oz Carton For FDA approval
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Part# Front: P9888220
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(b) (4)
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Part# Front: P9894797
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(b) (4)
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Total Adv Clean Between .75oz Paste Carton US
Date: 05/14/2014
Version# 1
Part# Front: P9897439
Morristown, TN
13 of 15
Reference ID: 3523812
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(b) (4)
(b) (4)
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Total Clean Between Paste .75oz Tube For FDA approval
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Version# 1
Part# Front: P9897437
Morristown, TN
15 of 15
Reference ID: 3523812
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(b) (4)
(b) (4)
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Labels for NDA 20231
Supplement S-073
Reference ID: 3523812
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Total Daily Repair 5.8oz Carton For FDA approval
Date: 05/08/2014
Part# Front: P9892686
Morristown, TN
Version# 1
4 of 15
Reference ID: 3523812
(b) (4)
(b) (4)
(b) (4)
This label may not be the latest approved by FDA.
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Reference ID: 3523812
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(b) (4)
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Total Daily Repair Gel 5.8oz Carton For FDA approval
Date: 05/08/2014
Part# Front: P9893094
Morristown, TN
Version# 1
8 of 15
Reference ID: 3523812
(b) (4)
(b) (4)
(b) (4)
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Total Daily Repair .75oz Carton For FDA approval
Date: 05/14/2014
Version# 1
Part# Front: P9897438
Morristown, TN
13 of 15
Reference ID: 3523812
(b) (4)
(b) (4)
(b) (4)
This label may not be the latest approved by FDA.
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Total Daily Repair .75oz Tube For FDA approval
Date: 05/14/2014
Version# 1
Part# Front: P9893436
Morristown, TN
15 of 15
Reference ID: 3523812
(b) (4)
(b) (4)
(b) (4)
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|
custom-source
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2025-02-12T13:47:06.654668
|
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Page 3
Tegretol®
carbamazepine USP
Chewable Tablets of 100 mg - red-speckled, pink
Tablets of 200 mg – pink
Suspension of 100 mg/5 mL
Tegretol®-XR
(carbamazepine extended-release tablets)
100 mg, 200 mg, 400 mg
Rx only
Prescribing Information
WARNING
SERIOUS DERMATOLOGIC REACTIONS AND HLA-B*1502 ALLELE
SERIOUS AND SOMETIMES FATAL DERMATOLOGIC REACTIONS, INCLUDING TOXIC
EPIDERMAL NECROLYSIS (TEN) AND STEVENS-JOHNSON SYNDROME (SJS), HAVE BEEN
REPORTED
DURING
TREATMENT
WITH
TEGRETOL.
THESE
REACTIONS
ARE
ESTIMATED TO OCCUR IN 1 TO 6 PER 10,000 NEW USERS IN COUNTRIES WITH MAINLY
CAUCASIAN POPULATIONS, BUT THE RISK IN SOME ASIAN COUNTRIES IS ESTIMATED
TO BE ABOUT 10 TIMES HIGHER. STUDIES IN PATIENTS OF CHINESE ANCESTRY HAVE
FOUND A STRONG ASSOCIATION BETWEEN THE RISK OF DEVELOPING SJS/TEN AND
THE PRESENCE OF HLA-B*1502, AN INHERITED ALLELIC VARIANT OF THE HLA-B
GENE. HLA-B*1502 IS FOUND ALMOST EXCLUSIVELY IN PATIENTS WITH ANCESTRY
ACROSS BROAD AREAS OF ASIA. PATIENTS WITH ANCESTRY IN GENETICALLY AT-
RISK POPULATIONS SHOULD BE SCREENED FOR THE PRESENCE OF HLA-B*1502 PRIOR
TO INITIATING TREATMENT WITH TEGRETOL. PATIENTS TESTING POSITIVE FOR THE
ALLELE SHOULD NOT BE TREATED WITH TEGRETOL UNLESS THE BENEFIT CLEARLY
OUTWEIGHS THE RISK (SEE WARNINGS AND PRECAUTIONS/LABORATORY TESTS).
APLASTIC ANEMIA AND AGRANULOCYTOSIS
APLASTIC ANEMIA AND AGRANULOCYTOSIS HAVE BEEN REPORTED IN ASSOCIATION
WITH THE USE OF TEGRETOL. DATA FROM A POPULATION-BASED CASE CONTROL
STUDY DEMONSTRATE THAT THE RISK OF DEVELOPING THESE REACTIONS IS 5-8
TIMES GREATER THAN IN THE GENERAL POPULATION. HOWEVER, THE OVERALL RISK
OF THESE REACTIONS IN THE UNTREATED GENERAL POPULATION IS LOW,
APPROXIMATELY SIX PATIENTS PER ONE MILLION POPULATION PER YEAR FOR
AGRANULOCYTOSIS AND TWO PATIENTS PER ONE MILLION POPULATION PER YEAR
FOR APLASTIC ANEMIA.
ALTHOUGH REPORTS OF TRANSIENT OR PERSISTENT DECREASED PLATELET OR
WHITE BLOOD CELL COUNTS ARE NOT UNCOMMON IN ASSOCIATION WITH THE USE
OF TEGRETOL, DATA ARE NOT AVAILABLE TO ESTIMATE ACCURATELY THEIR
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 4
INCIDENCE OR OUTCOME. HOWEVER, THE VAST MAJORITY OF THE CASES OF
LEUKOPENIA HAVE NOT PROGRESSED TO THE MORE SERIOUS CONDITIONS OF
APLASTIC ANEMIA OR AGRANULOCYTOSIS.
BECAUSE OF THE VERY LOW INCIDENCE OF AGRANULOCYTOSIS AND APLASTIC
ANEMIA, THE VAST MAJORITY OF MINOR HEMATOLOGIC CHANGES OBSERVED IN
MONITORING OF PATIENTS ON TEGRETOL ARE UNLIKELY TO SIGNAL THE
OCCURRENCE OF EITHER ABNORMALITY. NONETHELESS, COMPLETE PRETREATMENT
HEMATOLOGICAL TESTING SHOULD BE OBTAINED AS A BASELINE. IF A PATIENT IN
THE COURSE OF TREATMENT EXHIBITS LOW OR DECREASED WHITE BLOOD CELL OR
PLATELET
COUNTS,
THE
PATIENT
SHOULD
BE
MONITORED
CLOSELY.
DISCONTINUATION OF THE DRUG SHOULD BE CONSIDERED IF ANY EVIDENCE OF
SIGNIFICANT BONE MARROW DEPRESSION DEVELOPS.
Before prescribing Tegretol, the physician should be thoroughly familiar with the details of
this prescribing information, particularly regarding use with other drugs, especially those which
accentuate toxicity potential.
DESCRIPTION
Tegretol, carbamazepine USP, is an anticonvulsant and specific analgesic for trigeminal neuralgia,
available for oral administration as chewable tablets of 100 mg, tablets of 200 mg, XR tablets of 100,
200, and 400 mg, and as a suspension of 100 mg/5 mL (teaspoon). Its chemical name is 5H-dibenz[b,f
]azepine-5-carboxamide, and its structural formula is
Carbamazepine USP is a white to off-white powder, practically insoluble in water and soluble in
alcohol and in acetone. Its molecular weight is 236.27.
Inactive Ingredients. Tablets: Colloidal silicon dioxide, D&C Red No. 30 Aluminum Lake
(chewable tablets only), FD&C Red No. 40 (200-mg tablets only), flavoring (chewable tablets only),
gelatin, glycerin, magnesium stearate, sodium starch glycolate (chewable tablets only), starch, stearic
acid, and sucrose (chewable tablets only). Suspension: Citric acid, FD&C Yellow No. 6, flavoring,
polymer, potassium sorbate, propylene glycol, purified water, sorbitol, sucrose, and xanthan gum.
Tegretol-XR tablets: cellulose compounds, dextrates, iron oxides, magnesium stearate, mannitol,
polyethylene glycol, sodium lauryl sulfate, titanium dioxide (200-mg tablets only).
CLINICAL PHARMACOLOGY
In controlled clinical trials, Tegretol has been shown to be effective in the treatment of psychomotor
and grand mal seizures, as well as trigeminal neuralgia.
Mechanism of Action
Tegretol has demonstrated anticonvulsant properties in rats and mice with electrically and chemically
induced seizures. It appears to act by reducing polysynaptic responses and blocking the post-tetanic
potentiation. Tegretol greatly reduces or abolishes pain induced by stimulation of the infraorbital nerve
in cats and rats. It depresses thalamic potential and bulbar and polysynaptic reflexes, including the
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linguomandibular reflex in cats. Tegretol is chemically unrelated to other anticonvulsants or other
drugs used to control the pain of trigeminal neuralgia. The mechanism of action remains unknown.
The principal metabolite of Tegretol, carbamazepine-10,11-epoxide, has anticonvulsant activity as
demonstrated in several in vivo animal models of seizures. Though clinical activity for the epoxide
has been postulated, the significance of its activity with respect to the safety and efficacy of Tegretol
has not been established.
Pharmacokinetics
In clinical studies, Tegretol suspension, conventional tablets, and XR tablets delivered equivalent
amounts of drug to the systemic circulation. However, the suspension was absorbed somewhat faster,
and the XR tablet slightly slower, than the conventional tablet. The bioavailability of the XR tablet was
89% compared to suspension. Following a b.i.d. dosage regimen, the suspension provides higher peak
levels and lower trough levels than those obtained from the conventional tablet for the same dosage
regimen. On the other hand, following a t.i.d. dosage regimen, Tegretol suspension affords steady-state
plasma levels comparable to Tegretol tablets given b.i.d. when administered at the same total mg daily
dose. Following a b.i.d. dosage regimen, Tegretol-XR tablets afford steady-state plasma levels
comparable to conventional Tegretol tablets given q.i.d., when administered at the same total mg daily
dose. Tegretol in blood is 76% bound to plasma proteins. Plasma levels of Tegretol are variable and
may range from 0.5-25 µg/mL, with no apparent relationship to the daily intake of the drug. Usual
adult therapeutic levels are between 4 and 12 µg/mL. In polytherapy, the concentration of Tegretol
and concomitant drugs may be increased or decreased during therapy, and drug effects may be altered
(see PRECAUTIONS, Drug Interactions). Following chronic oral administration of suspension,
plasma levels peak at approximately 1.5 hours compared to 4-5 hours after administration of
conventional Tegretol tablets, and 3-12 hours after administration of Tegretol-XR tablets. The
CSF/serum ratio is 0.22, similar to the 24% unbound Tegretol in serum. Because Tegretol induces its
own metabolism, the half-life is also variable. Autoinduction is completed after 3-5 weeks of a fixed
dosing regimen. Initial half-life values range from 25-65 hours, decreasing to 12-17 hours on repeated
doses. Tegretol is metabolized in the liver. Cytochrome P450 3A4 was identified as the major isoform
responsible for the formation of carbamazepine-10,11-epoxide from Tegretol. After oral administration
of 14C-carbamazepine, 72% of the administered radioactivity was found in the urine and 28% in the
feces. This urinary radioactivity was composed largely of hydroxylated and conjugated metabolites,
with only 3% of unchanged Tegretol.
The pharmacokinetic parameters of Tegretol disposition are similar in children and in adults.
However, there is a poor correlation between plasma concentrations of carbamazepine and Tegretol
dose in children. Carbamazepine is more rapidly metabolized to carbamazepine-10,11-epoxide (a
metabolite shown to be equipotent to carbamazepine as an anticonvulsant in animal screens) in the
younger age groups than in adults. In children below the age of 15, there is an inverse relationship
between CBZ-E/CBZ ratio and increasing age (in one report from 0.44 in children below the age of 1
year to 0.18 in children between 10-15 years of age).
The effects of race and gender on carbamazepine pharmacokinetics have not been systematically
evaluated.
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INDICATIONS AND USAGE
Epilepsy
Tegretol is indicated for use as an anticonvulsant drug. Evidence supporting efficacy of Tegretol as an
anticonvulsant was derived from active drug-controlled studies that enrolled patients with the
following seizure types:
1. Partial seizures with complex symptomatology (psychomotor, temporal lobe). Patients with these
seizures appear to show greater improvement than those with other types.
2. Generalized tonic-clonic seizures (grand mal).
3. Mixed seizure patterns which include the above, or other partial or generalized seizures. Absence
seizures (petit mal) do not appear to be controlled by Tegretol (see PRECAUTIONS, General).
Trigeminal Neuralgia
Tegretol is indicated in the treatment of the pain associated with true trigeminal neuralgia.
Beneficial results have also been reported in glossopharyngeal neuralgia.
This drug is not a simple analgesic and should not be used for the relief of trivial aches or pains.
CONTRAINDICATIONS
Tegretol should not be used in patients with a history of previous bone marrow depression,
hypersensitivity to the drug, or known sensitivity to any of the tricyclic compounds, such as
amitriptyline, desipramine, imipramine, protriptyline, nortriptyline, etc. Likewise, on theoretical
grounds its use with monoamine oxidase inhibitors is not recommended. Before administration of
Tegretol, MAO inhibitors should be discontinued for a minimum of 14 days, or longer if the clinical
situation permits.
WARNINGS
Serious Dermatologic Reactions
Serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN)
and Stevens-Johnson syndrome (SJS), have been reported with Tegretol treatment. The risk of these
events is estimated to be about 1 to 6 per 10,000 new users in countries with mainly Caucasian
populations. However, the risk in some Asian countries is estimated to be about 10 times higher.
Tegretol should be discontinued at the first sign of a rash, unless the rash is clearly not drug-related. If
signs or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative therapy
should be considered.
SJS/TEN and HLA-B*1502 Allele
Retrospective case-control studies have found that in patients of Chinese ancestry there is a strong
association between the risk of developing SJS/TEN with carbamazepine treatment and the presence of
an inherited variant of the HLA-B gene, HLA-B*1502. The occurrence of higher rates of these
reactions in countries with higher frequencies of this allele suggests that the risk may be increased in
allele-positive individuals of any ethnicity.
Across Asian populations, notable variation exists in the prevalence of HLA-B*1502. Greater than
15% of the population is reported positive in Hong Kong, Thailand, Malaysia, and parts of the
Philippines, compared to about 10% in Taiwan and 4% in North China. South Asians, including
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Indians, appear to have intermediate prevalence of HLA-B*1502, averaging 2 to 4%, but higher in
some groups. HLA-B*1502 is present in <1% of the population in Japan and Korea.
HLA-B*1502 is largely absent in individuals not of Asian origin (e.g., Caucasians, African-
Americans, Hispanics, and Native Americans).
Prior to initiating Tegretol therapy, testing for HLA-B*1502 should be performed in patients
with ancestry in populations in which HLA-B*1502 may be present. In deciding which patients to
screen, the rates provided above for the prevalence of HLA-B*1502 may offer a rough guide, keeping
in mind the limitations of these figures due to wide variability in rates even within ethnic groups, the
difficulty in ascertaining ethnic ancestry, and the likelihood of mixed ancestry. Tegretol should not be
used in patients positive for HLA-B*1502 unless the benefits clearly outweigh the risks. Tested
patients who are found to be negative for the allele are thought to have a low risk of SJS/TEN (see
WARNINGS and PRECAUTIONS/Laboratory Tests).
Over 90% of Tegretol treated patients who will experience SJS/TEN have this reaction within the
first few months of treatment. This information may be taken into consideration in determining the
need for screening of genetically at-risk patients currently on Tegretol.
The HLA-B*1502 allele has not been found to predict risk of less severe adverse cutaneous
reactions from Tegretol, such as anticonvulsant hypersensitivity syndrome or non-serious rash
(maculopapular eruption [MPE]).
Limited evidence suggests that HLA-B*1502 may be a risk factor for the development of
SJS/TEN in patients of Chinese ancestry taking other anti-epileptic drugs associated with SJS/TEN.
Consideration should be given to avoiding use of other drugs associated with SJS/TEN in HLA-
B*1502 positive patients, when alternative therapies are otherwise equally acceptable.
Application of HLA-B*1502 genotyping as a screening tool has important limitations and must
never substitute for appropriate clinical vigilance and patient management. Many HLA-B*1502-
positive Asian patients treated with Tegretol will not develop SJS/TEN, and these reactions can still
occur infrequently in HLA-B*1502-negative patients of any ethnicity. The role of other possible
factors in the development of, and morbidity from, SJS/TEN, such as antiepileptic drug (AED) dose,
compliance, concomitant medications, co-morbidities, and the level of dermatologic monitoring have
not been studied.
Aplastic Anemia and Agranulocytosis
Patients with a history of adverse hematologic reaction to any drug may be particularly at risk of bone
marrow depression
General
Tegretol has shown mild anticholinergic activity; therefore, patients with increased intraocular
pressure should be closely observed during therapy.
Because of the relationship of the drug to other tricyclic compounds, the possibility of activation of
a latent psychosis and, in elderly patients, of confusion or agitation should be borne in mind.
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The use of Tegretol should be avoided in patients with a history of hepatic porphyria (e.g., acute
intermittent porphyria, variegate porphyria, porphyria cutanea tarda). Acute attacks have been reported
in such patients receiving Tegretol therapy. Carbamazepine administration has also been demonstrated
to increase porphyrin precursors in rodents, a presumed mechanism for the induction of acute attacks
of porphyria.
As with all antiepileptic drugs, Tegretol should be withdrawn gradually to minimize the potential
of increased seizure frequency.
Usage in Pregnancy
Carbamazepine can cause fetal harm when administered to a pregnant woman.
Epidemiological data suggest that there may be an association between the use of carbamazepine
during pregnancy and congenital malformations, including spina bifida. There have also been reports
that associate carbamazepine with developmental disorders and congenital anomalies (e.g., craniofacial
defects, cardiovascular malformations and anomalies involving various body systems). Developmental
delays based on neurobehavioral assessments have been reported. In treating or counseling women of
childbearing potential, the prescribing physician will wish to weigh the benefits of therapy against the
risks. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug,
the patient should be apprised of the potential hazard to the fetus.
Retrospective case reviews suggest that, compared with monotherapy, there may be a higher
prevalence of teratogenic effects associated with the use of anticonvulsants in combination therapy.
Therefore, if therapy is to be continued, monotherapy may be preferable for pregnant women.
In humans, transplacental passage of carbamazepine is rapid (30-60 minutes), and the drug is
accumulated in the fetal tissues, with higher levels found in liver and kidney than in brain and lung.
Carbamazepine has been shown to have adverse effects in reproduction studies in rats when given
orally in dosages 10-25 times the maximum human daily dosage (MHDD) of 1200 mg on a mg/kg
basis or 1.5-4 times the MHDD on a mg/m2 basis. In rat teratology studies, 2 of 135 offspring showed
kinked ribs at 250 mg/kg and 4 of 119 offspring at 650 mg/kg showed other anomalies (cleft palate, 1;
talipes, 1; anophthalmos, 2). In reproduction studies in rats, nursing offspring demonstrated a lack of
weight gain and an unkempt appearance at a maternal dosage level of 200 mg/kg.
Antiepileptic drugs should not be discontinued abruptly in patients in whom the drug is
administered to prevent major seizures because of the strong possibility of precipitating status
epilepticus with attendant hypoxia and threat to life. In individual cases where the severity and
frequency of the seizure disorder are such that removal of medication does not pose a serious threat to
the patient, discontinuation of the drug may be considered prior to and during pregnancy, although it
cannot be said with any confidence that even minor seizures do not pose some hazard to the
developing embryo or fetus.
Tests to detect defects using currently accepted procedures should be considered a part of routine
prenatal care in childbearing women receiving carbamazepine.
There have been a few cases of neonatal seizures and/or respiratory depression associated with
maternal Tegretol and other concomitant anticonvulsant drug use. A few cases of neonatal vomiting,
diarrhea, and/or decreased feeding have also been reported in association with maternal Tegretol use.
These symptoms may represent a neonatal withdrawal syndrome.
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PRECAUTIONS
General
Before initiating therapy, a detailed history and physical examination should be made.
Tegretol should be used with caution in patients with a mixed seizure disorder that includes
atypical absence seizures, since in these patients Tegretol has been associated with increased frequency
of generalized convulsions (see INDICATIONS AND USAGE).
Therapy should be prescribed only after critical benefit-to-risk appraisal in patients with a history
of cardiac conduction disturbance, including second and third degree AV heart block; cardiac, hepatic,
or renal damage; adverse hematologic or hypersensitivity reaction to other drugs, including reactions to
other anticonvulsants; or interrupted courses of therapy with Tegretol.
AV heart block, including second and third degree block, have been reported following, Tegretol
treatment. This occurred generally, but not solely, in patients with underling EKG abnormalities or risk
factors for conduction disturbances.
Hepatic effects, ranging from slight elevations in liver enzymes to rare cases of hepatic failure have
been reported (see ADVERSE REACTIONS and PRECAUTIONS, Laboratory Tests). In some cases,
hepatic effects may progress despite discontinuation of the drug.
Multi-organ hypersensitivity reactions occurring days to weeks or months after initiating treatment
have been reported in rare cases (see ADVERSE REACTIONS, Other and PRECAUTIONS,
Information for Patients).
Discontinuation of carbamazepine should be considered if any evidence of hypersensitivity
develops.
Hypersensitivity reactions to carbamazepine have been reported in patients who previously
experienced this reaction to anticonvulsants including phenytoin and phenobarbital. A history of
hypersensitivity reactions should be obtained for a patient and the immediate family members. If
positive, caution should be used in prescribing carbamazepine.
Since a given dose of Tegretol suspension will produce higher peak levels than the same dose
given as the tablet, it is recommended that patients given the suspension be started on lower doses and
increased slowly to avoid unwanted side effects (see DOSAGE AND ADMINISTRATION).
Information for Patients
Patients should be made aware of the early toxic signs and symptoms of a potential hematologic
problem, as well as dermatologic, hypersensitivity or hepatic reactions. These symptoms may include,
but are not limited to, fever, sore throat, rash, ulcers in the mouth, easy bruising, lymphadenopathy and
petechial or purpuric hemorrhage, and in the case of liver reactions, anorexia, nausea/vomiting, or
jaundice. The patient should be advised that, because these signs and symptoms may signal a serious
reaction, that they must report any occurrence immediately to a physician. In addition, the patient
should be advised that these signs and symptoms should be reported even if mild or when occurring
after extended use.
Tegretol may interact with some drugs. Therefore, patients should be advised to report to their doctors
the use of any other prescription or non-prescription medications or herbal products.
Caution should be exercised if alcohol is taken in combination with Tegretol therapy, due to a possible
additive sedative effect.
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Since dizziness and drowsiness may occur, patients should be cautioned about the hazards of
operating machinery or automobiles or engaging in other potentially dangerous tasks.
Laboratory Tests
For genetically at-risk patients (See WARNINGS), high-resolution ‘HLA-B*1502 typing’ is
recommended. The test is positive if either one or two HLA-B*1502 alleles are detected and negative
if no HLA-B*1502 alleles are detected.
Complete pretreatment blood counts, including platelets and possibly reticulocytes and serum iron,
should be obtained as a baseline. If a patient in the course of treatment exhibits low or decreased white
blood cell or platelet counts, the patient should be monitored closely. Discontinuation of the drug
should be considered if any evidence of significant bone marrow depression develops.
Baseline and periodic evaluations of liver function, particularly in patients with a history of liver
disease, must be performed during treatment with this drug since liver damage may occur (see
PRECAUTIONS, General and ADVERSE REACTIONS). Carbamazepine should be discontinued,
based on clinical judgment, if indicated by newly occurring or worsening clinical or laboratory
evidence of liver dysfunction or hepatic damage, or in the case of active liver disease.
Baseline and periodic eye examinations, including slit-lamp, funduscopy, and tonometry, are
recommended since many phenothiazines and related drugs have been shown to cause eye changes.
Baseline and periodic complete urinalysis and BUN determinations are recommended for patients
treated with this agent because of observed renal dysfunction.
Monitoring of blood levels (see CLINICAL PHARMACOLOGY) has increased the efficacy and
safety of anticonvulsants. This monitoring may be particularly useful in cases of dramatic increase in
seizure frequency and for verification of compliance. In addition, measurement of drug serum levels
may aid in determining the cause of toxicity when more than one medication is being used.
Thyroid function tests have been reported to show decreased values with Tegretol administered
alone.
Hyponatremia has been reported in association with Tegretol use, either alone or in combination
with other drugs.
Interference with some pregnancy tests has been reported.
Drug Interactions
There has been a report of a patient who passed an orange rubbery precipitate in his stool the day after
ingesting Tegretol suspension immediately followed by Thorazine® solution. Subsequent testing has
shown that mixing Tegretol suspension and chlorpromazine solution (both generic and brand name) as
well as Tegretol suspension and liquid Mellaril® resulted in the occurrence of this precipitate. Because
the extent to which this occurs with other liquid medications is not known, Tegretol suspension should
not be administered simultaneously with other liquid medicinal agents or diluents. (see Dosage and
Administration).
Clinically meaningful drug interactions have occurred with concomitant medications and include,
but are not limited to, the following:
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Agents That May Affect Tegretol Plasma Levels
CYP 3A4 inhibitors inhibit Tegretol metabolism and can thus increase plasma carbamazepine levels.
Drugs that have been shown, or would be expected, to increase plasma carbamazepine levels include
cimetidine, danazol, diltiazem, macrolides, erythromycin, troleandomycin, clarithromycin,
fluoxetine, fluvoxamine, nefazodone, loratadine, terfenadine, isoniazid, niacinamide,
nicotinamide,
propoxyphene,
azoles
(e.g.,
ketaconazole,
itraconazole,
fluconazole),
acetazolamide, verapamil, grapefruit juice, protease inhibitors, valproate.*
CYP 3A4 inducers can increase the rate of Tegretol metabolism. Drugs that have been shown, or that
would be expected, to decrease plasma carbamazepine levels include
cisplatin, doxorubicin HCl, felbamate,† rifampin, phenobarbital, phenytoin, primidone,
methsuximide, theophylline.
When carbamazepine is given with drugs that can increase or decrease carbamazepine levels, close
monitoring of carbamazepine levels is indicated and dosage adjustment may be required.
*increased levels of the active 10,11-epoxide
†decreased levels of carbamazepine and increased levels of the 10,11-epoxide
Effect of Tegretol on Plasma Levels of Concomitant Agents
Increased levels: clomipramine HCl, phenytoin, primidone
Tegretol induces hepatic CYP activity. Tegretol causes, or would be expected to cause, decreased
levels of the following:
acetaminophen, alprazolam, dihydropyridine calcium channel blockers (e.g., felodipine),
cyclosporine, corticosteroids (e.g., prednisolone, dexamethasone), clonazepam, clozapine,
dicumarol, doxycycline, ethosuximide, haloperidol, itraconazole, lamotrigine, levothyroxine,
methadone, methsuximide, midazolam, olanzapine, oral and other hormonal contraceptives,
oxcarbazepine, phensuximide, phenytoin, praziquantel, protease inhibitors, risperidone,
theophylline, tiagabine, topiramate, tramadol, tricyclic antidepressants (e.g., imipramine,
amitriptyline, nortriptyline), valproate, warfarin,ziprasidone, zonisamide.
In concomitant use with Tegretol, dosage adjustment of the above agents may be necessary.
Concomitant administration of carbamazepine and lithium may increase the risk of neurotoxic side
effects.
Co-administration of carbamazepine with nefazodone results in insufficient plasma concentrations of
nefazodone and its active metabolite to achieve a therapeutic effect. Co-administration of
carbamazepine with nefazodone is contraindicated. (See CONTRAINDICATIONS).
Alterations of thyroid function have been reported in combination therapy with other
anticonvulsant medications.
Concomitant use of Tegretol with hormonal contraceptive products (e.g., oral, and levonorgestrel
subdermal implant contraceptives) may render the contraceptives less effective because the plasma
concentrations of the hormones may be decreased. Breakthrough bleeding and unintended pregnancies
have been reported. Alternative or back-up methods of contraception should be considered.
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Carcinogenesis, Mutagenesis, Impairment of Fertility
Carbamazepine, when administered to Sprague-Dawley rats for two years in the diet at doses of 25, 75,
and 250 mg/kg/day, resulted in a dose-related increase in the incidence of hepatocellular tumors in
females and of benign interstitial cell adenomas in the testes of males.
Carbamazepine must, therefore, be considered to be carcinogenic in Sprague-Dawley rats.
Bacterial and mammalian mutagenicity studies using carbamazepine produced negative results. The
significance of these findings relative to the use of carbamazepine in humans is, at present, unknown.
Usage in Pregnancy
Pregnancy Category D (see WARNINGS).
Labor and Delivery
The effect of Tegretol on human labor and delivery is unknown.
Nursing Mothers
Tegretol and its epoxide metabolite are transferred to breast milk. The ratio of the concentration in
breast milk to that in maternal plasma is about 0.4 for Tegretol and about 0.5 for the epoxide. The
estimated doses given to the newborn during breast feeding are in the range of 2-5 mg daily for
Tegretol and 1-2 mg daily for the epoxide.
Because of the potential for serious adverse reactions in nursing infants from carbamazepine, a
decision should be made whether to discontinue nursing or to discontinue the drug, taking into account
the importance of the drug to the mother.
Pediatric Use
Substantial evidence of Tegretol’s effectiveness for use in the management of children with epilepsy
(see Indications for specific seizure types) is derived from clinical investigations performed in adults
and from studies in several in vitro systems which support the conclusion that (1) the pathogenetic
mechanisms underlying seizure propagation are essentially identical in adults and children, and (2) the
mechanism of action of carbamazepine in treating seizures is essentially identical in adults and
children.
Taken as a whole, this information supports a conclusion that the generally accepted therapeutic
range of total carbamazepine in plasma (i.e., 4-12 mcg/mL) is the same in children and adults.
The evidence assembled was primarily obtained from short-term use of carbamazepine. The safety
of carbamazepine in children has been systematically studied up to 6 months. No longer-term data
from clinical trials is available.
Geriatric Use
No systematic studies in geriatric patients have been conducted.
ADVERSE REACTIONS
If adverse reactions are of such severity that the drug must be discontinued, the physician must be
aware that abrupt discontinuation of any anticonvulsant drug in a responsive epileptic patient may lead
to seizures or even status epilepticus with its life-threatening hazards.
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The most severe adverse reactions have been observed in the hemopoietic system (see boxed
WARNING), the liver and the cardiovascular system.
The most frequently observed adverse reactions, particularly during the initial phases of therapy,
are dizziness, drowsiness, unsteadiness, nausea, and vomiting. To minimize the possibility of such
reactions, therapy should be initiated at the low dosage recommended.
The following additional adverse reactions have been reported:
Hemopoietic System: Aplastic anemia, agranulocytosis, pancytopenia, bone marrow depression,
thrombocytopenia, leukopenia, leukocytosis, eosinophilia, acute intermittent porphyria.
Skin: Toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) (see BOXED
WARNING), pruritic and erythematous rashes, urticaria, photosensitivity reactions, alterations in skin
pigmentation, exfoliative dermatitis, erythema multiforme and nodosum, purpura, aggravation of
disseminated lupus erythematosus, alopecia, and diaphoresis. In certain cases, discontinuation of
therapy may be necessary. Isolated cases of hirsutism have been reported, but a causal relationship is
not clear.
Cardiovascular System: Congestive heart failure, edema, aggravation of hypertension, hypotension,
syncope and collapse, aggravation of coronary artery disease, arrhythmias and AV block,
thrombophlebitis, thromboembolism, and adenopathy or lymphadenopathy.
Some of these cardiovascular complications have resulted in fatalities. Myocardial infarction has
been associated with other tricyclic compounds.
Liver: Abnormalities in liver function tests, cholestatic and hepatocellular jaundice, hepatitis; very
rare cases of hepatic failure.
Pancreatic: Pancreatitis.
Respiratory System: Pulmonary hypersensitivity characterized by fever, dyspnea, pneumonitis, or
pneumonia.
Genitourinary System: Urinary frequency, acute urinary retention, oliguria with elevated blood
pressure, azotemia, renal failure, and impotence. Albuminuria, glycosuria, elevated BUN, and
microscopic deposits in the urine have also been reported.
Testicular atrophy occurred in rats receiving Tegretol orally from 4-52 weeks at dosage levels of
50-400 mg/kg/day. Additionally, rats receiving Tegretol in the diet for 2 years at dosage levels of 25,
75, and 250 mg/kg/day had a dose-related incidence of testicular atrophy and aspermatogenesis. In
dogs, it produced a brownish discoloration, presumably a metabolite, in the urinary bladder at dosage
levels of 50 mg/kg and higher. Relevance of these findings to humans is unknown.
Nervous System: Dizziness, drowsiness, disturbances of coordination, confusion, headache, fatigue,
blurred vision, visual hallucinations, transient diplopia, oculomotor disturbances, nystagmus, speech
disturbances, abnormal involuntary movements, peripheral neuritis and paresthesias, depression with
agitation, talkativeness, tinnitus, and hyperacusis.
There have been reports of associated paralysis and other symptoms of cerebral arterial
insufficiency, but the exact relationship of these reactions to the drug has not been established.
Isolated cases of neuroleptic malignant syndrome have been reported with concomitant use of
psychotropic drugs.
Digestive System: Nausea, vomiting, gastric distress and abdominal pain, diarrhea, constipation,
anorexia, and dryness of the mouth and pharynx, including glossitis and stomatitis.
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Eyes: Scattered punctate cortical lens opacities, as well as conjunctivitis, have been reported. Although
a direct causal relationship has not been established, many phenothiazines and related drugs have been
shown to cause eye changes.
Musculoskeletal System: Aching joints and muscles, and leg cramps.
Metabolism: Fever and chills. Inappropriate antidiuretic hormone (ADH) secretion syndrome has
been reported. Cases of frank water intoxication, with decreased serum sodium (hyponatremia) and
confusion, have been reported in association with Tegretol use (see PRECAUTIONS, Laboratory
Tests). Decreased levels of plasma calcium have been reported.
Other: Multi-organ hypersensitivity reactions occurring days to weeks or months after initiating
treatment have been reported in rare cases. Signs or symptoms may include, but are not limited to
fever, skin rashes, vasculitis, lymphadenopathy, disorders mimicking lymphoma, arthralgia,
leukopenia, eosinophilia, hepato-splenomegaly and abnormal liver function tests. These signs and
symptoms may occur in various combinations and not necessarily concurrently. Signs and symptoms
may initially be mild. Various organs, including but not limited to, liver, skin, immune system, lungs,
kidneys, pancreas, myocardium, and colon may be affected (see PRECAUTIONS, General and
PRECAUTIONS, Information for Patients).
Isolated cases of a lupus erythematosus-like syndrome have been reported. There have been
occasional reports of elevated levels of cholesterol, HDL cholesterol, and triglycerides in patients
taking anticonvulsants.
A case of aseptic meningitis, accompanied by myoclonus and peripheral eosinophilia, has been
reported in a patient taking carbamazepine in combination with other medications. The patient was
successfully dechallenged, and the meningitis reappeared upon rechallenge with carbamazepine.
DRUG ABUSE AND DEPENDENCE
No evidence of abuse potential has been associated with Tegretol, nor is there evidence of
psychological or physical dependence in humans.
OVERDOSAGE
Acute Toxicity
Lowest known lethal dose: adults, 3.2 g (a 24-year-old woman died of a cardiac arrest and a 24-year-
old man died of pneumonia and hypoxic encephalopathy); children, 4 g (a 14-year-old girl died of a
cardiac arrest), 1.6 g (a 3-year-old girl died of aspiration pneumonia).
Oral LD50 in animals (mg/kg): mice, 1100-3750; rats, 3850-4025; rabbits, 1500-2680; guinea pigs,
920.
Signs and Symptoms
The first signs and symptoms appear after 1-3 hours. Neuromuscular disturbances are the most
prominent. Cardiovascular disorders are generally milder, and severe cardiac complications occur only
when very high doses (> 60 g) have been ingested.
Respiration: Irregular breathing, respiratory depression.
Cardiovascular System: Tachycardia, hypotension or hypertension, shock, conduction disorders.
Nervous System and Muscles: Impairment of consciousness ranging in severity to deep coma.
Convulsions, especially in small children. Motor restlessness, muscular twitching, tremor, athetoid
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Page 15
movements, opisthotonos, ataxia, drowsiness, dizziness, mydriasis, nystagmus, adiadochokinesia,
ballism, psychomotor disturbances, dysmetria. Initial hyperreflexia, followed by hyporeflexia.
Gastrointestinal Tract: Nausea, vomiting.
Kidneys and Bladder: Anuria or oliguria, urinary retention.
Laboratory Findings: Isolated instances of overdosage have included leukocytosis, reduced leukocyte
count, glycosuria, and acetonuria. EEG may show dysrhythmias.
Combined Poisoning: When alcohol, tricyclic antidepressants, barbiturates, or hydantoins are taken at
the same time, the signs and symptoms of acute poisoning with Tegretol may be aggravated or
modified.
Treatment
The prognosis in cases of severe poisoning is critically dependent upon prompt elimination of the drug,
which may be achieved by inducing vomiting, irrigating the stomach, and by taking appropriate steps
to diminish absorption. If these measures cannot be implemented without risk on the spot, the patient
should be transferred at once to a hospital, while ensuring that vital functions are safeguarded. There is
no specific antidote.
Elimination of the Drug: Induction of vomiting.
Gastric lavage. Even when more than 4 hours have elapsed following ingestion of the drug, the
stomach should be repeatedly irrigated, especially if the patient has also consumed alcohol.
Measures to Reduce Absorption: Activated charcoal, laxatives.
Measures to Accelerate Elimination: Forced diuresis.
Dialysis is indicated only in severe poisoning associated with renal failure. Replacement
transfusion is indicated in severe poisoning in small children.
Respiratory Depression: Keep the airways free; resort, if necessary, to endotracheal intubation,
artificial respiration, and administration of oxygen.
Hypotension, Shock: Keep the patient’s legs raised and administer a plasma expander. If blood
pressure fails to rise despite measures taken to increase plasma volume, use of vasoactive substances
should be considered.
Convulsions: Diazepam or barbiturates.
Warning: Diazepam or barbiturates may aggravate respiratory depression (especially in children),
hypotension, and coma. However, barbiturates should not be used if drugs that inhibit monoamine
oxidase have also been taken by the patient either in overdosage or in recent therapy (within 1 week).
Surveillance: Respiration, cardiac function (ECG monitoring), blood pressure, body temperature,
pupillary reflexes, and kidney and bladder function should be monitored for several days.
Treatment of Blood Count Abnormalities: If evidence of significant bone marrow depression
develops, the following recommendations are suggested: (1) stop the drug, (2) perform daily CBC,
platelet, and reticulocyte counts, (3) do a bone marrow aspiration and trephine biopsy immediately and
repeat with sufficient frequency to monitor recovery.
Special periodic studies might be helpful as follows: (1) white cell and platelet antibodies, (2)
59Fe-ferrokinetic studies, (3) peripheral blood cell typing, (4) cytogenetic studies on marrow and
peripheral blood, (5) bone marrow culture studies for colony-forming units, (6) hemoglobin
electrophoresis for A2 and F hemoglobin, and (7) serum folic acid and B12 levels.
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Page 16
A fully developed aplastic anemia will require appropriate, intensive monitoring and therapy, for
which specialized consultation should be sought.
DOSAGE AND ADMINISTRATION (see table below)
Tegretol suspension in combination with liquid chlorpromazine or thioridazine results in
precipitate formation, and, in the case of chlorpromazine, there has been a report of a patient passing
an orange rubbery precipitate in the stool following coadministration of the two drugs. (See Drug
Interactions). Because the extent to which this occurs with other liquid medications is not known,
Tegretol suspension should not be administered simultaneously with other liquid medications or
diluents.
Monitoring of blood levels has increased the efficacy and safety of anticonvulsants (see
PRECAUTIONS, Laboratory Tests). Dosage should be adjusted to the needs of the individual patient.
A low initial daily dosage with a gradual increase is advised. As soon as adequate control is achieved,
the dosage may be reduced very gradually to the minimum effective level. Medication should be taken
with meals.
Since a given dose of Tegretol suspension will produce higher peak levels than the same dose
given as the tablet, it is recommended to start with low doses (children 6-12 years: 1/2 teaspoon q.i.d.)
and to increase slowly to avoid unwanted side effects.
Conversion of patients from oral Tegretol tablets to Tegretol suspension: Patients should be
converted by administering the same number of mg per day in smaller, more frequent doses (i.e., b.i.d.
tablets to t.i.d. suspension).
Tegretol-XR is an extended-release formulation for twice-a-day administration. When converting
patients from Tegretol conventional tablets to Tegretol-XR, the same total daily mg dose of
Tegretol-XR should be administered. Tegretol-XR tablets must be swallowed whole and never
crushed or chewed. Tegretol-XR tablets should be inspected for chips or cracks. Damaged tablets, or
tablets without a release portal, should not be consumed. Tegretol-XR tablet coating is not absorbed
and is excreted in the feces; these coatings may be noticeable in the stool.
Epilepsy (see INDICATIONS AND USAGE)
Adults and children over 12 years of age - Initial: Either 200 mg b.i.d. for tablets and XR tablets, or
1 teaspoon q.i.d. for suspension (400 mg/day). Increase at weekly intervals by adding up to 200
mg/day using a b.i.d. regimen of Tegretol-XR or a t.i.d. or q.i.d. regimen of the other formulations until
the optimal response is obtained. Dosage generally should not exceed 1000 mg daily in children 12-15
years of age, and 1200 mg daily in patients above 15 years of age. Doses up to 1600 mg daily have
been used in adults in rare instances. Maintenance: Adjust dosage to the minimum effective level,
usually 800-1200 mg daily.
Children 6-12 years of age - Initial: Either 100 mg b.i.d. for tablets or XR tablets, or 1/2 teaspoon
q.i.d. for suspension (200 mg/day). Increase at weekly intervals by adding up to 100 mg/day using a
b.i.d. regimen of Tegretol-XR or a t.i.d. or q.i.d. regimen of the other formulations until the optimal
response is obtained. Dosage generally should not exceed 1000 mg daily. Maintenance: Adjust
dosage to the minimum effective level, usually 400-800 mg daily.
Children under 6 years of age - Initial: 10-20 mg/kg/day b.i.d. or t.i.d. as tablets, or q.i.d. as
suspension. Increase weekly to achieve optimal clinical response administered t.i.d. or q.i.d.
Maintenance: Ordinarily, optimal clinical response is achieved at daily doses below 35 mg/kg. If
satisfactory clinical response has not been achieved, plasma levels should be measured to determine
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Page 17
whether or not they are in the therapeutic range. No recommendation regarding the safety of
carbamazepine for use at doses above 35 mg/kg/24 hours can be made.
Combination Therapy: Tegretol may be used alone or with other anticonvulsants. When added to
existing anticonvulsant therapy, the drug should be added gradually while the other anticonvulsants are
maintained or gradually decreased, except phenytoin, which may have to be increased (see
PRECAUTIONS, Drug Interactions, and Pregnancy Category D).
Trigeminal Neuralgia (see INDICATIONS AND USAGE)
Initial: On the first day, either 100 mg b.i.d. for tablets or XR tablets, or 1/2 teaspoon q.i.d. for
suspension, for a total daily dose of 200 mg. This daily dose may be increased by up to 200 mg/day
using increments of 100 mg every 12 hours for tablets or XR tablets, or 50 mg (1/2 teaspoon) q.i.d. for
suspension, only as needed to achieve freedom from pain. Do not exceed 1200 mg daily.
Maintenance: Control of pain can be maintained in most patients with 400-800 mg daily. However,
some patients may be maintained on as little as 200 mg daily, while others may require as much as
1200 mg daily. At least once every 3 months throughout the treatment period, attempts should be made
to reduce the dose to the minimum effective level or even to discontinue the drug.
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Page 18
Dosage Information
Initial Dose
Subsequent Dose
Maximum Daily Dose
Indication
Tablet*
XR
†
Suspension
Tablet*
XR
†
Suspension
Tablet*
XR
†
Suspension
Epilepsy
Under 6 yr
10-20 mg/kg/day
b.i.d. or t.i.d.
10-20 mg/kg/day
q.i.d.
Increase
weekly to
achieve
optimal clinical
response,
t.i.d. or q.i.d.
Increase weekly
to achieve
optimal clinical
response, t.i.d. or
q.i.d.
35 mg/kg/24 hr
(see Dosage and
Administration
section above)
35 mg/kg/24 hr
(see Dosage and
Administration
section above)
6-12 yr
100 mg b.i.d.
(200 mg/day)
100 mg b.i.d.
(200 mg/day)
½ tsp q.i.d.
(200 mg/day)
Add up to 100
mg/day at
weekly
intervals, t.i.d.
or q.i.d.
Add
100 mg/day
at weekly
intervals,
b.i.d.
Add up to 1 tsp
(100 mg)/day at
weekly intervals,
t.i.d. or q.i.d.
1000 mg/24 hr
Over 12 yr
200 mg b.i.d.
(400 mg/day)
200 mg b.i.d.
(400 mg/day)
1 tsp q.i.d.
(400 mg/day)
Add up to 200
mg/day at
weekly
intervals, t.i.d.
or q.i.d.
Add up to
200 mg/day
at weekly
intervals,
b.i.d.
Add up to 2 tsp
(200 mg)/day at
weekly intervals,
t.i.d. or q.i.d.
1000 mg/24 hr (12-15 yr)
1200 mg/24 hr (>15 yr)
1600 mg/24 hr (adults, in rare instances)
Trigeminal
Neuralgia
100 mg b.i.d.
(200 mg/day)
100 mg b.i.d.
(200 mg/day)
½ tsp q.i.d.
(200 mg/day)
Add up to 200
mg/day in
increments of
100 mg every
12 hr
Add up to
200 mg/day
in increments
of 100 mg
every 12 hr
Add up to 2 tsp
(200 mg)/day
in increments of
50 mg
(½ tsp) q.i.d.
1200 mg/24 hr
*Tablet = Chewable or conventional tablets
†XR = Tegretol
®-XR extended-release tablets
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HOW SUPPLIED
Chewable Tablets 100 mg - round, red-speckled, pink, single-scored (imprinted Tegretol on one side
and 52 twice on the scored side)
Bottles of 100.........................................................................................NDC 0083-0052-30
Unit Dose (blister pack)
Box of 100 (strips of 10)..................................................................NDC 0083-0052-32
Do not store above 30°C (86°F). Protect from light and moisture.
Dispense in tight, light-resistant container (USP).
Meets USP Dissolution Test 1.
Tablets 200 mg - capsule-shaped, pink, single-scored (imprinted Tegretol on one side and 27 twice on
the partially scored side)
Bottles of 100.........................................................................................NDC 0083-0027-30
Bottles of 1000.......................................................................................NDC 0083-0027-40
Unit Dose (blister pack)
Box of 100 (strips of 10)..................................................................NDC 0083-0027-32
Do not store above 30°C (86°F). Protect from moisture. Dispense in tight container (USP).
Meets USP Dissolution Test 2.
XR Tablets 100 mg - round, yellow, coated (imprinted T on one side and 100 mg on the other), release
portal on one side
Bottles of 100.........................................................................................NDC 0083-0061-30
XR Tablets 200 mg - round, pink, coated (imprinted T on one side and 200 mg on the other), release
portal on one side
Bottles of 100.........................................................................................NDC 0083-0062-30
XR Tablets 400 mg - round, brown, coated (imprinted T on one side and 400 mg on the other), release
portal on one side
Bottles of 100.........................................................................................NDC 0083-0060-30
Store at controlled room temperature 15°C-30°C (59°F-86°F). Protect from moisture. Dispense in
tight, container (USP).
Suspension 100 mg/5 mL (teaspoon) - yellow-orange, citrus-vanilla flavored
Bottles of 450 mL..................................................................................NDC 0083-0019-76
Shake well before using.
Do not store above 30°C (86°F). Dispense in tight, light resistant container (USP).
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Tegretol Chewable Tablets Manufactured by:
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936
Tegretol Tablets Manufactured by:
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936
Tegretol Suspension Manufactured by:
Patheon Whitby Inc.Whitby Operations
Whitby Ontario, Canada
L1N 5Z5
Tegretol XR Tablets Manufactured by:
Novartis Pharma GmbH
D-79664 Wehr, Germany
Manufactured for
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936
Distributed by:
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936
December 2007
© 2007 Novartis
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:47:06.745746
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/020234s028lbl.pdf', 'application_number': 20234, 'submission_type': 'SUPPL ', 'submission_number': 28}
|
12,340
|
company logo
Tegretol®
carbamazepine USP
Chewable Tablets of 100 mg - red-speckled, pink
Tablets of 200 mg – pink
Suspension of 100 mg/5 mL
Tegretol®-XR
(carbamazepine extended-release tablets)
100 mg, 200 mg, 400 mg
Rx only
Prescribing Information
WARNINGS
SERIOUS DERMATOLOGIC REACTIONS AND HLA-B*1502 ALLELE
SERIOUS AND SOMETIMES FATAL DERMATOLOGIC REACTIONS, INCLUDING TOXIC
EPIDERMAL NECROLYSIS (TEN) AND STEVENS-JOHNSON SYNDROME (SJS), HAVE BEEN
REPORTED DURING TREATMENT WITH TEGRETOL. THESE REACTIONS ARE ESTIMATED TO
OCCUR IN 1 TO 6 PER 10,000 NEW USERS IN COUNTRIES WITH MAINLY CAUCASIAN
POPULATIONS, BUT THE RISK IN SOME ASIAN COUNTRIES IS ESTIMATED TO BE ABOUT 10
TIMES HIGHER. STUDIES IN PATIENTS OF CHINESE ANCESTRY HAVE FOUND A STRONG
ASSOCIATION BETWEEN THE RISK OF DEVELOPING SJS/TEN AND THE PRESENCE OF
HLA-B*1502, AN INHERITED ALLELIC VARIANT OF THE HLA-B GENE. HLA-B*1502 IS FOUND
ALMOST EXCLUSIVELY IN PATIENTS WITH ANCESTRY ACROSS BROAD AREAS OF ASIA.
PATIENTS WITH ANCESTRY IN GENETICALLY AT-RISK POPULATIONS SHOULD BE SCREENED
FOR THE PRESENCE OF HLA-B*1502 PRIOR TO INITIATING TREATMENT WITH TEGRETOL.
PATIENTS TESTING POSITIVE FOR THE ALLELE SHOULD NOT BE TREATED WITH TEGRETOL
UNLESS THE BENEFIT CLEARLY OUTWEIGHS THE RISK (SEE WARNINGS AND PRECAUTIONS,
LABORATORY TESTS).
APLASTIC ANEMIA AND AGRANULOCYTOSIS
APLASTIC ANEMIA AND AGRANULOCYTOSIS HAVE BEEN REPORTED IN ASSOCIATION WITH
THE USE OF TEGRETOL. DATA FROM A POPULATION-BASED CASE CONTROL STUDY
DEMONSTRATE THAT THE RISK OF DEVELOPING THESE REACTIONS IS 5-8 TIMES GREATER
THAN IN THE GENERAL POPULATION. HOWEVER, THE OVERALL RISK OF THESE REACTIONS
IN THE UNTREATED GENERAL POPULATION IS LOW, APPROXIMATELY SIX PATIENTS PER ONE
MILLION POPULATION PER YEAR FOR AGRANULOCYTOSIS AND TWO PATIENTS PER ONE
MILLION POPULATION PER YEAR FOR APLASTIC ANEMIA.
ALTHOUGH REPORTS OF TRANSIENT OR PERSISTENT DECREASED PLATELET OR WHITE
BLOOD CELL COUNTS ARE NOT UNCOMMON IN ASSOCIATION WITH THE USE OF TEGRETOL,
DATA ARE NOT AVAILABLE TO ESTIMATE ACCURATELY THEIR INCIDENCE OR OUTCOME.
HOWEVER, THE VAST MAJORITY OF THE CASES OF LEUKOPENIA HAVE NOT PROGRESSED TO
THE MORE SERIOUS CONDITIONS OF APLASTIC ANEMIA OR AGRANULOCYTOSIS.
Reference ID: 2912982
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For current labeling information, please visit https://www.fda.gov/drugsatfda
BECAUSE OF THE VERY LOW INCIDENCE OF AGRANULOCYTOSIS AND APLASTIC ANEMIA,
THE VAST MAJORITY OF MINOR HEMATOLOGIC CHANGES OBSERVED IN MONITORING OF
PATIENTS ON TEGRETOL ARE UNLIKELY TO SIGNAL THE OCCURRENCE OF EITHER
ABNORMALITY. NONETHELESS, COMPLETE PRETREATMENT HEMATOLOGICAL TESTING
SHOULD BE OBTAINED AS A BASELINE. IF A PATIENT IN THE COURSE OF TREATMENT
EXHIBITS LOW OR DECREASED WHITE BLOOD CELL OR PLATELET COUNTS, THE PATIENT
SHOULD BE MONITORED CLOSELY. DISCONTINUATION OF THE DRUG SHOULD BE
CONSIDERED IF ANY EVIDENCE OF SIGNIFICANT BONE MARROW DEPRESSION DEVELOPS.
Before prescribing Tegretol, the physician should be thoroughly familiar with the details of this
prescribing information, particularly regarding use with other drugs, especially those which accentuate
toxicity potential.
DESCRIPTION
Tegretol, carbamazepine USP, is an anticonvulsant and specific analgesic for trigeminal neuralgia, available for
oral administration as chewable tablets of 100 mg, tablets of 200 mg, XR tablets of 100, 200, and 400 mg, and
as a suspension of 100 mg/5 mL (teaspoon). Its chemical name is 5H-dibenz[b,f ]azepine-5-carboxamide, and
its structural formula is structural formula
Carbamazepine USP is a white to off-white powder, practically insoluble in water and soluble in alcohol and in
acetone. Its molecular weight is 236.27.
Inactive Ingredients Tablets: Colloidal silicon dioxide, D&C Red No. 30 Aluminum Lake (chewable tablets
only), FD&C Red No. 40 (200-mg tablets only), flavoring (chewable tablets only), gelatin, glycerin, magnesium
stearate, sodium starch glycolate (chewable tablets only), starch, stearic acid, and sucrose (chewable tablets
only). Suspension: Citric acid, FD&C Yellow No. 6, flavoring, polymer, potassium sorbate, propylene glycol,
purified water, sorbitol, sucrose, and xanthan gum. Tegretol-XR tablets: cellulose compounds, dextrates, iron
oxides, magnesium stearate, mannitol, polyethylene glycol, sodium lauryl sulfate, titanium dioxide (200-mg
tablets only).
CLINICAL PHARMACOLOGY
In controlled clinical trials, Tegretol has been shown to be effective in the treatment of psychomotor and grand
mal seizures, as well as trigeminal neuralgia.
Mechanism of Action
Tegretol has demonstrated anticonvulsant properties in rats and mice with electrically and chemically induced
seizures. It appears to act by reducing polysynaptic responses and blocking the post-tetanic potentiation.
Tegretol greatly reduces or abolishes pain induced by stimulation of the infraorbital nerve in cats and rats. It
depresses thalamic potential and bulbar and polysynaptic reflexes, including the linguomandibular reflex in
cats. Tegretol is chemically unrelated to other anticonvulsants or other drugs used to control the pain of
trigeminal neuralgia. The mechanism of action remains unknown.
The principal metabolite of Tegretol, carbamazepine-10,11-epoxide, has anticonvulsant activity as
demonstrated in several in vivo animal models of seizures. Though clinical activity for the epoxide has been
postulated, the significance of its activity with respect to the safety and efficacy of Tegretol has not been
established.
Reference ID: 2912982
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Pharmacokinetics
In clinical studies, Tegretol suspension, conventional tablets, and XR tablets delivered equivalent amounts of
drug to the systemic circulation. However, the suspension was absorbed somewhat faster, and the XR tablet
slightly slower, than the conventional tablet. The bioavailability of the XR tablet was 89% compared to
suspension. Following a b.i.d. dosage regimen, the suspension provides higher peak levels and lower trough
levels than those obtained from the conventional tablet for the same dosage regimen. On the other hand,
following a t.i.d. dosage regimen, Tegretol suspension affords steady-state plasma levels comparable to
Tegretol tablets given b.i.d. when administered at the same total mg daily dose. Following a b.i.d. dosage
regimen, Tegretol-XR tablets afford steady-state plasma levels comparable to conventional Tegretol tablets
given q.i.d., when administered at the same total mg daily dose. Tegretol in blood is 76% bound to plasma
proteins. Plasma levels of Tegretol are variable and may range from 0.5-25 µg/mL, with no apparent
relationship to the daily intake of the drug. Usual adult therapeutic levels are between 4 and 12 µg/mL. In
polytherapy, the concentration of Tegretol and concomitant drugs may be increased or decreased during
therapy, and drug effects may be altered (see PRECAUTIONS, Drug Interactions). Following chronic oral
administration of suspension, plasma levels peak at approximately 1.5 hours compared to 4-5 hours after
administration of conventional Tegretol tablets, and 3-12 hours after administration of Tegretol-XR tablets. The
CSF/serum ratio is 0.22, similar to the 24% unbound Tegretol in serum. Because Tegretol induces its own
metabolism, the half-life is also variable. Autoinduction is completed after 3-5 weeks of a fixed dosing regimen.
Initial half-life values range from 25-65 hours, decreasing to 12-17 hours on repeated doses. Tegretol is
metabolized in the liver. Cytochrome P450 3A4 was identified as the major isoform responsible for the
formation of carbamazepine-10,11-epoxide from Tegretol. After oral administration of 14C-carbamazepine, 72%
of the administered radioactivity was found in the urine and 28% in the feces. This urinary radioactivity was
composed largely of hydroxylated and conjugated metabolites, with only 3% of unchanged Tegretol.
The pharmacokinetic parameters of Tegretol disposition are similar in children and in adults. However, there is
a poor correlation between plasma concentrations of carbamazepine and Tegretol dose in children.
Carbamazepine is more rapidly metabolized to carbamazepine-10,11-epoxide (a metabolite shown to be
equipotent to carbamazepine as an anticonvulsant in animal screens) in the younger age groups than in adults. In
children below the age of 15, there is an inverse relationship between CBZ-E/CBZ ratio and increasing age (in
one report from 0.44 in children below the age of 1 year to 0.18 in children between 10-15 years of age).
The effects of race and gender on carbamazepine pharmacokinetics have not been systematically evaluated.
INDICATIONS AND USAGE
Epilepsy
Tegretol is indicated for use as an anticonvulsant drug. Evidence supporting efficacy of Tegretol as an
anticonvulsant was derived from active drug-controlled studies that enrolled patients with the following seizure
types:
1. Partial seizures with complex symptomatology (psychomotor, temporal lobe). Patients with these seizures
appear to show greater improvement than those with other types.
2. Generalized tonic-clonic seizures (grand mal).
3. Mixed seizure patterns which include the above, or other partial or generalized seizures. Absence seizures
(petit mal) do not appear to be controlled by Tegretol (see PRECAUTIONS, General).
Trigeminal Neuralgia
Tegretol is indicated in the treatment of the pain associated with true trigeminal neuralgia.
Beneficial results have also been reported in glossopharyngeal neuralgia.
This drug is not a simple analgesic and should not be used for the relief of trivial aches or pains.
Reference ID: 2912982
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
CONTRAINDICATIONS
Tegretol should not be used in patients with a history of previous bone marrow depression, hypersensitivity to
the drug, or known sensitivity to any of the tricyclic compounds, such as amitriptyline, desipramine,
imipramine, protriptyline, nortriptyline, etc. Likewise, on theoretical grounds its use with monoamine oxidase
inhibitors is not recommended. Before administration of Tegretol, MAO inhibitors should be discontinued for a
minimum of 14 days, or longer if the clinical situation permits.
Coadministration of carbamazepine and nefazodone may result in insufficient plasma concentrations of
nefazodone and its active metabolite to achieve a therapeutic effect. Coadministration of carbamazepine with
nefazodone is contraindicated.
WARNINGS
Serious Dermatologic Reactions
Serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN) and
Stevens-Johnson syndrome (SJS), have been reported with Tegretol treatment. The risk of these events is
estimated to be about 1 to 6 per 10,000 new users in countries with mainly Caucasian populations. However, the
risk in some Asian countries is estimated to be about 10 times higher. Tegretol should be discontinued at the
first sign of a rash, unless the rash is clearly not drug-related. If signs or symptoms suggest SJS/TEN, use of this
drug should not be resumed and alternative therapy should be considered.
SJS/TEN and HLA-B*1502 Allele
Retrospective case-control studies have found that in patients of Chinese ancestry there is a strong association
between the risk of developing SJS/TEN with carbamazepine treatment and the presence of an inherited variant
of the HLA-B gene, HLA-B*1502. The occurrence of higher rates of these reactions in countries with higher
frequencies of this allele suggests that the risk may be increased in allele-positive individuals of any ethnicity.
Across Asian populations, notable variation exists in the prevalence of HLA-B*1502. Greater than 15% of the
population is reported positive in Hong Kong, Thailand, Malaysia, and parts of the Philippines, compared to
about 10% in Taiwan and 4% in North China. South Asians, including Indians, appear to have intermediate
prevalence of HLA-B*1502, averaging 2 to 4%, but higher in some groups. HLA-B*1502 is present in <1% of
the population in Japan and Korea.
HLA-B*1502 is largely absent in individuals not of Asian origin (e.g., Caucasians, African-Americans,
Hispanics, and Native Americans).
Prior to initiating Tegretol therapy, testing for HLA-B*1502 should be performed in patients with
ancestry in populations in which HLA-B*1502 may be present. In deciding which patients to screen, the
rates provided above for the prevalence of HLA-B*1502 may offer a rough guide, keeping in mind the
limitations of these figures due to wide variability in rates even within ethnic groups, the difficulty in
ascertaining ethnic ancestry, and the likelihood of mixed ancestry. Tegretol should not be used in patients
positive for HLA-B*1502 unless the benefits clearly outweigh the risks. Tested patients who are found to be
negative for the allele are thought to have a low risk of SJS/TEN (see WARNINGS and PRECAUTIONS,
Laboratory Tests).
Over 90% of Tegretol treated patients who will experience SJS/TEN have this reaction within the first few
months of treatment. This information may be taken into consideration in determining the need for screening of
genetically at-risk patients currently on Tegretol.
The HLA-B*1502 allele has not been found to predict risk of less severe adverse cutaneous reactions from
Tegretol, such as anticonvulsant hypersensitivity syndrome or nonserious rash (maculopapular eruption [MPE]).
Limited evidence suggests that HLA-B*1502 may be a risk factor for the development of SJS/TEN in patients
of Chinese ancestry taking other antiepileptic drugs associated with SJS/TEN. Consideration should be given to
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avoiding use of other drugs associated with SJS/TEN in HLA-B*1502 positive patients, when alternative
therapies are otherwise equally acceptable.
Application of HLA-B*1502 genotyping as a screening tool has important limitations and must never substitute
for appropriate clinical vigilance and patient management. Many HLA-B*1502-positive Asian patients treated
with Tegretol will not develop SJS/TEN, and these reactions can still occur infrequently in
HLA-B*1502-negative patients of any ethnicity. The role of other possible factors in the development of, and
morbidity from, SJS/TEN, such as antiepileptic drug (AED) dose, compliance, concomitant medications,
comorbidities, and the level of dermatologic monitoring have not been studied.
Aplastic Anemia and Agranulocytosis
Patients with a history of adverse hematologic reaction to any drug may be particularly at risk of bone marrow
depression.
Suicidal Behavior and Ideation
Antiepileptic drugs (AEDs), including Tegretol, increase the risk of suicidal thoughts or behavior in patients
taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for
the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood
or behavior.
Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs
showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk
1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these
trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or
ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated
patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530
patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated
patients, but the number is too small to allow any conclusion about drug effect on suicide.
The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting
drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in
the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could
not be assessed.
The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The
finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests
that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years)
in the clinical trials analyzed. Table 1 shows absolute and relative risk by indication for all evaluated AEDs.
Table 1 Risk by Indication for Antiepileptic Drugs in the Pooled Analysis
Indication
Placebo Patients
with Events Per
1,000 Patients
Drug Patients
with Events Per
1,000 Patients
Relative Risk:
Incidence of
Events in Drug
Patients/Incidence
in Placebo
Patients
Risk Difference:
Additional Drug
Patients with
Events Per 1,000
Patients
Epilepsy
1.0
3.4
3.5
2.4
Psychiatric
5.7
8.5
1.5
2.9
Other
1.0
1.8
1.9
0.9
Total
2.4
4.3
1.8
1.9
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The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials
for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric
indications.
Anyone considering prescribing Tegretol or any other AED must balance the risk of suicidal thoughts or
behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are
themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior.
Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the
emergence of these symptoms in any given patient may be related to the illness being treated.
Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and
behavior and should be advised of the need to be alert for the emergence or worsening of the signs and
symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts,
behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare
providers.
General
Tegretol has shown mild anticholinergic activity; therefore, patients with increased intraocular pressure should
be closely observed during therapy.
Because of the relationship of the drug to other tricyclic compounds, the possibility of activation of a latent
psychosis and, in elderly patients, of confusion or agitation should be borne in mind.
The use of Tegretol should be avoided in patients with a history of hepatic porphyria (e.g., acute intermittent
porphyria, variegate porphyria, porphyria cutanea tarda). Acute attacks have been reported in such patients
receiving Tegretol therapy. Carbamazepine administration has also been demonstrated to increase porphyrin
precursors in rodents, a presumed mechanism for the induction of acute attacks of porphyria.
As with all antiepileptic drugs, Tegretol should be withdrawn gradually to minimize the potential of increased
seizure frequency.
Usage in Pregnancy
Carbamazepine can cause fetal harm when administered to a pregnant woman.
Epidemiological data suggest that there may be an association between the use of carbamazepine during
pregnancy and congenital malformations, including spina bifida. There have also been reports that associate
carbamazepine with developmental disorders and congenital anomalies (e.g., craniofacial defects,
cardiovascular malformations, hypospadias and anomalies involving various body systems). Developmental
delays based on neurobehavioral assessments have been reported. In treating or counseling women of
childbearing potential, the prescribing physician will wish to weigh the benefits of therapy against the risks. If
this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should
be apprised of the potential hazard to the fetus.
Retrospective case reviews suggest that, compared with monotherapy, there may be a higher prevalence of
teratogenic effects associated with the use of anticonvulsants in combination therapy. Therefore, if therapy is to
be continued, monotherapy may be preferable for pregnant women.
In humans, transplacental passage of carbamazepine is rapid (30-60 minutes), and the drug is accumulated in
the fetal tissues, with higher levels found in liver and kidney than in brain and lung.
Carbamazepine has been shown to have adverse effects in reproduction studies in rats when given orally in
dosages 10-25 times the maximum human daily dosage (MHDD) of 1200 mg on a mg/kg basis or 1.5-4 times
the MHDD on a mg/m2 basis. In rat teratology studies, 2 of 135 offspring showed kinked ribs at 250 mg/kg and
4 of 119 offspring at 650 mg/kg showed other anomalies (cleft palate, 1; talipes, 1; anophthalmos, 2). In
reproduction studies in rats, nursing offspring demonstrated a lack of weight gain and an unkempt appearance at
a maternal dosage level of 200 mg/kg.
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Antiepileptic drugs should not be discontinued abruptly in patients in whom the drug is administered to prevent
major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and
threat to life. In individual cases where the severity and frequency of the seizure disorder are such that removal
of medication does not pose a serious threat to the patient, discontinuation of the drug may be considered prior
to and during pregnancy, although it cannot be said with any confidence that even minor seizures do not pose
some hazard to the developing embryo or fetus.
Tests to detect defects using currently accepted procedures should be considered a part of routine prenatal care
in childbearing women receiving carbamazepine.
There have been a few cases of neonatal seizures and/or respiratory depression associated with maternal
Tegretol and other concomitant anticonvulsant drug use. A few cases of neonatal vomiting, diarrhea, and/or
decreased feeding have also been reported in association with maternal Tegretol use. These symptoms may
represent a neonatal withdrawal syndrome.
To provide information regarding the effects of in utero exposure to Tegretol, physicians are advised to
recommend that pregnant patients taking Tegretol enroll in the North American Antiepileptic Drug (NAAED)
Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by
patients themselves. Information on the registry can also be found at the website
http://www.aedpregnancyregistry.org/.
PRECAUTIONS
General
Before initiating therapy, a detailed history and physical examination should be made.
Tegretol should be used with caution in patients with a mixed seizure disorder that includes atypical absence
seizures, since in these patients Tegretol has been associated with increased frequency of generalized
convulsions (see INDICATIONS AND USAGE).
Therapy should be prescribed only after critical benefit-to-risk appraisal in patients with a history of cardiac
conduction disturbance, including second and third degree AV heart block; cardiac, hepatic, or renal damage;
adverse hematologic or hypersensitivity reaction to other drugs, including reactions to other anticonvulsants; or
interrupted courses of therapy with Tegretol.
AV heart block, including second and third degree block, have been reported following Tegretol treatment. This
occurred generally, but not solely, in patients with underlying EKG abnormalities or risk factors for conduction
disturbances.
Hepatic effects, ranging from slight elevations in liver enzymes to rare cases of hepatic failure have been
reported (see ADVERSE REACTIONS and PRECAUTIONS, Laboratory Tests). In some cases, hepatic effects
may progress despite discontinuation of the drug.
Multiorgan hypersensitivity reactions which can affect the skin, liver, hemopoietic organs and lymphatic system
or other organs and occurring days to weeks or months after initiating treatment have been reported in rare cases
(see ADVERSE REACTIONS, Other and PRECAUTIONS, Information for Patients).
Discontinuation of carbamazepine should be considered if any evidence of hypersensitivity develops.
Hypersensitivity reactions to carbamazepine have been reported in patients who previously experienced this
reaction to anticonvulsants including phenytoin and phenobarbital. A history of hypersensitivity reactions
should be obtained for a patient and the immediate family members. If positive, caution should be used in
prescribing carbamazepine.
In patients who have exhibited hypersensitivity reactions to carbamazepine approximately 25 to 30% of these
patients may experience hypersensitivity reactions with oxcarbazepine (Trileptal®).
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Since a given dose of Tegretol suspension will produce higher peak levels than the same dose given as the
tablet, it is recommended that patients given the suspension be started on lower doses and increased slowly to
avoid unwanted side effects (see DOSAGE AND ADMINISTRATION).
Tegretol suspension contains sorbitol and, therefore, should not be administered to patients with rare hereditary
problems of fructose intolerance.
Information for Patients
Patients should be informed of the availability of a Medication Guide and they should be instructed to read the
Medication Guide before taking Tegretol.
Patients should be made aware of the early toxic signs and symptoms of a potential hematologic problem, as
well as dermatologic, hypersensitivity or hepatic reactions. These symptoms may include, but are not limited to,
fever, sore throat, rash, ulcers in the mouth, easy bruising, lymphadenopathy and petechial or purpuric
hemorrhage, and in the case of liver reactions, anorexia, nausea/vomiting, or jaundice. The patient should be
advised that, because these signs and symptoms may signal a serious reaction, that they must report any
occurrence immediately to a physician. In addition, the patient should be advised that these signs and symptoms
should be reported even if mild or when occurring after extended use.
Patients, their caregivers, and families should be counseled that AEDs, including Tegretol, may increase the risk
of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening
of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts,
behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare
providers
Patients should be advised that serious skin reactions have been reported in association with Tegretol. In the
event a skin reaction should occur while taking Tegretol, patients should consult with their physician
immediately (see WARNINGS).
Tegretol may interact with some drugs. Therefore, patients should be advised to report to their doctors the use
of any other prescription or nonprescription medications or herbal products.
Caution should be exercised if alcohol is taken in combination with Tegretol therapy, due to a possible additive
sedative effect.
Since dizziness and drowsiness may occur, patients should be cautioned about the hazards of operating
machinery or automobiles or engaging in other potentially dangerous tasks.
Patients should be encouraged to enroll in the NAAED Pregnancy Registry if they become pregnant. This
registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients
can call the toll free number 1-888-233-2334 (see WARNINGS, Usage in Pregnancy subsection).
Laboratory Tests
For genetically at-risk patients (see WARNINGS), high-resolution ‘HLA-B*1502 typing’ is recommended. The
test is positive if either one or two HLA-B*1502 alleles are detected and negative if no HLA-B*1502 alleles are
detected.
Complete pretreatment blood counts, including platelets and possibly reticulocytes and serum iron, should be
obtained as a baseline. If a patient in the course of treatment exhibits low or decreased white blood cell or
platelet counts, the patient should be monitored closely. Discontinuation of the drug should be considered if any
evidence of significant bone marrow depression develops.
Baseline and periodic evaluations of liver function, particularly in patients with a history of liver disease, must
be performed during treatment with this drug since liver damage may occur (see PRECAUTIONS, General and
ADVERSE REACTIONS). Carbamazepine should be discontinued, based on clinical judgment, if indicated by
newly occurring or worsening clinical or laboratory evidence of liver dysfunction or hepatic damage, or in the
case of active liver disease.
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Baseline and periodic eye examinations, including slit-lamp, funduscopy, and tonometry, are recommended
since many phenothiazines and related drugs have been shown to cause eye changes.
Baseline and periodic complete urinalysis and BUN determinations are recommended for patients treated with
this agent because of observed renal dysfunction.
Monitoring of blood levels (see CLINICAL PHARMACOLOGY) has increased the efficacy and safety of
anticonvulsants. This monitoring may be particularly useful in cases of dramatic increase in seizure frequency
and for verification of compliance. In addition, measurement of drug serum levels may aid in determining the
cause of toxicity when more than one medication is being used.
Thyroid function tests have been reported to show decreased values with Tegretol administered alone.
Hyponatremia has been reported in association with Tegretol use, either alone or in combination with other
drugs.
Interference with some pregnancy tests has been reported.
Drug Interactions
There has been a report of a patient who passed an orange rubbery precipitate in his stool the day after ingesting
Tegretol suspension immediately followed by Thorazine®* solution. Subsequent testing has shown that mixing
Tegretol suspension and chlorpromazine solution (both generic and brand name) as well as Tegretol suspension
and liquid Mellaril® resulted in the occurrence of this precipitate. Because the extent to which this occurs with
other liquid medications is not known, Tegretol suspension should not be administered simultaneously with
other liquid medicinal agents or diluents (see DOSAGE AND ADMINISTRATION).
Clinically meaningful drug interactions have occurred with concomitant medications and include, but are not
limited to, the following:
Agents That May Affect Tegretol Plasma Levels
CYP 3A4 inhibitors inhibit Tegretol metabolism and can thus increase plasma carbamazepine levels. Drugs that
have been shown, or would be expected, to increase plasma carbamazepine levels include:
cimetidine, danazol, diltiazem, macrolides, erythromycin, troleandomycin, clarithromycin, fluoxetine,
fluvoxamine, nefazodone, trazodone, loxapine*, olanzapine, quetiapine*, loratadine, terfenadine,
omeprazole, oxybutynin, dantrolene, isoniazid, niacinamide, nicotinamide, ibuprofen, propoxyphene,
azoles (e.g., ketaconazole, itraconazole, fluconazole, voriconazole), acetazolamide, verapamil,
ticlopidine, grapefruit juice, protease inhibitors, valproate*.
CYP 3A4 inducers can increase the rate of Tegretol metabolism. Drugs that have been shown, or that would be
expected, to decrease plasma carbamazepine levels include:
cisplatin, doxorubicin HCl, felbamate†, fosphenytoin, rifampin, phenobarbital, phenytoin, primidone,
methsuximide, theophylline, aminophylline.
When carbamazepine is given with drugs that can increase or decrease carbamazepine levels, close monitoring
of carbamazepine levels is indicated and dosage adjustment may be required.
*increased levels of the active 10,11-epoxide
†decreased levels of carbamazepine and increased levels of the 10,11-epoxide
Effect of Tegretol on Plasma Levels of Concomitant Agents
Increased levels: clomipramine HCl, phenytoin, primidone
Tegretol is a potent inducer of hepatic CYP 3A4 and may therefore reduce plasma concentrations of
comedications mainly metabolized by 3A4 through induction of their metabolism. Tegretol causes, or would be
expected to cause, decreased levels of the following:
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acetaminophen, alprazolam, bupropion, dihydropyridine calcium channel blockers (e.g., felodipine),
citalopram, cyclosporine, corticosteroids (e.g., prednisolone, dexamethasone), clonazepam, clozapine,
dicumarol, doxycycline, ethosuximide, everolimus, haloperidol, imatinib, itraconazole, lamotrigine,
levothyroxine, methadone, methsuximide, midazolam, olanzapine, oral and other hormonal
contraceptives, oxcarbazepine, phensuximide, phenytoin, praziquantel, protease inhibitors, risperidone,
theophylline, tiagabine, topiramate, tramadol, trazodone, tricyclic antidepressants (e.g., imipramine,
amitriptyline, nortriptyline), valproate, warfarin, ziprasidone, zonisamide.
In concomitant use with Tegretol, dosage adjustment of the above agents may be necessary.
Coadministration of carbamazepine with nefazodone results in insufficient plasma concentrations of nefazodone
and its active metabolite to achieve a therapeutic effect. Coadministration of carbamazepine with nefazodone is
contraindicated (see CONTRAINDICATIONS).
Concomitant administration of carbamazepine and lithium may increase the risk of neurotoxic side effects.
Concomitant use of carbamazepine and isoniazid has been reported to increase isoniazid-induced
hepatotoxicity.
Concomitant medication with Tegretol and some diuretics (hydrochlorothiazide, furosemide) may lead to
symptomatic hyponatremia.
Carbamazepine may antagonize the effects of nondepolarizing muscle relaxants (e.g., pancuronium).
Their dosage may need to be raised, and patients should be monitored closely for more rapid recovery from
neuromuscular blockade than expected.
Alterations of thyroid function have been reported in combination therapy with other anticonvulsant
medications.
Concomitant use of Tegretol with hormonal contraceptive products (e.g., oral, and levonorgestrel subdermal
implant contraceptives) may render the contraceptives less effective because the plasma concentrations of the
hormones may be decreased. Breakthrough bleeding and unintended pregnancies have been reported.
Alternative or back-up methods of contraception should be considered.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carbamazepine, when administered to Sprague-Dawley rats for two years in the diet at doses of 25, 75, and
250 mg/kg/day, resulted in a dose-related increase in the incidence of hepatocellular tumors in females and of
benign interstitial cell adenomas in the testes of males.
Carbamazepine must, therefore, be considered to be carcinogenic in Sprague-Dawley rats. Bacterial and
mammalian mutagenicity studies using carbamazepine produced negative results. The significance of these
findings relative to the use of carbamazepine in humans is, at present, unknown.
Usage in Pregnancy
Pregnancy Category D (see WARNINGS).
Labor and Delivery
The effect of Tegretol on human labor and delivery is unknown.
Nursing Mothers
Tegretol and its epoxide metabolite are transferred to breast milk. The ratio of the concentration in breast milk
to that in maternal plasma is about 0.4 for Tegretol and about 0.5 for the epoxide. The estimated doses given to
the newborn during breast-feeding are in the range of 2-5 mg daily for Tegretol and 1-2 mg daily for the
epoxide.
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Because of the potential for serious adverse reactions in nursing infants from carbamazepine, a decision should
be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the
drug to the mother.
Pediatric Use
Substantial evidence of Tegretol’s effectiveness for use in the management of children with epilepsy (see
INDICATIONS AND USAGE for specific seizure types) is derived from clinical investigations performed in
adults and from studies in several in vitro systems which support the conclusion that (1) the pathogenetic
mechanisms underlying seizure propagation are essentially identical in adults and children, and (2) the
mechanism of action of carbamazepine in treating seizures is essentially identical in adults and children.
Taken as a whole, this information supports a conclusion that the generally accepted therapeutic range of total
carbamazepine in plasma (i.e., 4-12 mcg/mL) is the same in children and adults.
The evidence assembled was primarily obtained from short-term use of carbamazepine. The safety of
carbamazepine in children has been systematically studied up to 6 months. No longer-term data from clinical
trials is available.
Geriatric Use
No systematic studies in geriatric patients have been conducted.
ADVERSE REACTIONS
If adverse reactions are of such severity that the drug must be discontinued, the physician must be aware that
abrupt discontinuation of any anticonvulsant drug in a responsive epileptic patient may lead to seizures or even
status epilepticus with its life-threatening hazards.
The most severe adverse reactions have been observed in the hemopoietic system and skin (see BOXED
WARNING), the liver, and the cardiovascular system.
The most frequently observed adverse reactions, particularly during the initial phases of therapy, are dizziness,
drowsiness, unsteadiness, nausea, and vomiting. To minimize the possibility of such reactions, therapy should
be initiated at the low dosage recommended.
The following additional adverse reactions have been reported:
Hemopoietic System: Aplastic anemia, agranulocytosis, pancytopenia, bone marrow depression,
thrombocytopenia, leukopenia, leukocytosis, eosinophilia, anemia, acute intermittent porphyria, variegate
porphyria, porphyria cutanea tarda.
Skin: Toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) (see BOXED WARNING),
pruritic and erythematous rashes, urticaria, photosensitivity reactions, alterations in skin pigmentation,
exfoliative dermatitis, erythema multiforme and nodosum, purpura, aggravation of disseminated lupus
erythematosus, alopecia, and diaphoresis. In certain cases, discontinuation of therapy may be necessary. Isolated
cases of hirsutism have been reported, but a causal relationship is not clear.
Cardiovascular System: Congestive heart failure, edema, aggravation of hypertension, hypotension, syncope
and collapse, aggravation of coronary artery disease, arrhythmias and AV block, thrombophlebitis,
thromboembolism (e.g., pulmonary embolism), and adenopathy or lymphadenopathy.
Some of these cardiovascular complications have resulted in fatalities. Myocardial infarction has been
associated with other tricyclic compounds.
Liver: Abnormalities in liver function tests, cholestatic and hepatocellular jaundice, hepatitis; very rare cases of
hepatic failure.
Pancreatic: Pancreatitis.
Respiratory System: Pulmonary hypersensitivity characterized by fever, dyspnea, pneumonitis, or pneumonia.
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Genitourinary System: Urinary frequency, acute urinary retention, oliguria with elevated blood pressure,
azotemia, renal failure, and impotence. Albuminuria, glycosuria, elevated BUN, and microscopic deposits in the
urine have also been reported. There have been very rare reports of impaired male fertility and/or abnormal
spermatogenesis.
Testicular atrophy occurred in rats receiving Tegretol orally from 4-52 weeks at dosage levels of 50-400
mg/kg/day. Additionally, rats receiving Tegretol in the diet for 2 years at dosage levels of 25, 75, and 250
mg/kg/day had a dose-related incidence of testicular atrophy and aspermatogenesis. In dogs, it produced a
brownish discoloration, presumably a metabolite, in the urinary bladder at dosage levels of 50 mg/kg and
higher. Relevance of these findings to humans is unknown.
Nervous System: Dizziness, drowsiness, disturbances of coordination, confusion, headache, fatigue, blurred
vision, visual hallucinations, transient diplopia, oculomotor disturbances, nystagmus, speech disturbances,
abnormal involuntary movements, peripheral neuritis and paresthesias, depression with agitation, talkativeness,
tinnitus, hyperacusis, neuroleptic malignant syndrome.
There have been reports of associated paralysis and other symptoms of cerebral arterial insufficiency, but the
exact relationship of these reactions to the drug has not been established.
Isolated cases of neuroleptic malignant syndrome have been reported both with and without concomitant use of
psychotropic drugs.
Digestive System: Nausea, vomiting, gastric distress and abdominal pain, diarrhea, constipation, anorexia, and
dryness of the mouth and pharynx, including glossitis and stomatitis.
Eyes: Scattered punctate cortical lens opacities, increased intraocular pressure as well as conjunctivitis, have
been reported. Although a direct causal relationship has not been established, many phenothiazines and related
drugs have been shown to cause eye changes.
Musculoskeletal System: Aching joints and muscles, and leg cramps.
Metabolism: Fever and chills. Inappropriate antidiuretic hormone (ADH) secretion syndrome has been reported.
Cases of frank water intoxication, with decreased serum sodium (hyponatremia) and confusion, have been
reported in association with Tegretol use (see PRECAUTIONS, Laboratory Tests). Decreased levels of plasma
calcium leading to osteoporosis have been reported.
Other: Multiorgan hypersensitivity reactions occurring days to weeks or months after initiating treatment have
been reported in rare cases. Signs or symptoms may include, but are not limited to fever, skin rashes, vasculitis,
lymphadenopathy, disorders mimicking lymphoma, arthralgia, leukopenia, eosinophilia, hepatosplenomegaly
and abnormal liver function tests. These signs and symptoms may occur in various combinations and not
necessarily concurrently. Signs and symptoms may initially be mild. Various organs, including but not limited
to, liver, skin, immune system, lungs, kidneys, pancreas, myocardium, and colon may be affected (see
PRECAUTIONS, General and PRECAUTIONS, Information for Patients).
Isolated cases of a lupus erythematosus-like syndrome have been reported. There have been occasional reports
of elevated levels of cholesterol, HDL cholesterol, and triglycerides in patients taking anticonvulsants.
A case of aseptic meningitis, accompanied by myoclonus and peripheral eosinophilia, has been reported in a
patient taking carbamazepine in combination with other medications. The patient was successfully
dechallenged, and the meningitis reappeared upon rechallenge with carbamazepine.
DRUG ABUSE AND DEPENDENCE
No evidence of abuse potential has been associated with Tegretol, nor is there evidence of psychological or
physical dependence in humans.
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OVERDOSAGE
Acute Toxicity
Lowest known lethal dose: adults, 3.2 g (a 24-year-old woman died of a cardiac arrest and a 24-year-old man
died of pneumonia and hypoxic encephalopathy); children, 4 g (a 14-year-old girl died of a cardiac arrest), 1.6 g
(a 3-year-old girl died of aspiration pneumonia).
Oral LD50 in animals (mg/kg): mice, 1100-3750; rats, 3850-4025; rabbits, 1500-2680; guinea pigs, 920.
Signs and Symptoms
The first signs and symptoms appear after 1-3 hours. Neuromuscular disturbances are the most prominent.
Cardiovascular disorders are generally milder, and severe cardiac complications occur only when very high
doses (>60 g) have been ingested.
Respiration: Irregular breathing, respiratory depression.
Cardiovascular System: Tachycardia, hypotension or hypertension, shock, conduction disorders.
Nervous System and Muscles: Impairment of consciousness ranging in severity to deep coma. Convulsions,
especially in small children. Motor restlessness, muscular twitching, tremor, athetoid movements, opisthotonos,
ataxia, drowsiness, dizziness, mydriasis, nystagmus, adiadochokinesia, ballism, psychomotor disturbances,
dysmetria. Initial hyperreflexia, followed by hyporeflexia.
Gastrointestinal Tract: Nausea, vomiting.
Kidneys and Bladder: Anuria or oliguria, urinary retention.
Laboratory Findings: Isolated instances of overdosage have included leukocytosis, reduced leukocyte count,
glycosuria, and acetonuria. EEG may show dysrhythmias.
Combined Poisoning: When alcohol, tricyclic antidepressants, barbiturates, or hydantoins are taken at the same
time, the signs and symptoms of acute poisoning with Tegretol may be aggravated or modified.
Treatment
The prognosis in cases of severe poisoning is critically dependent upon prompt elimination of the drug, which
may be achieved by inducing vomiting, irrigating the stomach, and by taking appropriate steps to diminish
absorption. If these measures cannot be implemented without risk on the spot, the patient should be transferred
at once to a hospital, while ensuring that vital functions are safeguarded. There is no specific antidote.
Elimination of the Drug: Induction of vomiting.
Gastric lavage. Even when more than 4 hours have elapsed following ingestion of the drug, the stomach should
be repeatedly irrigated, especially if the patient has also consumed alcohol.
Measures to Reduce Absorption: Activated charcoal, laxatives.
Measures to Accelerate Elimination: Forced diuresis.
Dialysis is indicated only in severe poisoning associated with renal failure. Replacement transfusion is indicated
in severe poisoning in small children.
Respiratory Depression: Keep the airways free; resort, if necessary, to endotracheal intubation, artificial
respiration, and administration of oxygen.
Hypotension, Shock: Keep the patient’s legs raised and administer a plasma expander. If blood pressure fails to
rise despite measures taken to increase plasma volume, use of vasoactive substances should be considered.
Convulsions: Diazepam or barbiturates.
Reference ID: 2912982
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Warning: Diazepam or barbiturates may aggravate respiratory depression (especially in children), hypotension,
and coma. However, barbiturates should not be used if drugs that inhibit monoamine oxidase have also been
taken by the patient either in overdosage or in recent therapy (within 1 week).
Surveillance: Respiration, cardiac function (ECG monitoring), blood pressure, body temperature, pupillary
reflexes, and kidney and bladder function should be monitored for several days.
Treatment of Blood Count Abnormalities: If evidence of significant bone marrow depression develops, the
following recommendations are suggested: (1) stop the drug, (2) perform daily CBC, platelet, and reticulocyte
counts, (3) do a bone marrow aspiration and trephine biopsy immediately and repeat with sufficient frequency
to monitor recovery.
Special periodic studies might be helpful as follows: (1) white cell and platelet antibodies, (2) 59Fe-ferrokinetic
studies, (3) peripheral blood cell typing, (4) cytogenetic studies on marrow and peripheral blood, (5) bone
marrow culture studies for colony-forming units, (6) hemoglobin electrophoresis for A2 and F hemoglobin, and
(7) serum folic acid and B12 levels.
A fully developed aplastic anemia will require appropriate, intensive monitoring and therapy, for which
specialized consultation should be sought.
DOSAGE AND ADMINISTRATION (SEE TABLE BELOW)
Tegretol suspension in combination with liquid chlorpromazine or thioridazine results in precipitate formation,
and, in the case of chlorpromazine, there has been a report of a patient passing an orange rubbery precipitate in
the stool following coadministration of the two drugs (see PRECAUTIONS, Drug Interactions). Because the
extent to which this occurs with other liquid medications is not known, Tegretol suspension should not be
administered simultaneously with other liquid medications or diluents.
Monitoring of blood levels has increased the efficacy and safety of anticonvulsants (see PRECAUTIONS,
Laboratory Tests). Dosage should be adjusted to the needs of the individual patient. A low initial daily dosage
with a gradual increase is advised. As soon as adequate control is achieved, the dosage may be reduced very
gradually to the minimum effective level. Medication should be taken with meals.
Since a given dose of Tegretol suspension will produce higher peak levels than the same dose given as the
tablet, it is recommended to start with low doses (children 6-12 years: 1/2 teaspoon q.i.d.) and to increase
slowly to avoid unwanted side effects.
Conversion of patients from oral Tegretol tablets to Tegretol suspension: Patients should be converted by
administering the same number of mg per day in smaller, more frequent doses (i.e., b.i.d. tablets to t.i.d.
suspension).
Tegretol-XR is an extended-release formulation for twice-a-day administration. When converting patients from
Tegretol conventional tablets to Tegretol-XR, the same total daily mg dose of Tegretol-XR should be
administered. Tegretol-XR tablets must be swallowed whole and never crushed or chewed. Tegretol-XR
tablets should be inspected for chips or cracks. Damaged tablets, or tablets without a release portal, should not
be consumed. Tegretol-XR tablet coating is not absorbed and is excreted in the feces; these coatings may be
noticeable in the stool.
Epilepsy (SEE INDICATIONS AND USAGE)
Adults and children over 12 years of age - Initial: Either 200 mg b.i.d. for tablets and XR tablets, or 1 teaspoon
q.i.d. for suspension (400 mg/day). Increase at weekly intervals by adding up to 200 mg/day using a b.i.d.
regimen of Tegretol-XR or a t.i.d. or q.i.d. regimen of the other formulations until the optimal response is
obtained. Dosage generally should not exceed 1000 mg daily in children 12-15 years of age, and 1200 mg daily
in patients above 15 years of age. Doses up to 1600 mg daily have been used in adults in rare instances.
Maintenance: Adjust dosage to the minimum effective level, usually 800-1200 mg daily.
Reference ID: 2912982
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Children 6-12 years of age - Initial: Either 100 mg b.i.d. for tablets or XR tablets, or 1/2 teaspoon q.i.d. for
suspension (200 mg/day). Increase at weekly intervals by adding up to 100 mg/day using a b.i.d. regimen of
Tegretol-XR or a t.i.d. or q.i.d. regimen of the other formulations until the optimal response is obtained. Dosage
generally should not exceed 1000 mg daily. Maintenance: Adjust dosage to the minimum effective level,
usually 400-800 mg daily.
Children under 6 years of age - Initial: 10-20 mg/kg/day b.i.d. or t.i.d. as tablets, or q.i.d. as suspension.
Increase weekly to achieve optimal clinical response administered t.i.d. or q.i.d. Maintenance: Ordinarily,
optimal clinical response is achieved at daily doses below 35 mg/kg. If satisfactory clinical response has not
been achieved, plasma levels should be measured to determine whether or not they are in the therapeutic range.
No recommendation regarding the safety of carbamazepine for use at doses above 35 mg/kg/24 hours can be
made.
Combination Therapy: Tegretol may be used alone or with other anticonvulsants. When added to existing
anticonvulsant therapy, the drug should be added gradually while the other anticonvulsants are maintained or
gradually decreased, except phenytoin, which may have to be increased (see PRECAUTIONS, Drug
Interactions, and Pregnancy Category D).
Trigeminal Neuralgia (SEE INDICATIONS AND USAGE)
Initial: On the first day, either 100 mg b.i.d. for tablets or XR tablets, or 1/2 teaspoon q.i.d. for suspension, for a
total daily dose of 200 mg. This daily dose may be increased by up to 200 mg/day using increments of 100 mg
every 12 hours for tablets or XR tablets, or 50 mg (1/2 teaspoon) q.i.d. for suspension, only as needed to
achieve freedom from pain. Do not exceed 1200 mg daily. Maintenance: Control of pain can be maintained in
most patients with 400-800 mg daily. However, some patients may be maintained on as little as 200 mg daily,
while others may require as much as 1200 mg daily. At least once every 3 months throughout the treatment
period, attempts should be made to reduce the dose to the minimum effective level or even to discontinue the
drug.
Reference ID: 2912982
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Dosage Information
Initial Dose
Subsequent Dose
Maximum Daily Dose
Indication
Tablet*
XR
†
Suspension
Tablet*
XR
†
Suspension
Tablet*
XR
†
Suspension
Epilepsy
Under 6 yr
10-20 mg/kg/day
b.i.d. or t.i.d.
10-20 mg/kg/day
q.i.d.
Increase weekly
to achieve
optimal clinical
response, t.i.d.
or q.i.d.
Increase
weekly to
achieve optimal
clinical
response, t.i.d.
or q.i.d.
35 mg/kg/24 hr
(see Dosage
and
Administration
section above)
35 mg/kg/24 hr
(see Dosage
and
Administration
section above)
6-12 yr
100 mg b.i.d.
(200 mg/day)
100 mg b.i.d.
(200 mg/day)
½ tsp q.i.d.
(200 mg/day)
Add up to
100 mg/day at
weekly intervals,
t.i.d. or q.i.d.
Add
100 mg/day
at weekly
intervals,
b.i.d.
Add up to 1 tsp
(100 mg)/day at
weekly
intervals, t.i.d.
or q.i.d.
1000 mg/24 hr
Over 12 yr
200 mg b.i.d.
200 mg b.i.d.
1 tsp q.i.d.
Add up to
Add up to
Add up to 2 tsp
1000 mg/24 hr (12-15 yr)
(400 mg/day)
(400 mg/day)
(400 mg/day)
200 mg/day at
200 mg/day
(200 mg)/day at
1200 mg/24 hr (>15 yr)
weekly intervals,
t.i.d. or q.i.d.
at weekly
intervals,
b.i.d.
weekly
intervals, t.i.d.
or q.i.d.
1600 mg/24 hr (adults, in rare instances)
Trigeminal
100 mg b.i.d.
100 mg b.i.d.
½ tsp q.i.d.
Add up to
Add up to
Add up to 2 tsp
1200 mg/24 hr
Neuralgia
(200 mg/day)
(200 mg/day)
(200 mg/day)
200 mg/day in
increments of
100 mg every
12 hr
200 mg/day
in increments
of 100 mg
every 12 hr
(200 mg)/day
in increments
of 50 mg
(½ tsp) q.i.d.
*Tablet = Chewable or conventional tablets
†XR = Tegretol
®-XR extended-release tablets
Reference ID: 2912982
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HOW SUPPLIED
Chewable Tablets 100 mg - round, red-speckled, pink, single-scored (imprinted Tegretol on one side and 52
twice on the scored side)
Bottles of 100............................................................................................................................ NDC 0078-0492-05
Unit Dose (blister pack)
Box of 100 (strips of 10)........................................................................................................... NDC 0078-0492-35
Do not store above 30°C (86°F). Protect from light and moisture.
Dispense in tight, light-resistant container (USP).
Meets USP Dissolution Test 1.
Tablets 200 mg - capsule-shaped, pink, single-scored (imprinted Tegretol on one side and 27 twice on the
partially scored side)
Bottles of 100............................................................................................................................ NDC 0078-0509-05
Do not store above 30°C (86°F). Protect from moisture.
Dispense in tight container (USP).
Meets USP Dissolution Test 2.
XR Tablets 100 mg - round, yellow, coated (imprinted T on one side and 100 mg on the other), release portal on
one side
Bottles of 100............................................................................................................................ NDC 0078-0510-05
XR Tablets 200 mg - round, pink, coated (imprinted T on one side and 200 mg on the other), release portal on
one side
Bottles of 100............................................................................................................................ NDC 0078-0511-05
XR Tablets 400 mg - round, brown, coated (imprinted T on one side and 400 mg on the other), release portal on
one side
Bottles of 100............................................................................................................................ NDC 0078-0512-05
Store at controlled room temperature 15°C-30°C (59°F-86°F). Protect from moisture.
Dispense in tight container (USP).
Suspension 100 mg/5 mL (teaspoon) – yellow-orange, citrus-vanilla flavored
Bottles of 450 mL ..................................................................................................................... NDC 0078-0508-83
Shake well before using.
Do not store above 30°C (86°F). Dispense in tight, light-resistant container (USP).
*Thorazine® is a registered trademark of GlaxoSmithKline.
Distributed by:
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936
REV: AUGUST 2010
T2010-XX
© Novartis
Reference ID: 2912982
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|
custom-source
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2025-02-12T13:47:07.122968
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/016608s100s102,018281s049s050,018927s041s042,020234s031s033lbl.pdf', 'application_number': 20234, 'submission_type': 'SUPPL ', 'submission_number': 31}
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company logo
Tegretol®
carbamazepine USP
Chewable Tablets of 100 mg - red-speckled, pink
Tablets of 200 mg – pink
Suspension of 100 mg/5 mL
Tegretol®-XR
(carbamazepine extended-release tablets)
100 mg, 200 mg, 400 mg
Rx only
Prescribing Information
WARNINGS
SERIOUS DERMATOLOGIC REACTIONS AND HLA-B*1502 ALLELE
SERIOUS AND SOMETIMES FATAL DERMATOLOGIC REACTIONS, INCLUDING TOXIC
EPIDERMAL NECROLYSIS (TEN) AND STEVENS-JOHNSON SYNDROME (SJS), HAVE BEEN
REPORTED DURING TREATMENT WITH TEGRETOL. THESE REACTIONS ARE ESTIMATED TO
OCCUR IN 1 TO 6 PER 10,000 NEW USERS IN COUNTRIES WITH MAINLY CAUCASIAN
POPULATIONS, BUT THE RISK IN SOME ASIAN COUNTRIES IS ESTIMATED TO BE ABOUT 10
TIMES HIGHER. STUDIES IN PATIENTS OF CHINESE ANCESTRY HAVE FOUND A STRONG
ASSOCIATION BETWEEN THE RISK OF DEVELOPING SJS/TEN AND THE PRESENCE OF
HLA-B*1502, AN INHERITED ALLELIC VARIANT OF THE HLA-B GENE. HLA-B*1502 IS FOUND
ALMOST EXCLUSIVELY IN PATIENTS WITH ANCESTRY ACROSS BROAD AREAS OF ASIA.
PATIENTS WITH ANCESTRY IN GENETICALLY AT-RISK POPULATIONS SHOULD BE SCREENED
FOR THE PRESENCE OF HLA-B*1502 PRIOR TO INITIATING TREATMENT WITH TEGRETOL.
PATIENTS TESTING POSITIVE FOR THE ALLELE SHOULD NOT BE TREATED WITH TEGRETOL
UNLESS THE BENEFIT CLEARLY OUTWEIGHS THE RISK (SEE WARNINGS AND PRECAUTIONS,
LABORATORY TESTS).
APLASTIC ANEMIA AND AGRANULOCYTOSIS
APLASTIC ANEMIA AND AGRANULOCYTOSIS HAVE BEEN REPORTED IN ASSOCIATION WITH
THE USE OF TEGRETOL. DATA FROM A POPULATION-BASED CASE CONTROL STUDY
DEMONSTRATE THAT THE RISK OF DEVELOPING THESE REACTIONS IS 5-8 TIMES GREATER
THAN IN THE GENERAL POPULATION. HOWEVER, THE OVERALL RISK OF THESE REACTIONS
IN THE UNTREATED GENERAL POPULATION IS LOW, APPROXIMATELY SIX PATIENTS PER ONE
MILLION POPULATION PER YEAR FOR AGRANULOCYTOSIS AND TWO PATIENTS PER ONE
MILLION POPULATION PER YEAR FOR APLASTIC ANEMIA.
ALTHOUGH REPORTS OF TRANSIENT OR PERSISTENT DECREASED PLATELET OR WHITE
BLOOD CELL COUNTS ARE NOT UNCOMMON IN ASSOCIATION WITH THE USE OF TEGRETOL,
DATA ARE NOT AVAILABLE TO ESTIMATE ACCURATELY THEIR INCIDENCE OR OUTCOME.
HOWEVER, THE VAST MAJORITY OF THE CASES OF LEUKOPENIA HAVE NOT PROGRESSED TO
THE MORE SERIOUS CONDITIONS OF APLASTIC ANEMIA OR AGRANULOCYTOSIS.
Reference ID: 2912982
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BECAUSE OF THE VERY LOW INCIDENCE OF AGRANULOCYTOSIS AND APLASTIC ANEMIA,
THE VAST MAJORITY OF MINOR HEMATOLOGIC CHANGES OBSERVED IN MONITORING OF
PATIENTS ON TEGRETOL ARE UNLIKELY TO SIGNAL THE OCCURRENCE OF EITHER
ABNORMALITY. NONETHELESS, COMPLETE PRETREATMENT HEMATOLOGICAL TESTING
SHOULD BE OBTAINED AS A BASELINE. IF A PATIENT IN THE COURSE OF TREATMENT
EXHIBITS LOW OR DECREASED WHITE BLOOD CELL OR PLATELET COUNTS, THE PATIENT
SHOULD BE MONITORED CLOSELY. DISCONTINUATION OF THE DRUG SHOULD BE
CONSIDERED IF ANY EVIDENCE OF SIGNIFICANT BONE MARROW DEPRESSION DEVELOPS.
Before prescribing Tegretol, the physician should be thoroughly familiar with the details of this
prescribing information, particularly regarding use with other drugs, especially those which accentuate
toxicity potential.
DESCRIPTION
Tegretol, carbamazepine USP, is an anticonvulsant and specific analgesic for trigeminal neuralgia, available for
oral administration as chewable tablets of 100 mg, tablets of 200 mg, XR tablets of 100, 200, and 400 mg, and
as a suspension of 100 mg/5 mL (teaspoon). Its chemical name is 5H-dibenz[b,f ]azepine-5-carboxamide, and
its structural formula is structural formula
Carbamazepine USP is a white to off-white powder, practically insoluble in water and soluble in alcohol and in
acetone. Its molecular weight is 236.27.
Inactive Ingredients Tablets: Colloidal silicon dioxide, D&C Red No. 30 Aluminum Lake (chewable tablets
only), FD&C Red No. 40 (200-mg tablets only), flavoring (chewable tablets only), gelatin, glycerin, magnesium
stearate, sodium starch glycolate (chewable tablets only), starch, stearic acid, and sucrose (chewable tablets
only). Suspension: Citric acid, FD&C Yellow No. 6, flavoring, polymer, potassium sorbate, propylene glycol,
purified water, sorbitol, sucrose, and xanthan gum. Tegretol-XR tablets: cellulose compounds, dextrates, iron
oxides, magnesium stearate, mannitol, polyethylene glycol, sodium lauryl sulfate, titanium dioxide (200-mg
tablets only).
CLINICAL PHARMACOLOGY
In controlled clinical trials, Tegretol has been shown to be effective in the treatment of psychomotor and grand
mal seizures, as well as trigeminal neuralgia.
Mechanism of Action
Tegretol has demonstrated anticonvulsant properties in rats and mice with electrically and chemically induced
seizures. It appears to act by reducing polysynaptic responses and blocking the post-tetanic potentiation.
Tegretol greatly reduces or abolishes pain induced by stimulation of the infraorbital nerve in cats and rats. It
depresses thalamic potential and bulbar and polysynaptic reflexes, including the linguomandibular reflex in
cats. Tegretol is chemically unrelated to other anticonvulsants or other drugs used to control the pain of
trigeminal neuralgia. The mechanism of action remains unknown.
The principal metabolite of Tegretol, carbamazepine-10,11-epoxide, has anticonvulsant activity as
demonstrated in several in vivo animal models of seizures. Though clinical activity for the epoxide has been
postulated, the significance of its activity with respect to the safety and efficacy of Tegretol has not been
established.
Reference ID: 2912982
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Pharmacokinetics
In clinical studies, Tegretol suspension, conventional tablets, and XR tablets delivered equivalent amounts of
drug to the systemic circulation. However, the suspension was absorbed somewhat faster, and the XR tablet
slightly slower, than the conventional tablet. The bioavailability of the XR tablet was 89% compared to
suspension. Following a b.i.d. dosage regimen, the suspension provides higher peak levels and lower trough
levels than those obtained from the conventional tablet for the same dosage regimen. On the other hand,
following a t.i.d. dosage regimen, Tegretol suspension affords steady-state plasma levels comparable to
Tegretol tablets given b.i.d. when administered at the same total mg daily dose. Following a b.i.d. dosage
regimen, Tegretol-XR tablets afford steady-state plasma levels comparable to conventional Tegretol tablets
given q.i.d., when administered at the same total mg daily dose. Tegretol in blood is 76% bound to plasma
proteins. Plasma levels of Tegretol are variable and may range from 0.5-25 µg/mL, with no apparent
relationship to the daily intake of the drug. Usual adult therapeutic levels are between 4 and 12 µg/mL. In
polytherapy, the concentration of Tegretol and concomitant drugs may be increased or decreased during
therapy, and drug effects may be altered (see PRECAUTIONS, Drug Interactions). Following chronic oral
administration of suspension, plasma levels peak at approximately 1.5 hours compared to 4-5 hours after
administration of conventional Tegretol tablets, and 3-12 hours after administration of Tegretol-XR tablets. The
CSF/serum ratio is 0.22, similar to the 24% unbound Tegretol in serum. Because Tegretol induces its own
metabolism, the half-life is also variable. Autoinduction is completed after 3-5 weeks of a fixed dosing regimen.
Initial half-life values range from 25-65 hours, decreasing to 12-17 hours on repeated doses. Tegretol is
metabolized in the liver. Cytochrome P450 3A4 was identified as the major isoform responsible for the
formation of carbamazepine-10,11-epoxide from Tegretol. After oral administration of 14C-carbamazepine, 72%
of the administered radioactivity was found in the urine and 28% in the feces. This urinary radioactivity was
composed largely of hydroxylated and conjugated metabolites, with only 3% of unchanged Tegretol.
The pharmacokinetic parameters of Tegretol disposition are similar in children and in adults. However, there is
a poor correlation between plasma concentrations of carbamazepine and Tegretol dose in children.
Carbamazepine is more rapidly metabolized to carbamazepine-10,11-epoxide (a metabolite shown to be
equipotent to carbamazepine as an anticonvulsant in animal screens) in the younger age groups than in adults. In
children below the age of 15, there is an inverse relationship between CBZ-E/CBZ ratio and increasing age (in
one report from 0.44 in children below the age of 1 year to 0.18 in children between 10-15 years of age).
The effects of race and gender on carbamazepine pharmacokinetics have not been systematically evaluated.
INDICATIONS AND USAGE
Epilepsy
Tegretol is indicated for use as an anticonvulsant drug. Evidence supporting efficacy of Tegretol as an
anticonvulsant was derived from active drug-controlled studies that enrolled patients with the following seizure
types:
1. Partial seizures with complex symptomatology (psychomotor, temporal lobe). Patients with these seizures
appear to show greater improvement than those with other types.
2. Generalized tonic-clonic seizures (grand mal).
3. Mixed seizure patterns which include the above, or other partial or generalized seizures. Absence seizures
(petit mal) do not appear to be controlled by Tegretol (see PRECAUTIONS, General).
Trigeminal Neuralgia
Tegretol is indicated in the treatment of the pain associated with true trigeminal neuralgia.
Beneficial results have also been reported in glossopharyngeal neuralgia.
This drug is not a simple analgesic and should not be used for the relief of trivial aches or pains.
Reference ID: 2912982
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CONTRAINDICATIONS
Tegretol should not be used in patients with a history of previous bone marrow depression, hypersensitivity to
the drug, or known sensitivity to any of the tricyclic compounds, such as amitriptyline, desipramine,
imipramine, protriptyline, nortriptyline, etc. Likewise, on theoretical grounds its use with monoamine oxidase
inhibitors is not recommended. Before administration of Tegretol, MAO inhibitors should be discontinued for a
minimum of 14 days, or longer if the clinical situation permits.
Coadministration of carbamazepine and nefazodone may result in insufficient plasma concentrations of
nefazodone and its active metabolite to achieve a therapeutic effect. Coadministration of carbamazepine with
nefazodone is contraindicated.
WARNINGS
Serious Dermatologic Reactions
Serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN) and
Stevens-Johnson syndrome (SJS), have been reported with Tegretol treatment. The risk of these events is
estimated to be about 1 to 6 per 10,000 new users in countries with mainly Caucasian populations. However, the
risk in some Asian countries is estimated to be about 10 times higher. Tegretol should be discontinued at the
first sign of a rash, unless the rash is clearly not drug-related. If signs or symptoms suggest SJS/TEN, use of this
drug should not be resumed and alternative therapy should be considered.
SJS/TEN and HLA-B*1502 Allele
Retrospective case-control studies have found that in patients of Chinese ancestry there is a strong association
between the risk of developing SJS/TEN with carbamazepine treatment and the presence of an inherited variant
of the HLA-B gene, HLA-B*1502. The occurrence of higher rates of these reactions in countries with higher
frequencies of this allele suggests that the risk may be increased in allele-positive individuals of any ethnicity.
Across Asian populations, notable variation exists in the prevalence of HLA-B*1502. Greater than 15% of the
population is reported positive in Hong Kong, Thailand, Malaysia, and parts of the Philippines, compared to
about 10% in Taiwan and 4% in North China. South Asians, including Indians, appear to have intermediate
prevalence of HLA-B*1502, averaging 2 to 4%, but higher in some groups. HLA-B*1502 is present in <1% of
the population in Japan and Korea.
HLA-B*1502 is largely absent in individuals not of Asian origin (e.g., Caucasians, African-Americans,
Hispanics, and Native Americans).
Prior to initiating Tegretol therapy, testing for HLA-B*1502 should be performed in patients with
ancestry in populations in which HLA-B*1502 may be present. In deciding which patients to screen, the
rates provided above for the prevalence of HLA-B*1502 may offer a rough guide, keeping in mind the
limitations of these figures due to wide variability in rates even within ethnic groups, the difficulty in
ascertaining ethnic ancestry, and the likelihood of mixed ancestry. Tegretol should not be used in patients
positive for HLA-B*1502 unless the benefits clearly outweigh the risks. Tested patients who are found to be
negative for the allele are thought to have a low risk of SJS/TEN (see WARNINGS and PRECAUTIONS,
Laboratory Tests).
Over 90% of Tegretol treated patients who will experience SJS/TEN have this reaction within the first few
months of treatment. This information may be taken into consideration in determining the need for screening of
genetically at-risk patients currently on Tegretol.
The HLA-B*1502 allele has not been found to predict risk of less severe adverse cutaneous reactions from
Tegretol, such as anticonvulsant hypersensitivity syndrome or nonserious rash (maculopapular eruption [MPE]).
Limited evidence suggests that HLA-B*1502 may be a risk factor for the development of SJS/TEN in patients
of Chinese ancestry taking other antiepileptic drugs associated with SJS/TEN. Consideration should be given to
Reference ID: 2912982
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For current labeling information, please visit https://www.fda.gov/drugsatfda
avoiding use of other drugs associated with SJS/TEN in HLA-B*1502 positive patients, when alternative
therapies are otherwise equally acceptable.
Application of HLA-B*1502 genotyping as a screening tool has important limitations and must never substitute
for appropriate clinical vigilance and patient management. Many HLA-B*1502-positive Asian patients treated
with Tegretol will not develop SJS/TEN, and these reactions can still occur infrequently in
HLA-B*1502-negative patients of any ethnicity. The role of other possible factors in the development of, and
morbidity from, SJS/TEN, such as antiepileptic drug (AED) dose, compliance, concomitant medications,
comorbidities, and the level of dermatologic monitoring have not been studied.
Aplastic Anemia and Agranulocytosis
Patients with a history of adverse hematologic reaction to any drug may be particularly at risk of bone marrow
depression.
Suicidal Behavior and Ideation
Antiepileptic drugs (AEDs), including Tegretol, increase the risk of suicidal thoughts or behavior in patients
taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for
the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood
or behavior.
Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs
showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk
1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these
trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or
ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated
patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530
patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated
patients, but the number is too small to allow any conclusion about drug effect on suicide.
The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting
drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in
the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could
not be assessed.
The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The
finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests
that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years)
in the clinical trials analyzed. Table 1 shows absolute and relative risk by indication for all evaluated AEDs.
Table 1 Risk by Indication for Antiepileptic Drugs in the Pooled Analysis
Indication
Placebo Patients
with Events Per
1,000 Patients
Drug Patients
with Events Per
1,000 Patients
Relative Risk:
Incidence of
Events in Drug
Patients/Incidence
in Placebo
Patients
Risk Difference:
Additional Drug
Patients with
Events Per 1,000
Patients
Epilepsy
1.0
3.4
3.5
2.4
Psychiatric
5.7
8.5
1.5
2.9
Other
1.0
1.8
1.9
0.9
Total
2.4
4.3
1.8
1.9
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The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials
for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric
indications.
Anyone considering prescribing Tegretol or any other AED must balance the risk of suicidal thoughts or
behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are
themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior.
Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the
emergence of these symptoms in any given patient may be related to the illness being treated.
Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and
behavior and should be advised of the need to be alert for the emergence or worsening of the signs and
symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts,
behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare
providers.
General
Tegretol has shown mild anticholinergic activity; therefore, patients with increased intraocular pressure should
be closely observed during therapy.
Because of the relationship of the drug to other tricyclic compounds, the possibility of activation of a latent
psychosis and, in elderly patients, of confusion or agitation should be borne in mind.
The use of Tegretol should be avoided in patients with a history of hepatic porphyria (e.g., acute intermittent
porphyria, variegate porphyria, porphyria cutanea tarda). Acute attacks have been reported in such patients
receiving Tegretol therapy. Carbamazepine administration has also been demonstrated to increase porphyrin
precursors in rodents, a presumed mechanism for the induction of acute attacks of porphyria.
As with all antiepileptic drugs, Tegretol should be withdrawn gradually to minimize the potential of increased
seizure frequency.
Usage in Pregnancy
Carbamazepine can cause fetal harm when administered to a pregnant woman.
Epidemiological data suggest that there may be an association between the use of carbamazepine during
pregnancy and congenital malformations, including spina bifida. There have also been reports that associate
carbamazepine with developmental disorders and congenital anomalies (e.g., craniofacial defects,
cardiovascular malformations, hypospadias and anomalies involving various body systems). Developmental
delays based on neurobehavioral assessments have been reported. In treating or counseling women of
childbearing potential, the prescribing physician will wish to weigh the benefits of therapy against the risks. If
this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should
be apprised of the potential hazard to the fetus.
Retrospective case reviews suggest that, compared with monotherapy, there may be a higher prevalence of
teratogenic effects associated with the use of anticonvulsants in combination therapy. Therefore, if therapy is to
be continued, monotherapy may be preferable for pregnant women.
In humans, transplacental passage of carbamazepine is rapid (30-60 minutes), and the drug is accumulated in
the fetal tissues, with higher levels found in liver and kidney than in brain and lung.
Carbamazepine has been shown to have adverse effects in reproduction studies in rats when given orally in
dosages 10-25 times the maximum human daily dosage (MHDD) of 1200 mg on a mg/kg basis or 1.5-4 times
the MHDD on a mg/m2 basis. In rat teratology studies, 2 of 135 offspring showed kinked ribs at 250 mg/kg and
4 of 119 offspring at 650 mg/kg showed other anomalies (cleft palate, 1; talipes, 1; anophthalmos, 2). In
reproduction studies in rats, nursing offspring demonstrated a lack of weight gain and an unkempt appearance at
a maternal dosage level of 200 mg/kg.
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Antiepileptic drugs should not be discontinued abruptly in patients in whom the drug is administered to prevent
major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and
threat to life. In individual cases where the severity and frequency of the seizure disorder are such that removal
of medication does not pose a serious threat to the patient, discontinuation of the drug may be considered prior
to and during pregnancy, although it cannot be said with any confidence that even minor seizures do not pose
some hazard to the developing embryo or fetus.
Tests to detect defects using currently accepted procedures should be considered a part of routine prenatal care
in childbearing women receiving carbamazepine.
There have been a few cases of neonatal seizures and/or respiratory depression associated with maternal
Tegretol and other concomitant anticonvulsant drug use. A few cases of neonatal vomiting, diarrhea, and/or
decreased feeding have also been reported in association with maternal Tegretol use. These symptoms may
represent a neonatal withdrawal syndrome.
To provide information regarding the effects of in utero exposure to Tegretol, physicians are advised to
recommend that pregnant patients taking Tegretol enroll in the North American Antiepileptic Drug (NAAED)
Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by
patients themselves. Information on the registry can also be found at the website
http://www.aedpregnancyregistry.org/.
PRECAUTIONS
General
Before initiating therapy, a detailed history and physical examination should be made.
Tegretol should be used with caution in patients with a mixed seizure disorder that includes atypical absence
seizures, since in these patients Tegretol has been associated with increased frequency of generalized
convulsions (see INDICATIONS AND USAGE).
Therapy should be prescribed only after critical benefit-to-risk appraisal in patients with a history of cardiac
conduction disturbance, including second and third degree AV heart block; cardiac, hepatic, or renal damage;
adverse hematologic or hypersensitivity reaction to other drugs, including reactions to other anticonvulsants; or
interrupted courses of therapy with Tegretol.
AV heart block, including second and third degree block, have been reported following Tegretol treatment. This
occurred generally, but not solely, in patients with underlying EKG abnormalities or risk factors for conduction
disturbances.
Hepatic effects, ranging from slight elevations in liver enzymes to rare cases of hepatic failure have been
reported (see ADVERSE REACTIONS and PRECAUTIONS, Laboratory Tests). In some cases, hepatic effects
may progress despite discontinuation of the drug.
Multiorgan hypersensitivity reactions which can affect the skin, liver, hemopoietic organs and lymphatic system
or other organs and occurring days to weeks or months after initiating treatment have been reported in rare cases
(see ADVERSE REACTIONS, Other and PRECAUTIONS, Information for Patients).
Discontinuation of carbamazepine should be considered if any evidence of hypersensitivity develops.
Hypersensitivity reactions to carbamazepine have been reported in patients who previously experienced this
reaction to anticonvulsants including phenytoin and phenobarbital. A history of hypersensitivity reactions
should be obtained for a patient and the immediate family members. If positive, caution should be used in
prescribing carbamazepine.
In patients who have exhibited hypersensitivity reactions to carbamazepine approximately 25 to 30% of these
patients may experience hypersensitivity reactions with oxcarbazepine (Trileptal®).
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Since a given dose of Tegretol suspension will produce higher peak levels than the same dose given as the
tablet, it is recommended that patients given the suspension be started on lower doses and increased slowly to
avoid unwanted side effects (see DOSAGE AND ADMINISTRATION).
Tegretol suspension contains sorbitol and, therefore, should not be administered to patients with rare hereditary
problems of fructose intolerance.
Information for Patients
Patients should be informed of the availability of a Medication Guide and they should be instructed to read the
Medication Guide before taking Tegretol.
Patients should be made aware of the early toxic signs and symptoms of a potential hematologic problem, as
well as dermatologic, hypersensitivity or hepatic reactions. These symptoms may include, but are not limited to,
fever, sore throat, rash, ulcers in the mouth, easy bruising, lymphadenopathy and petechial or purpuric
hemorrhage, and in the case of liver reactions, anorexia, nausea/vomiting, or jaundice. The patient should be
advised that, because these signs and symptoms may signal a serious reaction, that they must report any
occurrence immediately to a physician. In addition, the patient should be advised that these signs and symptoms
should be reported even if mild or when occurring after extended use.
Patients, their caregivers, and families should be counseled that AEDs, including Tegretol, may increase the risk
of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening
of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts,
behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare
providers
Patients should be advised that serious skin reactions have been reported in association with Tegretol. In the
event a skin reaction should occur while taking Tegretol, patients should consult with their physician
immediately (see WARNINGS).
Tegretol may interact with some drugs. Therefore, patients should be advised to report to their doctors the use
of any other prescription or nonprescription medications or herbal products.
Caution should be exercised if alcohol is taken in combination with Tegretol therapy, due to a possible additive
sedative effect.
Since dizziness and drowsiness may occur, patients should be cautioned about the hazards of operating
machinery or automobiles or engaging in other potentially dangerous tasks.
Patients should be encouraged to enroll in the NAAED Pregnancy Registry if they become pregnant. This
registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients
can call the toll free number 1-888-233-2334 (see WARNINGS, Usage in Pregnancy subsection).
Laboratory Tests
For genetically at-risk patients (see WARNINGS), high-resolution ‘HLA-B*1502 typing’ is recommended. The
test is positive if either one or two HLA-B*1502 alleles are detected and negative if no HLA-B*1502 alleles are
detected.
Complete pretreatment blood counts, including platelets and possibly reticulocytes and serum iron, should be
obtained as a baseline. If a patient in the course of treatment exhibits low or decreased white blood cell or
platelet counts, the patient should be monitored closely. Discontinuation of the drug should be considered if any
evidence of significant bone marrow depression develops.
Baseline and periodic evaluations of liver function, particularly in patients with a history of liver disease, must
be performed during treatment with this drug since liver damage may occur (see PRECAUTIONS, General and
ADVERSE REACTIONS). Carbamazepine should be discontinued, based on clinical judgment, if indicated by
newly occurring or worsening clinical or laboratory evidence of liver dysfunction or hepatic damage, or in the
case of active liver disease.
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Baseline and periodic eye examinations, including slit-lamp, funduscopy, and tonometry, are recommended
since many phenothiazines and related drugs have been shown to cause eye changes.
Baseline and periodic complete urinalysis and BUN determinations are recommended for patients treated with
this agent because of observed renal dysfunction.
Monitoring of blood levels (see CLINICAL PHARMACOLOGY) has increased the efficacy and safety of
anticonvulsants. This monitoring may be particularly useful in cases of dramatic increase in seizure frequency
and for verification of compliance. In addition, measurement of drug serum levels may aid in determining the
cause of toxicity when more than one medication is being used.
Thyroid function tests have been reported to show decreased values with Tegretol administered alone.
Hyponatremia has been reported in association with Tegretol use, either alone or in combination with other
drugs.
Interference with some pregnancy tests has been reported.
Drug Interactions
There has been a report of a patient who passed an orange rubbery precipitate in his stool the day after ingesting
Tegretol suspension immediately followed by Thorazine®* solution. Subsequent testing has shown that mixing
Tegretol suspension and chlorpromazine solution (both generic and brand name) as well as Tegretol suspension
and liquid Mellaril® resulted in the occurrence of this precipitate. Because the extent to which this occurs with
other liquid medications is not known, Tegretol suspension should not be administered simultaneously with
other liquid medicinal agents or diluents (see DOSAGE AND ADMINISTRATION).
Clinically meaningful drug interactions have occurred with concomitant medications and include, but are not
limited to, the following:
Agents That May Affect Tegretol Plasma Levels
CYP 3A4 inhibitors inhibit Tegretol metabolism and can thus increase plasma carbamazepine levels. Drugs that
have been shown, or would be expected, to increase plasma carbamazepine levels include:
cimetidine, danazol, diltiazem, macrolides, erythromycin, troleandomycin, clarithromycin, fluoxetine,
fluvoxamine, nefazodone, trazodone, loxapine*, olanzapine, quetiapine*, loratadine, terfenadine,
omeprazole, oxybutynin, dantrolene, isoniazid, niacinamide, nicotinamide, ibuprofen, propoxyphene,
azoles (e.g., ketaconazole, itraconazole, fluconazole, voriconazole), acetazolamide, verapamil,
ticlopidine, grapefruit juice, protease inhibitors, valproate*.
CYP 3A4 inducers can increase the rate of Tegretol metabolism. Drugs that have been shown, or that would be
expected, to decrease plasma carbamazepine levels include:
cisplatin, doxorubicin HCl, felbamate†, fosphenytoin, rifampin, phenobarbital, phenytoin, primidone,
methsuximide, theophylline, aminophylline.
When carbamazepine is given with drugs that can increase or decrease carbamazepine levels, close monitoring
of carbamazepine levels is indicated and dosage adjustment may be required.
*increased levels of the active 10,11-epoxide
†decreased levels of carbamazepine and increased levels of the 10,11-epoxide
Effect of Tegretol on Plasma Levels of Concomitant Agents
Increased levels: clomipramine HCl, phenytoin, primidone
Tegretol is a potent inducer of hepatic CYP 3A4 and may therefore reduce plasma concentrations of
comedications mainly metabolized by 3A4 through induction of their metabolism. Tegretol causes, or would be
expected to cause, decreased levels of the following:
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acetaminophen, alprazolam, bupropion, dihydropyridine calcium channel blockers (e.g., felodipine),
citalopram, cyclosporine, corticosteroids (e.g., prednisolone, dexamethasone), clonazepam, clozapine,
dicumarol, doxycycline, ethosuximide, everolimus, haloperidol, imatinib, itraconazole, lamotrigine,
levothyroxine, methadone, methsuximide, midazolam, olanzapine, oral and other hormonal
contraceptives, oxcarbazepine, phensuximide, phenytoin, praziquantel, protease inhibitors, risperidone,
theophylline, tiagabine, topiramate, tramadol, trazodone, tricyclic antidepressants (e.g., imipramine,
amitriptyline, nortriptyline), valproate, warfarin, ziprasidone, zonisamide.
In concomitant use with Tegretol, dosage adjustment of the above agents may be necessary.
Coadministration of carbamazepine with nefazodone results in insufficient plasma concentrations of nefazodone
and its active metabolite to achieve a therapeutic effect. Coadministration of carbamazepine with nefazodone is
contraindicated (see CONTRAINDICATIONS).
Concomitant administration of carbamazepine and lithium may increase the risk of neurotoxic side effects.
Concomitant use of carbamazepine and isoniazid has been reported to increase isoniazid-induced
hepatotoxicity.
Concomitant medication with Tegretol and some diuretics (hydrochlorothiazide, furosemide) may lead to
symptomatic hyponatremia.
Carbamazepine may antagonize the effects of nondepolarizing muscle relaxants (e.g., pancuronium).
Their dosage may need to be raised, and patients should be monitored closely for more rapid recovery from
neuromuscular blockade than expected.
Alterations of thyroid function have been reported in combination therapy with other anticonvulsant
medications.
Concomitant use of Tegretol with hormonal contraceptive products (e.g., oral, and levonorgestrel subdermal
implant contraceptives) may render the contraceptives less effective because the plasma concentrations of the
hormones may be decreased. Breakthrough bleeding and unintended pregnancies have been reported.
Alternative or back-up methods of contraception should be considered.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carbamazepine, when administered to Sprague-Dawley rats for two years in the diet at doses of 25, 75, and
250 mg/kg/day, resulted in a dose-related increase in the incidence of hepatocellular tumors in females and of
benign interstitial cell adenomas in the testes of males.
Carbamazepine must, therefore, be considered to be carcinogenic in Sprague-Dawley rats. Bacterial and
mammalian mutagenicity studies using carbamazepine produced negative results. The significance of these
findings relative to the use of carbamazepine in humans is, at present, unknown.
Usage in Pregnancy
Pregnancy Category D (see WARNINGS).
Labor and Delivery
The effect of Tegretol on human labor and delivery is unknown.
Nursing Mothers
Tegretol and its epoxide metabolite are transferred to breast milk. The ratio of the concentration in breast milk
to that in maternal plasma is about 0.4 for Tegretol and about 0.5 for the epoxide. The estimated doses given to
the newborn during breast-feeding are in the range of 2-5 mg daily for Tegretol and 1-2 mg daily for the
epoxide.
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Because of the potential for serious adverse reactions in nursing infants from carbamazepine, a decision should
be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the
drug to the mother.
Pediatric Use
Substantial evidence of Tegretol’s effectiveness for use in the management of children with epilepsy (see
INDICATIONS AND USAGE for specific seizure types) is derived from clinical investigations performed in
adults and from studies in several in vitro systems which support the conclusion that (1) the pathogenetic
mechanisms underlying seizure propagation are essentially identical in adults and children, and (2) the
mechanism of action of carbamazepine in treating seizures is essentially identical in adults and children.
Taken as a whole, this information supports a conclusion that the generally accepted therapeutic range of total
carbamazepine in plasma (i.e., 4-12 mcg/mL) is the same in children and adults.
The evidence assembled was primarily obtained from short-term use of carbamazepine. The safety of
carbamazepine in children has been systematically studied up to 6 months. No longer-term data from clinical
trials is available.
Geriatric Use
No systematic studies in geriatric patients have been conducted.
ADVERSE REACTIONS
If adverse reactions are of such severity that the drug must be discontinued, the physician must be aware that
abrupt discontinuation of any anticonvulsant drug in a responsive epileptic patient may lead to seizures or even
status epilepticus with its life-threatening hazards.
The most severe adverse reactions have been observed in the hemopoietic system and skin (see BOXED
WARNING), the liver, and the cardiovascular system.
The most frequently observed adverse reactions, particularly during the initial phases of therapy, are dizziness,
drowsiness, unsteadiness, nausea, and vomiting. To minimize the possibility of such reactions, therapy should
be initiated at the low dosage recommended.
The following additional adverse reactions have been reported:
Hemopoietic System: Aplastic anemia, agranulocytosis, pancytopenia, bone marrow depression,
thrombocytopenia, leukopenia, leukocytosis, eosinophilia, anemia, acute intermittent porphyria, variegate
porphyria, porphyria cutanea tarda.
Skin: Toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) (see BOXED WARNING),
pruritic and erythematous rashes, urticaria, photosensitivity reactions, alterations in skin pigmentation,
exfoliative dermatitis, erythema multiforme and nodosum, purpura, aggravation of disseminated lupus
erythematosus, alopecia, and diaphoresis. In certain cases, discontinuation of therapy may be necessary. Isolated
cases of hirsutism have been reported, but a causal relationship is not clear.
Cardiovascular System: Congestive heart failure, edema, aggravation of hypertension, hypotension, syncope
and collapse, aggravation of coronary artery disease, arrhythmias and AV block, thrombophlebitis,
thromboembolism (e.g., pulmonary embolism), and adenopathy or lymphadenopathy.
Some of these cardiovascular complications have resulted in fatalities. Myocardial infarction has been
associated with other tricyclic compounds.
Liver: Abnormalities in liver function tests, cholestatic and hepatocellular jaundice, hepatitis; very rare cases of
hepatic failure.
Pancreatic: Pancreatitis.
Respiratory System: Pulmonary hypersensitivity characterized by fever, dyspnea, pneumonitis, or pneumonia.
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Genitourinary System: Urinary frequency, acute urinary retention, oliguria with elevated blood pressure,
azotemia, renal failure, and impotence. Albuminuria, glycosuria, elevated BUN, and microscopic deposits in the
urine have also been reported. There have been very rare reports of impaired male fertility and/or abnormal
spermatogenesis.
Testicular atrophy occurred in rats receiving Tegretol orally from 4-52 weeks at dosage levels of 50-400
mg/kg/day. Additionally, rats receiving Tegretol in the diet for 2 years at dosage levels of 25, 75, and 250
mg/kg/day had a dose-related incidence of testicular atrophy and aspermatogenesis. In dogs, it produced a
brownish discoloration, presumably a metabolite, in the urinary bladder at dosage levels of 50 mg/kg and
higher. Relevance of these findings to humans is unknown.
Nervous System: Dizziness, drowsiness, disturbances of coordination, confusion, headache, fatigue, blurred
vision, visual hallucinations, transient diplopia, oculomotor disturbances, nystagmus, speech disturbances,
abnormal involuntary movements, peripheral neuritis and paresthesias, depression with agitation, talkativeness,
tinnitus, hyperacusis, neuroleptic malignant syndrome.
There have been reports of associated paralysis and other symptoms of cerebral arterial insufficiency, but the
exact relationship of these reactions to the drug has not been established.
Isolated cases of neuroleptic malignant syndrome have been reported both with and without concomitant use of
psychotropic drugs.
Digestive System: Nausea, vomiting, gastric distress and abdominal pain, diarrhea, constipation, anorexia, and
dryness of the mouth and pharynx, including glossitis and stomatitis.
Eyes: Scattered punctate cortical lens opacities, increased intraocular pressure as well as conjunctivitis, have
been reported. Although a direct causal relationship has not been established, many phenothiazines and related
drugs have been shown to cause eye changes.
Musculoskeletal System: Aching joints and muscles, and leg cramps.
Metabolism: Fever and chills. Inappropriate antidiuretic hormone (ADH) secretion syndrome has been reported.
Cases of frank water intoxication, with decreased serum sodium (hyponatremia) and confusion, have been
reported in association with Tegretol use (see PRECAUTIONS, Laboratory Tests). Decreased levels of plasma
calcium leading to osteoporosis have been reported.
Other: Multiorgan hypersensitivity reactions occurring days to weeks or months after initiating treatment have
been reported in rare cases. Signs or symptoms may include, but are not limited to fever, skin rashes, vasculitis,
lymphadenopathy, disorders mimicking lymphoma, arthralgia, leukopenia, eosinophilia, hepatosplenomegaly
and abnormal liver function tests. These signs and symptoms may occur in various combinations and not
necessarily concurrently. Signs and symptoms may initially be mild. Various organs, including but not limited
to, liver, skin, immune system, lungs, kidneys, pancreas, myocardium, and colon may be affected (see
PRECAUTIONS, General and PRECAUTIONS, Information for Patients).
Isolated cases of a lupus erythematosus-like syndrome have been reported. There have been occasional reports
of elevated levels of cholesterol, HDL cholesterol, and triglycerides in patients taking anticonvulsants.
A case of aseptic meningitis, accompanied by myoclonus and peripheral eosinophilia, has been reported in a
patient taking carbamazepine in combination with other medications. The patient was successfully
dechallenged, and the meningitis reappeared upon rechallenge with carbamazepine.
DRUG ABUSE AND DEPENDENCE
No evidence of abuse potential has been associated with Tegretol, nor is there evidence of psychological or
physical dependence in humans.
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OVERDOSAGE
Acute Toxicity
Lowest known lethal dose: adults, 3.2 g (a 24-year-old woman died of a cardiac arrest and a 24-year-old man
died of pneumonia and hypoxic encephalopathy); children, 4 g (a 14-year-old girl died of a cardiac arrest), 1.6 g
(a 3-year-old girl died of aspiration pneumonia).
Oral LD50 in animals (mg/kg): mice, 1100-3750; rats, 3850-4025; rabbits, 1500-2680; guinea pigs, 920.
Signs and Symptoms
The first signs and symptoms appear after 1-3 hours. Neuromuscular disturbances are the most prominent.
Cardiovascular disorders are generally milder, and severe cardiac complications occur only when very high
doses (>60 g) have been ingested.
Respiration: Irregular breathing, respiratory depression.
Cardiovascular System: Tachycardia, hypotension or hypertension, shock, conduction disorders.
Nervous System and Muscles: Impairment of consciousness ranging in severity to deep coma. Convulsions,
especially in small children. Motor restlessness, muscular twitching, tremor, athetoid movements, opisthotonos,
ataxia, drowsiness, dizziness, mydriasis, nystagmus, adiadochokinesia, ballism, psychomotor disturbances,
dysmetria. Initial hyperreflexia, followed by hyporeflexia.
Gastrointestinal Tract: Nausea, vomiting.
Kidneys and Bladder: Anuria or oliguria, urinary retention.
Laboratory Findings: Isolated instances of overdosage have included leukocytosis, reduced leukocyte count,
glycosuria, and acetonuria. EEG may show dysrhythmias.
Combined Poisoning: When alcohol, tricyclic antidepressants, barbiturates, or hydantoins are taken at the same
time, the signs and symptoms of acute poisoning with Tegretol may be aggravated or modified.
Treatment
The prognosis in cases of severe poisoning is critically dependent upon prompt elimination of the drug, which
may be achieved by inducing vomiting, irrigating the stomach, and by taking appropriate steps to diminish
absorption. If these measures cannot be implemented without risk on the spot, the patient should be transferred
at once to a hospital, while ensuring that vital functions are safeguarded. There is no specific antidote.
Elimination of the Drug: Induction of vomiting.
Gastric lavage. Even when more than 4 hours have elapsed following ingestion of the drug, the stomach should
be repeatedly irrigated, especially if the patient has also consumed alcohol.
Measures to Reduce Absorption: Activated charcoal, laxatives.
Measures to Accelerate Elimination: Forced diuresis.
Dialysis is indicated only in severe poisoning associated with renal failure. Replacement transfusion is indicated
in severe poisoning in small children.
Respiratory Depression: Keep the airways free; resort, if necessary, to endotracheal intubation, artificial
respiration, and administration of oxygen.
Hypotension, Shock: Keep the patient’s legs raised and administer a plasma expander. If blood pressure fails to
rise despite measures taken to increase plasma volume, use of vasoactive substances should be considered.
Convulsions: Diazepam or barbiturates.
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Warning: Diazepam or barbiturates may aggravate respiratory depression (especially in children), hypotension,
and coma. However, barbiturates should not be used if drugs that inhibit monoamine oxidase have also been
taken by the patient either in overdosage or in recent therapy (within 1 week).
Surveillance: Respiration, cardiac function (ECG monitoring), blood pressure, body temperature, pupillary
reflexes, and kidney and bladder function should be monitored for several days.
Treatment of Blood Count Abnormalities: If evidence of significant bone marrow depression develops, the
following recommendations are suggested: (1) stop the drug, (2) perform daily CBC, platelet, and reticulocyte
counts, (3) do a bone marrow aspiration and trephine biopsy immediately and repeat with sufficient frequency
to monitor recovery.
Special periodic studies might be helpful as follows: (1) white cell and platelet antibodies, (2) 59Fe-ferrokinetic
studies, (3) peripheral blood cell typing, (4) cytogenetic studies on marrow and peripheral blood, (5) bone
marrow culture studies for colony-forming units, (6) hemoglobin electrophoresis for A2 and F hemoglobin, and
(7) serum folic acid and B12 levels.
A fully developed aplastic anemia will require appropriate, intensive monitoring and therapy, for which
specialized consultation should be sought.
DOSAGE AND ADMINISTRATION (SEE TABLE BELOW)
Tegretol suspension in combination with liquid chlorpromazine or thioridazine results in precipitate formation,
and, in the case of chlorpromazine, there has been a report of a patient passing an orange rubbery precipitate in
the stool following coadministration of the two drugs (see PRECAUTIONS, Drug Interactions). Because the
extent to which this occurs with other liquid medications is not known, Tegretol suspension should not be
administered simultaneously with other liquid medications or diluents.
Monitoring of blood levels has increased the efficacy and safety of anticonvulsants (see PRECAUTIONS,
Laboratory Tests). Dosage should be adjusted to the needs of the individual patient. A low initial daily dosage
with a gradual increase is advised. As soon as adequate control is achieved, the dosage may be reduced very
gradually to the minimum effective level. Medication should be taken with meals.
Since a given dose of Tegretol suspension will produce higher peak levels than the same dose given as the
tablet, it is recommended to start with low doses (children 6-12 years: 1/2 teaspoon q.i.d.) and to increase
slowly to avoid unwanted side effects.
Conversion of patients from oral Tegretol tablets to Tegretol suspension: Patients should be converted by
administering the same number of mg per day in smaller, more frequent doses (i.e., b.i.d. tablets to t.i.d.
suspension).
Tegretol-XR is an extended-release formulation for twice-a-day administration. When converting patients from
Tegretol conventional tablets to Tegretol-XR, the same total daily mg dose of Tegretol-XR should be
administered. Tegretol-XR tablets must be swallowed whole and never crushed or chewed. Tegretol-XR
tablets should be inspected for chips or cracks. Damaged tablets, or tablets without a release portal, should not
be consumed. Tegretol-XR tablet coating is not absorbed and is excreted in the feces; these coatings may be
noticeable in the stool.
Epilepsy (SEE INDICATIONS AND USAGE)
Adults and children over 12 years of age - Initial: Either 200 mg b.i.d. for tablets and XR tablets, or 1 teaspoon
q.i.d. for suspension (400 mg/day). Increase at weekly intervals by adding up to 200 mg/day using a b.i.d.
regimen of Tegretol-XR or a t.i.d. or q.i.d. regimen of the other formulations until the optimal response is
obtained. Dosage generally should not exceed 1000 mg daily in children 12-15 years of age, and 1200 mg daily
in patients above 15 years of age. Doses up to 1600 mg daily have been used in adults in rare instances.
Maintenance: Adjust dosage to the minimum effective level, usually 800-1200 mg daily.
Reference ID: 2912982
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Children 6-12 years of age - Initial: Either 100 mg b.i.d. for tablets or XR tablets, or 1/2 teaspoon q.i.d. for
suspension (200 mg/day). Increase at weekly intervals by adding up to 100 mg/day using a b.i.d. regimen of
Tegretol-XR or a t.i.d. or q.i.d. regimen of the other formulations until the optimal response is obtained. Dosage
generally should not exceed 1000 mg daily. Maintenance: Adjust dosage to the minimum effective level,
usually 400-800 mg daily.
Children under 6 years of age - Initial: 10-20 mg/kg/day b.i.d. or t.i.d. as tablets, or q.i.d. as suspension.
Increase weekly to achieve optimal clinical response administered t.i.d. or q.i.d. Maintenance: Ordinarily,
optimal clinical response is achieved at daily doses below 35 mg/kg. If satisfactory clinical response has not
been achieved, plasma levels should be measured to determine whether or not they are in the therapeutic range.
No recommendation regarding the safety of carbamazepine for use at doses above 35 mg/kg/24 hours can be
made.
Combination Therapy: Tegretol may be used alone or with other anticonvulsants. When added to existing
anticonvulsant therapy, the drug should be added gradually while the other anticonvulsants are maintained or
gradually decreased, except phenytoin, which may have to be increased (see PRECAUTIONS, Drug
Interactions, and Pregnancy Category D).
Trigeminal Neuralgia (SEE INDICATIONS AND USAGE)
Initial: On the first day, either 100 mg b.i.d. for tablets or XR tablets, or 1/2 teaspoon q.i.d. for suspension, for a
total daily dose of 200 mg. This daily dose may be increased by up to 200 mg/day using increments of 100 mg
every 12 hours for tablets or XR tablets, or 50 mg (1/2 teaspoon) q.i.d. for suspension, only as needed to
achieve freedom from pain. Do not exceed 1200 mg daily. Maintenance: Control of pain can be maintained in
most patients with 400-800 mg daily. However, some patients may be maintained on as little as 200 mg daily,
while others may require as much as 1200 mg daily. At least once every 3 months throughout the treatment
period, attempts should be made to reduce the dose to the minimum effective level or even to discontinue the
drug.
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Dosage Information
Initial Dose
Subsequent Dose
Maximum Daily Dose
Indication
Tablet*
XR
†
Suspension
Tablet*
XR
†
Suspension
Tablet*
XR
†
Suspension
Epilepsy
Under 6 yr
10-20 mg/kg/day
b.i.d. or t.i.d.
10-20 mg/kg/day
q.i.d.
Increase weekly
to achieve
optimal clinical
response, t.i.d.
or q.i.d.
Increase
weekly to
achieve optimal
clinical
response, t.i.d.
or q.i.d.
35 mg/kg/24 hr
(see Dosage
and
Administration
section above)
35 mg/kg/24 hr
(see Dosage
and
Administration
section above)
6-12 yr
100 mg b.i.d.
(200 mg/day)
100 mg b.i.d.
(200 mg/day)
½ tsp q.i.d.
(200 mg/day)
Add up to
100 mg/day at
weekly intervals,
t.i.d. or q.i.d.
Add
100 mg/day
at weekly
intervals,
b.i.d.
Add up to 1 tsp
(100 mg)/day at
weekly
intervals, t.i.d.
or q.i.d.
1000 mg/24 hr
Over 12 yr
200 mg b.i.d.
200 mg b.i.d.
1 tsp q.i.d.
Add up to
Add up to
Add up to 2 tsp
1000 mg/24 hr (12-15 yr)
(400 mg/day)
(400 mg/day)
(400 mg/day)
200 mg/day at
200 mg/day
(200 mg)/day at
1200 mg/24 hr (>15 yr)
weekly intervals,
t.i.d. or q.i.d.
at weekly
intervals,
b.i.d.
weekly
intervals, t.i.d.
or q.i.d.
1600 mg/24 hr (adults, in rare instances)
Trigeminal
100 mg b.i.d.
100 mg b.i.d.
½ tsp q.i.d.
Add up to
Add up to
Add up to 2 tsp
1200 mg/24 hr
Neuralgia
(200 mg/day)
(200 mg/day)
(200 mg/day)
200 mg/day in
increments of
100 mg every
12 hr
200 mg/day
in increments
of 100 mg
every 12 hr
(200 mg)/day
in increments
of 50 mg
(½ tsp) q.i.d.
*Tablet = Chewable or conventional tablets
†XR = Tegretol
®-XR extended-release tablets
Reference ID: 2912982
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HOW SUPPLIED
Chewable Tablets 100 mg - round, red-speckled, pink, single-scored (imprinted Tegretol on one side and 52
twice on the scored side)
Bottles of 100............................................................................................................................ NDC 0078-0492-05
Unit Dose (blister pack)
Box of 100 (strips of 10)........................................................................................................... NDC 0078-0492-35
Do not store above 30°C (86°F). Protect from light and moisture.
Dispense in tight, light-resistant container (USP).
Meets USP Dissolution Test 1.
Tablets 200 mg - capsule-shaped, pink, single-scored (imprinted Tegretol on one side and 27 twice on the
partially scored side)
Bottles of 100............................................................................................................................ NDC 0078-0509-05
Do not store above 30°C (86°F). Protect from moisture.
Dispense in tight container (USP).
Meets USP Dissolution Test 2.
XR Tablets 100 mg - round, yellow, coated (imprinted T on one side and 100 mg on the other), release portal on
one side
Bottles of 100............................................................................................................................ NDC 0078-0510-05
XR Tablets 200 mg - round, pink, coated (imprinted T on one side and 200 mg on the other), release portal on
one side
Bottles of 100............................................................................................................................ NDC 0078-0511-05
XR Tablets 400 mg - round, brown, coated (imprinted T on one side and 400 mg on the other), release portal on
one side
Bottles of 100............................................................................................................................ NDC 0078-0512-05
Store at controlled room temperature 15°C-30°C (59°F-86°F). Protect from moisture.
Dispense in tight container (USP).
Suspension 100 mg/5 mL (teaspoon) – yellow-orange, citrus-vanilla flavored
Bottles of 450 mL ..................................................................................................................... NDC 0078-0508-83
Shake well before using.
Do not store above 30°C (86°F). Dispense in tight, light-resistant container (USP).
*Thorazine® is a registered trademark of GlaxoSmithKline.
Distributed by:
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936
REV: AUGUST 2010
T2010-XX
© Novartis
Reference ID: 2912982
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For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:47:07.295484
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/016608s100s102,018281s049s050,018927s041s042,020234s031s033lbl.pdf', 'application_number': 20234, 'submission_type': 'SUPPL ', 'submission_number': 33}
|
12,342
|
NDA 016608/S-107
NDA 018281/S-055
NDA 018927/S-048
NDA 020234/S-040
FDA Approved Labeling Text dated 12/11/2012
Page 1 company logo
Tegretol®
carbamazepine USP
Chewable Tablets of 100 mg - red-speckled, pink
Tablets of 200 mg – pink
Suspension of 100 mg/5 mL
Tegretol®-XR
(carbamazepine extended-release tablets)
100 mg, 200 mg, 400 mg
Rx only
Prescribing Information
WARNINGS
SERIOUS DERMATOLOGIC REACTIONS AND HLA-B*1502 ALLELE
SERIOUS AND SOMETIMES FATAL DERMATOLOGIC REACTIONS, INCLUDING TOXIC
EPIDERMAL NECROLYSIS (TEN) AND STEVENS-JOHNSON SYNDROME (SJS), HAVE BEEN
REPORTED DURING TREATMENT WITH TEGRETOL. THESE REACTIONS ARE ESTIMATED TO
OCCUR IN 1 TO 6 PER 10,000 NEW USERS IN COUNTRIES WITH MAINLY CAUCASIAN
POPULATIONS, BUT THE RISK IN SOME ASIAN COUNTRIES IS ESTIMATED TO BE ABOUT 10
TIMES HIGHER. STUDIES IN PATIENTS OF CHINESE ANCESTRY HAVE FOUND A STRONG
ASSOCIATION BETWEEN THE RISK OF DEVELOPING SJS/TEN AND THE PRESENCE OF
HLA-B*1502, AN INHERITED ALLELIC VARIANT OF THE HLA-B GENE. HLA-B*1502 IS FOUND
ALMOST EXCLUSIVELY IN PATIENTS WITH ANCESTRY ACROSS BROAD AREAS OF ASIA.
PATIENTS WITH ANCESTRY IN GENETICALLY AT-RISK POPULATIONS SHOULD BE SCREENED
FOR THE PRESENCE OF HLA-B*1502 PRIOR TO INITIATING TREATMENT WITH TEGRETOL.
PATIENTS TESTING POSITIVE FOR THE ALLELE SHOULD NOT BE TREATED WITH TEGRETOL
UNLESS THE BENEFIT CLEARLY OUTWEIGHS THE RISK (SEE WARNINGS AND PRECAUTIONS,
LABORATORY TESTS).
APLASTIC ANEMIA AND AGRANULOCYTOSIS
APLASTIC ANEMIA AND AGRANULOCYTOSIS HAVE BEEN REPORTED IN ASSOCIATION WITH
THE USE OF TEGRETOL. DATA FROM A POPULATION-BASED CASE CONTROL STUDY
DEMONSTRATE THAT THE RISK OF DEVELOPING THESE REACTIONS IS 5-8 TIMES GREATER
THAN IN THE GENERAL POPULATION. HOWEVER, THE OVERALL RISK OF THESE REACTIONS
IN THE UNTREATED GENERAL POPULATION IS LOW, APPROXIMATELY SIX PATIENTS PER ONE
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FDA Approved Labeling Text dated 12/11/2012
Page 2
MILLION POPULATION PER YEAR FOR AGRANULOCYTOSIS AND TWO PATIENTS PER ONE
MILLION POPULATION PER YEAR FOR APLASTIC ANEMIA.
ALTHOUGH REPORTS OF TRANSIENT OR PERSISTENT DECREASED PLATELET OR WHITE
BLOOD CELL COUNTS ARE NOT UNCOMMON IN ASSOCIATION WITH THE USE OF TEGRETOL,
DATA ARE NOT AVAILABLE TO ESTIMATE ACCURATELY THEIR INCIDENCE OR OUTCOME.
HOWEVER, THE VAST MAJORITY OF THE CASES OF LEUKOPENIA HAVE NOT PROGRESSED TO
THE MORE SERIOUS CONDITIONS OF APLASTIC ANEMIA OR AGRANULOCYTOSIS.
BECAUSE OF THE VERY LOW INCIDENCE OF AGRANULOCYTOSIS AND APLASTIC ANEMIA,
THE VAST MAJORITY OF MINOR HEMATOLOGIC CHANGES OBSERVED IN MONITORING OF
PATIENTS ON TEGRETOL ARE UNLIKELY TO SIGNAL THE OCCURRENCE OF EITHER
ABNORMALITY. NONETHELESS, COMPLETE PRETREATMENT HEMATOLOGICAL TESTING
SHOULD BE OBTAINED AS A BASELINE. IF A PATIENT IN THE COURSE OF TREATMENT
EXHIBITS LOW OR DECREASED WHITE BLOOD CELL OR PLATELET COUNTS, THE PATIENT
SHOULD BE MONITORED CLOSELY. DISCONTINUATION OF THE DRUG SHOULD BE
CONSIDERED IF ANY EVIDENCE OF SIGNIFICANT BONE MARROW DEPRESSION DEVELOPS.
Before prescribing Tegretol, the physician should be thoroughly familiar with the details of this
prescribing information, particularly regarding use with other drugs, especially those which accentuate
toxicity potential.
DESCRIPTION
Tegretol, carbamazepine USP, is an anticonvulsant and specific analgesic for trigeminal neuralgia, available for
oral administration as chewable tablets of 100 mg, tablets of 200 mg, XR tablets of 100, 200, and 400 mg, and
as a suspension of 100 mg/5 mL (teaspoon). Its chemical name is 5H-dibenz[b,f ]azepine-5-carboxamide, and
its structural formula is structural formula
Carbamazepine USP is a white to off-white powder, practically insoluble in water and soluble in alcohol and in
acetone. Its molecular weight is 236.27.
Inactive Ingredients Tablets: Colloidal silicon dioxide, D&C Red No. 30 Aluminum Lake (chewable tablets
only), FD&C Red No. 40 (200-mg tablets only), flavoring (chewable tablets only), gelatin, glycerin, magnesium
stearate, sodium starch glycolate (chewable tablets only), starch, stearic acid, and sucrose (chewable tablets
only). Suspension: Citric acid, FD&C Yellow No. 6, flavoring, polymer, potassium sorbate, propylene glycol,
purified water, sorbitol, sucrose, and xanthan gum. Tegretol-XR tablets: cellulose compounds, dextrates, iron
oxides, magnesium stearate, mannitol, polyethylene glycol, sodium lauryl sulfate, titanium dioxide (200-mg
tablets only).
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FDA Approved Labeling Text dated 12/11/2012
Page 3
CLINICAL PHARMACOLOGY
In controlled clinical trials, Tegretol has been shown to be effective in the treatment of psychomotor and grand
mal seizures, as well as trigeminal neuralgia.
Mechanism of Action
Tegretol has demonstrated anticonvulsant properties in rats and mice with electrically and chemically induced
seizures. It appears to act by reducing polysynaptic responses and blocking the post-tetanic potentiation.
Tegretol greatly reduces or abolishes pain induced by stimulation of the infraorbital nerve in cats and rats. It
depresses thalamic potential and bulbar and polysynaptic reflexes, including the linguomandibular reflex in
cats. Tegretol is chemically unrelated to other anticonvulsants or other drugs used to control the pain of
trigeminal neuralgia. The mechanism of action remains unknown.
The principal metabolite of Tegretol, carbamazepine-10,11-epoxide, has anticonvulsant activity as
demonstrated in several in vivo animal models of seizures. Though clinical activity for the epoxide has been
postulated, the significance of its activity with respect to the safety and efficacy of Tegretol has not been
established.
Pharmacokinetics
In clinical studies, Tegretol suspension, conventional tablets, and XR tablets delivered equivalent amounts of
drug to the systemic circulation. However, the suspension was absorbed somewhat faster, and the XR tablet
slightly slower, than the conventional tablet. The bioavailability of the XR tablet was 89% compared to
suspension. Following a b.i.d. dosage regimen, the suspension provides higher peak levels and lower trough
levels than those obtained from the conventional tablet for the same dosage regimen. On the other hand,
following a t.i.d. dosage regimen, Tegretol suspension affords steady-state plasma levels comparable to
Tegretol tablets given b.i.d. when administered at the same total mg daily dose. Following a b.i.d. dosage
regimen, Tegretol-XR tablets afford steady-state plasma levels comparable to conventional Tegretol tablets
given q.i.d., when administered at the same total mg daily dose. Tegretol in blood is 76% bound to plasma
proteins. Plasma levels of Tegretol are variable and may range from 0.5-25 µg/mL, with no apparent
relationship to the daily intake of the drug. Usual adult therapeutic levels are between 4 and 12 µg/mL. In
polytherapy, the concentration of Tegretol and concomitant drugs may be increased or decreased during
therapy, and drug effects may be altered (see PRECAUTIONS, Drug Interactions). Following chronic oral
administration of suspension, plasma levels peak at approximately 1.5 hours compared to 4-5 hours after
administration of conventional Tegretol tablets, and 3-12 hours after administration of Tegretol-XR tablets. The
CSF/serum ratio is 0.22, similar to the 24% unbound Tegretol in serum. Because Tegretol induces its own
metabolism, the half-life is also variable. Autoinduction is completed after 3-5 weeks of a fixed dosing regimen.
Initial half-life values range from 25-65 hours, decreasing to 12-17 hours on repeated doses. Tegretol is
metabolized in the liver. Cytochrome P450 3A4 was identified as the major isoform responsible for the
formation of carbamazepine-10,11-epoxide from Tegretol. After oral administration of 14C-carbamazepine, 72%
of the administered radioactivity was found in the urine and 28% in the feces. This urinary radioactivity was
composed largely of hydroxylated and conjugated metabolites, with only 3% of unchanged Tegretol.
The pharmacokinetic parameters of Tegretol disposition are similar in children and in adults. However, there is
a poor correlation between plasma concentrations of carbamazepine and Tegretol dose in children.
Carbamazepine is more rapidly metabolized to carbamazepine-10,11-epoxide (a metabolite shown to be
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NDA 018927/S-048
NDA 020234/S-040
FDA Approved Labeling Text dated 12/11/2012
Page 4
equipotent to carbamazepine as an anticonvulsant in animal screens) in the younger age groups than in adults. In
children below the age of 15, there is an inverse relationship between CBZ-E/CBZ ratio and increasing age (in
one report from 0.44 in children below the age of 1 year to 0.18 in children between 10-15 years of age).
The effects of race and gender on carbamazepine pharmacokinetics have not been systematically evaluated.
INDICATIONS AND USAGE
Epilepsy
Tegretol is indicated for use as an anticonvulsant drug. Evidence supporting efficacy of Tegretol as an
anticonvulsant was derived from active drug-controlled studies that enrolled patients with the following seizure
types:
1. Partial seizures with complex symptomatology (psychomotor, temporal lobe). Patients with these seizures
appear to show greater improvement than those with other types.
2. Generalized tonic-clonic seizures (grand mal).
3. Mixed seizure patterns which include the above, or other partial or generalized seizures. Absence seizures
(petit mal) do not appear to be controlled by Tegretol (see PRECAUTIONS, General).
Trigeminal Neuralgia
Tegretol is indicated in the treatment of the pain associated with true trigeminal neuralgia.
Beneficial results have also been reported in glossopharyngeal neuralgia.
This drug is not a simple analgesic and should not be used for the relief of trivial aches or pains.
CONTRAINDICATIONS
Tegretol should not be used in patients with a history of previous bone marrow depression, hypersensitivity to
the drug, or known sensitivity to any of the tricyclic compounds, such as amitriptyline, desipramine,
imipramine, protriptyline, nortriptyline, etc. Likewise, on theoretical grounds its use with monoamine oxidase
inhibitors is not recommended. Before administration of Tegretol, MAO inhibitors should be discontinued for a
minimum of 14 days, or longer if the clinical situation permits.
Coadministration of carbamazepine and nefazodone may result in insufficient plasma concentrations of
nefazodone and its active metabolite to achieve a therapeutic effect. Coadministration of carbamazepine with
nefazodone is contraindicated.
WARNINGS
Serious Dermatologic Reactions
Serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN) and
Stevens-Johnson syndrome (SJS), have been reported with Tegretol treatment. The risk of these events is
estimated to be about 1 to 6 per 10,000 new users in countries with mainly Caucasian populations. However, the
risk in some Asian countries is estimated to be about 10 times higher. Tegretol should be discontinued at the
first sign of a rash, unless the rash is clearly not drug-related. If signs or symptoms suggest SJS/TEN, use of this
drug should not be resumed and alternative therapy should be considered.
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FDA Approved Labeling Text dated 12/11/2012
Page 5
SJS/TEN and HLA-B*1502 Allele
Retrospective case-control studies have found that in patients of Chinese ancestry there is a strong association
between the risk of developing SJS/TEN with carbamazepine treatment and the presence of an inherited variant
of the HLA-B gene, HLA-B*1502. The occurrence of higher rates of these reactions in countries with higher
frequencies of this allele suggests that the risk may be increased in allele-positive individuals of any ethnicity.
Across Asian populations, notable variation exists in the prevalence of HLA-B*1502. Greater than 15% of the
population is reported positive in Hong Kong, Thailand, Malaysia, and parts of the Philippines, compared to
about 10% in Taiwan and 4% in North China. South Asians, including Indians, appear to have intermediate
prevalence of HLA-B*1502, averaging 2 to 4%, but higher in some groups. HLA-B*1502 is present in <1% of
the population in Japan and Korea.
HLA-B*1502 is largely absent in individuals not of Asian origin (e.g., Caucasians, African-Americans,
Hispanics, and Native Americans).
Prior to initiating Tegretol therapy, testing for HLA-B*1502 should be performed in patients with
ancestry in populations in which HLA-B*1502 may be present. In deciding which patients to screen, the
rates provided above for the prevalence of HLA-B*1502 may offer a rough guide, keeping in mind the
limitations of these figures due to wide variability in rates even within ethnic groups, the difficulty in
ascertaining ethnic ancestry, and the likelihood of mixed ancestry. Tegretol should not be used in patients
positive for HLA-B*1502 unless the benefits clearly outweigh the risks. Tested patients who are found to be
negative for the allele are thought to have a low risk of SJS/TEN (see WARNINGS and PRECAUTIONS,
Laboratory Tests).
Over 90% of Tegretol treated patients who will experience SJS/TEN have this reaction within the first few
months of treatment. This information may be taken into consideration in determining the need for screening of
genetically at-risk patients currently on Tegretol.
The HLA-B*1502 allele has not been found to predict risk of less severe adverse cutaneous reactions from
Tegretol, such as anticonvulsant hypersensitivity syndrome or nonserious rash (maculopapular eruption [MPE]).
Limited evidence suggests that HLA-B*1502 may be a risk factor for the development of SJS/TEN in patients
of Chinese ancestry taking other antiepileptic drugs associated with SJS/TEN. Consideration should be given to
avoiding use of other drugs associated with SJS/TEN in HLA-B*1502 positive patients, when alternative
therapies are otherwise equally acceptable.
Application of HLA-B*1502 genotyping as a screening tool has important limitations and must never substitute
for appropriate clinical vigilance and patient management. Many HLA-B*1502-positive Asian patients treated
with Tegretol will not develop SJS/TEN, and these reactions can still occur infrequently in
HLA-B*1502-negative patients of any ethnicity. The role of other possible factors in the development of, and
morbidity from, SJS/TEN, such as antiepileptic drug (AED) dose, compliance, concomitant medications,
comorbidities, and the level of dermatologic monitoring have not been studied.
Aplastic Anemia and Agranulocytosis
Patients with a history of adverse hematologic reaction to any drug may be particularly at risk of bone marrow
depression.
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NDA 018927/S-048
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FDA Approved Labeling Text dated 12/11/2012
Page 6
Suicidal Behavior and Ideation
Antiepileptic drugs (AEDs), including Tegretol, increase the risk of suicidal thoughts or behavior in patients
taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for
the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood
or behavior.
Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs
showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk
1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these
trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or
ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated
patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530
patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated
patients, but the number is too small to allow any conclusion about drug effect on suicide.
The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting
drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in
the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could
not be assessed.
The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The
finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests
that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years)
in the clinical trials analyzed. Table 1 shows absolute and relative risk by indication for all evaluated AEDs.
Table 1 Risk by Indication for Antiepileptic Drugs in the Pooled Analysis
Indication
Placebo Patients
with Events Per
1,000 Patients
Drug Patients
with Events Per
1,000 Patients
Relative Risk:
Incidence of
Events in Drug
Patients/Incidence
in Placebo
Patients
Risk Difference:
Additional Drug
Patients with
Events Per 1,000
Patients
Epilepsy
1.0
3.4
3.5
2.4
Psychiatric
5.7
8.5
1.5
2.9
Other
1.0
1.8
1.9
0.9
Total
2.4
4.3
1.8
1.9
The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials
for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric
indications.
Anyone considering prescribing Tegretol or any other AED must balance the risk of suicidal thoughts or
behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are
themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior.
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Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the
emergence of these symptoms in any given patient may be related to the illness being treated.
Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and
behavior and should be advised of the need to be alert for the emergence or worsening of the signs and
symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts,
behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare
providers.
General
Tegretol has shown mild anticholinergic activity; therefore, patients with increased intraocular pressure should
be closely observed during therapy.
Because of the relationship of the drug to other tricyclic compounds, the possibility of activation of a latent
psychosis and, in elderly patients, of confusion or agitation should be borne in mind.
The use of Tegretol should be avoided in patients with a history of hepatic porphyria (e.g., acute intermittent
porphyria, variegate porphyria, porphyria cutanea tarda). Acute attacks have been reported in such patients
receiving Tegretol therapy. Carbamazepine administration has also been demonstrated to increase porphyrin
precursors in rodents, a presumed mechanism for the induction of acute attacks of porphyria.
As with all antiepileptic drugs, Tegretol should be withdrawn gradually to minimize the potential of increased
seizure frequency.
Usage in Pregnancy
Carbamazepine can cause fetal harm when administered to a pregnant woman.
Epidemiological data suggest that there may be an association between the use of carbamazepine during
pregnancy and congenital malformations, including spina bifida. There have also been reports that associate
carbamazepine with developmental disorders and congenital anomalies (e.g., craniofacial defects,
cardiovascular malformations, hypospadias and anomalies involving various body systems). Developmental
delays based on neurobehavioral assessments have been reported. In treating or counseling women of
childbearing potential, the prescribing physician will wish to weigh the benefits of therapy against the risks. If
this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should
be apprised of the potential hazard to the fetus.
Retrospective case reviews suggest that, compared with monotherapy, there may be a higher prevalence of
teratogenic effects associated with the use of anticonvulsants in combination therapy. Therefore, if therapy is to
be continued, monotherapy may be preferable for pregnant women.
In humans, transplacental passage of carbamazepine is rapid (30-60 minutes), and the drug is accumulated in
the fetal tissues, with higher levels found in liver and kidney than in brain and lung.
Carbamazepine has been shown to have adverse effects in reproduction studies in rats when given orally in
dosages 10-25 times the maximum human daily dosage (MHDD) of 1200 mg on a mg/kg basis or 1.5-4 times
the MHDD on a mg/m2 basis. In rat teratology studies, 2 of 135 offspring showed kinked ribs at 250 mg/kg and
4 of 119 offspring at 650 mg/kg showed other anomalies (cleft palate, 1; talipes, 1; anophthalmos, 2). In
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reproduction studies in rats, nursing offspring demonstrated a lack of weight gain and an unkempt appearance at
a maternal dosage level of 200 mg/kg.
Antiepileptic drugs should not be discontinued abruptly in patients in whom the drug is administered to prevent
major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and
threat to life. In individual cases where the severity and frequency of the seizure disorder are such that removal
of medication does not pose a serious threat to the patient, discontinuation of the drug may be considered prior
to and during pregnancy, although it cannot be said with any confidence that even minor seizures do not pose
some hazard to the developing embryo or fetus.
Tests to detect defects using currently accepted procedures should be considered a part of routine prenatal care
in childbearing women receiving carbamazepine.
There have been a few cases of neonatal seizures and/or respiratory depression associated with maternal
Tegretol and other concomitant anticonvulsant drug use. A few cases of neonatal vomiting, diarrhea, and/or
decreased feeding have also been reported in association with maternal Tegretol use. These symptoms may
represent a neonatal withdrawal syndrome.
To provide information regarding the effects of in utero exposure to Tegretol, physicians are advised to
recommend that pregnant patients taking Tegretol enroll in the North American Antiepileptic Drug (NAAED)
Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by
patients themselves. Information on the registry can also be found at the website
http://www.aedpregnancyregistry.org/.
PRECAUTIONS
General
Before initiating therapy, a detailed history and physical examination should be made.
Tegretol should be used with caution in patients with a mixed seizure disorder that includes atypical absence
seizures, since in these patients Tegretol has been associated with increased frequency of generalized
convulsions (see INDICATIONS AND USAGE).
Therapy should be prescribed only after critical benefit-to-risk appraisal in patients with a history of cardiac
conduction disturbance, including second and third degree AV heart block; cardiac, hepatic, or renal damage;
adverse hematologic or hypersensitivity reaction to other drugs, including reactions to other anticonvulsants; or
interrupted courses of therapy with Tegretol.
AV heart block, including second and third degree block, have been reported following Tegretol treatment. This
occurred generally, but not solely, in patients with underlying EKG abnormalities or risk factors for conduction
disturbances.
Hepatic effects, ranging from slight elevations in liver enzymes to rare cases of hepatic failure have been
reported (see ADVERSE REACTIONS and PRECAUTIONS, Laboratory Tests). In some cases, hepatic effects
may progress despite discontinuation of the drug.
Multiorgan hypersensitivity reactions which can affect the skin, liver, hemopoietic organs and lymphatic system
or other organs and occurring days to weeks or months after initiating treatment have been reported in rare cases
(see ADVERSE REACTIONS, Other and PRECAUTIONS, Information for Patients).
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Discontinuation of carbamazepine should be considered if any evidence of hypersensitivity develops.
Hypersensitivity reactions to carbamazepine have been reported in patients who previously experienced this
reaction to anticonvulsants including phenytoin and phenobarbital. A history of hypersensitivity reactions
should be obtained for a patient and the immediate family members. If positive, caution should be used in
prescribing carbamazepine.
In patients who have exhibited hypersensitivity reactions to carbamazepine approximately 25 to 30% of these
patients may experience hypersensitivity reactions with oxcarbazepine (Trileptal®).
Since a given dose of Tegretol suspension will produce higher peak levels than the same dose given as the
tablet, it is recommended that patients given the suspension be started on lower doses and increased slowly to
avoid unwanted side effects (see DOSAGE AND ADMINISTRATION).
Tegretol suspension contains sorbitol and, therefore, should not be administered to patients with rare hereditary
problems of fructose intolerance.
Information for Patients
Patients should be informed of the availability of a Medication Guide and they should be instructed to read the
Medication Guide before taking Tegretol.
Patients should be made aware of the early toxic signs and symptoms of a potential hematologic problem, as
well as dermatologic, hypersensitivity or hepatic reactions. These symptoms may include, but are not limited to,
fever, sore throat, rash, ulcers in the mouth, easy bruising, lymphadenopathy and petechial or purpuric
hemorrhage, and in the case of liver reactions, anorexia, nausea/vomiting, or jaundice. The patient should be
advised that, because these signs and symptoms may signal a serious reaction, that they must report any
occurrence immediately to a physician. In addition, the patient should be advised that these signs and symptoms
should be reported even if mild or when occurring after extended use.
Patients, their caregivers, and families should be counseled that AEDs, including Tegretol, may increase the risk
of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening
of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts,
behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare
providers
Patients should be advised that serious skin reactions have been reported in association with Tegretol. In the
event a skin reaction should occur while taking Tegretol, patients should consult with their physician
immediately (see WARNINGS).
Tegretol may interact with some drugs. Therefore, patients should be advised to report to their doctors the use
of any other prescription or nonprescription medications or herbal products.
Caution should be exercised if alcohol is taken in combination with Tegretol therapy, due to a possible additive
sedative effect.
Since dizziness and drowsiness may occur, patients should be cautioned about the hazards of operating
machinery or automobiles or engaging in other potentially dangerous tasks.
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Patients should be encouraged to enroll in the NAAED Pregnancy Registry if they become pregnant. This
registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients
can call the toll free number 1-888-233-2334 (see WARNINGS, Usage in Pregnancy subsection).
Laboratory Tests
For genetically at-risk patients (see WARNINGS), high-resolution ‘HLA-B*1502 typing’ is recommended. The
test is positive if either one or two HLA-B*1502 alleles are detected and negative if no HLA-B*1502 alleles are
detected.
Complete pretreatment blood counts, including platelets and possibly reticulocytes and serum iron, should be
obtained as a baseline. If a patient in the course of treatment exhibits low or decreased white blood cell or
platelet counts, the patient should be monitored closely. Discontinuation of the drug should be considered if any
evidence of significant bone marrow depression develops.
Baseline and periodic evaluations of liver function, particularly in patients with a history of liver disease, must
be performed during treatment with this drug since liver damage may occur (see PRECAUTIONS, General and
ADVERSE REACTIONS). Carbamazepine should be discontinued, based on clinical judgment, if indicated by
newly occurring or worsening clinical or laboratory evidence of liver dysfunction or hepatic damage, or in the
case of active liver disease.
Baseline and periodic eye examinations, including slit-lamp, funduscopy, and tonometry, are recommended
since many phenothiazines and related drugs have been shown to cause eye changes.
Baseline and periodic complete urinalysis and BUN determinations are recommended for patients treated with
this agent because of observed renal dysfunction.
Monitoring of blood levels (see CLINICAL PHARMACOLOGY) has increased the efficacy and safety of
anticonvulsants. This monitoring may be particularly useful in cases of dramatic increase in seizure frequency
and for verification of compliance. In addition, measurement of drug serum levels may aid in determining the
cause of toxicity when more than one medication is being used.
Thyroid function tests have been reported to show decreased values with Tegretol administered alone.
Hyponatremia has been reported in association with Tegretol use, either alone or in combination with other
drugs.
Interference with some pregnancy tests has been reported.
Drug Interactions
There has been a report of a patient who passed an orange rubbery precipitate in his stool the day after ingesting
Tegretol suspension immediately followed by Thorazine®* solution. Subsequent testing has shown that mixing
Tegretol suspension and chlorpromazine solution (both generic and brand name) as well as Tegretol suspension
and liquid Mellaril® resulted in the occurrence of this precipitate. Because the extent to which this occurs with
other liquid medications is not known, Tegretol suspension should not be administered simultaneously with
other liquid medicinal agents or diluents (see DOSAGE AND ADMINISTRATION).
Clinically meaningful drug interactions have occurred with concomitant medications and include, but are not
limited to, the following:
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Agents That May Affect Tegretol Plasma Levels
CYP 3A4 inhibitors inhibit Tegretol metabolism and can thus increase plasma carbamazepine levels. Drugs that
have been shown, or would be expected, to increase plasma carbamazepine levels include:
cimetidine, danazol, diltiazem, macrolides, erythromycin, troleandomycin, clarithromycin, fluoxetine,
fluvoxamine, nefazodone, trazodone, loxapine*, olanzapine, quetiapine*, loratadine, terfenadine,
omeprazole, oxybutynin, dantrolene, isoniazid, niacinamide, nicotinamide, ibuprofen, propoxyphene,
azoles (e.g., ketaconazole, itraconazole, fluconazole, voriconazole), acetazolamide, verapamil,
ticlopidine, grapefruit juice, protease inhibitors, valproate*.
CYP 3A4 inducers can increase the rate of Tegretol metabolism. Drugs that have been shown, or that would be
expected, to decrease plasma carbamazepine levels include:
cisplatin, doxorubicin HCl, felbamate†, fosphenytoin, rifampin, phenobarbital, phenytoin, primidone,
methsuximide, theophylline, aminophylline.
When carbamazepine is given with drugs that can increase or decrease carbamazepine levels, close monitoring
of carbamazepine levels is indicated and dosage adjustment may be required.
*increased levels of the active 10,11-epoxide
†decreased levels of carbamazepine and increased levels of the 10,11-epoxide
Effect of Tegretol on Plasma Levels of Concomitant Agents
Increased levels: clomipramine HCl, phenytoin, primidone
Tegretol is a potent inducer of hepatic CYP 3A4 and may therefore reduce plasma concentrations of co
medications mainly metabolized by 3A4 through induction of their metabolism. Tegretol causes, or would be
expected to cause, decreased levels of the following:
acetaminophen, alprazolam, bupropion, dihydropyridine calcium channel blockers (e.g., felodipine),
citalopram, cyclosporine, corticosteroids (e.g., prednisolone, dexamethasone), clonazepam, clozapine,
dicumarol, doxycycline, ethosuximide, everolimus, haloperidol, imatinib, itraconazole, lamotrigine,
levothyroxine, methadone, methsuximide, midazolam, olanzapine, oral and other hormonal
contraceptives, oxcarbazepine, phensuximide, phenytoin, praziquantel, protease inhibitors,
risperidone, theophylline, tiagabine, topiramate, tramadol, trazodone, tricyclic antidepressants (e.g.,
imipramine, amitriptyline, nortriptyline), valproate, warfarin, ziprasidone, zonisamide.
In concomitant use with Tegretol, dosage adjustment of the above agents may be necessary.
Coadministration of carbamazepine with nefazodone results in insufficient plasma concentrations of nefazodone
and its active metabolite to achieve a therapeutic effect. Coadministration of carbamazepine with nefazodone is
contraindicated (see CONTRAINDICATIONS).
Concomitant administration of carbamazepine and lithium may increase the risk of neurotoxic side effects.
Concomitant use of carbamazepine and isoniazid has been reported to increase isoniazid-induced
hepatotoxicity.
Concomitant medication with Tegretol and some diuretics (hydrochlorothiazide, furosemide) may lead to
symptomatic hyponatremia.
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Carbamazepine may antagonize the effects of nondepolarizing muscle relaxants (e.g., pancuronium).
Their dosage may need to be raised, and patients should be monitored closely for more rapid recovery from
neuromuscular blockade than expected.
Alterations of thyroid function have been reported in combination therapy with other anticonvulsant
medications.
Concomitant use of Tegretol with hormonal contraceptive products (e.g., oral, and levonorgestrel subdermal
implant contraceptives) may render the contraceptives less effective because the plasma concentrations of the
hormones may be decreased. Breakthrough bleeding and unintended pregnancies have been reported.
Alternative or back-up methods of contraception should be considered.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carbamazepine, when administered to Sprague-Dawley rats for two years in the diet at doses of 25, 75, and
250 mg/kg/day, resulted in a dose-related increase in the incidence of hepatocellular tumors in females and of
benign interstitial cell adenomas in the testes of males.
Carbamazepine must, therefore, be considered to be carcinogenic in Sprague-Dawley rats. Bacterial and
mammalian mutagenicity studies using carbamazepine produced negative results. The significance of these
findings relative to the use of carbamazepine in humans is, at present, unknown.
Usage in Pregnancy
Pregnancy Category D (see WARNINGS).
Labor and Delivery
The effect of Tegretol on human labor and delivery is unknown.
Nursing Mothers
Tegretol and its epoxide metabolite are transferred to breast milk. The ratio of the concentration in breast milk
to that in maternal plasma is about 0.4 for Tegretol and about 0.5 for the epoxide. The estimated doses given to
the newborn during breast-feeding are in the range of 2-5 mg daily for Tegretol and 1-2 mg daily for the
epoxide.
Because of the potential for serious adverse reactions in nursing infants from carbamazepine, a decision should
be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the
drug to the mother.
Pediatric Use
Substantial evidence of Tegretol’s effectiveness for use in the management of children with epilepsy (see
INDICATIONS AND USAGE for specific seizure types) is derived from clinical investigations performed in
adults and from studies in several in vitro systems which support the conclusion that (1) the pathogenetic
mechanisms underlying seizure propagation are essentially identical in adults and children, and (2) the
mechanism of action of carbamazepine in treating seizures is essentially identical in adults and children.
Taken as a whole, this information supports a conclusion that the generally accepted therapeutic range of total
carbamazepine in plasma (i.e., 4-12 mcg/mL) is the same in children and adults.
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The evidence assembled was primarily obtained from short-term use of carbamazepine. The safety of
carbamazepine in children has been systematically studied up to 6 months. No longer-term data from clinical
trials is available.
Geriatric Use
No systematic studies in geriatric patients have been conducted.
ADVERSE REACTIONS
If adverse reactions are of such severity that the drug must be discontinued, the physician must be aware that
abrupt discontinuation of any anticonvulsant drug in a responsive epileptic patient may lead to seizures or even
status epilepticus with its life-threatening hazards.
The most severe adverse reactions have been observed in the hemopoietic system and skin (see BOXED
WARNING), the liver, and the cardiovascular system.
The most frequently observed adverse reactions, particularly during the initial phases of therapy, are dizziness,
drowsiness, unsteadiness, nausea, and vomiting. To minimize the possibility of such reactions, therapy should
be initiated at the low dosage recommended.
The following additional adverse reactions have been reported:
Hemopoietic System: Aplastic anemia, agranulocytosis, pancytopenia, bone marrow depression,
thrombocytopenia, leukopenia, leukocytosis, eosinophilia, anemia, acute intermittent porphyria, variegate
porphyria, porphyria cutanea tarda.
Skin: Toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) (see BOXED WARNING),
pruritic and erythematous rashes, urticaria, photosensitivity reactions, alterations in skin pigmentation,
exfoliative dermatitis, erythema multiforme and nodosum, purpura, aggravation of disseminated lupus
erythematosus, alopecia, diaphoresis, and onychomadesis. In certain cases, discontinuation of therapy may be
necessary. Isolated cases of hirsutism have been reported, but a causal relationship is not clear.
Cardiovascular System: Congestive heart failure, edema, aggravation of hypertension, hypotension, syncope
and collapse, aggravation of coronary artery disease, arrhythmias and AV block, thrombophlebitis,
thromboembolism (e.g., pulmonary embolism), and adenopathy or lymphadenopathy.
Some of these cardiovascular complications have resulted in fatalities. Myocardial infarction has been
associated with other tricyclic compounds.
Liver: Abnormalities in liver function tests, cholestatic and hepatocellular jaundice, hepatitis; very rare cases of
hepatic failure.
Pancreatic: Pancreatitis.
Respiratory System: Pulmonary hypersensitivity characterized by fever, dyspnea, pneumonitis, or pneumonia.
Genitourinary System: Urinary frequency, acute urinary retention, oliguria with elevated blood pressure,
azotemia, renal failure, and impotence. Albuminuria, glycosuria, elevated BUN, and microscopic deposits in the
urine have also been reported. There have been very rare reports of impaired male fertility and/or abnormal
spermatogenesis.
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Testicular atrophy occurred in rats receiving Tegretol orally from 4-52 weeks at dosage levels of 50-400
mg/kg/day. Additionally, rats receiving Tegretol in the diet for 2 years at dosage levels of 25, 75, and 250
mg/kg/day had a dose-related incidence of testicular atrophy and aspermatogenesis. In dogs, it produced a
brownish discoloration, presumably a metabolite, in the urinary bladder at dosage levels of 50 mg/kg and
higher. Relevance of these findings to humans is unknown.
Nervous System: Dizziness, drowsiness, disturbances of coordination, confusion, headache, fatigue, blurred
vision, visual hallucinations, transient diplopia, oculomotor disturbances, nystagmus, speech disturbances,
abnormal involuntary movements, peripheral neuritis and paresthesias, depression with agitation, talkativeness,
tinnitus, hyperacusis, neuroleptic malignant syndrome.
There have been reports of associated paralysis and other symptoms of cerebral arterial insufficiency, but the
exact relationship of these reactions to the drug has not been established.
Isolated cases of neuroleptic malignant syndrome have been reported both with and without concomitant use of
psychotropic drugs.
Digestive System: Nausea, vomiting, gastric distress and abdominal pain, diarrhea, constipation, anorexia, and
dryness of the mouth and pharynx, including glossitis and stomatitis.
Eyes: Scattered punctate cortical lens opacities, increased intraocular pressure as well as conjunctivitis, have
been reported. Although a direct causal relationship has not been established, many phenothiazines and related
drugs have been shown to cause eye changes.
Musculoskeletal System: Aching joints and muscles, and leg cramps.
Metabolism: Fever and chills. Inappropriate antidiuretic hormone (ADH) secretion syndrome has been reported.
Cases of frank water intoxication, with decreased serum sodium (hyponatremia) and confusion, have been
reported in association with Tegretol use (see PRECAUTIONS, Laboratory Tests). Decreased levels of plasma
calcium leading to osteoporosis have been reported.
Other: Multiorgan hypersensitivity reactions occurring days to weeks or months after initiating treatment have
been reported in rare cases. Signs or symptoms may include, but are not limited to fever, skin rashes, vasculitis,
lymphadenopathy, disorders mimicking lymphoma, arthralgia, leukopenia, eosinophilia, hepatosplenomegaly
and abnormal liver function tests. These signs and symptoms may occur in various combinations and not
necessarily concurrently. Signs and symptoms may initially be mild. Various organs, including but not limited
to, liver, skin, immune system, lungs, kidneys, pancreas, myocardium, and colon may be affected (see
PRECAUTIONS, General and PRECAUTIONS, Information for Patients).
Isolated cases of a lupus erythematosus-like syndrome have been reported. There have been occasional reports
of elevated levels of cholesterol, HDL cholesterol, and triglycerides in patients taking anticonvulsants.
A case of aseptic meningitis, accompanied by myoclonus and peripheral eosinophilia, has been reported in a
patient taking carbamazepine in combination with other medications. The patient was successfully
dechallenged, and the meningitis reappeared upon rechallenge with carbamazepine.
DRUG ABUSE AND DEPENDENCE
No evidence of abuse potential has been associated with Tegretol, nor is there evidence of psychological or
physical dependence in humans.
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OVERDOSAGE
Acute Toxicity
Lowest known lethal dose: adults, 3.2 g (a 24-year-old woman died of a cardiac arrest and a 24-year-old man
died of pneumonia and hypoxic encephalopathy); children, 4 g (a 14-year-old girl died of a cardiac arrest), 1.6 g
(a 3-year-old girl died of aspiration pneumonia).
Oral LD50 in animals (mg/kg): mice, 1100-3750; rats, 3850-4025; rabbits, 1500-2680; guinea pigs, 920.
Signs and Symptoms
The first signs and symptoms appear after 1-3 hours. Neuromuscular disturbances are the most prominent.
Cardiovascular disorders are generally milder, and severe cardiac complications occur only when very high
doses (>60 g) have been ingested.
Respiration: Irregular breathing, respiratory depression.
Cardiovascular System: Tachycardia, hypotension or hypertension, shock, conduction disorders.
Nervous System and Muscles: Impairment of consciousness ranging in severity to deep coma. Convulsions,
especially in small children. Motor restlessness, muscular twitching, tremor, athetoid movements, opisthotonos,
ataxia, drowsiness, dizziness, mydriasis, nystagmus, adiadochokinesia, ballism, psychomotor disturbances,
dysmetria. Initial hyperreflexia, followed by hyporeflexia.
Gastrointestinal Tract: Nausea, vomiting.
Kidneys and Bladder: Anuria or oliguria, urinary retention.
Laboratory Findings: Isolated instances of overdosage have included leukocytosis, reduced leukocyte count,
glycosuria, and acetonuria. EEG may show dysrhythmias.
Combined Poisoning: When alcohol, tricyclic antidepressants, barbiturates, or hydantoins are taken at the same
time, the signs and symptoms of acute poisoning with Tegretol may be aggravated or modified.
Treatment
The prognosis in cases of severe poisoning is critically dependent upon prompt elimination of the drug, which
may be achieved by inducing vomiting, irrigating the stomach, and by taking appropriate steps to diminish
absorption. If these measures cannot be implemented without risk on the spot, the patient should be transferred
at once to a hospital, while ensuring that vital functions are safeguarded. There is no specific antidote.
Elimination of the Drug: Induction of vomiting.
Gastric lavage. Even when more than 4 hours have elapsed following ingestion of the drug, the stomach should
be repeatedly irrigated, especially if the patient has also consumed alcohol.
Measures to Reduce Absorption: Activated charcoal, laxatives.
Measures to Accelerate Elimination: Forced diuresis.
Dialysis is indicated only in severe poisoning associated with renal failure. Replacement transfusion is indicated
in severe poisoning in small children.
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Respiratory Depression: Keep the airways free; resort, if necessary, to endotracheal intubation, artificial
respiration, and administration of oxygen.
Hypotension, Shock: Keep the patient’s legs raised and administer a plasma expander. If blood pressure fails to
rise despite measures taken to increase plasma volume, use of vasoactive substances should be considered.
Convulsions: Diazepam or barbiturates.
Warning: Diazepam or barbiturates may aggravate respiratory depression (especially in children), hypotension,
and coma. However, barbiturates should not be used if drugs that inhibit monoamine oxidase have also been
taken by the patient either in overdosage or in recent therapy (within 1 week).
Surveillance: Respiration, cardiac function (ECG monitoring), blood pressure, body temperature, pupillary
reflexes, and kidney and bladder function should be monitored for several days.
Treatment of Blood Count Abnormalities: If evidence of significant bone marrow depression develops, the
following recommendations are suggested: (1) stop the drug, (2) perform daily CBC, platelet, and reticulocyte
counts, (3) do a bone marrow aspiration and trephine biopsy immediately and repeat with sufficient frequency
to monitor recovery.
Special periodic studies might be helpful as follows: (1) white cell and platelet antibodies, (2) 59Fe-ferrokinetic
studies, (3) peripheral blood cell typing, (4) cytogenetic studies on marrow and peripheral blood, (5) bone
marrow culture studies for colony-forming units, (6) hemoglobin electrophoresis for A2 and F hemoglobin, and
(7) serum folic acid and B12 levels.
A fully developed aplastic anemia will require appropriate, intensive monitoring and therapy, for which
specialized consultation should be sought.
DOSAGE AND ADMINISTRATION (SEE TABLE BELOW)
Tegretol suspension in combination with liquid chlorpromazine or thioridazine results in precipitate formation,
and, in the case of chlorpromazine, there has been a report of a patient passing an orange rubbery precipitate in
the stool following coadministration of the two drugs (see PRECAUTIONS, Drug Interactions). Because the
extent to which this occurs with other liquid medications is not known, Tegretol suspension should not be
administered simultaneously with other liquid medications or diluents.
Monitoring of blood levels has increased the efficacy and safety of anticonvulsants (see PRECAUTIONS,
Laboratory Tests). Dosage should be adjusted to the needs of the individual patient. A low initial daily dosage
with a gradual increase is advised. As soon as adequate control is achieved, the dosage may be reduced very
gradually to the minimum effective level. Medication should be taken with meals.
Since a given dose of Tegretol suspension will produce higher peak levels than the same dose given as the
tablet, it is recommended to start with low doses (children 6-12 years: 1/2 teaspoon q.i.d.) and to increase
slowly to avoid unwanted side effects.
Conversion of patients from oral Tegretol tablets to Tegretol suspension: Patients should be converted by
administering the same number of mg per day in smaller, more frequent doses (i.e., b.i.d. tablets to t.i.d.
suspension).
Reference ID: 3219002
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 016608/S-107
NDA 018281/S-055
NDA 018927/S-048
NDA 020234/S-040
FDA Approved Labeling Text dated 12/11/2012
Page 17
Tegretol-XR is an extended-release formulation for twice-a-day administration. When converting patients from
Tegretol conventional tablets to Tegretol-XR, the same total daily mg dose of Tegretol-XR should be
administered. Tegretol-XR tablets must be swallowed whole and never crushed or chewed. Tegretol-XR
tablets should be inspected for chips or cracks. Damaged tablets, or tablets without a release portal, should not
be consumed. Tegretol-XR tablet coating is not absorbed and is excreted in the feces; these coatings may be
noticeable in the stool.
Epilepsy (SEE INDICATIONS AND USAGE)
Adults and children over 12 years of age - Initial: Either 200 mg b.i.d. for tablets and XR tablets, or 1 teaspoon
q.i.d. for suspension (400 mg/day). Increase at weekly intervals by adding up to 200 mg/day using a b.i.d.
regimen of Tegretol-XR or a t.i.d. or q.i.d. regimen of the other formulations until the optimal response is
obtained. Dosage generally should not exceed 1000 mg daily in children 12-15 years of age, and 1200 mg daily
in patients above 15 years of age. Doses up to 1600 mg daily have been used in adults in rare instances.
Maintenance: Adjust dosage to the minimum effective level, usually 800-1200 mg daily.
Children 6-12 years of age - Initial: Either 100 mg b.i.d. for tablets or XR tablets, or 1/2 teaspoon q.i.d. for
suspension (200 mg/day). Increase at weekly intervals by adding up to 100 mg/day using a b.i.d. regimen of
Tegretol-XR or a t.i.d. or q.i.d. regimen of the other formulations until the optimal response is obtained. Dosage
generally should not exceed 1000 mg daily. Maintenance: Adjust dosage to the minimum effective level,
usually 400-800 mg daily.
Children under 6 years of age - Initial: 10-20 mg/kg/day b.i.d. or t.i.d. as tablets, or q.i.d. as suspension.
Increase weekly to achieve optimal clinical response administered t.i.d. or q.i.d. Maintenance: Ordinarily,
optimal clinical response is achieved at daily doses below 35 mg/kg. If satisfactory clinical response has not
been achieved, plasma levels should be measured to determine whether or not they are in the therapeutic range.
No recommendation regarding the safety of carbamazepine for use at doses above 35 mg/kg/24 hours can be
made.
Combination Therapy: Tegretol may be used alone or with other anticonvulsants. When added to existing
anticonvulsant therapy, the drug should be added gradually while the other anticonvulsants are maintained or
gradually decreased, except phenytoin, which may have to be increased (see PRECAUTIONS, Drug
Interactions, and Pregnancy Category D).
Trigeminal Neuralgia (SEE INDICATIONS AND USAGE)
Initial: On the first day, either 100 mg b.i.d. for tablets or XR tablets, or 1/2 teaspoon q.i.d. for suspension, for a
total daily dose of 200 mg. This daily dose may be increased by up to 200 mg/day using increments of 100 mg
every 12 hours for tablets or XR tablets, or 50 mg (1/2 teaspoon) q.i.d. for suspension, only as needed to
achieve freedom from pain. Do not exceed 1200 mg daily. Maintenance: Control of pain can be maintained in
most patients with 400-800 mg daily. However, some patients may be maintained on as little as 200 mg daily,
while others may require as much as 1200 mg daily. At least once every 3 months throughout the treatment
period, attempts should be made to reduce the dose to the minimum effective level or even to discontinue the
drug.
Reference ID: 3219002
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Dosage Information
Initial Dose
Subsequent Dos
e
Maximum Dail y Dose
Indication
Tablet*
XR
†
Suspension
Tablet*
XR
†
Suspension
Tablet*
XR
†
Suspension
Epileps
y
Under 6 yr
10-20 mg/kg/day
10-20 mg/kg/day
Increase weekl y
Increase
35 mg/kg/24 hr
35 mg/kg/24 hr
b.i.d. or t.i.d.
q.i.d.
to achieve
weekly to
(see Dosage
(see Dosage
optimal clinical
achieve optimal
and
and
response, t.i.d.
clinical
Administration
Administration
or q.i.d.
response, t.i.d.
section above)
section above)
or q.i.d.
6-12 yr
100 mg b.i.d.
100 mg b.i.d.
½ tsp q.i.d.
Add up to
Add
Add up to 1 tsp
1000 mg/24 h r
(200 mg/day)
(200 mg/day)
(200 mg/day)
100 mg/day at
100 mg/da y
(100 mg)/day at
weekly intervals,
at weekl y
weekl y
t.i.d. or q.i.d.
intervals,
intervals, t.i.d.
b.i.d.
or q.i.d.
Over 12 yr
200 mg b.i.d.
200 mg b.i.d.
1 tsp q.i.d.
Add up to
Add up to
Add up to 2 tsp
1000 mg/24 hr (12-15 yr)
(400 mg/day)
(400 mg/day)
(400 mg/day)
200 mg/day at
200 mg/da y
(200 mg)/day at
1200 mg/24 hr (>15 yr)
weekly intervals,
at weekl y
weekl y
1600 mg/24 hr (adults, in rare instances)
t.i.d. or q.i.d.
intervals,
intervals, t.i.d.
b.i.d.
or q.i.d.
Trigeminal
100 mg b.i.d.
100 mg b.i.d.
½ tsp q.i.d.
Add up to
Add up to
Add up to 2 tsp
1200 mg/24 h r
Neuralgia
(200 mg/day)
(200 mg/day)
(200 mg/day)
200 mg/day in
200 mg/da y
(200 mg)/day
increments of
in increments
in increments
100 mg every
of 100 mg
of 50 mg
12 hr
every 12 hr
(½ tsp) q.i.d.
*Tablet = Chewable or conventional tablets
†XR = Tegretol
®-XR extended-release tablets
Reference ID: 3219002
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
HOW SUPPLIED
Chewable Tablets 100 mg - round, red-speckled, pink, single-scored (imprinted Tegretol on one side and 52
twice on the scored side)
Bottles of 100………………………………………………………………………………….NDC 0078-0492-05
Unit Dose (blister pack)
Box of 100 (strips of 10)……………………………………………………………………....NDC 0078-0492-35
Do not store above 30°C (86°F). Protect from light and moisture.
Dispense in tight, light-resistant container (USP).
Meets USP Dissolution Test 1.
Tablets 200 mg - capsule-shaped, pink, single-scored (imprinted Tegretol on one side and 27 twice on the
partially scored side)
Bottles of 100.............................................................................................................................NDC 0078-0509-05
Do not store above 30°C (86°F). Protect from moisture.
Dispense in tight container (USP).
Meets USP Dissolution Test 2.
XR Tablets 100 mg - round, yellow, coated (imprinted T on one side and 100 mg on the other), release portal on
one side
Bottles of 100.............................................................................................................................NDC 0078-0510-05
XR Tablets 200 mg - round, pink, coated (imprinted T on one side and 200 mg on the other), release portal on
one side
Bottles of 100.............................................................................................................................NDC 0078-0511-05
XR Tablets 400 mg - round, brown, coated (imprinted T on one side and 400 mg on the other), release portal on
one side
Bottles of 100.............................................................................................................................NDC 0078-0512-05
Store at controlled room temperature 15°C-30°C (59°F-86°F). Protect from moisture.
Dispense in tight container (USP).
Suspension 100 mg/5 mL (teaspoon) – yellow-orange, citrus-vanilla flavored
Bottles of
450 mL.......................................................................................................................................NDC 0078-0508-83
Shake well before using.
Do not store above 30°C (86°F). Dispense in tight, light-resistant container (USP).
*Thorazine® is a registered trademark of GlaxoSmithKline.
Reference ID: 3219002
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEDICATION GUIDE
TEGRETOL® and TEGRETOL®-XR (Teg-ret-ol)
(carbamazepine)
Tablets, Suspension, Chewable Tablets, Extended-Release Tablets
Read this Medication Guide before you start taking Tegretol or Tegretol –XR (TEGRETOL) and each time you
get a refill. There may be new information. This information does not take the place of talking to your
healthcare provider about your medical condition or treatment.
What is the most important information I should know about TEGRETOL?
Do not stop taking TEGRETOL without first talking to your healthcare provider.
Stopping TEGRETOL suddenly can cause serious problems.
TEGRETOL can cause serious side effects, including:
1. TEGRETOL may cause rare but serious skin rashes that may lead to death. These serious skin
reactions are more likely to happen when you begin taking TEGRETOL within the first four
months of treatment but may occur at later times. These reactions can happen in anyone, but
are more likely in people of Asian descent. If you are of Asian descent, you may need a genetic
blood test before you take TEGRETOL to see if you are at a higher risk for serious skin
reactions with this medicine. Symptoms may include:
skin rash
hives
sores in your mouth
blistering or peeling of the skin
2. TEGRETOL may cause rare but serious blood problems. Symptoms may include:
fever, sore throat or other infections that come and go or do not go away
easy bruising
red or purple spots on your body
bleeding gums or nose bleeds
severe fatigue or weakness
3. Like other antiepileptic drugs, TEGRETOL may cause suicidal thoughts or actions in a very
small number of people, about 1 in 500.
Call your healthcare provider right away if you have any of these symptoms, especially if they
are new, worse, or worry you:
thoughts about suicide or dying
attempts to commit suicide
new or worse depression
new or worse anxiety
feeling agitated or restless
panic attacks
trouble sleeping (insomnia)
new or worse irritability
acting aggressive, being angry, or violent
Reference ID: 3219002
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
acting on dangerous impulses
an extreme increase in activity and talking (mania)
other unusual changes in behavior or mood
How can I watch for early symptoms of suicidal thoughts and actions?
Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings.
Keep all follow-up visits with your healthcare provider as scheduled.
Call your healthcare provider between visits as needed, especially if you are worried about symptoms.
Do not stop TEGRETOL without first talking to a healthcare provider.
Stopping TEGRETOL suddenly can cause serious problems. You should talk to your healthcare
provider before stopping.
Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts
or actions, your healthcare provider may check for other causes.
What is TEGRETOL?
TEGRETOL is a prescription medicine used to treat:
certain types of seizures (partial, tonic-clonic, mixed)
certain types of nerve pain (trigeminal and glossopharyngeal neuralgia)
TEGRETOL is not a regular pain medicine and should not be used for aches or pains.
Who should not take TEGRETOL?
Do not take TEGRETOL if you:
have a history of bone marrow depression.
are allergic to carbamazepine or any of the ingredients in TEGRETOL. See the end of this Medication
Guide for a complete list of ingredients in TEGRETOL.
take nefazodone.
are allergic to medicines called tricyclic antidepressants (TCAs). Ask your healthcare provider or
pharmacist for a list of these medicines if you are not sure.
have taken a medicine called a Monoamine Oxidase Inhibitor (MAOI) in the last 14 days. Ask your
healthcare provider or pharmacist for a list of these medicines if you are not sure.
What should I tell my healthcare provider before taking TEGRETOL?
Before you take TEGRETOL, tell your healthcare provider if you:
have or have had suicidal thoughts or actions, depression or mood problems
have or ever had heart problems
have or ever had blood problems
have or ever had liver problems
have or ever had kidney problems
Reference ID: 3219002
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
have or ever had allergic reactions to medicines
have or ever had increased pressure in your eye
have any other medical conditions
drink grapefruit juice or eat grapefruit
use birth control. TEGRETOL may make your birth control less effective. Tell your healthcare
provider if your menstrual bleeding changes while you take birth control and TEGRETOL.
are pregnant or plan to become pregnant. TEGRETOL may harm your unborn baby. Tell your
healthcare provider right away if you become pregnant while taking TEGRETOL. You and your
healthcare provider should decide if you should take TEGRETOL while you are pregnant.
▪ If you become pregnant while taking TEGRETOL, talk to your healthcare provider about registering
with the North American Antiepileptic Drug (NAAED) Pregnancy Registry. The purpose of this
registry is to collect information about the safety of antiepileptic medicine during pregnancy. You can
enroll in this registry by calling 1-888-233-2334.
are breastfeeding or plan to breastfeed. TEGRETOL passes into breast milk. You and your healthcare
provider should discuss whether you should take TEGRETOL or breastfeed; you should not do both.
Tell your healthcare provider about all the medicines you take, including prescription and non-prescription
medicines, vitamins, and herbal supplements.
Taking TEGRETOL with certain other medicines may cause side effects or affect how well they work. Do not
start or stop other medicines without talking to your healthcare provider.
Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when
you get a new medicine.
How should I take TEGRETOL?
Do not stop taking TEGRETOL without first talking to your healthcare provider. Stopping TEGRETOL
suddenly can cause serious problems. Stopping seizure medicine suddenly in a patient who has epilepsy
may cause seizures that will not stop (status epilepticus).
Take TEGRETOL exactly as prescribed. Your healthcare provider will tell you how much TEGRETOL to
take.
Your healthcare provider may change your dose. Do not change your dose of TEGRETOL without talking
to your healthcare provider.
Take TEGRETOL with food.
TEGRETOL-XR tablets:
Do not crush, chew, or break TEGRETOL-XR tablets.
Tell you healthcare provider if you can not swallow TEGRETOL-XR whole.
TEGRETOL Suspension:
Shake the bottle well each time before use.
Do not take TEGRETOL suspension at the same time you take other liquid medicines.
If you take too much TEGRETOL, call your healthcare provider or local Poison Control Center right away.
What should I avoid while taking TEGRETOL?
Reference ID: 3219002
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Do not drink alcohol or take other drugs that make you sleepy or dizzy while taking TEGRETOL until
you talk to your healthcare provider. TEGRETOL taken with alcohol or drugs that cause sleepiness or
dizziness may make your sleepiness or dizziness worse.
Do not drive, operate heavy machinery, or do other dangerous activities until you know how
TEGRETOL affects you. TEGRETOL may slow your thinking and motor skills.
What are the possible side effects of TEGRETOL?
See “What is the most important information I should know about TEGRETOL?”
TEGRETOL may cause other serious side effects. These include:
Irregular heartbeat - symptoms include:
o Fast, slow, or pounding heartbeat
o Shortness of breath
o Feeling lightheaded
o Fainting
Liver problems - symptoms include:
o yellowing of your skin or the whites of your eyes
o dark urine
o pain on the right side of your stomach area (abdominal pain)
o easy bruising
o loss of appetite
o nausea or vomiting
Get medical help right away if you have any of the symptoms listed above or listed in “What is the most
important information I should know about TEGRETOL”.
The most common side effects of TEGRETOL include:
dizziness
drowsiness
problems with walking and coordination (unsteadiness)
nausea
vomiting
These are not all the possible side effects of TEGRETOL. For more information, ask your healthcare provider
or pharmacist.
Tell your healthcare provider if you have any side effect that bothers you or that does not go away.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA
1088.
How should I store TEGRETOL?
Do not store TEGRETOL Tablets above 30°C (86°F).
Keep TEGRETOL tablets dry.
Reference ID: 3219002
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Do not store TEGRETOL Chewable Tablets above 30°C (86°F).
Keep TEGRETOL Chewable Tablets out of the light.
Keep TEGRETOL Chewable Tablets tablets dry.
Store TEGRETOL-XR tablets between 15°C to 30°C (59°F to 86°F).
Keep TEGRETOL XR tablets dry.
Do not store TEGRETOL Suspension above 30°C (86°F).
Shake well before using.
Keep TEGRETOL Suspension in a tight, light-resistant container.
Keep TEGRETOL and all medicines out of the reach of children.
General Information about TEGRETOL
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use
TEGRETOL for a condition for which it was not prescribed. Do not give TEGRETOL to other people, even if
they have the same symptoms that you have. It may harm them.
This Medication Guide summarizes the most important information about TEGRETOL. If you would like more
information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for the full
prescribing information about TEGRETOL that is written for health professionals.
For more information, go to www.pharma.us.novartis.com or call 1-888-669-6682.
What are the ingredients in TEGRETOL?
Active ingredient: carbamazepine
Inactive ingredients:
TEGRETOL tablets: colloidal silicon dioxide, D&C Red No. 30 Aluminum Lake (chewable tablets
only), FD&C Red No. 40 (200-mg tablets only), flavoring (chewable tablets only), gelatin, glycerin,
magnesium stearate, sodium starch glycolate (chewable tablets only), starch, stearic acid, and sucrose
(chewable tablets only).
TEGRETOL Suspension: Citric acid, FD&C Yellow No. 6, flavoring, polymer, potassium sorbate,
propylene glycol, purified water, sorbitol, sucrose, and xanthan gum.
TEGRETOL-XR tablets: cellulose compounds, dextrates, iron oxides, magnesium stearate, mannitol,
polyethylene glycol, sodium lauryl sulfate, titanium dioxide (200-mg tablets only).
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Distributed by:
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936
© Novartis
T2012-167/T2011-32
November 2012/March 2011
Reference ID: 3219002
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
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2025-02-12T13:47:07.360160
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/016608s107,018281s055,018927s048,020234s040lbl.pdf', 'application_number': 20234, 'submission_type': 'SUPPL ', 'submission_number': 40}
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Labels for NDA 20231
Supplement S-072
Reference ID: 3523812
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Total Adv Clean Between Paste 5.8oz Carton For FDA approval
Date: 05/09/2014
Part# Front: P9888149
Morristown, TN
Version# 1
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(b) (4)
(b) (4)
(b) (4)
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Total Adv Clean Between .75oz Paste Carton US
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Part# Front: P9897439
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Labels for NDA 20231
Supplement S-073
Reference ID: 3523812
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Total Daily Repair 5.8oz Carton For FDA approval
Date: 05/08/2014
Part# Front: P9892686
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Total Daily Repair Gel 5.8oz Carton For FDA approval
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Part# Front: P9893094
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Total Daily Repair .75oz Carton For FDA approval
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Version# 1
Part# Front: P9897438
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Reference ID: 3523812
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(b) (4)
(b) (4)
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Total Daily Repair .75oz Tube For FDA approval
Date: 05/14/2014
Version# 1
Part# Front: P9893436
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Reference ID: 3523812
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custom-source
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2025-02-12T13:47:09.022057
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/020231Orig1s072, 020231Orig1s073lbl.pdf', 'application_number': 20231, 'submission_type': 'SUPPL ', 'submission_number': 73}
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NDA 21-216, NDA 20-235/S-015, NDA 20-882/S-002, NDA 21-129/S-005
Page 1
FDA approved labeling text (dated 10/12/00)
Neurontin® (gabapentin) capsules,
Neurontin® (gabapentin) tablets
Neurontin® (gabapentin) oral solution
DESCRIPTION
Neurontin® (gabapentin) capsules, Neurontin® (gabapentin) tablets, and Neurontin®
(gabapentin) oral solution are supplied as imprinted hard shell capsules containing 100
mg, 300 mg, and 400 mg of gabapentin, elliptical film-coated tablets containing 600 mg
and 800 mg of gabapentin or an oral solution containing 250 mg/5 mL of gabapentin.
The inactive ingredients for the capsules are lactose, cornstarch, and talc. The 100 mg
capsule shell contains gelatin and titanium dioxide. The 300 mg capsule shell contains
gelatin, titanium dioxide, and yellow iron oxide. The 400 mg capsule shell contains
gelatin, red iron oxide, titanium dioxide, and yellow iron oxide. The imprinting ink
contains FD&C Blue No. 2 and titanium dioxide.
The inactive ingredients for the tablets are poloxamer 407, copolyvidonum, cornstarch,
magnesium stearate, hydroxypropyl cellulose, talc, candelilla wax and purified water.
The imprinting ink for the 600 mg tablets contains synthetic black iron oxide,
pharmaceutical shellac, pharmaceutical glaze, propylene glycol, ammonium hydroxide,
isopropyl alcohol and n-butyl alcohol. The imprinting ink for the 800 mg tablets contains
synthetic yellow iron oxide, synthetic red iron oxide, hydroxypropyl methylcellulose,
propylene glycol, methanol, isopropyl alcohol and deionized water.
The inactive ingredients for the oral solution are glycerin, xylitol, purified water and
artificial cool strawberry anise flavor.
Gabapentin is described as 1-(aminomethyl)cyclohexaneacetic acid with an empirical
formula of C9 H17NO2 and a molecular weight of 171.24. The molecular structure of
gabapentin is:
Gabapentin is a white to off-white crystalline solid. It is freely soluble in water and both
basic and acidic aqueous solutions.
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CLINICAL PHARMACOLOGY
Mechanism of Action
The mechanism by which gabapentin exerts its anticonvulsant action is unknown, but in
animal test systems designed to detect anticonvulsant activity, gabapentin prevents
seizures as do other marketed anticonvulsants. Gabapentin exhibits antiseizure activity in
mice and rats in both the maximal electroshock and pentylenetetrazole seizure models
and other preclinical models (e.g., strains with genetic epilepsy, etc.). The relevance of
these models to human epilepsy is not known.
Gabapentin is structurally related to the neurotransmitter GABA (gamma-aminobutyric
acid) but it does not interact with GABA receptors, it is not converted metabolically into
GABA or a GABA agonist, and it is not an inhibitor of GABA uptake or degradation.
Gabapentin was tested in radioligand binding assays at concentrations up to 100 µM and
did not exhibit affinity for a number of other common receptor sites, including
benzodiazepine, glutamate, N-methyl-D-aspartate (NMDA), quisqualate, kainate,
strychnine-insensitive or strychnine-sensitive glycine, alpha 1, alpha 2, or beta
adrenergic, adenosine A1 or A2, cholinergic muscarinic or nicotinic, dopamine D1 or D2,
histamine H1, serotonin S1 or S2, opiate mu, delta or kappa, voltage-sensitive calcium
channel sites labeled with nitrendipine or diltiazem, or at voltage-sensitive sodium
channel sites with batrachotoxinin A 20-alpha-benzoate.
Several test systems ordinarily used to assess activity at the NMDA receptor have been
examined. Results are contradictory. Accordingly, no general statement about the effects,
if any, of gabapentin at the NMDA receptor can be made.
In vitro studies with radiolabeled gabapentin have revealed a gabapentin binding site in
areas of rat brain including neocortex and hippocampus. A high-affinity binding protein
in animal brain tissue has been identified as an auxiliary subunit of voltage-activated
calcium channels. However, functional correlates of gabapentin binding, if any, remain
to be elucidated.
Pharmacokinetics and Drug Metabolism
All pharmacological actions following gabapentin administration are due to the activity
of the parent compound; gabapentin is not appreciably metabolized in humans.
Oral Bioavailability: Gabapentin bioavailability is not dose proportional; i.e., as dose is
increased, bioavailability decreases. A 400 mg dose, for example, is about 25% less
bioavailable than a 100 mg dose. Over the recommended dose range of 300 to 600 mg
T.I.D., however, the differences in bioavailability are not large, and bioavailability is
about 60 percent. Food has only a slight effect on the rate and extent of absorption of
gabapentin (14% increase in AUC and Cmax).
Distribution: Gabapentin circulates largely unbound (<3%) to plasma protein. The
apparent volume of distribution of gabapentin after 150 mg intravenous administration is
58±6 L (Mean ±SD). In patients with epilepsy, steady-state predose (Cmin)
concentrations of gabapentin in cerebrospinal fluid were approximately 20% of the
corresponding plasma concentrations.
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Elimination: Gabapentin is eliminated from the systemic circulation by renal excretion
as unchanged drug. Gabapentin is not appreciably metabolized in humans.
Gabapentin elimination half-life is 5 to 7 hours and is unaltered by dose or following
multiple dosing. Gabapentin elimination rate constant, plasma clearance, and renal
clearance are directly proportional to creatinine clearance (see Special Populations:
Patients With Renal Insufficiency, below). In elderly patients, and in patients with
impaired renal function, gabapentin plasma clearance is reduced. Gabapentin can be
removed from plasma by hemodialysis.
Dosage adjustment in patients with compromised renal function or undergoing
hemodialysis is recommended (see DOSAGE AND ADMINISTRATION, Table 2).
Special Populations: Adult Patients With Renal Insufficiency: Subjects (N=60) with
renal insufficiency (mean creatinine clearance ranging from 13-114 mL/min) were
administered single 400-mg oral doses of gabapentin. The mean gabapentin half-life
ranged from about 6.5 hours (patients with creatinine clearance >60 mL/min) to 52 hours
(creatinine clearance <30 mL/min) and gabapentin renal clearance from about 90 mL/min
(>60 mL/min group) to about 10 mL/min (<30 mL/min). Mean plasma clearance (CL/F)
decreased from approximately 190 mL/min to 20 mL/min.
Dosage adjustment in adult patients with compromised renal function is necessary (see
DOSAGE AND ADMINISTRATION). Pediatric patients with renal insufficiency have
not been studied.
Hemodialysis: In a study in anuric adult subjects (N=11), the apparent elimination half-
life of gabapentin on nondialysis days was about 132 hours; dialysis three times a week
(4 hours duration) lowered the apparent half-life of gabapentin by about 60%, from 132
hours to 51 hours. Hemodialysis thus has a significant effect on gabapentin elimination in
anuric subjects.
Dosage adjustment in patients undergoing hemodialysis is necessary (see DOSAGE AND
ADMINISTRATION).
Hepatic Disease: Because gabapentin is not metabolized, no study was performed in
patients with hepatic impairment.
Age: The effect of age was studied in subjects 20-80 years of age. Apparent oral
clearance (CL/F) of gabapentin decreased as age increased, from about 225 mL/min in
those under 30 years of age to about 125 mL/min in those over 70 years of age. Renal
clearance (CLr) and CLr adjusted for body surface area also declined with age; however,
the decline in the renal clearance of gabapentin with age can largely be explained by the
decline in renal function. Reduction of gabapentin dose may be required in patients who
have age related compromised renal function. (See PRECAUTIONS, Geriatric Use, and
DOSAGE AND ADMINISTRATION.)
Pediatric: Gabapentin pharmacokinetics were determined in 48 pediatric subjects
between the ages of 1 month and 12 years following a dose of approximately 10 mg/kg.
Peak plasma concentrations were similar across the entire age group and occurred 2 to
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3 hours postdose. In general, pediatric subjects between 1 month and <5 years of age
achieved approximately 30% lower exposure (AUC) than that observed in those 5 years
of age and older. Accordingly, oral clearance normalized per body weight was higher in
the younger children. Apparent oral clearance of gabapentin was directly proportional to
creatinine clearance. Gabapentin elimination half-life averaged 4.7 hours and was similar
across the age groups studied.
A population pharmacokinetic analysis was performed in 253 pediatric subjects between
1 month and 13 years of age. Patients received 10 to 65 mg/kg/day given T.I.D. Apparent
oral clearance (CL/F) was directly proportional to creatinine clearance and this
relationship was similar following a single dose and at steady state. Higher oral clearance
values were observed in children <5 years of age compared to those observed in children
5 years of age and older, when normalized per body weight. The clearance was highly
variable in infants < 1 year of age. The normalized CL/F values observed in pediatric
patients 5 years of age and older were consistent with values observed in adults after a
single dose. The oral volume of distribution normalized per body weight was constant
across the age range.
These pharmacokinetic data indicate that the effective daily dose in pediatric patients
ages 3 and 4 years should be 40 mg/kg/day to achieve average plasma concentrations
similar to those achieved in patients 5 years of age and older receiving gabapentin at
30 mg/kg/day. (See DOSAGE AND ADMINISTRATION).
Gender: Although no formal study has been conducted to compare the pharmacokinetics
of gabapentin in men and women, it appears that the pharmacokinetic parameters for
males and females are similar and there are no significant gender differences.
Race: Pharmacokinetic differences due to race have not been studied. Because
gabapentin is primarily renally excreted and there are no important racial differences in
creatinine clearance, pharmacokinetic differences due to race are not expected.
Clinical Studies
The effectiveness of Neurontin® as adjunctive therapy (added to other antiepileptic
drugs) was established in multicenter placebo-controlled, double-blind, parallel-group
clinical trials in adult and pediatric patients (3 years and older) with refractory partial
seizures.
Evidence of effectiveness was obtained in three trials conducted in 705 patients (age
12 years and above) and one trial conducted in 247 pediatric patients (3 to 12 years of
age). The patients enrolled had a history of at least 4 partial seizures per month in spite of
receiving one or more antiepileptic drugs at therapeutic levels and were observed on their
established antiepileptic drug regimen during a 12-week baseline period (6 weeks in the
study of pediatric patients). In patients continuing to have at least 2 (or 4 in some studies)
seizures per month, Neurontin® or placebo was then added on to the existing therapy
during a 12-week treatment period. Effectiveness was assessed primarily on the basis of
the percent of patients with a 50% or greater reduction in seizure frequency from baseline
to treatment (the “responder rate”) and a derived measure called response ratio, a measure
of change defined as (T - B)/(T + B), where B is the patient’s baseline seizure frequency
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and T is the patient’s seizure frequency during treatment. Response ratio is distributed
within the range -1 to +1. A zero value indicates no change while complete elimination of
seizures would give a value of -1; increased seizure rates would give positive values. A
response ratio of -0.33 corresponds to a 50% reduction in seizure frequency. The results
given below are for all partial seizures in the intent-to-treat (all patients who received any
doses of treatment) population in each study, unless otherwise indicated.
One study compared Neurontin® 1200 mg/day T.I.D. with placebo. Responder rate was
23% (14/61) in the Neurontin® group and 9% (6/66) in the placebo group; the difference
between groups was statistically significant. Response ratio was also better in the
Neurontin® group (-0.199) than in the placebo group (-0.044), a difference that also
achieved statistical significance.
A second study compared primarily 1200 mg/day T.I.D. Neurontin® (N=101) with
placebo (N=98). Additional smaller Neurontin® dosage groups (600 mg/day, N=53;
1800 mg/day, N=54) were also studied for information regarding dose response.
Responder rate was higher in the Neurontin® 1200 mg/day group (16%) than in the
placebo group (8%), but the difference was not statistically significant. The responder
rate at 600 mg (17%) was also not significantly higher than in the placebo, but the
responder rate in the 1800 mg group (26%) was statistically significantly superior to the
placebo rate. Response ratio was better in the Neurontin® 1200 mg/day group (-0.103)
than in the placebo group (-0.022); but this difference was also not statistically significant
(p = 0.224). A better response was seen in the Neurontin® 600 mg/day group (-0.105)
and 1800 mg/day group (-0.222) than in the 1200 mg/day group, with the 1800 mg/day
group achieving statistical significance compared to the placebo group.
A third study compared Neurontin® 900 mg/day T.I.D. (N=111) and placebo (N=109).
An additional Neurontin® 1200 mg/day dosage group (N=52) provided dose-response
data. A statistically significant difference in responder rate was seen in the Neurontin®
900 mg/day group (22%) compared to that in the placebo group (10%). Response ratio
was also statistically significantly superior in the Neurontin® 900 mg/day group (-0.119)
compared to that in the placebo group (-0.027), as was response ratio in 1200 mg/day
Neurontin® (-0.184) compared to placebo.
Analyses were also performed in each study to examine the effect of Neurontin® on
preventing secondarily generalized tonic-clonic seizures. Patients who experienced a
secondarily generalized tonic-clonic seizure in either the baseline or in the treatment
period in all three placebo-controlled studies were included in these analyses. There were
several response ratio comparisons that showed a statistically significant advantage for
Neurontin® compared to placebo and favorable trends for almost all comparisons.
Analysis of responder rate using combined data from all three studies and all doses
(N=162, Neurontin®; N=89, placebo) also showed a significant advantage for
Neurontin® over placebo in reducing the frequency of secondarily generalized tonic-
clonic seizures.
In two of the three controlled studies, more than one dose of Neurontin® was used.
Within each study the results did not show a consistently increased response to dose.
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However, looking across studies, a trend toward increasing efficacy with increasing dose
is evident (see Figure 1).
FIGURE 1. Responder Rate in Patients Receiving Neurontin® Expressed as a
Difference from Placebo by Dose and Study
In the figure, treatment effect magnitude, measured on the Y axis in terms of the
difference in the proportion of gabapentin and placebo assigned patients attaining a 50%
or greater reduction in seizure frequency from baseline, is plotted against the daily dose
of gabapentin administered (X axis).
Although no formal analysis by gender has been performed, estimates of response
(Response Ratio) derived from clinical trials (398 men, 307 women) indicate no
important gender differences exist. There was no consistent pattern indicating that age
had any effect on the response to Neurontin®. There were insufficient numbers of
patients of races other than Caucasian to permit a comparison of efficacy among racial
groups.
A fourth study in pediatric patients age 3 to 12 years compared 25 - 35 mg/kg/day
Neurontin (N=118) with placebo (N=127). For all partial seizures in the intent-to-treat
population, the response ratio was statistically significantly better for the Neurontin group
(-0.146) than for the placebo group (-0.079). For the same population, the responder rate
for Neurontin (21%) was not significantly different from placebo (18%).
A study in pediatric patients age 1 month to 3 years compared 40 mg/kg/day Neurontin
(N=38) with placebo (N=38) in patients who were receiving at least one marketed
antiepileptic drug and had at least one partial seizure during the screening period (within
2 weeks prior to baseline). Patients had up to 48 hours of baseline and up to 72 hours of
double-blind video EEG monitoring to record and count the occurrence of seizures.
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There were no statistically significant differences between treatments in either the
response ratio or responder rate.
INDICATIONS AND USAGE
Neurontin® (gabapentin) is indicated as adjunctive therapy in the treatment of partial
seizures with and without secondary generalization in patients over 12 years of age with
epilepsy. Neurontin is also indicated as adjunctive therapy in the treatment of partial
seizures in pediatric patients age 3 – 12 years.
CONTRAINDICATIONS
Neurontin® is contraindicated in patients who have demonstrated hypersensitivity to the
drug or its ingredients.
WARNINGS
Neuropsychiatric Adverse Events– Pediatric Patients 3 – 12 years of age
Gabapentin use in pediatric patients with epilepsy 3 –12 years of age is associated with
the occurrence of central nervous system related adverse events. The most significant of
these can be classified into the following categories: 1) emotional lability (primarily
behavioral problems), 2) hostility, including aggressive behaviors, 3) thought disorder,
including concentration problems and change in school performance, and 4) hyperkinesia
(primarily restlessness and hyperactivity). Among the gabapentin-treated patients, most
of the events were mild to moderate in intensity.
In controlled trials in pediatric patients 3-12 years of age the incidence of these adverse
events was: emotional lability 6% (gabapentin-treated patients) vs 1.3% (placebo-treated
patients); hostility 5.2% vs 1.3%; hyperkinesia 4.7% vs 2.9%; and thought disorder 1.7%
vs 0%. One of these events, a report of hostility, was considered serious. Discontinuation
of gabapentin treatment occurred in 1.3% of patients reporting emotional lability and
hyperkinesia and 0.9% of gabapentin-treated patients reporting hostility and thought
disorder. One placebo-treated patient (0.4%) withdrew due to emotional lability.
Withdrawal Precipitated Seizure, Status Epilepticus
Antiepileptic drugs should not be abruptly discontinued because of the possibility of
increasing seizure frequency.
In the placebo-controlled studies in patients > 12 years of age, the incidence of status
epilepticus in patients receiving Neurontin® was 0.6% (3 of 543) versus 0.5% in patients
receiving placebo (2 of 378). Among the 2074 patients > 12 years of age treated with
Neurontin® across all studies (controlled and uncontrolled) 31(1.5%) had status
epilepticus. Of these, 14 patients had no prior history of status epilepticus either before
treatment or while on other medications. Because adequate historical data are not
available, it is impossible to say whether or not treatment with Neurontin® is associated
with a higher or lower rate of status epilepticus than would be expected to occur in a
similar population not treated with Neurontin® .
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Tumorigenic Potential
In standard preclinical in vivo lifetime carcinogenicity studies, an unexpectedly high
incidence of pancreatic acinar adenocarcinomas was identified in male, but not female,
rats. (See PRECAUTIONS: Carcinogenesis, Mutagenesis, Impairment of Fertility.) The
clinical significance of this finding is unknown. Clinical experience during gabapentin’s
premarketing development provides no direct means to assess its potential for inducing
tumors in humans.
In clinical studies comprising 2085 patient-years of exposure in patients > 12 years of
age, new tumors were reported in 10 patients (2 breast, 3 brain, 2 lung, 1 adrenal, 1 non-
Hodgkin’s lymphoma, 1 endometrial carcinoma in situ), and preexisting tumors worsened
in 11 patients (9 brain, 1 breast, 1 prostate) during or up to 2 years following
discontinuation of Neurontin®. Without knowledge of the background incidence and
recurrence in a similar population not treated with Neurontin®, it is impossible to know
whether the incidence seen in this cohort is or is not affected by treatment.
Sudden and Unexplained Deaths
During the course of premarketing development of Neurontin®, 8 sudden and
unexplained deaths were recorded among a cohort of 2203 patients treated (2103 patient-
years of exposure).
Some of these could represent seizure-related deaths in which the seizure was not
observed, e.g., at night. This represents an incidence of 0.0038 deaths per patient-year.
Although this rate exceeds that expected in a healthy population matched for age and sex,
it is within the range of estimates for the incidence of sudden unexplained deaths in
patients with epilepsy not receiving Neurontin® (ranging from 0.0005 for the general
population of epileptics to 0.003 for a clinical trial population similar to that in the
Neurontin® program, to 0.005 for patients with refractory epilepsy). Consequently,
whether these figures are reassuring or raise further concern depends on comparability of
the populations reported upon to the Neurontin® cohort and the accuracy of the estimates
provided.
PRECAUTIONS
Information for Patients
Patients should be instructed to take Neurontin® only as prescribed.
Patients should be advised that Neurontin® may cause dizziness, somnolence and other
symptoms and signs of CNS depression. Accordingly, they should be advised neither to
drive a car nor to operate other complex machinery until they have gained sufficient
experience on Neurontin® to gauge whether or not it affects their mental and/or motor
performance adversely.
Laboratory Tests
Clinical trials data do not indicate that routine monitoring of clinical laboratory
parameters is necessary for the safe use of Neurontin®. The value of monitoring
Neurontin® blood concentrations has not been established. Neurontin® may be used in
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combination with other antiepileptic drugs without concern for alteration of the blood
concentrations of gabapentin or of other antiepileptic drugs.
Drug Interactions
Gabapentin is not appreciably metabolized nor does it interfere with the metabolism of
commonly coadministered antiepileptic drugs.
The drug interaction data described in this section were obtained from studies involving
healthy adults and adult patients with epilepsy.
Phenytoin: In a single and multiple dose study of Neurontin® (400 mg T.I.D.) in
epileptic patients (N=8) maintained on phenytoin monotherapy for at least 2 months,
gabapentin had no effect on the steady-state trough plasma concentrations of phenytoin
and phenytoin had no effect on gabapentin pharmacokinetics.
Carbamazepine: Steady-state trough plasma carbamazepine and carbamazepine 10, 11
epoxide concentrations were not affected by concomitant gabapentin (400 mg T.I.D.;
N=12) administration. Likewise, gabapentin pharmacokinetics were unaltered by
carbamazepine administration.
Valproic Acid: The mean steady-state trough serum valproic acid concentrations prior to
and during concomitant gabapentin administration (400 mg T.I.D.; N=17) were not
different and neither were gabapentin pharmacokinetic parameters affected by valproic
acid.
Phenobarbital: Estimates of steady-state pharmacokinetic parameters for phenobarbital
or gabapentin (300 mg T.I.D.; N=12) are identical whether the drugs are administered
alone or together.
Cimetidine: In the presence of cimetidine at 300 mg Q.I.D. (N=12) the mean apparent
oral clearance of gabapentin fell by 14% and creatinine clearance fell by 10%. Thus
cimetidine appeared to alter the renal excretion of both gabapentin and creatinine, an
endogenous marker of renal function. This small decrease in excretion of gabapentin by
cimetidine is not expected to be of clinical importance. The effect of gabapentin on
cimetidine was not evaluated.
Oral Contraceptive: Based on AUC and half-life, multiple-dose pharmacokinetic
profiles of norethindrone and ethinyl estradiol following administration of tablets
containing 2.5 mg of norethindrone acetate and 50 mcg of ethinyl estradiol were similar
with and without coadministration of gabapentin (400 mg T.I.D.; N=13). The Cmax of
norethindrone was 13% higher when it was coadministered with gabapentin; this
interaction is not expected to be of clinical importance.
Antacid (Maalox®): Maalox reduced the bioavailability of gabapentin (N=16) by about
20%. This decrease in bioavailability was about 5% when gabapentin was administered 2
hours after Maalox. It is recommended that gabapentin be taken at least 2 hours following
Maalox administration.
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Effect of Probenecid: Probenecid is a blocker of renal tubular secretion. Gabapentin
pharmacokinetic parameters without and with probenecid were comparable. This
indicates that gabapentin does not undergo renal tubular secretion by the pathway that is
blocked by probenecid.
Drug/Laboratory Tests Interactions
Because false positive readings were reported with the Ames N-Multistix SG® dipstick
test for urinary protein when gabapentin was added to other antiepileptic drugs, the more
specific sul-fosalicylic acid precipitation procedure is recommended to determine the
presence of urine protein.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Gabapentin was given in the diet to mice at 200, 600, and 2000 mg/kg/day and to rats at
250, 1000, and 2000 mg/kg/day for 2 years. A statistically significant increase in the
incidence of pancreatic acinar cell adenomas and carcinomas was found in male rats
receiving the high dose; the no-effect dose for the occurrence of carcinomas was 1000
mg/kg/day. Peak plasma concentrations of gabapentin in rats receiving the high dose of
2000 mg/kg were 10 times higher than plasma concentrations in humans receiving 3600
mg per day, and in rats receiving 1000 mg/kg/day peak plasma concentrations were 6.5
times higher than in humans receiving 3600 mg/day. The pancreatic acinar cell
carcinomas did not affect survival, did not metastasize and were not locally invasive. The
relevance of this finding to carcinogenic risk in humans is unclear.
Studies designed to investigate the mechanism of gabapentin-induced pancreatic
carcinogenesis in rats indicate that gabapentin stimulates DNA synthesis in rat pancreatic
acinar cells in vitro and, thus, may be acting as a tumor promoter by enhancing mitogenic
activity. It is not known whether gabapentin has the ability to increase cell proliferation
in other cell types or in other species, including humans.
Gabapentin did not demonstrate mutagenic or genotoxic potential in three in vitro and
four in vivo assays. It was negative in the Ames test and the in vitro HGPRT forward
mutation assay in Chinese hamster lung cells; it did not produce significant increases in
chromosomal aberrations in the in vitro Chinese hamster lung cell assay; it was negative
in the in vivo chromosomal aberration assay and in the in vivo micronucleus test in
Chinese hamster bone marrow; it was negative in the in vivo mouse micronucleus assay;
and it did not induce unscheduled DNA synthesis in hepatocytes from rats given
gabapentin.
No adverse effects on fertility or reproduction were observed in rats at doses up to
2000 mg/kg (approximately 5 times the maximum recommended human dose on an
mg/m2 basis).
Pregnancy
Pregnancy Category C: Gabapentin has been shown to be fetotoxic in rodents, causing
delayed ossification of several bones in the skull, vertebrae, forelimbs, and hindlimbs.
These effects occurred when pregnant mice received oral doses of 1000 or
3000 mg/kg/day during the period of organogenesis, or approximately 1 to 4 times the
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maximum dose of 3600 mg/day given to epileptic patients on a mg/m2 basis. The no-
effect level was 500 mg/kg/day or approximately ½ of the human dose on a mg/m2 basis.
When rats were dosed prior to and during mating, and throughout gestation, pups from all
dose groups (500, 1000 and 2000 mg/kg/day) were affected. These doses are equivalent
to less than approximately 1 to 5 times the maximum human dose on a mg/m2 basis.
There was an increased incidence of hydroureter and/or hydronephrosis in rats in a study
of fertility and general reproductive performance at 2000 mg/kg/day with no effect at
1000 mg/kg/day, in a teratology study at 1500 mg/kg/day with no effect at
300 mg/kg/day, and in a perinatal and postnatal study at all doses studied (500, 1000 and
2000 mg/kg/day). The doses at which the effects occurred are approximately 1 to 5 times
the maximum human dose of 3600 mg/day on a mg/m2 basis; the no-effect doses were
approximately 3 times (Fertility and General Reproductive Performance study) and
approximately equal to (Teratogenicity study) the maximum human dose on a mg/m2
basis. Other than hydroureter and hydronephrosis, the etiologies of which are unclear, the
incidence of malformations was not increased compared to controls in off-spring of mice,
rats, or rabbits given doses up to 50 times (mice), 30 times (rats), and 25 times (rabbits)
the human daily dose on a mg/kg basis, or 4 times (mice), 5 times (rats), or 8 times
(rabbits) the human daily dose on a mg/m2 basis.
In a teratology study in rabbits, an increased incidence of postimplantation fetal loss
occurred in dams exposed to 60, 300 and 1500 mg/kg/day, or less than approximately
¼ to 8 times the maximum human dose on a mg/m2 basis. There are no adequate and
well-controlled studies in pregnant women. Because animal reproduction studies are not
always predictive of human response, this drug should be used during pregnancy only if
the potential benefit justifies the potential risk to the fetus.
Use in Nursing Mothers
Gabapentin is secreted into human milk following oral administration. A nursed infant
could be exposed to a maximum dose of approximately 1 mg/kg/day of gabapentin.
Because the effect on the nursing infant is unknown, Neurontin® should be used in
women who are nursing only if the benefits clearly outweigh the risks.
Pediatric Use
Effectiveness in pediatric patients below the age of 3 years has not been established (see
CLINICAL PHARMACOLOGY, Clinical Studies).
Geriatric Use
Clinical studies of Neurontin did not include sufficient numbers of subjects aged 65 and
over to determine whether they responded differently from younger subjects. Other
reported clinical experience has not identified differences in responses between the
elderly and younger patients. In general, dose selection for an elderly patient should be
cautious, usually starting at the low end of the dosing range, reflecting the greater
frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or
other drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk of toxic
reactions to this drug may be greater in patients with impaired renal function. Because
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FDA approved labeling text (dated 10/12/00)
elderly patients are more likely to have decreased renal function, care should be taken in
dose selection, and it may be useful to monitor renal function (see CLINICAL
PHARMACOLOGY, ADVERSE REACTIONS, and DOSAGE AND
ADMINISTRATION sections).
ADVERSE REACTIONS
The most commonly observed adverse events associated with the use of Neurontin® in
combination with other antiepileptic drugs in patients > 12 years of age, not seen at an
equivalent frequency among placebo-treated patients, were somnolence, dizziness, ataxia,
fatigue, and nystagmus. The most commonly observed adverse events reported with the
use of Neurontin in combination with other antiepileptic drugs in pediatric patients 3 to
12 years of age, not seen at an equal frequency among placebo-treated patients, were viral
infection, fever, nausea and/or vomiting, somnolence, and hostility (see WARNINGS,
Neuropsychiatric Adverse Events).
Approximately 7% of the 2074 patients > 12 years of age and approximately 7% of the
449 pediatric patients 3 to 12 years of age who received Neurontin® in premarketing
clinical trials discontinued treatment because of an adverse event. The adverse events
most commonly associated with withdrawal in patients > 12 years of age were
somnolence (1.2%), ataxia (0.8%), fatigue (0.6%), nausea and/or vomiting (0.6%), and
dizziness (0.6%). The adverse events most commonly associated with withdrawal in
pediatric patients were emotional lability (1.6%), hostility (1.3%), and hyperkinesia
(1.1%).
Incidence in Controlled Clinical Trials
Table 1 lists treatment-emergent signs and symptoms that occurred in at least 1% of
Neurontin® -treated patients > 12 years of age with epilepsy participating in placebo-
controlled trials and were numerically more common in the Neurontin® group. In these
studies, either Neurontin® or placebo was added to the patient’s current antiepileptic
drug therapy. Adverse events were usually mild to moderate in intensity.
The prescriber should be aware that these figures, obtained when Neurontin® was added
to concurrent antiepileptic drug therapy, cannot be used to predict the frequency of
adverse events in the course of usual medical practice where patient characteristics and
other factors may differ from those prevailing during clinical studies. Similarly, the cited
frequencies cannot be directly compared with figures obtained from other clinical
investigations involving different treatments, uses, or investigators. An inspection of
these frequencies, however, does provide the prescribing physician with one basis to
estimate the relative contribution of drug and nondrug factors to the adverse event
incidences in the population studied.
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FDA approved labeling text (dated 10/12/00)
TABLE 1.
Treatment-Emergent Adverse Event Incidence in Controlled Add-On
Trials In Patients > 12 years of age (Events in at least 1% of Neurontin
patients and numerically more frequent than in the placebo group)
Body System/
Adverse Event
Neurontin®a
N=543
%
Placeboa
N=378
%
Body As A Whole
Fatigue
Weight Increase
Back Pain
Peripheral Edema
11.0
2.9
1.8
1.7
5.0
1.6
0.5
0.5
Cardiovascular
Vasodilatation
1.1
0.3
Digestive System
Dyspepsia
Mouth or Throat Dry
Constipation
Dental Abnormalities
Increased Appetite
2.2
1.7
1.5
1.5
1.1
0.5
0.5
0.8
0.3
0.8
Hematologic and Lymphatic Systems
Leukopenia
1.1
0.5
Musculoskeletal System
Myalgia
Fracture
2.0
1.1
1.9
0.8
Nervous System
Somnolence
Dizziness
Ataxia
Nystagmus
Tremor
Nervousness
Dysarthria
Amnesia
Depression
Thinking Abnormal
Twitching
Coordination Abnormal
19.3
17.1
12.5
8.3
6.8
2.4
2.4
2.2
1.8
1.7
1.3
1.1
8.7
6.9
5.6
4.0
3.2
1.9
0.5
0.0
1.1
1.3
0.5
0.3
Respiratory System
Rhinitis
Pharyngitis
Coughing
4.1
2.8
1.8
3.7
1.6
1.3
Skin and Appendages
Abrasion
Pruritus
1.3
1.3
0.0
0.5
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TABLE 1.
Treatment-Emergent Adverse Event Incidence in Controlled Add-On
Trials In Patients > 12 years of age (Events in at least 1% of Neurontin
patients and numerically more frequent than in the placebo group)
Body System/
Adverse Event
Neurontin®a
N=543
%
Placeboa
N=378
%
Urogenital System
Impotence
1.5
1.1
Special Senses
Diplopia
Amblyopiab
5.9
4.2
1.9
1.1
Laboratory Deviations
WBC Decreased
1.1
0.5
a
Plus background antiepileptic drug therapy
b
Amblyopia was often described as blurred vision.
Other events in more than 1% of patients > 12 years of age but equally or more frequent
in the placebo group included: headache, viral infection, fever, nausea and/or vomiting,
abdominal pain, diarrhea, convulsions, confusion, insomnia, emotional lability, rash,
acne.
Among the treatment-emergent adverse events occurring at an incidence of at least 10%
of Neurontin-treated patients, somnolence and ataxia appeared to exhibit a positive dose-
response relationship.
The overall incidence of adverse events and the types of adverse events seen were similar
among men and women treated with Neurontin® . The incidence of adverse events
increased slightly with increasing age in patients treated with either Neurontin® or
placebo. Because only 3% of patients (28/921) in placebo-controlled studies were
identified as nonwhite (black or other), there are insufficient data to support a statement
regarding the distribution of adverse events by race.
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Table 2 lists treatment-emergent signs and symptoms that occurred in at least 2% of
Neurontin-treated patients age 3 to 12 years of age with epilepsy participating in placebo-
controlled trials and were numerically more common in the Neurontin group. Adverse
events were usually mild to moderate in intensity.
TABLE 2.
Treatment Emergent Adverse Event Incidence in Pediatric Patients
Age 3 to 12 Years in a Controlled Add-On Trial (Events in at least
2% of Neurontin patients and numerically more frequent than in the
placebo group)
Body System/
Adverse Event
Neurontina
N = 119
%
Placeboa
N = 128
%
Body As A Whole
Viral Infection
10.9
3.1
Fever
10.1
3.1
Weight Increase
3.4
0.8
Fatigue
3.4
1.6
Digestive System
Nausea and/or Vomiting
8.4
7.0
Nervous System
Somnolence
8.4
4.7
Hostility
7.6
2.3
Emotional Lability
4.2
1.6
Dizziness
2.5
1.6
Hyperkinesia
2.5
0.8
Respiratory System
Bronchitis
3.4
0.8
Respiratory Infection
2.5
0.8
a
Plus background antiepileptic drug therapy
Other events in more than 2% of pediatric patients 3 to 12 years of age but equally or
more frequent in the placebo group included: pharyngitis, upper respiratory infection,
headache, rhinitis, convulsions, diarrhea, anorexia, coughing, and otitis media.
Other Adverse Events Observed During All Clinical Trials
Neurontin® has been administered to 2074 patients > 12 years of age during all clinical
trials, only some of which were placebo-controlled. During these trials, all adverse events
were recorded by the clinical investigators using terminology of their own choosing. To
provide a meaningful estimate of the proportion of individuals having adverse events,
similar types of events were grouped into a smaller number of standardized categories
using modified COSTART dictionary terminology. These categories are used in the
listing below. The frequencies presented represent the proportion of the 2074 patients >
12 years of age exposed to Neurontin® who experienced an event of the type cited on at
least one occasion while receiving Neurontin® . All reported events are included except
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those already listed in the previous table, those too general to be informative, and those
not reasonably associated with the use of the drug.
Events are further classified within body system categories and enumerated in order of
decreasing frequency using the following definitions: frequent adverse events are defined
as those occurring in at least 1/100 patients; infrequent adverse events are those occurring
in 1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients.
Body As A Whole: Frequent: asthenia, malaise, face edema; Infrequent: allergy,
generalized edema, weight decrease, chill; Rare: strange feelings, lassitude, alcohol
intolerance, hangover effect.
Cardiovascular System: Frequent: hypertension; Infrequent: hypotension, angina
pectoris, peripheral vascular disorder, palpitation, tachycardia, migraine, murmur; Rare:
atrial fibrillation, heart failure, thrombophlebitis, deep thrombophlebitis, myocardial
infarction, cerebrovascular accident, pulmonary thrombosis, ventricular extrasystoles,
bradycardia, premature atrial contraction, pericardial rub, heart block, pulmonary
embolus, hyperlipidemia, hypercholesterolemia, pericardial effusion, pericarditis.
Digestive System: Frequent: anorexia, flatulence, gingivitis; Infrequent: glossitis, gum
hemorrhage, thirst, stomatitis, increased salivation, gastroenteritis, hemorrhoids, bloody
stools, fecal incontinence, hepatomegaly; Rare: dysphagia, eructation, pancreatitis, peptic
ulcer, colitis, blisters in mouth, tooth discolor, perleche, salivary gland enlarged, lip
hemorrhage, esophagitis, hiatal hernia, hematemesis, proctitis, irritable bowel syndrome,
rectal hemorrhage, esophageal spasm.
Endocrine System: Rare: hyperthyroid, hypothyroid, goiter, hypoestrogen, ovarian
failure, epididymitis, swollen testicle, cushingoid appearance.
Hematologic and Lymphatic System: Frequent: purpura most often described as
bruises resulting from physical trauma; Infrequent: anemia, thrombocytopenia,
lymphadenopathy; Rare: WBC count increased, lymphocytosis, non-Hodgkin’s
lymphoma, bleeding time increased.
Musculoskeletal System: Frequent: arthralgia; Infrequent: tendinitis, arthritis, joint
stiffness, joint swelling, positive Romberg test; Rare: costochondritis, osteoporosis,
bursitis, contracture.
Nervous System: Frequent: vertigo, hyperkinesia, paresthesia, decreased or absent
reflexes, increased reflexes, anxiety, hostility; Infrequent: CNS tumors, syncope,
dreaming abnormal, aphasia, hypesthesia, intracranial hemorrhage, hypotonia,
dysesthesia, paresis, dystonia, hemiplegia, facial paralysis, stupor, cerebellar dysfunction,
positive Babinski sign, decreased position sense, subdural hematoma, apathy,
hallucination, decrease or loss of libido, agitation, paranoia, depersonalization, euphoria,
feeling high, doped-up sensation, suicidal, psychosis; Rare: choreoathetosis, orofacial
dyskinesia, encephalopathy, nerve palsy, personality disorder, increased libido, subdued
temperament, apraxia, fine motor control disorder, meningismus, local myoclonus,
hyperesthesia, hypokinesia, mania, neurosis, hysteria, antisocial reaction, suicide gesture.
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Respiratory System: Frequent: pneumonia; Infrequent: epistaxis, dyspnea, apnea, Rare:
mucositis, aspiration pneumonia, hyperventilation, hiccup, laryngitis, nasal obstruction,
snoring, bronchospasm, hypoventilation, lung edema.
Dermatological: Infrequent: alopecia, eczema, dry skin, increased sweating, urticaria,
hirsutism, seborrhea, cyst, herpes simplex; Rare: herpes zoster, skin discolor, skin
papules, photosensitive reaction, leg ulcer, scalp seborrhea, psoriasis, desquamation,
maceration, skin nodules, subcutaneous nodule, melanosis, skin necrosis, local swelling.
Urogenital System: Infrequent: hematuria, dysuria, urination frequency, cystitis, urinary
retention, urinary incontinence, vaginal hemorrhage, amenorrhea, dysmenorrhea,
menorrhagia, breast cancer, unable to climax, ejaculation abnormal; Rare: kidney pain,
leukorrhea, pruritus genital, renal stone, acute renal failure, anuria, glycosuria, nephrosis,
nocturia, pyuria, urination urgency, vaginal pain, breast pain, testicle pain.
Special Senses: Frequent: abnormal vision; Infrequent: cataract, conjunctivitis, eyes dry,
eye pain, visual field defect, photophobia, bilateral or unilateral ptosis, eye hemorrhage,
hordeolum, hearing loss, earache, tinnitus, inner ear infection, otitis, taste loss, unusual
taste, eye twitching, ear fullness; Rare: eye itching, abnormal accommodation,
perforated ear drum, sensitivity to noise, eye focusing problem, watery eyes, retinopathy,
glaucoma, iritis, corneal disorders, lacrimal dysfunction, degenerative eye changes,
blindness, retinal degeneration, miosis, chorioretinitis, strabismus, eustachian tube
dysfunction, labyrinthitis, otitis externa, odd smell.
Adverse events occurring during clinical trials in 449 pediatric patients 3 to 12 years of
age treated with gabapentin that were not reported in adjunctive trials in adults are:
Body as a Whole: dehydration, infectious mononucleosis
Digestive System: hepatitis
Hemic and Lymphatic System: coagulation defect
Nervous System: aura disappeared, occipital neuralgia
Psychobiologic Function: sleep walking
Respiratory System: pseudocroup, hoarseness
Postmarketing and Other Experience
In addition to the adverse experiences reported during clinical testing of Neurontin®, the
following adverse experiences have been reported in patients receiving marketed
Neurontin®. These adverse experiences have not been listed above and data are
insufficient to support an estimate of their incidence or to establish causation. The listing
is alphabetized: angioedema, blood glucose fluctuation, erythema multiforme, elevated
liver function tests, fever, hyponatremia, jaundice, Stevens-Johnson syndrome.
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DRUG ABUSE AND DEPENDENCE
The abuse and dependence potential of Neurontin® has not been evaluated in human
studies.
OVERDOSAGE
A lethal dose of gabapentin was not identified in mice and rats receiving single oral doses
as high as 8000 mg/kg. Signs of acute toxicity in animals included ataxia, labored
breathing, ptosis, sedation, hypoactivity, or excitation.
Acute oral overdoses of Neurontin® up to 49 grams have been reported. In these cases,
double vision, slurred speech, drowsiness, lethargy and diarrhea were observed. All
patients recovered with supportive care.
Gabapentin can be removed by hemodialysis. Although hemodialysis has not been
performed in the few overdose cases reported, it may be indicated by the patient’s clinical
state or in patients with significant renal impairment.
DOSAGE AND ADMINISTRATION
Neurontin® is recommended for add-on therapy in patients 3 years of age and older.
Effectiveness in pediatric patients below the age of 3 years has not been established.
Neurontin® is given orally with or without food.
Patients > 12 years of age: The effective dose of Neurontin® is 900 to 1800 mg/day and
given in divided doses (three times a day) using 300 or 400 mg capsules, or 600 or 800
mg tablets. The starting dose is 300 mg three times a day. If necessary, the dose may be
increased using 300 or 400 mg capsules, or 600 or 800 mg tablets three times a day up to
1800 mg/day. Dosages up to 2400 mg/day have been well tolerated in long-term clinical
studies. Doses of 3600 mg/day have also been administered to a small number of patients
for a relatively short duration, and have been well tolerated. The maximum time between
doses in the T.I.D. schedule should not exceed 12 hours.
Pediatric Patients Age 3 – 12 years: The starting dose should range from 10 – 15
mg/kg/day in 3 divided doses, and the effective dose reached by upward titration over a
period of approximately 3 days. The effective dose of Neurontin in patients 5 years of
age and older is 25 -35 mg/kg/day and given in divided doses (three times a day). The
effective dose in pediatric patients ages 3 and 4 years is 40 mg/kg/day and given in
divided doses (three times a day). (See CLINICAL PHARMACOLOGY, Pediatrics.)
Neurontin may be administered as the oral solution, capsule, or tablet, or using
combinations of these formulations. Dosages up to 50 mg/kg/day have been well-
tolerated in a long-term clinical study. The maximum time interval between doses should
not exceed 12 hours.
It is not necessary to monitor gabapentin plasma concentrations to optimize Neurontin®
therapy. Further, because there are no significant pharmacokinetic interactions among
Neurontin® and other commonly used antiepileptic drugs, the addition of Neurontin®
does not alter the plasma levels of these drugs appreciably.
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If Neurontin® is discontinued and/or an alternate anticonvulsant medication is added to
the therapy, this should be done gradually over a minimum of 1 week.
Creatinine clearance is difficult to measure in outpatients. In patients with stable renal
function, creatinine clearance (CCr) can be reasonably well estimated using the equation
of Cockcroft and Gault:
for females CCr=(0.85)(140-age)(weight)/[(72)(SCr)]
for males CCr=(140-age)(weight)/[(72)(SCr)]
where age is in years, weight is in kilograms and Scr is serum creatinine in mg/dL.
Dosage adjustment in patients ≥12 years of age with compromised renal function or
undergoing hemodialysis is recommended as follows:
TABLE 3. Neurontin® Dosage Based on Renal Function
Renal Function
Creatinine Clearance
(mL/min)
Total Daily Dose
(mg/day)
Dose Regimen
(mg)
>60
30—60
15—30
<15
Hemodialysis
1200
600
300
150
—
400 T.I.D.
300 B.I.D.
300 Q.D.
300 Q.O.D.a
200-300b
a
Every other day
b
Loading dose of 300 to 400 mg in patients who have never received Neurontin®, then
200 to 300 mg Neurontin® following each 4 hours of hemodialysis.
The use of Neurontin® in patients <12 years of age with compromised renal function has
not been studied.
HOW SUPPLIED
Neurontin® (gabapentin) capsules, tablets and oral solution is supplied as follows:
100 mg capsules;
White hard gelatin capsules printed with “PD” on one side and “Neurontin®/100
mg” on the other; available in:
Bottles of 100: N 0071-0803-24
Unit dose 50’s: N 0071-0803-40
300 mg capsules;
Yellow hard gelatin capsules printed with “PD” on one side and “Neurontin®/300
mg” on the other; available in:
Bottles of 100: N 0071-0805-24
Unit dose 50’s: N 0071-0805-40
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FDA approved labeling text (dated 10/12/00)
400 mg capsules;
Orange hard gelatin capsules printed with “PD” on one side and “Neurontin®/400
mg” on the other; available in:
Bottles of 100: N 0071-0806-24
Unit dose 50’s: N 0071-0806-40
600 mg tablets;
White elliptical film-coated tablets printed in black ink with “Neurontin® 600” on
one side; available in:
Bottles of 100: N 0071-0416-24
Bottles of 500: N 0071-0416-30
Unit dose 50’s: N 0071-0416-40
800 mg tablets;
White elliptical film-coated tablets printed in orange with “Neurontin® 800” on
one side; available in:
Bottles of 100: N 0071-0426-24
Bottles of 500: N 0071-0426-30
Unit dose 50’s: N 0071-0426-40
250 mg/5 mL oral solution
Clear colorless to slightly yellow solution; each 5 mL of oral solution contains
250 mg of gabapentin; available in:
Bottles containing 480 mL: N 0071-2012-23
Storage (Capsules)
Store at controlled room temperature 15°-30°C (59°-86°F).
Storage (Tablets)
Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP
Controlled Room Temperature].
Storage (Oral Solution)
Store refrigerated, 2°°°°-8°°°°C (36°°°°-46°°°°F)
Rx only
Revised
Capsules and Tablets:
Manufactured by:
Parke Davis Pharmaceuticals, Ltd.
Vega Baja, PR 00694
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FDA approved labeling text (dated 10/12/00)
Oral Solution:
Manufactured for:
Parke-Davis Pharmaceuticals, Ltd.
Vega Baja, PR 00694
Distributed by:
PARKE-DAVIS
Div of Warner-Lambert Co
Morris Plains, NJ 07950 USA
©1999, PDPL
0416G030
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|
custom-source
|
2025-02-12T13:47:09.047676
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2000/21216lbl.pdf', 'application_number': 20235, 'submission_type': 'SUPPL ', 'submission_number': 15}
|
12,344
|
NDA 20-235/S-029; NDA 20-882/S-015; NDA 21-129/S-016
FDA Approved Labeling Text dated February 2005
Page 1 of 29
Neurontin® (gabapentin) Capsules
Neurontin® (gabapentin) Tablets
Neurontin®(gabapentin) Oral Solution
DESCRIPTION
Neurontin® (gabapentin) Capsules, Neurontin® (gabapentin) Tablets, and Neurontin®
(gabapentin) Oral Solution are supplied as imprinted hard shell capsules containing 100 mg,
300 mg, and 400 mg of gabapentin, elliptical film-coated tablets containing 600 mg and 800 mg
of gabapentin or an oral solution containing 250 mg/5 mL of gabapentin.
The inactive ingredients for the capsules are lactose, cornstarch, and talc. The 100 mg capsule
shell contains gelatin and titanium dioxide. The 300 mg capsule shell contains gelatin, titanium
dioxide, and yellow iron oxide. The 400 mg capsule shell contains gelatin, red iron oxide,
titanium dioxide, and yellow iron oxide. The imprinting ink contains FD&C Blue No. 2 and
titanium dioxide.
The inactive ingredients for the tablets are poloxamer 407, copolyvidonum, cornstarch,
magnesium stearate, hydroxypropyl cellulose, talc, candelilla wax and purified water.
The inactive ingredients for the oral solution are glycerin, xylitol, purified water and artificial
cool strawberry anise flavor.
Gabapentin is described as 1-(aminomethyl)cyclohexaneacetic acid with a molecular formula of
C9 H17NO2 and a molecular weight of 171.24. The structural formula of gabapentin is:
Gabapentin is a white to off-white crystalline solid with a pKa1 of 3.7 and a pKa2 of 10.7. It is
freely soluble in water and both basic and acidic aqueous solutions. The log of the partition
coefficient (n-octanol/0.05M phosphate buffer) at pH 7.4 is –1.25.
CLINICAL PHARMACOLOGY
Mechanism of Action
The mechanism by which gabapentin exerts its analgesic action is unknown, but in animal
models of analgesia, gabapentin prevents allodynia (pain-related behavior in response to a
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FDA Approved Labeling Text dated February 2005
Page 2 of 29
normally innocuous stimulus) and hyperalgesia (exaggerated response to painful stimuli). In
particular, gabapentin prevents pain-related responses in several models of neuropathic pain in
rats or mice (e.g. spinal nerve ligation models, streptozocin-induced diabetes model, spinal cord
injury model, acute herpes zoster infection model). Gabapentin also decreases pain-related
responses after peripheral inflammation (carrageenan footpad test, late phase of formalin test).
Gabapentin did not alter immediate pain-related behaviors (rat tail flick test, formalin footpad
acute phase, acetic acid abdominal constriction test, footpad heat irradiation test). The relevance
of these models to human pain is not known.
The mechanism by which gabapentin exerts its anticonvulsant action is unknown, but in animal
test systems designed to detect anticonvulsant activity, gabapentin prevents seizures as do other
marketed anticonvulsants. Gabapentin exhibits antiseizure activity in mice and rats in both the
maximal electroshock and pentylenetetrazole seizure models and other preclinical models (e.g.,
strains with genetic epilepsy, etc.). The relevance of these models to human epilepsy is not
known.
Gabapentin is structurally related to the neurotransmitter GABA (gamma-aminobutyric acid) but
it does not modify GABAA or GABAB radioligand binding, it is not converted metabolically into
GABA or a GABA agonist, and it is not an inhibitor of GABA uptake or degradation.
Gabapentin was tested in radioligand binding assays at concentrations up to 100 µM and did not
exhibit affinity for a number of other common receptor sites, including benzodiazepine,
glutamate, N-methyl-D-aspartate (NMDA), quisqualate, kainate, strychnine-insensitive or
strychnine-sensitive glycine, alpha 1, alpha 2, or beta adrenergic, adenosine A1 or A2,
cholinergic muscarinic or nicotinic, dopamine D1 or D2, histamine H1, serotonin S1 or S2,
opiate mu, delta or kappa, cannabinoid 1, voltage-sensitive calcium channel sites labeled with
nitrendipine or diltiazem, or at voltage-sensitive sodium channel sites labeled with
batrachotoxinin A 20-alpha-benzoate. Furthermore, gabapentin did not alter the cellular uptake
of dopamine, noradrenaline, or serotonin.
In vitro studies with radiolabeled gabapentin have revealed a gabapentin binding site in areas of
rat brain including neocortex and hippocampus. A high-affinity binding protein in animal brain
tissue has been identified as an auxiliary subunit of voltage-activated calcium channels.
However, functional correlates of gabapentin binding, if any, remain to be elucidated.
Pharmacokinetics and Drug Metabolism
All pharmacological actions following gabapentin administration are due to the activity of the
parent compound; gabapentin is not appreciably metabolized in humans.
Oral Bioavailability: Gabapentin bioavailability is not dose proportional; i.e., as dose is
increased, bioavailability decreases. Bioavailability of gabapentin is approximately 60%, 47%,
34%, 33%, and 27% following 900, 1200, 2400, 3600, and 4800 mg/day given in 3 divided
doses, respectively. Food has only a slight effect on the rate and extent of absorption of
gabapentin (14% increase in AUC and Cmax).
Distribution: Less than 3% of gabapentin circulates bound to plasma protein. The apparent
volume of distribution of gabapentin after 150 mg intravenous administration is 58±6 L (Mean
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±SD). In patients with epilepsy, steady-state predose (Cmin) concentrations of gabapentin in
cerebrospinal fluid were approximately 20% of the corresponding plasma concentrations.
Elimination: Gabapentin is eliminated from the systemic circulation by renal excretion as
unchanged drug. Gabapentin is not appreciably metabolized in humans.
Gabapentin elimination half-life is 5 to 7 hours and is unaltered by dose or following multiple
dosing. Gabapentin elimination rate constant, plasma clearance, and renal clearance are directly
proportional to creatinine clearance (see Special Populations: Patients With Renal Insufficiency,
below). In elderly patients, and in patients with impaired renal function, gabapentin plasma
clearance is reduced. Gabapentin can be removed from plasma by hemodialysis.
Dosage adjustment in patients with compromised renal function or undergoing hemodialysis is
recommended (see DOSAGE AND ADMINISTRATION, Table 5).
Special Populations: Adult Patients With Renal Insufficiency: Subjects (N=60) with renal
insufficiency (mean creatinine clearance ranging from 13-114 mL/min) were administered single
400 mg oral doses of gabapentin. The mean gabapentin half-life ranged from about 6.5 hours
(patients with creatinine clearance >60 mL/min) to 52 hours (creatinine clearance <30 mL/min)
and gabapentin renal clearance from about 90 mL/min (>60 mL/min group) to about 10 mL/min
(<30 mL/min). Mean plasma clearance (CL/F) decreased from approximately 190 mL/min to
20 mL/min.
Dosage adjustment in adult patients with compromised renal function is necessary (see
DOSAGE AND ADMINISTRATION). Pediatric patients with renal insufficiency have not been
studied.
Hemodialysis: In a study in anuric adult subjects (N=11), the apparent elimination half-life of
gabapentin on nondialysis days was about 132 hours; during dialysis the apparent half-life of
gabapentin was reduced to 3.8 hours. Hemodialysis thus has a significant effect on gabapentin
elimination in anuric subjects.
Dosage adjustment in patients undergoing hemodialysis is necessary (see DOSAGE AND
ADMINISTRATION).
Hepatic Disease: Because gabapentin is not metabolized, no study was performed in patients
with hepatic impairment.
Age: The effect of age was studied in subjects 20-80 years of age. Apparent oral clearance
(CL/F) of gabapentin decreased as age increased, from about 225 mL/min in those under 30
years of age to about 125 mL/min in those over 70 years of age. Renal clearance (CLr) and CLr
adjusted for body surface area also declined with age; however, the decline in the renal clearance
of gabapentin with age can largely be explained by the decline in renal function. Reduction of
gabapentin dose may be required in patients who have age related compromised renal function.
(See PRECAUTIONS, Geriatric Use, and DOSAGE AND ADMINISTRATION.)
Pediatric: Gabapentin pharmacokinetics were determined in 48 pediatric subjects between the
ages of 1 month and 12 years following a dose of approximately 10 mg/kg. Peak plasma
concentrations were similar across the entire age group and occurred 2 to 3 hours postdose. In
general, pediatric subjects between 1 month and <5 years of age achieved approximately 30%
lower exposure (AUC) than that observed in those 5 years of age and older. Accordingly, oral
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clearance normalized per body weight was higher in the younger children. Apparent oral
clearance of gabapentin was directly proportional to creatinine clearance. Gabapentin elimination
half-life averaged 4.7 hours and was similar across the age groups studied.
A population pharmacokinetic analysis was performed in 253 pediatric subjects between 1 month
and 13 years of age. Patients received 10 to 65 mg/kg/day given TID. Apparent oral clearance
(CL/F) was directly proportional to creatinine clearance and this relationship was similar
following a single dose and at steady state. Higher oral clearance values were observed in
children <5 years of age compared to those observed in children 5 years of age and older, when
normalized per body weight. The clearance was highly variable in infants <1 year of age. The
normalized CL/F values observed in pediatric patients 5 years of age and older were consistent
with values observed in adults after a single dose. The oral volume of distribution normalized per
body weight was constant across the age range.
These pharmacokinetic data indicate that the effective daily dose in pediatric patients with
epilepsy ages 3 and 4 years should be 40 mg/kg/day to achieve average plasma concentrations
similar to those achieved in patients 5 years of age and older receiving gabapentin at 30
mg/kg/day (see DOSAGE AND ADMINISTRATION).
Gender: Although no formal study has been conducted to compare the pharmacokinetics of
gabapentin in men and women, it appears that the pharmacokinetic parameters for males and
females are similar and there are no significant gender differences.
Race: Pharmacokinetic differences due to race have not been studied. Because gabapentin is
primarily renally excreted and there are no important racial differences in creatinine clearance,
pharmacokinetic differences due to race are not expected.
Clinical Studies
Postherpetic Neuralgia
Neurontin® was evaluated for the management of postherpetic neuralgia (PHN) in 2 randomized,
double-blind, placebo-controlled, multicenter studies; N=563 patients in the intent-to-treat (ITT)
population (Table 1). Patients were enrolled if they continued to have pain for more than 3
months after healing of the herpes zoster skin rash.
TABLE 1. Controlled PHN Studies: Duration, Dosages, and
Number of Patients
Study
Study
Duration
Gabapentin
(mg/day)a
Target Dose
Patients
Receiving
Gabapentin
Patients
Receiving
Placebo
1
8 weeks
3600
113
116
2
7 weeks
1800, 2400
223
111
Total
336
227
a
Given in 3 divided doses (TID)
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Each study included a 1-week baseline during which patients were screened for eligibility and a
7- or 8-week double-blind phase (3 or 4 weeks of titration and 4 weeks of fixed dose). Patients
initiated treatment with titration to a maximum of 900 mg/day gabapentin over 3 days. Dosages
were then to be titrated in 600 to 1200 mg/day increments at 3- to 7-day intervals to target dose
over 3 to 4 weeks. In Study 1, patients were continued on lower doses if not able to achieve the
target dose. During baseline and treatment, patients recorded their pain in a daily diary using an
11-point numeric pain rating scale ranging from 0 (no pain) to 10 (worst possible pain). A mean
pain score during baseline of at least 4 was required for randomization (baseline mean pain score
for Studies 1 and 2 combined was 6.4). Analyses were conducted using the ITT population (all
randomized patients who received at least one dose of study medication).
Both studies showed significant differences from placebo at all doses tested.
A significant reduction in weekly mean pain scores was seen by Week 1 in both studies, and
significant differences were maintained to the end of treatment. Comparable treatment effects
were observed in all active treatment arms. Pharmacokinetic/pharmacodynamic modeling
provided confirmatory evidence of efficacy across all doses. Figures 1 and 2 show these changes
for Studies 1 and 2.
0
1
2
3
4
5
6
7
8
9
10
Baseline
1
2
3
4
5
6
7
8
Weeks
Placebo
Gabapentin, 3600 mg/day
**
**
**
**
**
**
** p < 0.01
**
**
4-Week Dose Titration Period
4-Week Fixed Dose Period
Figure 1. Weekly Mean Pain Scores (Observed Cases in ITT Population): Study 1
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0
1
2
3
4
5
6
7
8
9
10
Baseline
1
2
3
4
5
6
7
Weeks
Placebo
Gabapentin, 1800 mg/day
Gabapentin, 2400 mg/day
**
**p < 0.01
**
**
**
**
**
**
**
**
**
**
**
**
**
Mean Pain Score
3 - Week Dose Titration Period
4-Week Fixed Dose Period
Figure 2. Weekly Mean Pain Scores (Observed Cases in ITT Population): Study 2
The proportion of responders (those patients reporting at least 50% improvement in endpoint
pain score compared with baseline) was calculated for each study (Figure 3).
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12%
29%
14%
32%
34%
0
5
10
15
20
25
30
35
40
45
50
Percentage of Responders at Endpoint
PBO
GBP
3600
PBO
GBP
1800
GBP
2400
Study 1
Study 2
***
**
p <0.01
p <0.001
**
***
***
Figure 3.
Proportion of Responders (patients with ≥50% reduction in pain score) at
Endpoint: Controlled PHN Studies
Epilepsy
The effectiveness of Neurontin® as adjunctive therapy (added to other antiepileptic drugs) was
established in multicenter placebo-controlled, double-blind, parallel-group clinical trials in adult
and pediatric patients (3 years and older) with refractory partial seizures.
Evidence of effectiveness was obtained in three trials conducted in 705 patients (age 12 years
and above) and one trial conducted in 247 pediatric patients (3 to 12 years of age). The patients
enrolled had a history of at least 4 partial seizures per month in spite of receiving one or more
antiepileptic drugs at therapeutic levels and were observed on their established antiepileptic drug
regimen during a 12-week baseline period (6 weeks in the study of pediatric patients). In patients
continuing to have at least 2 (or 4 in some studies) seizures per month, Neurontin® or placebo
was then added on to the existing therapy during a 12-week treatment period. Effectiveness was
assessed primarily on the basis of the percent of patients with a 50% or greater reduction in
seizure frequency from baseline to treatment (the “responder rate”) and a derived measure called
response ratio, a measure of change defined as (T - B)/(T + B), where B is the patient’s baseline
seizure frequency and T is the patient’s seizure frequency during treatment. Response ratio is
distributed within the range -1 to +1. A zero value indicates no change while complete
elimination of seizures would give a value of -1; increased seizure rates would give positive
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values. A response ratio of -0.33 corresponds to a 50% reduction in seizure frequency. The
results given below are for all partial seizures in the intent-to-treat (all patients who received any
doses of treatment) population in each study, unless otherwise indicated.
One study compared Neurontin® 1200 mg/day divided TID with placebo. Responder rate was
23% (14/61) in the Neurontin® group and 9% (6/66) in the placebo group; the difference between
groups was statistically significant. Response ratio was also better in the Neurontin® group
(-0.199) than in the placebo group (-0.044), a difference that also achieved statistical
significance.
A second study compared primarily 1200 mg/day divided TID Neurontin® (N=101) with placebo
(N=98). Additional smaller Neurontin® dosage groups (600 mg/day, N=53; 1800 mg/day, N=54)
were also studied for information regarding dose response. Responder rate was higher in the
Neurontin® 1200 mg/day group (16%) than in the placebo group (8%), but the difference was not
statistically significant. The responder rate at 600 mg (17%) was also not significantly higher
than in the placebo, but the responder rate in the 1800 mg group (26%) was statistically
significantly superior to the placebo rate. Response ratio was better in the Neurontin®
1200 mg/day group (-0.103) than in the placebo group (-0.022); but this difference was also not
statistically significant (p = 0.224). A better response was seen in the Neurontin® 600 mg/day
group (-0.105) and 1800 mg/day group (-0.222) than in the 1200 mg/day group, with the
1800 mg/day group achieving statistical significance compared to the placebo group.
A third study compared Neurontin® 900 mg/day divided TID (N=111) and placebo (N=109). An
additional Neurontin® 1200 mg/day dosage group (N=52) provided dose-response data. A
statistically significant difference in responder rate was seen in the Neurontin® 900 mg/day
group (22%) compared to that in the placebo group (10%). Response ratio was also statistically
significantly superior in the Neurontin® 900 mg/day group (-0.119) compared to that in the
placebo group (-0.027), as was response ratio in 1200 mg/day Neurontin® (-0.184) compared to
placebo.
Analyses were also performed in each study to examine the effect of Neurontin® on preventing
secondarily generalized tonic-clonic seizures. Patients who experienced a secondarily
generalized tonic-clonic seizure in either the baseline or in the treatment period in all three
placebo-controlled studies were included in these analyses. There were several response ratio
comparisons that showed a statistically significant advantage for Neurontin® compared to
placebo and favorable trends for almost all comparisons.
Analysis of responder rate using combined data from all three studies and all doses (N=162,
Neurontin®; N=89, placebo) also showed a significant advantage for Neurontin® over placebo in
reducing the frequency of secondarily generalized tonic-clonic seizures.
In two of the three controlled studies, more than one dose of Neurontin® was used. Within each
study the results did not show a consistently increased response to dose. However, looking across
studies, a trend toward increasing efficacy with increasing dose is evident (see Figure 4).
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Figure 4. Responder Rate in Patients Receiving Neurontin® Expressed as a Difference
from Placebo by Dose and Study: Adjunctive Therapy Studies in Patients ≥12
Years of Age with Partial Seizures
In the figure, treatment effect magnitude, measured on the Y axis in terms of the difference in the
proportion of gabapentin and placebo assigned patients attaining a 50% or greater reduction in
seizure frequency from baseline, is plotted against the daily dose of gabapentin administered
(X axis).
Although no formal analysis by gender has been performed, estimates of response (Response
Ratio) derived from clinical trials (398 men, 307 women) indicate no important gender
differences exist. There was no consistent pattern indicating that age had any effect on the
response to Neurontin®. There were insufficient numbers of patients of races other than
Caucasian to permit a comparison of efficacy among racial groups.
A fourth study in pediatric patients age 3 to 12 years compared 25 – 35 mg/kg/day Neurontin®
(N=118) with placebo (N=127). For all partial seizures in the intent-to-treat population, the
response ratio was statistically significantly better for the Neurontin® group (-0.146) than for the
placebo group (-0.079). For the same population, the responder rate for Neurontin® (21%) was
not significantly different from placebo (18%).
A study in pediatric patients age 1 month to 3 years compared 40 mg/kg/day Neurontin® (N=38)
with placebo (N=38) in patients who were receiving at least one marketed antiepileptic drug and
had at least one partial seizure during the screening period (within 2 weeks prior to baseline).
Patients had up to 48 hours of baseline and up to 72 hours of double-blind video EEG monitoring
to record and count the occurrence of seizures. There were no statistically significant differences
between treatments in either the response ratio or responder rate.
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INDICATIONS AND USAGE
Postherpetic Neuralgia
Neurontin® (gabapentin) is indicated for the management of postherpetic neuralgia in adults.
Epilepsy
Neurontin® (gabapentin) is indicated as adjunctive therapy in the treatment of partial seizures
with and without secondary generalization in patients over 12 years of age with epilepsy.
Neurontin is also indicated as adjunctive therapy in the treatment of partial seizures in pediatric
patients age 3 – 12 years.
CONTRAINDICATIONS
Neurontin® is contraindicated in patients who have demonstrated hypersensitivity to the drug or
its ingredients.
WARNINGS
Neuropsychiatric Adverse Events—Pediatric Patients 3-12 years of age
Gabapentin use in pediatric patients with epilepsy 3–12 years of age is associated with the
occurrence of central nervous system related adverse events. The most significant of these can be
classified into the following categories: 1) emotional lability (primarily behavioral problems),
2) hostility, including aggressive behaviors, 3) thought disorder, including concentration
problems and change in school performance, and 4) hyperkinesia (primarily restlessness and
hyperactivity). Among the gabapentin-treated patients, most of the events were mild to moderate
in intensity.
In controlled trials in pediatric patients 3–12 years of age the incidence of these adverse events
was: emotional lability 6% (gabapentin-treated patients) vs 1.3% (placebo-treated patients);
hostility 5.2% vs 1.3%; hyperkinesia 4.7% vs 2.9%; and thought disorder 1.7% vs 0%. One of
these events, a report of hostility, was considered serious. Discontinuation of gabapentin
treatment occurred in 1.3% of patients reporting emotional lability and hyperkinesia and 0.9% of
gabapentin-treated patients reporting hostility and thought disorder. One placebo-treated patient
(0.4%) withdrew due to emotional lability.
Withdrawal Precipitated Seizure, Status Epilepticus
Antiepileptic drugs should not be abruptly discontinued because of the possibility of increasing
seizure frequency.
In the placebo-controlled studies in patients >12 years of age, the incidence of status epilepticus
in patients receiving Neurontin® was 0.6% (3 of 543) versus 0.5% in patients receiving placebo
(2 of 378). Among the 2074 patients >12 years of age treated with Neurontin® across all studies
(controlled and uncontrolled) 31 (1.5%) had status epilepticus. Of these, 14 patients had no prior
history of status epilepticus either before treatment or while on other medications. Because
adequate historical data are not available, it is impossible to say whether or not treatment with
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Neurontin® is associated with a higher or lower rate of status epilepticus than would be expected
to occur in a similar population not treated with Neurontin®.
Tumorigenic Potential
In standard preclinical in vivo lifetime carcinogenicity studies, an unexpectedly high incidence of
pancreatic acinar adenocarcinomas was identified in male, but not female, rats. (See
PRECAUTIONS: Carcinogenesis, Mutagenesis, Impairment of Fertility.) The clinical
significance of this finding is unknown. Clinical experience during gabapentin’s premarketing
development provides no direct means to assess its potential for inducing tumors in humans.
In clinical studies in adjunctive therapy in epilepsy comprising 2085 patient-years of exposure in
patients >12 years of age, new tumors were reported in 10 patients (2 breast, 3 brain, 2 lung, 1
adrenal, 1 non-Hodgkin’s lymphoma, 1 endometrial carcinoma in situ), and preexisting tumors
worsened in 11 patients (9 brain, 1 breast, 1 prostate) during or up to 2 years following
discontinuation of Neurontin®. Without knowledge of the background incidence and recurrence
in a similar population not treated with Neurontin®, it is impossible to know whether the
incidence seen in this cohort is or is not affected by treatment.
Sudden and Unexplained Death in Patients With Epilepsy
During the course of premarketing development of Neurontin® 8 sudden and unexplained deaths
were recorded among a cohort of 2203 patients treated (2103 patient-years of exposure).
Some of these could represent seizure-related deaths in which the seizure was not observed, e.g.,
at night. This represents an incidence of 0.0038 deaths per patient-year. Although this rate
exceeds that expected in a healthy population matched for age and sex, it is within the range of
estimates for the incidence of sudden unexplained deaths in patients with epilepsy not receiving
Neurontin® (ranging from 0.0005 for the general population of epileptics to 0.003 for a clinical
trial population similar to that in the Neurontin® program, to 0.005 for patients with refractory
epilepsy). Consequently, whether these figures are reassuring or raise further concern depends on
comparability of the populations reported upon to the Neurontin® cohort and the accuracy of the
estimates provided.
PRECAUTIONS
Information for Patients
Patients should be instructed to take Neurontin® only as prescribed.
Patients should be advised that Neurontin® may cause dizziness, somnolence and other
symptoms and signs of CNS depression. Accordingly, they should be advised neither to drive a
car nor to operate other complex machinery until they have gained sufficient experience on
Neurontin® to gauge whether or not it affects their mental and/or motor performance adversely.
Patients who require concomitant treatment with morphine may experience increases in
gabapentin concentrations. Patients should be carefully observed for signs of CNS depression,
such as somnolence, and the dose of Neurontin® or morphine should be reduced appropriately
(see Drug Interactions).
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Laboratory Tests
Clinical trials data do not indicate that routine monitoring of clinical laboratory parameters is
necessary for the safe use of Neurontin®. The value of monitoring gabapentin blood
concentrations has not been established. Neurontin® may be used in combination with other
antiepileptic drugs without concern for alteration of the blood concentrations of gabapentin or of
other antiepileptic drugs.
Drug Interactions
In vitro studies were conducted to investigate the potential of gabapentin to inhibit the major
cytochrome P450 enzymes (CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and
CYP3A4) that mediate drug and xenobiotic metabolism using isoform selective marker
substrates and human liver microsomal preparations. Only at the highest concentration tested
(171 µg/mL; 1 mM) was a slight degree of inhibition (14%-30%) of isoform CYP2A6 observed.
No inhibition of any of the other isoforms tested was observed at gabapentin concentrations up to
171 µg/mL (approximately 15 times the Cmax at 3600 mg/day).
Gabapentin is not appreciably metabolized nor does it interfere with the metabolism of
commonly coadministered antiepileptic drugs.
The drug interaction data described in this section were obtained from studies involving healthy
adults and adult patients with epilepsy.
Phenytoin: In a single (400 mg) and multiple dose (400 mg TID) study of Neurontin® in
epileptic patients (N=8) maintained on phenytoin monotherapy for at least 2 months, gabapentin
had no effect on the steady-state trough plasma concentrations of phenytoin and phenytoin had
no effect on gabapentin pharmacokinetics.
Carbamazepine: Steady-state trough plasma carbamazepine and carbamazepine 10, 11 epoxide
concentrations were not affected by concomitant gabapentin (400 mg TID; N=12)
administration. Likewise, gabapentin pharmacokinetics were unaltered by carbamazepine
administration.
Valproic Acid: The mean steady-state trough serum valproic acid concentrations prior to and
during concomitant gabapentin administration (400 mg TID; N=17) were not different and
neither were gabapentin pharmacokinetic parameters affected by valproic acid.
Phenobarbital: Estimates of steady-state pharmacokinetic parameters for phenobarbital or
gabapentin (300 mg TID; N=12) are identical whether the drugs are administered alone or
together.
Naproxen: Coadministration (N=18) of naproxen sodium capsules (250 mg) with Neurontin®
(125 mg) appears to increase the amount of gabapentin absorbed by 12% to 15%. Gabapentin
had no effect on naproxen pharmacokinetic parameters. These doses are lower than the
therapeutic doses for both drugs. The magnitude of interaction within the recommended dose
ranges of either drug is not known.
Hydrocodone: Coadministration of Neurontin® (125 to 500 mg; N=48) decreases hydrocodone
(10 mg; N=50) Cmax and AUC values in a dose-dependent manner relative to administration of
hydrocodone alone; Cmax and AUC values are 3% to 4% lower, respectively, after administration
of 125 mg Neurontin® and 21% to 22% lower, respectively, after administration of 500 mg
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Neurontin®. The mechanism for this interaction is unknown. Hydrocodone increases gabapentin
AUC values by 14%. The magnitude of interaction at other doses is not known.
Morphine: A literature article reported that when a 60-mg controlled-release morphine capsule
was administered 2 hours prior to a 600-mg Neurontin® capsule (N=12), mean gabapentin AUC
increased by 44% compared to gabapentin administered without morphine (see
PRECAUTIONS). Morphine pharmacokinetic parameter values were not affected by
administration of Neurontin® 2 hours after morphine. The magnitude of interaction at other doses
is not known.
Cimetidine: In the presence of cimetidine at 300 mg QID (N=12) the mean apparent oral
clearance of gabapentin fell by 14% and creatinine clearance fell by 10%. Thus cimetidine
appeared to alter the renal excretion of both gabapentin and creatinine, an endogenous marker of
renal function. This small decrease in excretion of gabapentin by cimetidine is not expected to be
of clinical importance. The effect of gabapentin on cimetidine was not evaluated.
Oral Contraceptive: Based on AUC and half-life, multiple-dose pharmacokinetic profiles of
norethindrone and ethinyl estradiol following administration of tablets containing 2.5 mg of
norethindrone acetate and 50 mcg of ethinyl estradiol were similar with and without
coadministration of gabapentin (400 mg TID; N=13). The Cmax of norethindrone was 13%
higher when it was coadministered with gabapentin; this interaction is not expected to be of
clinical importance.
Antacid (Maalox®): Maalox reduced the bioavailability of gabapentin (N=16) by about 20%.
This decrease in bioavailability was about 5% when gabapentin was administered 2 hours after
Maalox. It is recommended that gabapentin be taken at least 2 hours following Maalox
administration.
Effect of Probenecid: Probenecid is a blocker of renal tubular secretion. Gabapentin
pharmacokinetic parameters without and with probenecid were comparable. This indicates that
gabapentin does not undergo renal tubular secretion by the pathway that is blocked by
probenecid.
Drug/Laboratory Tests Interactions
Because false positive readings were reported with the Ames N-Multistix SG® dipstick test for
urinary protein when gabapentin was added to other antiepileptic drugs, the more specific
sulfosalicylic acid precipitation procedure is recommended to determine the presence of urine
protein.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Gabapentin was given in the diet to mice at 200, 600, and 2000 mg/kg/day and to rats at 250,
1000, and 2000 mg/kg/day for 2 years. A statistically significant increase in the incidence of
pancreatic acinar cell adenomas and carcinomas was found in male rats receiving the high dose;
the no-effect dose for the occurrence of carcinomas was 1000 mg/kg/day. Peak plasma
concentrations of gabapentin in rats receiving the high dose of 2000 mg/kg were 10 times higher
than plasma concentrations in humans receiving 3600 mg per day, and in rats receiving
1000 mg/kg/day peak plasma concentrations were 6.5 times higher than in humans receiving
3600 mg/day. The pancreatic acinar cell carcinomas did not affect survival, did not metastasize
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Page 14 of 29
and were not locally invasive. The relevance of this finding to carcinogenic risk in humans is
unclear.
Studies designed to investigate the mechanism of gabapentin-induced pancreatic carcinogenesis
in rats indicate that gabapentin stimulates DNA synthesis in rat pancreatic acinar cells in vitro
and, thus, may be acting as a tumor promoter by enhancing mitogenic activity. It is not known
whether gabapentin has the ability to increase cell proliferation in other cell types or in other
species, including humans.
Gabapentin did not demonstrate mutagenic or genotoxic potential in three in vitro and four in
vivo assays. It was negative in the Ames test and the in vitro HGPRT forward mutation assay in
Chinese hamster lung cells; it did not produce significant increases in chromosomal aberrations
in the in vitro Chinese hamster lung cell assay; it was negative in the in vivo chromosomal
aberration assay and in the in vivo micronucleus test in Chinese hamster bone marrow; it was
negative in the in vivo mouse micronucleus assay; and it did not induce unscheduled DNA
synthesis in hepatocytes from rats given gabapentin.
No adverse effects on fertility or reproduction were observed in rats at doses up to 2000 mg/kg
(approximately 5 times the maximum recommended human dose on a mg/m2 basis).
Pregnancy
Pregnancy Category C: Gabapentin has been shown to be fetotoxic in rodents, causing delayed
ossification of several bones in the skull, vertebrae, forelimbs, and hindlimbs. These effects
occurred when pregnant mice received oral doses of 1000 or 3000 mg/kg/day during the period
of organogenesis, or approximately 1 to 4 times the maximum dose of 3600 mg/day given to
epileptic patients on a mg/m2 basis. The no-effect level was 500 mg/kg/day or approximately ½
of the human dose on a mg/m2 basis.
When rats were dosed prior to and during mating, and throughout gestation, pups from all dose
groups (500, 1000 and 2000 mg/kg/day) were affected. These doses are equivalent to less than
approximately 1 to 5 times the maximum human dose on a mg/m2 basis. There was an increased
incidence of hydroureter and/or hydronephrosis in rats in a study of fertility and general
reproductive performance at 2000 mg/kg/day with no effect at 1000 mg/kg/day, in a teratology
study at 1500 mg/kg/day with no effect at 300 mg/kg/day, and in a perinatal and postnatal study
at all doses studied (500, 1000 and 2000 mg/kg/day). The doses at which the effects occurred are
approximately 1 to 5 times the maximum human dose of 3600 mg/day on a mg/m2 basis; the no-
effect doses were approximately 3 times (Fertility and General Reproductive Performance study)
and approximately equal to (Teratogenicity study) the maximum human dose on a mg/m2 basis.
Other than hydroureter and hydronephrosis, the etiologies of which are unclear, the incidence of
malformations was not increased compared to controls in offspring of mice, rats, or rabbits given
doses up to 50 times (mice), 30 times (rats), and 25 times (rabbits) the human daily dose on a
mg/kg basis, or 4 times (mice), 5 times (rats), or 8 times (rabbits) the human daily dose on a
mg/m2 basis.
In a teratology study in rabbits, an increased incidence of postimplantation fetal loss occurred in
dams exposed to 60, 300, and 1500 mg/kg/day, or less than approximately ¼ to 8 times the
maximum human dose on a mg/m2 basis. There are no adequate and well-controlled studies in
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Page 15 of 29
pregnant women. This drug should be used during pregnancy only if the potential benefit
justifies the potential risk to the fetus.
Use in Nursing Mothers
Gabapentin is secreted into human milk following oral administration. A nursed infant could be
exposed to a maximum dose of approximately 1 mg/kg/day of gabapentin. Because the effect on
the nursing infant is unknown, Neurontin® should be used in women who are nursing only if the
benefits clearly outweigh the risks.
Pediatric Use
Safety and effectiveness of Neurontin® (gabapentin) in the management of postherpetic neuralgia
in pediatric patients have not been established.
Effectiveness as adjunctive therapy in the treatment of partial seizures in pediatric patients below
the age of 3 years has not been established (see CLINICAL PHARMACOLOGY, Clinical
Studies).
Geriatric Use
The total number of patients treated with Neurontin® in controlled clinical trials in patients with
postherpetic neuralgia was 336, of which 102 (30%) were 65 to 74 years of age, and 168 (50%)
were 75 years of age and older. There was a larger treatment effect in patients 75 years of age
and older compared with younger patients who received the same dosage. Since gabapentin is
almost exclusively eliminated by renal excretion, the larger treatment effect observed in patients
≥75 years may be a consequence of increased gabapentin exposure for a given dose that results
from an age-related decrease in renal function. However, other factors cannot be excluded. The
types and incidence of adverse events were similar across age groups except for peripheral
edema and ataxia, which tended to increase in incidence with age.
Clinical studies of Neurontin® in epilepsy did not include sufficient numbers of subjects aged 65
and over to determine whether they responded differently from younger subjects. Other reported
clinical experience has not identified differences in responses between the elderly and younger
patients. In general, dose selection for an elderly patient should be cautious, usually starting at
the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or
cardiac function, and of concomitant disease or other drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to
this drug may be greater in patients with impaired renal function. Because elderly patients are
more likely to have decreased renal function, care should be taken in dose selection, and dose
should be adjusted based on creatinine clearance values in these patients (see CLINICAL
PHARMACOLOGY, ADVERSE REACTIONS, and DOSAGE AND ADMINISTRATION
sections).
ADVERSE REACTIONS
Postherpetic Neuralgia
The most commonly observed adverse events associated with the use of Neurontin® in adults,
not seen at an equivalent frequency among placebo-treated patients, were dizziness, somnolence,
and peripheral edema.
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In the 2 controlled studies in postherpetic neuralgia, 16% of the 336 patients who received
Neurontin® and 9% of the 227 patients who received placebo discontinued treatment because of
an adverse event. The adverse events that most frequently led to withdrawal in Neurontin®-
treated patients were dizziness, somnolence, and nausea.
Incidence in Controlled Clinical Trials
Table 2 lists treatment-emergent signs and symptoms that occurred in at least 1% of Neurontin®-
treated patients with postherpetic neuralgia participating in placebo-controlled trials and that
were numerically more frequent in the Neurontin® group than in the placebo group. Adverse
events were usually mild to moderate in intensity.
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TABLE 2. Treatment-Emergent Adverse Event Incidence in
Controlled Trials in Postherpetic Neuralgia (Events
in at least 1% of Neurontin®-Treated Patients and
Numerically More Frequent Than in the Placebo
Group)
Body System/
Neurontin®
Placebo
Preferred Term
N=336
%
N=227
%
Body as a Whole
Asthenia
5.7
4.8
Infection
5.1
3.5
Headache
3.3
3.1
Accidental injury
3.3
1.3
Abdominal pain
2.7
2.6
Digestive System
Diarrhea
5.7
3.1
Dry mouth
4.8
1.3
Constipation
3.9
1.8
Nausea
3.9
3.1
Vomiting
3.3
1.8
Flatulence
2.1
1.8
Metabolic and Nutritional Disorders
Peripheral edema
8.3
2.2
Weight gain
1.8
0.0
Hyperglycemia
1.2
0.4
Nervous System
Dizziness
28.0
7.5
Somnolence
21.4
5.3
Ataxia
3.3
0.0
Thinking abnormal
2.7
0.0
Abnormal gait
1.5
0.0
Incoordination
1.5
0.0
Amnesia
1.2
0.9
Hypesthesia
1.2
0.9
Respiratory System
Pharyngitis
1.2
0.4
Skin and Appendages
Rash
1.2
0.9
Special Senses
Amblyopiaa
2.7
0.9
Conjunctivitis
1.2
0.0
Diplopia
1.2
0.0
Otitis media
1.2
0.0
a Reported as blurred vision
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Other events in more than 1% of patients but equally or more frequent in the placebo group
included pain, tremor, neuralgia, back pain, dyspepsia, dyspnea, and flu syndrome.
There were no clinically important differences between men and women in the types and
incidence of adverse events. Because there were few patients whose race was reported as other
than white, there are insufficient data to support a statement regarding the distribution of adverse
events by race.
Epilepsy
The most commonly observed adverse events associated with the use of Neurontin® in
combination with other antiepileptic drugs in patients >12 years of age, not seen at an equivalent
frequency among placebo-treated patients, were somnolence, dizziness, ataxia, fatigue, and
nystagmus. The most commonly observed adverse events reported with the use of Neurontin® in
combination with other antiepileptic drugs in pediatric patients 3 to 12 years of age, not seen at
an equal frequency among placebo-treated patients, were viral infection, fever, nausea and/or
vomiting, somnolence, and hostility (see WARNINGS, Neuropsychiatric Adverse Events).
Approximately 7% of the 2074 patients >12 years of age and approximately 7% of the 449
pediatric patients 3 to 12 years of age who received Neurontin® in premarketing clinical trials
discontinued treatment because of an adverse event. The adverse events most commonly
associated with withdrawal in patients >12 years of age were somnolence (1.2%), ataxia (0.8%),
fatigue (0.6%), nausea and/or vomiting (0.6%), and dizziness (0.6%). The adverse events most
commonly associated with withdrawal in pediatric patients were emotional lability (1.6%),
hostility (1.3%), and hyperkinesia (1.1%).
Incidence in Controlled Clinical Trials
Table 3 lists treatment-emergent signs and symptoms that occurred in at least 1% of Neurontin®-
treated patients >12 years of age with epilepsy participating in placebo-controlled trials and were
numerically more common in the Neurontin® group. In these studies, either Neurontin® or
placebo was added to the patient’s current antiepileptic drug therapy. Adverse events were
usually mild to moderate in intensity.
The prescriber should be aware that these figures, obtained when Neurontin® was added to
concurrent antiepileptic drug therapy, cannot be used to predict the frequency of adverse events
in the course of usual medical practice where patient characteristics and other factors may differ
from those prevailing during clinical studies. Similarly, the cited frequencies cannot be directly
compared with figures obtained from other clinical investigations involving different treatments,
uses, or investigators. An inspection of these frequencies, however, does provide the prescribing
physician with one basis to estimate the relative contribution of drug and nondrug factors to the
adverse event incidences in the population studied.
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TABLE 3.
Treatment-Emergent Adverse Event Incidence in Controlled Add-On
Trials In Patients >12 years of age (Events in at least 1% of Neurontin®
patients and numerically more frequent than in the placebo group)
Body System/
Adverse Event
Neurontin®a
N=543
%
Placeboa
N=378
%
Body As A Whole
Fatigue
Weight Increase
Back Pain
Peripheral Edema
11.0
2.9
1.8
1.7
5.0
1.6
0.5
0.5
Cardiovascular
Vasodilatation
1.1
0.3
Digestive System
Dyspepsia
Mouth or Throat Dry
Constipation
Dental Abnormalities
Increased Appetite
2.2
1.7
1.5
1.5
1.1
0.5
0.5
0.8
0.3
0.8
Hematologic and Lymphatic Systems
Leukopenia
1.1
0.5
Musculoskeletal System
Myalgia
Fracture
2.0
1.1
1.9
0.8
Nervous System
Somnolence
Dizziness
Ataxia
Nystagmus
Tremor
Nervousness
Dysarthria
Amnesia
Depression
Thinking Abnormal
Twitching
Coordination Abnormal
19.3
17.1
12.5
8.3
6.8
2.4
2.4
2.2
1.8
1.7
1.3
1.1
8.7
6.9
5.6
4.0
3.2
1.9
0.5
0.0
1.1
1.3
0.5
0.3
Respiratory System
Rhinitis
Pharyngitis
Coughing
4.1
2.8
1.8
3.7
1.6
1.3
Skin and Appendages
Abrasion
Pruritus
1.3
1.3
0.0
0.5
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TABLE 3.
Treatment-Emergent Adverse Event Incidence in Controlled Add-On
Trials In Patients >12 years of age (Events in at least 1% of Neurontin®
patients and numerically more frequent than in the placebo group)
Body System/
Adverse Event
Neurontin®a
N=543
%
Placeboa
N=378
%
Urogenital System
Impotence
1.5
1.1
Special Senses
Diplopia
Amblyopiab
5.9
4.2
1.9
1.1
Laboratory Deviations
WBC Decreased
1.1
0.5
a Plus background antiepileptic drug therapy
b Amblyopia was often described as blurred vision.
Other events in more than 1% of patients >12 years of age but equally or more frequent in the
placebo group included: headache, viral infection, fever, nausea and/or vomiting, abdominal
pain, diarrhea, convulsions, confusion, insomnia, emotional lability, rash, acne.
Among the treatment-emergent adverse events occurring at an incidence of at least 10% of
Neurontin®-treated patients, somnolence and ataxia appeared to exhibit a positive dose-response
relationship.
The overall incidence of adverse events and the types of adverse events seen were similar among
men and women treated with Neurontin®. The incidence of adverse events increased slightly
with increasing age in patients treated with either Neurontin® or placebo. Because only 3% of
patients (28/921) in placebo-controlled studies were identified as nonwhite (black or other), there
are insufficient data to support a statement regarding the distribution of adverse events by race.
Table 4 lists treatment-emergent signs and symptoms that occurred in at least 2% of Neurontin®-
treated patients age 3 to 12 years of age with epilepsy participating in placebo-controlled trials
and were numerically more common in the Neurontin® group. Adverse events were usually mild
to moderate in intensity.
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TABLE 4.
Treatment-Emergent Adverse Event Incidence in Pediatric Patients
Age 3 to 12 Years in a Controlled Add-On Trial (Events in at least
2% of Neurontin® patients and numerically more frequent than in the
placebo group)
Body System/
Adverse Event
Neurontin®a
N=119
%
Placeboa
N=128
%
Body As A Whole
Viral Infection
Fever
Weight Increase
Fatigue
10.9
10.1
3.4
3.4
3.1
3.1
0.8
1.6
Digestive System
Nausea and/or Vomiting
8.4
7.0
Nervous System
Somnolence
Hostility
Emotional Lability
Dizziness
Hyperkinesia
8.4
7.6
4.2
2.5
2.5
4.7
2.3
1.6
1.6
0.8
Respiratory System
Bronchitis
Respiratory Infection
3.4
2.5
0.8
0.8
a Plus background antiepileptic drug therapy
Other events in more than 2% of pediatric patients 3 to 12 years of age but equally or more
frequent in the placebo group included: pharyngitis, upper respiratory infection, headache,
rhinitis, convulsions, diarrhea, anorexia, coughing, and otitis media.
Other Adverse Events Observed During All Clinical Trials
Clinical Trials in Adults and Adolescents (Except Clinical Trials in Neuropathic Pain)
Neurontin® has been administered to 2074 patients >12 years of age during all adjunctive
therapy clinical trials (except clinical trials in patients with neuropathic pain), only some of
which were placebo-controlled. During these trials, all adverse events were recorded by the
clinical investigators using terminology of their own choosing. To provide a meaningful estimate
of the proportion of individuals having adverse events, similar types of events were grouped into
a smaller number of standardized categories using modified COSTART dictionary terminology.
These categories are used in the listing below. The frequencies presented represent the
proportion of the 2074 patients >12 years of age exposed to Neurontin® who experienced an
event of the type cited on at least one occasion while receiving Neurontin®. All reported events
are included except those already listed in Table 3, those too general to be informative, and those
not reasonably associated with the use of the drug.
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Events are further classified within body system categories and enumerated in order of
decreasing frequency using the following definitions: frequent adverse events are defined as
those occurring in at least 1/100 patients; infrequent adverse events are those occurring in 1/100
to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients.
Body As A Whole: Frequent: asthenia, malaise, face edema; Infrequent: allergy, generalized
edema, weight decrease, chill; Rare: strange feelings, lassitude, alcohol intolerance, hangover
effect.
Cardiovascular System: Frequent: hypertension; Infrequent: hypotension, angina pectoris,
peripheral vascular disorder, palpitation, tachycardia, migraine, murmur; Rare: atrial fibrillation,
heart failure, thrombophlebitis, deep thrombophlebitis, myocardial infarction, cerebrovascular
accident, pulmonary thrombosis, ventricular extrasystoles, bradycardia, premature atrial
contraction, pericardial rub, heart block, pulmonary embolus, hyperlipidemia,
hypercholesterolemia, pericardial effusion, pericarditis.
Digestive System: Frequent: anorexia, flatulence, gingivitis; Infrequent: glossitis, gum
hemorrhage, thirst, stomatitis, increased salivation, gastroenteritis, hemorrhoids, bloody stools,
fecal incontinence, hepatomegaly; Rare: dysphagia, eructation, pancreatitis, peptic ulcer, colitis,
blisters in mouth, tooth discolor, perlèche, salivary gland enlarged, lip hemorrhage, esophagitis,
hiatal hernia, hematemesis, proctitis, irritable bowel syndrome, rectal hemorrhage, esophageal
spasm.
Endocrine System: Rare: hyperthyroid, hypothyroid, goiter, hypoestrogen, ovarian failure,
epididymitis, swollen testicle, cushingoid appearance.
Hematologic and Lymphatic System: Frequent: purpura most often described as bruises
resulting from physical trauma; Infrequent: anemia, thrombocytopenia, lymphadenopathy; Rare:
WBC count increased, lymphocytosis, non-Hodgkin’s lymphoma, bleeding time increased.
Musculoskeletal System: Frequent: arthralgia; Infrequent: tendinitis, arthritis, joint stiffness,
joint swelling, positive Romberg test; Rare: costochondritis, osteoporosis, bursitis, contracture.
Nervous System: Frequent: vertigo, hyperkinesia, paresthesia, decreased or absent reflexes,
increased reflexes, anxiety, hostility; Infrequent: CNS tumors, syncope, dreaming abnormal,
aphasia, hypesthesia, intracranial hemorrhage, hypotonia, dysesthesia, paresis, dystonia,
hemiplegia, facial paralysis, stupor, cerebellar dysfunction, positive Babinski sign, decreased
position sense, subdural hematoma, apathy, hallucination, decrease or loss of libido, agitation,
paranoia, depersonalization, euphoria, feeling high, doped-up sensation, suicidal, psychosis;
Rare: choreoathetosis, orofacial dyskinesia, encephalopathy, nerve palsy, personality disorder,
increased libido, subdued temperament, apraxia, fine motor control disorder, meningismus, local
myoclonus, hyperesthesia, hypokinesia, mania, neurosis, hysteria, antisocial reaction, suicide
gesture.
Respiratory System: Frequent: pneumonia; Infrequent: epistaxis, dyspnea, apnea; Rare:
mucositis, aspiration pneumonia, hyperventilation, hiccup, laryngitis, nasal obstruction, snoring,
bronchospasm, hypoventilation, lung edema.
Dermatological: Infrequent: alopecia, eczema, dry skin, increased sweating, urticaria, hirsutism,
seborrhea, cyst, herpes simplex; Rare: herpes zoster, skin discolor, skin papules, photosensitive
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Page 23 of 29
reaction, leg ulcer, scalp seborrhea, psoriasis, desquamation, maceration, skin nodules,
subcutaneous nodule, melanosis, skin necrosis, local swelling.
Urogenital System: Infrequent: hematuria, dysuria, urination frequency, cystitis, urinary
retention, urinary incontinence, vaginal hemorrhage, amenorrhea, dysmenorrhea, menorrhagia,
breast cancer, unable to climax, ejaculation abnormal; Rare: kidney pain, leukorrhea, pruritus
genital, renal stone, acute renal failure, anuria, glycosuria, nephrosis, nocturia, pyuria, urination
urgency, vaginal pain, breast pain, testicle pain.
Special Senses: Frequent: abnormal vision; Infrequent: cataract, conjunctivitis, eyes dry, eye
pain, visual field defect, photophobia, bilateral or unilateral ptosis, eye hemorrhage, hordeolum,
hearing loss, earache, tinnitus, inner ear infection, otitis, taste loss, unusual taste, eye twitching,
ear fullness; Rare: eye itching, abnormal accommodation, perforated ear drum, sensitivity to
noise, eye focusing problem, watery eyes, retinopathy, glaucoma, iritis, corneal disorders,
lacrimal dysfunction, degenerative eye changes, blindness, retinal degeneration, miosis,
chorioretinitis, strabismus, eustachian tube dysfunction, labyrinthitis, otitis externa, odd smell.
Clinical trials in Pediatric Patients With Epilepsy
Adverse events occurring during epilepsy clinical trials in 449 pediatric patients 3 to 12 years of
age treated with gabapentin that were not reported in adjunctive trials in adults are:
Body as a Whole: dehydration, infectious mononucleosis
Digestive System: hepatitis
Hemic and Lymphatic System: coagulation defect
Nervous System: aura disappeared, occipital neuralgia
Psychobiologic Function: sleepwalking
Respiratory System: pseudocroup, hoarseness
Clinical Trials in Adults With Neuropathic Pain of Various Etiologies
Safety information was obtained in 1173 patients during double-blind and open-label clinical
trials including neuropathic pain conditions for which efficacy has not been demonstrated.
Adverse events reported by investigators were grouped into standardized categories using
modified COSTART IV terminology. Listed below are all reported events except those already
listed in Table 2 and those not reasonably associated with the use of the drug.
Events are further classified within body system categories and enumerated in order of
decreasing frequency using the following definitions: frequent adverse events are defined as
those occurring in at least 1/100 patients; infrequent adverse events are those occurring in 1/100
to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients.
Body as a Whole: Infrequent: chest pain, cellulitis, malaise, neck pain, face edema, allergic
reaction, abscess, chills, chills and fever, mucous membrane disorder; Rare: body odor, cyst,
fever, hernia, abnormal BUN value, lump in neck, pelvic pain, sepsis, viral infection.
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Cardiovascular System: Infrequent: hypertension, syncope, palpitation, migraine, hypotension,
peripheral vascular disorder, cardiovascular disorder, cerebrovascular accident, congestive heart
failure, myocardial infarction, vasodilatation; Rare: angina pectoris, heart failure, increased
capillary fragility, phlebitis, thrombophlebitis, varicose vein.
Digestive System: Infrequent: gastroenteritis, increased appetite, gastrointestinal disorder, oral
moniliasis, gastritis, tongue disorder, thirst, tooth disorder, abnormal stools, anorexia, liver
function tests abnormal, periodontal abscess; Rare: cholecystitis, cholelithiasis, duodenal ulcer,
fecal incontinence, gamma glutamyl transpeptidase increased, gingivitis, intestinal obstruction,
intestinal ulcer, melena, mouth ulceration, rectal disorder, rectal hemorrhage, stomatitis.
Endocrine System: Infrequent: diabetes mellitus.
Hemic and Lymphatic System: Infrequent: ecchymosis, anemia; Rare: lymphadenopathy,
lymphoma-like reaction, prothrombin decreased.
Metabolic and Nutritional: Infrequent: edema, gout, hypoglycemia, weight loss; Rare: alkaline
phosphatase increased, diabetic ketoacidosis, lactic dehydrogenase increased.
Musculoskeletal: Infrequent: arthritis, arthralgia, myalgia, arthrosis, leg cramps, myasthenia;
Rare: shin bone pain, joint disorder, tendon disorder.
Nervous System: Frequent: confusion, depression; Infrequent: vertigo, nervousness,
paresthesia, insomnia, neuropathy, libido decreased, anxiety, depersonalization, reflexes
decreased, speech disorder, abnormal dreams, dysarthria, emotional lability, nystagmus, stupor,
circumoral paresthesia, euphoria, hyperesthesia, hypokinesia; Rare: agitation, hypertonia, libido
increased, movement disorder, myoclonus, vestibular disorder.
Respiratory System: Infrequent: cough increased, bronchitis, rhinitis, sinusitis, pneumonia,
asthma, lung disorder, epistaxis; Rare: hemoptysis, voice alteration.
Skin and Appendages: Infrequent: pruritus, skin ulcer, dry skin, herpes zoster, skin disorder,
fungal dermatitis, furunculosis, herpes simplex, psoriasis, sweating, urticaria, vesiculobullous
rash; Rare: acne, hair disorder, maculopapular rash, nail disorder, skin carcinoma, skin
discoloration, skin hypertrophy.
Special Senses: Infrequent: abnormal vision, ear pain, eye disorder, taste perversion, deafness;
Rare: conjunctival hyperemia, diabetic retinopathy, eye pain, fundi with microhemorrhage,
retinal vein thrombosis, taste loss.
Urogenital System: Infrequent: urinary tract infection, dysuria, impotence, urinary
incontinence, vaginal moniliasis, breast pain, menstrual disorder, polyuria, urinary retention;
Rare: cystitis, ejaculation abnormal, swollen penis, gynecomastia, nocturia, pyelonephritis,
swollen scrotum, urinary frequency, urinary urgency, urine abnormality.
Postmarketing and Other Experience
In addition to the adverse experiences reported during clinical testing of Neurontin®, the
following adverse experiences have been reported in patients receiving marketed Neurontin®.
These adverse experiences have not been listed above and data are insufficient to support an
estimate of their incidence or to establish causation. The listing is alphabetized: angioedema,
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-235/S-029; NDA 20-882/S-015; NDA 21-129/S-016
FDA Approved Labeling Text dated February 2005
Page 25 of 29
blood glucose fluctuation, erythema multiforme, elevated liver function tests, fever,
hyponatremia, jaundice, movement disorder, Stevens-Johnson syndrome.
Adverse events following the abrupt discontinuation of gabapentin have also been reported. The
most frequently reported events were anxiety, insomnia, nausea, pain and sweating.
DRUG ABUSE AND DEPENDENCE
The abuse and dependence potential of Neurontin® has not been evaluated in human studies.
OVERDOSAGE
A lethal dose of gabapentin was not identified in mice and rats receiving single oral doses as
high as 8000 mg/kg. Signs of acute toxicity in animals included ataxia, labored breathing, ptosis,
sedation, hypoactivity, or excitation.
Acute oral overdoses of Neurontin® up to 49 grams have been reported. In these cases, double
vision, slurred speech, drowsiness, lethargy and diarrhea were observed. All patients recovered
with supportive care.
Gabapentin can be removed by hemodialysis. Although hemodialysis has not been performed in
the few overdose cases reported, it may be indicated by the patient’s clinical state or in patients
with significant renal impairment.
DOSAGE AND ADMlNlSTRATION
Neurontin® is given orally with or without food. Patients should be informed that, should they
break the scored 600 or 800 mg tablet in order to administer a half-tablet, they should take the
unused half-tablet as the next dose. Half-tablets not used within several days of breaking the
scored tablet should be discarded.
If Neurontin® dose is reduced, discontinued or substituted with an alternative medication, this
should be done gradually over a minimum of 1 week (a longer period may be needed at the at the
discretion of the prescriber).
Postherpetic Neuralgia
In adults with postherpetic neuralgia, Neurontin® therapy may be initiated as a single 300-mg
dose on Day 1, 600 mg/day on Day 2 (divided BID), and 900 mg/day on Day 3 (divided TID).
The dose can subsequently be titrated up as needed for pain relief to a daily dose of 1800 mg
(divided TID). In clinical studies, efficacy was demonstrated over a range of doses from
1800 mg/day to 3600 mg/day with comparable effects across the dose range. Additional benefit
of using doses greater than 1800 mg/day was not demonstrated.
Epilepsy
Neurontin® is recommended for add-on therapy in patients 3 years of age and older.
Effectiveness in pediatric patients below the age of 3 years has not been established.
Patients >12 years of age: The effective dose of Neurontin® is 900 to 1800 mg/day and given in
divided doses (three times a day) using 300 or 400 mg capsules, or 600 or 800 mg tablets. The
starting dose is 300 mg three times a day. If necessary, the dose may be increased using 300 or
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-235/S-029; NDA 20-882/S-015; NDA 21-129/S-016
FDA Approved Labeling Text dated February 2005
Page 26 of 29
400 mg capsules, or 600 or 800 mg tablets three times a day up to 1800 mg/day. Dosages up to
2400 mg/day have been well tolerated in long-term clinical studies. Doses of 3600 mg/day have
also been administered to a small number of patients for a relatively short duration, and have
been well tolerated. The maximum time between doses in the TID schedule should not exceed 12
hours.
Pediatric Patients Age 3–12 years: The starting dose should range from 10-15 mg/kg/day in
3 divided doses, and the effective dose reached by upward titration over a period of
approximately 3 days. The effective dose of Neurontin® in patients 5 years of age and older is
25–35 mg/kg/day and given in divided doses (three times a day). The effective dose in pediatric
patients ages 3 and 4 years is 40 mg/kg/day and given in divided doses (three times a day) (see
CLINICAL PHARMACOLOGY, Pediatrics.) Neurontin® may be administered as the oral
solution, capsule, or tablet, or using combinations of these formulations. Dosages up to
50 mg/kg/day have been well-tolerated in a long-term clinical study. The maximum time interval
between doses should not exceed 12 hours.
It is not necessary to monitor gabapentin plasma concentrations to optimize Neurontin® therapy.
Further, because there are no significant pharmacokinetic interactions among Neurontin® and
other commonly used antiepileptic drugs, the addition of Neurontin® does not alter the plasma
levels of these drugs appreciably.
If Neurontin® is discontinued and/or an alternate anticonvulsant medication is added to the
therapy, this should be done gradually over a minimum of 1 week.
Dosage in Renal Impairment
Creatinine clearance is difficult to measure in outpatients. In patients with stable renal function,
creatinine clearance (CCr) can be reasonably well estimated using the equation of Cockcroft and
Gault:
for females CCr=(0.85)(140-age)(weight)/[(72)(SCr)]
for males CCr=(140-age)(weight)/[(72)(SCr)]
where age is in years, weight is in kilograms and SCr is serum creatinine in mg/dL.
Dosage adjustment in patients ≥12 years of age with compromised renal function or undergoing
hemodialysis is recommended as follows (see dosing recommendations above for effective doses
in each indication).
TABLE 5. Neurontin® Dosage Based on Renal Function
Renal Function
Creatinine Clearance
(mL/min)
Total Daily
Dose Range
(mg/day)
Dose Regimen
(mg)
≥60
900-3600
300 TID
400 TID
600 TID
800 TID 1200 TID
>30-59
400-1400
200 BID
300 BID 400 BID
500 BID
700 BID
>15-29
200-700
200 QD
300 QD
400 QD
500 QD
700 QD
15a
100-300
100 QD
125 QD
150 QD
200 QD
300 QD
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-235/S-029; NDA 20-882/S-015; NDA 21-129/S-016
FDA Approved Labeling Text dated February 2005
Page 27 of 29
Post-Hemodialysis Supplemental Dose (mg)b
Hemodialysis
125b
150b
200b
250b
350b
a
For patients with creatinine clearance <15 mL/min, reduce daily dose in proportion to creatinine clearance
(e.g., patients with a creatinine clearance of 7.5 mL/min should receive one-half the daily dose that patients
with a creatinine clearance of 15 mL/min receive).
b
Patients on hemodialysis should receive maintenance doses based on estimates of creatinine clearance as
indicated in the upper portion of the table and a supplemental post-hemodialysis dose administered after each
4 hours of hemodialysis as indicated in the lower portion of the table.
The use of Neurontin® in patients <12 years of age with compromised renal function has not
been studied.
Dosage in Elderly
Because elderly patients are more likely to have decreased renal function, care should be taken in
dose selection, and dose should be adjusted based on creatinine clearance values in these
patients.
HOW SUPPLIED
Neurontin® (gabapentin) capsules, tablets and oral solution are supplied as follows:
100 mg capsules;
White hard gelatin capsules printed with “PD” on one side and “Neurontin®/100 mg” on
the other; available in:
Bottles of 100: N 0071-0803-24
Unit dose 50’s: N 0071-0803-40
300 mg capsules;
Yellow hard gelatin capsules printed with “PD” on one side and “Neurontin®/300 mg” on
the other; available in:
Bottles of 100: N 0071-0805-24
Unit dose 50’s: N 0071-0805-40
400 mg capsules;
Orange hard gelatin capsules printed with “PD” on one side and “Neurontin®/400 mg” on
the other; available in:
Bottles of 100: N 0071-0806-24
Unit dose 50’s: N 0071-0806-40
600 mg tablets;
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-235/S-029; NDA 20-882/S-015; NDA 21-129/S-016
FDA Approved Labeling Text dated February 2005
Page 28 of 29
White elliptical film-coated scored tablets debossed with “NT” and “16” on one side;
available in:
Bottles of 100: N 0071-0513-24
800 mg tablets;
White elliptical film-coated scored tablets debossed with “NT” and “26” on one side;
available in:
Bottles of 100: N 0071-0401-24
250 mg/5 mL oral solution;
Clear colorless to slightly yellow solution; each 5 mL of oral solution contains 250 mg of
gabapentin; available in:
Bottles containing 470 mL: N0071-2012-23
Storage (Capsules)
Store at 25°C (77°F); excursions permitted to 15° - 30°C (59° - 86°F) [see USP Controlled
Room Temperature].
Storage (Tablets)
Store at 25°C (77°F); excursions permitted to 15° - 30°C (59° - 86°F) [see USP Controlled
Room Temperature].
Storage (Oral Solution)
Store refrigerated, 2°-8°C (36°-46°F)
Rx only
Revised May 2004
Capsules and Tablets:
Manufactured by:
Pfizer Pharmaceuticals, Ltd.
Vega Baja, PR 00694
Oral Solution:
Manufactured for:
Pfizer Pharmaceuticals, Ltd.
Vega Baja, PR 00694
Distributed by:
Α Parke-Davis
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-235/S-029; NDA 20-882/S-015; NDA 21-129/S-016
FDA Approved Labeling Text dated February 2005
Page 29 of 29
Division of Pfizer Inc, NY, NY 10017
©2004 PPL
LAB-0106-6
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:47:09.250463
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/20235s029,20882s015,21129s016lbl.pdf', 'application_number': 20235, 'submission_type': 'SUPPL ', 'submission_number': 29}
|
12,346
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Neurontin® (gabapentin) Capsules
Neurontin® (gabapentin) Tablets
Neurontin® (gabapentin) Oral Solution
DESCRIPTION
Neurontin® (gabapentin) Capsules, Neurontin (gabapentin) Tablets, and Neurontin (gabapentin)
Oral Solution are supplied as imprinted hard shell capsules containing 100 mg,
300 mg, and 400 mg of gabapentin, elliptical film-coated tablets containing 600 mg and 800 mg
of gabapentin or an oral solution containing 250 mg/5 mL of gabapentin.
The inactive ingredients for the capsules are lactose, cornstarch, and talc. The 100 mg capsule
shell contains gelatin and titanium dioxide. The 300 mg capsule shell contains gelatin, titanium
dioxide, and yellow iron oxide. The 400 mg capsule shell contains gelatin, red iron oxide,
titanium dioxide, and yellow iron oxide. The imprinting ink contains FD&C Blue No. 2 and
titanium dioxide.
The inactive ingredients for the tablets are poloxamer 407, copolyvidonum, cornstarch,
magnesium stearate, hydroxypropyl cellulose, talc, candelilla wax and purified water.
The inactive ingredients for the oral solution are glycerin, xylitol, purified water and artificial
cool strawberry anise flavor.
Gabapentin is described as 1-(aminomethyl)cyclohexaneacetic acid with a molecular formula of
C9H17NO2 and a molecular weight of 171.24. The structural formula of gabapentin is: structural formula
Gabapentin is a white to off-white crystalline solid with a pKa1 of 3.7 and a pKa2 of 10.7. It is
freely soluble in water and both basic and acidic aqueous solutions. The log of the partition
coefficient (n-octanol/0.05M phosphate buffer) at pH 7.4 is –1.25.
CLINICAL PHARMACOLOGY
Mechanism of Action
The mechanism by which gabapentin exerts its analgesic action is unknown, but in animal
models of analgesia, gabapentin prevents allodynia (pain-related behavior in response to a
normally innocuous stimulus) and hyperalgesia (exaggerated response to painful stimuli). In
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particular, gabapentin prevents pain-related responses in several models of neuropathic pain in
rats or mice (e.g. spinal nerve ligation models, streptozocin-induced diabetes model, spinal cord
injury model, acute herpes zoster infection model). Gabapentin also decreases pain-related
responses after peripheral inflammation (carrageenan footpad test, late phase of formalin test).
Gabapentin did not alter immediate pain-related behaviors (rat tail flick test, formalin footpad
acute phase, acetic acid abdominal constriction test, footpad heat irradiation test). The relevance
of these models to human pain is not known.
The mechanism by which gabapentin exerts its anticonvulsant action is unknown, but in animal
test systems designed to detect anticonvulsant activity, gabapentin prevents seizures as do other
marketed anticonvulsants. Gabapentin exhibits antiseizure activity in mice and rats in both the
maximal electroshock and pentylenetetrazole seizure models and other preclinical models (e.g.,
strains with genetic epilepsy, etc.). The relevance of these models to human epilepsy is not
known.
Gabapentin is structurally related to the neurotransmitter GABA (gamma-aminobutyric acid) but
it does not modify GABAA or GABAB radioligand binding, it is not converted metabolically into
GABA or a GABA agonist, and it is not an inhibitor of GABA uptake or degradation.
Gabapentin was tested in radioligand binding assays at concentrations up to 100 µM and did not
exhibit affinity for a number of other common receptor sites, including benzodiazepine,
glutamate, N-methyl-D-aspartate (NMDA), quisqualate, kainate, strychnine-insensitive or
strychnine-sensitive glycine, alpha 1, alpha 2, or beta adrenergic, adenosine A1 or A2,
cholinergic muscarinic or nicotinic, dopamine D1 or D2, histamine H1, serotonin S1 or S2,
opiate mu, delta or kappa, cannabinoid 1, voltage-sensitive calcium channel sites labeled with
nitrendipine or diltiazem, or at voltage-sensitive sodium channel sites labeled with
batrachotoxinin A 20-alpha-benzoate. Furthermore, gabapentin did not alter the cellular uptake
of dopamine, noradrenaline, or serotonin.
In vitro studies with radiolabeled gabapentin have revealed a gabapentin binding site in areas of
rat brain including neocortex and hippocampus. A high-affinity binding protein in animal brain
tissue has been identified as an auxiliary subunit of voltage-activated calcium channels.
However, functional correlates of gabapentin binding, if any, remain to be elucidated.
Pharmacokinetics and Drug Metabolism
All pharmacological actions following gabapentin administration are due to the activity of the
parent compound; gabapentin is not appreciably metabolized in humans.
Oral Bioavailability: Gabapentin bioavailability is not dose proportional; i.e., as dose is
increased, bioavailability decreases. Bioavailability of gabapentin is approximately 60%, 47%,
34%, 33%, and 27% following 900, 1200, 2400, 3600, and 4800 mg/day given in 3 divided
doses, respectively. Food has only a slight effect on the rate and extent of absorption of
gabapentin (14% increase in AUC and Cmax).
Distribution: Less than 3% of gabapentin circulates bound to plasma protein. The apparent
volume of distribution of gabapentin after 150 mg intravenous administration is 58±6 L (Mean
±SD). In patients with epilepsy, steady-state predose (Cmin) concentrations of gabapentin in
cerebrospinal fluid were approximately 20% of the corresponding plasma concentrations.
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Elimination: Gabapentin is eliminated from the systemic circulation by renal excretion as
unchanged drug. Gabapentin is not appreciably metabolized in humans.
Gabapentin elimination half-life is 5 to 7 hours and is unaltered by dose or following multiple
dosing. Gabapentin elimination rate constant, plasma clearance, and renal clearance are directly
proportional to creatinine clearance (see Special Populations: Patients With Renal Insufficiency,
below). In elderly patients, and in patients with impaired renal function, gabapentin plasma
clearance is reduced. Gabapentin can be removed from plasma by hemodialysis.
Dosage adjustment in patients with compromised renal function or undergoing hemodialysis is
recommended (see DOSAGE AND ADMINISTRATION, Table 6).
Special Populations: Adult Patients With Renal Insufficiency: Subjects (N=60) with renal
insufficiency (mean creatinine clearance ranging from 13-114 mL/min) were administered single
400 mg oral doses of gabapentin. The mean gabapentin half-life ranged from about 6.5 hours
(patients with creatinine clearance >60 mL/min) to 52 hours (creatinine clearance <30 mL/min)
and gabapentin renal clearance from about 90 mL/min (>60 mL/min group) to about 10 mL/min
(<30 mL/min). Mean plasma clearance (CL/F) decreased from approximately 190 mL/min to
20 mL/min.
Dosage adjustment in adult patients with compromised renal function is necessary (see
DOSAGE AND ADMINISTRATION). Pediatric patients with renal insufficiency have not been
studied.
Hemodialysis: In a study in anuric adult subjects (N=11), the apparent elimination half-life of
gabapentin on nondialysis days was about 132 hours; during dialysis the apparent half-life of
gabapentin was reduced to 3.8 hours. Hemodialysis thus has a significant effect on gabapentin
elimination in anuric subjects.
Dosage adjustment in patients undergoing hemodialysis is necessary (see DOSAGE AND
ADMINISTRATION).
Hepatic Disease: Because gabapentin is not metabolized, no study was performed in patients
with hepatic impairment.
Age: The effect of age was studied in subjects 20-80 years of age. Apparent oral clearance
(CL/F) of gabapentin decreased as age increased, from about 225 mL/min in those under 30
years of age to about 125 mL/min in those over 70 years of age. Renal clearance (CLr) and CLr
adjusted for body surface area also declined with age; however, the decline in the renal clearance
of gabapentin with age can largely be explained by the decline in renal function. Reduction of
gabapentin dose may be required in patients who have age related compromised renal function.
(See PRECAUTIONS, Geriatric Use, and DOSAGE AND ADMINISTRATION.)
Pediatric: Gabapentin pharmacokinetics were determined in 48 pediatric subjects between the
ages of 1 month and 12 years following a dose of approximately 10 mg/kg. Peak plasma
concentrations were similar across the entire age group and occurred 2 to 3 hours postdose. In
general, pediatric subjects between 1 month and <5 years of age achieved approximately 30%
lower exposure (AUC) than that observed in those 5 years of age and older. Accordingly, oral
clearance normalized per body weight was higher in the younger children. Apparent oral
clearance of gabapentin was directly proportional to creatinine clearance. Gabapentin elimination
half-life averaged 4.7 hours and was similar across the age groups studied.
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A population pharmacokinetic analysis was performed in 253 pediatric subjects between 1 month
and 13 years of age. Patients received 10 to 65 mg/kg/day given TID. Apparent oral clearance
(CL/F) was directly proportional to creatinine clearance and this relationship was similar
following a single dose and at steady state. Higher oral clearance values were observed in
children <5 years of age compared to those observed in children 5 years of age and older, when
normalized per body weight. The clearance was highly variable in infants <1 year of age. The
normalized CL/F values observed in pediatric patients 5 years of age and older were consistent
with values observed in adults after a single dose. The oral volume of distribution normalized per
body weight was constant across the age range.
These pharmacokinetic data indicate that the effective daily dose in pediatric patients with
epilepsy ages 3 and 4 years should be 40 mg/kg/day to achieve average plasma concentrations
similar to those achieved in patients 5 years of age and older receiving gabapentin at 30
mg/kg/day (see DOSAGE AND ADMINISTRATION).
Gender: Although no formal study has been conducted to compare the pharmacokinetics of
gabapentin in men and women, it appears that the pharmacokinetic parameters for males and
females are similar and there are no significant gender differences.
Race: Pharmacokinetic differences due to race have not been studied. Because gabapentin is
primarily renally excreted and there are no important racial differences in creatinine clearance,
pharmacokinetic differences due to race are not expected.
Clinical Studies
Postherpetic Neuralgia
Neurontin was evaluated for the management of postherpetic neuralgia (PHN) in 2 randomized,
double-blind, placebo-controlled, multicenter studies; N=563 patients in the intent-to-treat (ITT)
population (Table 1). Patients were enrolled if they continued to have pain for more than 3
months after healing of the herpes zoster skin rash.
TABLE 1. Controlled PHN Studies: Duration, Dosages, and
Number of Patients
Study
Study
Duration
Gabapentin
(mg/day)a
Target Dose
Patients
Receiving
Gabapentin
Patients
Receiving
Placebo
1
8 weeks
3600
113
116
2
7 weeks
1800, 2400
223
111
Total
336
227
a
Given in 3 divided doses (TID)
Each study included a 1-week baseline during which patients were screened for eligibility and a
7- or 8-week double-blind phase (3 or 4 weeks of titration and 4 weeks of fixed dose). Patients
initiated treatment with titration to a maximum of 900 mg/day gabapentin over 3 days. Dosages
were then to be titrated in 600 to 1200 mg/day increments at 3- to 7-day intervals to target dose
over 3 to 4 weeks. In Study 1, patients were continued on lower doses if not able to achieve the
target dose. During baseline and treatment, patients recorded their pain in a daily diary using an
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11-point numeric pain rating scale ranging from 0 (no pain) to 10 (worst possible pain). A mean
pain score during baseline of at least 4 was required for randomization (baseline mean pain score
for Studies 1 and 2 combined was 6.4). Analyses were conducted using the ITT population (all
randomized patients who received at least one dose of study medication).
Both studies showed significant differences from placebo at all doses tested.
A significant reduction in weekly mean pain scores was seen by Week 1 in both studies, and
significant differences were maintained to the end of treatment. Comparable treatment effects
were observed in all active treatment arms. Pharmacokinetic/pharmacodynamic modeling
provided confirmatory evidence of efficacy across all doses. Figures 1 and 2 show these changes
for Studies 1 and 2.
We
ek
ly
M
ea
n
Pa
in
S
co
res
(Observ
ed Cases in ITT Populati
on)
: S
tud
y 1
Baseline
1
2
3
4
5
6
7
8
Weeks
Figure 1. Weekly Mean Pain Scores (Observed Cases in ITT Population): Study 1
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For current labeling information, please visit https://www.fda.gov/drugsatfda
W
e
e
k
l
y
M
e
a
n
P
a
i
n
S
c
o
r
e
s
(Observed Cases i
n ITT Population): Study 2
Weeks
Figure 2. Weekly Mean Pain Scores (Observed Cases in ITT Population): Study 2
The proportion of responders (those patients reporting at least 50% improvement in endpoint
pain score compared with baseline) was calculated for each study (Figure 3).
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Prop
orti
on o
f Re
spon
de
rs
(p
ati
ent
s w
ith
≥5
0%
red
uc
tion in pain score) at Endpoint: Cont
roll
ed
PHN Stu
dies
PBO
GBP
PBO
GBP
GBP
3600
1800
2400
Study 1
Study 2
Figure 3.
Proportion of Responders (patients with ≥50% reduction in pain score) at
Endpoint: Controlled PHN Studies
Epilepsy
The effectiveness of Neurontin as adjunctive therapy (added to other antiepileptic drugs) was
established in multicenter placebo-controlled, double-blind, parallel-group clinical trials in adult
and pediatric patients (3 years and older) with refractory partial seizures.
Evidence of effectiveness was obtained in three trials conducted in 705 patients (age 12 years
and above) and one trial conducted in 247 pediatric patients (3 to 12 years of age). The patients
enrolled had a history of at least 4 partial seizures per month in spite of receiving one or more
antiepileptic drugs at therapeutic levels and were observed on their established antiepileptic drug
regimen during a 12-week baseline period (6 weeks in the study of pediatric patients). In patients
continuing to have at least 2 (or 4 in some studies) seizures per month, Neurontin or placebo was
then added on to the existing therapy during a 12-week treatment period. Effectiveness was
assessed primarily on the basis of the percent of patients with a 50% or greater reduction in
seizure frequency from baseline to treatment (the “responder rate”) and a derived measure called
response ratio, a measure of change defined as (T - B)/(T + B), where B is the patient’s baseline
seizure frequency and T is the patient’s seizure frequency during treatment. Response ratio is
distributed within the range -1 to +1. A zero value indicates no change while complete
elimination of seizures would give a value of -1; increased seizure rates would give positive
values. A response ratio of -0.33 corresponds to a 50% reduction in seizure frequency. The
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results given below are for all partial seizures in the intent-to-treat (all patients who received any
doses of treatment) population in each study, unless otherwise indicated.
One study compared Neurontin 1200 mg/day divided TID with placebo. Responder rate was
23% (14/61) in the Neurontin group and 9% (6/66) in the placebo group; the difference between
groups was statistically significant. Response ratio was also better in the Neurontin group
(-0.199) than in the placebo group (-0.044), a difference that also achieved statistical
significance.
A second study compared primarily 1200 mg/day divided TID Neurontin (N=101) with placebo
(N=98). Additional smaller Neurontin dosage groups (600 mg/day, N=53; 1800 mg/day, N=54)
were also studied for information regarding dose response. Responder rate was higher in the
Neurontin 1200 mg/day group (16%) than in the placebo group (8%), but the difference was not
statistically significant. The responder rate at 600 mg (17%) was also not significantly higher
than in the placebo, but the responder rate in the 1800 mg group (26%) was statistically
significantly superior to the placebo rate. Response ratio was better in the Neurontin
1200 mg/day group (-0.103) than in the placebo group (-0.022); but this difference was also not
statistically significant (p = 0.224). A better response was seen in the Neurontin 600 mg/day
group (-0.105) and 1800 mg/day group (-0.222) than in the 1200 mg/day group, with the
1800 mg/day group achieving statistical significance compared to the placebo group.
A third study compared Neurontin 900 mg/day divided TID (N=111) and placebo (N=109). An
additional Neurontin 1200 mg/day dosage group (N=52) provided dose-response data. A
statistically significant difference in responder rate was seen in the Neurontin 900 mg/day group
(22%) compared to that in the placebo group (10%). Response ratio was also statistically
significantly superior in the Neurontin 900 mg/day group (-0.119) compared to that in the
placebo group (-0.027), as was response ratio in 1200 mg/day Neurontin (-0.184) compared to
placebo.
Analyses were also performed in each study to examine the effect of Neurontin on preventing
secondarily generalized tonic-clonic seizures. Patients who experienced a secondarily
generalized tonic-clonic seizure in either the baseline or in the treatment period in all three
placebo-controlled studies were included in these analyses. There were several response ratio
comparisons that showed a statistically significant advantage for Neurontin compared to placebo
and favorable trends for almost all comparisons.
Analysis of responder rate using combined data from all three studies and all doses (N=162,
Neurontin; N=89, placebo) also showed a significant advantage for Neurontin over placebo in
reducing the frequency of secondarily generalized tonic-clonic seizures.
In two of the three controlled studies, more than one dose of Neurontin was used. Within each
study the results did not show a consistently increased response to dose. However, looking across
studies, a trend toward increasing efficacy with increasing dose is evident (see Figure 4).
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Responder Rate in Patients Receiving Neurontin Expressed as a Difference from Placebo by Dose and Study: Adjunctive Therapy Studies in Patients ≥12 Years of Age with Partial Seizures
Figure 4. Responder Rate in Patients Receiving Neurontin Expressed as a Difference
from Placebo by Dose and Study: Adjunctive Therapy Studies in Patients ≥12
Years of Age with Partial Seizures
In the figure, treatment effect magnitude, measured on the Y axis in terms of the difference in the
proportion of gabapentin and placebo assigned patients attaining a 50% or greater reduction in
seizure frequency from baseline, is plotted against the daily dose of gabapentin administered
(X axis).
Although no formal analysis by gender has been performed, estimates of response (Response
Ratio) derived from clinical trials (398 men, 307 women) indicate no important gender
differences exist. There was no consistent pattern indicating that age had any effect on the
response to Neurontin. There were insufficient numbers of patients of races other than Caucasian
to permit a comparison of efficacy among racial groups.
A fourth study in pediatric patients age 3 to 12 years compared 25 – 35 mg/kg/day Neurontin
(N=118) with placebo (N=127). For all partial seizures in the intent-to-treat population, the
response ratio was statistically significantly better for the Neurontin group (-0.146) than for the
placebo group (-0.079). For the same population, the responder rate for Neurontin (21%) was not
significantly different from placebo (18%).
A study in pediatric patients age 1 month to 3 years compared 40 mg/kg/day Neurontin (N=38)
with placebo (N=38) in patients who were receiving at least one marketed antiepileptic drug and
had at least one partial seizure during the screening period (within 2 weeks prior to baseline).
Patients had up to 48 hours of baseline and up to 72 hours of double-blind video EEG monitoring
to record and count the occurrence of seizures. There were no statistically significant differences
between treatments in either the response ratio or responder rate.
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INDICATIONS AND USAGE
Postherpetic Neuralgia
Neurontin (gabapentin) is indicated for the management of postherpetic neuralgia in adults.
Epilepsy
Neurontin (gabapentin) is indicated as adjunctive therapy in the treatment of partial seizures with
and without secondary generalization in patients over 12 years of age with epilepsy. Neurontin is
also indicated as adjunctive therapy in the treatment of partial seizures in pediatric patients age 3
– 12 years.
CONTRAINDICATIONS
Neurontin is contraindicated in patients who have demonstrated hypersensitivity to the drug or
its ingredients.
WARNINGS
Suicidal Behavior and Ideation
Antiepileptic drugs (AEDs), including Neurontin, increase the risk of suicidal thoughts or
behavior in patients taking these drugs for any indication. Patients treated with any AED for any
indication should be monitored for the emergence or worsening of depression, suicidal thoughts
or behavior, and/or any unusual changes in mood or behavior.
Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11
different AEDs showed that patients randomized to one of the AEDs had approximately twice
the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared
to patients randomized to placebo. In these trials, which had a median treatment duration of 12
weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated
patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an
increase of approximately one case of suicidal thinking or behavior for every 530 patients
treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated
patients, but the number is too small to allow any conclusion about drug effect on suicide.
The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one
week after starting drug treatment with AEDs and persisted for the duration of treatment
assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk
of suicidal thoughts or behavior beyond 24 weeks could not be assessed.
The risk of suicidal thoughts or behavior was generally consistent among drugs in the data
analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a
range of indications suggests that the risk applies to all AEDs used for any indication. The risk
did not vary substantially by age (5-100 years) in the clinical trials analyzed.
Table 2 shows absolute and relative risk by indication for all evaluated AEDs.
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Table 2
Risk by indication for antiepileptic drugs in the pooled analysis
Indication
Placebo Patients Drug Patients
Relative Risk:
Risk Difference:
with Events Per
with Events Per
Incidence of Events in
Additional Drug
1000 Patients
1000 Patients
Drug
Patients with
Patients/Incidence in
Events Per 1000
Placebo Patients
Patients
Epilepsy
1.0
3.4
3.5
2.4
Psychiatric
5.7
8.5
1.5
2.9
Other
1.0
1.8
1.9
0.9
Total
2.4
4.3
1.8
1.9
The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in
clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for
the epilepsy and psychiatric indications.
Anyone considering prescribing Neurontin or any other AED must balance the risk of suicidal
thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for
which AEDs are prescribed are themselves associated with morbidity and mortality and an
increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge
during treatment, the prescriber needs to consider whether the emergence of these symptoms in
any given patient may be related to the illness being treated.
Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal
thoughts and behavior and should be advised of the need to be alert for the emergence or
worsening of the signs and symptoms of depression, any unusual changes in mood or behavior,
or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of
concern should be reported immediately to healthcare providers.
Neuropsychiatric Adverse Events—Pediatric Patients 3-12 years of age
Gabapentin use in pediatric patients with epilepsy 3–12 years of age is associated with the
occurrence of central nervous system related adverse events. The most significant of these can be
classified into the following categories: 1) emotional lability (primarily behavioral problems),
2) hostility, including aggressive behaviors, 3) thought disorder, including concentration
problems and change in school performance, and 4) hyperkinesia (primarily restlessness and
hyperactivity). Among the gabapentin-treated patients, most of the events were mild to moderate
in intensity.
In controlled trials in pediatric patients 3–12 years of age the incidence of these adverse events
was: emotional lability 6% (gabapentin-treated patients) vs 1.3% (placebo-treated patients);
hostility 5.2% vs 1.3%; hyperkinesia 4.7% vs 2.9%; and thought disorder 1.7% vs 0%. One of
these events, a report of hostility, was considered serious. Discontinuation of gabapentin
treatment occurred in 1.3% of patients reporting emotional lability and hyperkinesia and 0.9% of
gabapentin-treated patients reporting hostility and thought disorder. One placebo-treated patient
(0.4%) withdrew due to emotional lability.
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Withdrawal Precipitated Seizure, Status Epilepticus
Antiepileptic drugs should not be abruptly discontinued because of the possibility of increasing
seizure frequency.
In the placebo-controlled studies in patients >12 years of age, the incidence of status epilepticus
in patients receiving Neurontin was 0.6% (3 of 543) versus 0.5% in patients receiving placebo (2
of 378). Among the 2074 patients >12 years of age treated with Neurontin across all studies
(controlled and uncontrolled) 31 (1.5%) had status epilepticus. Of these, 14 patients had no prior
history of status epilepticus either before treatment or while on other medications. Because
adequate historical data are not available, it is impossible to say whether or not treatment with
Neurontin is associated with a higher or lower rate of status epilepticus than would be expected
to occur in a similar population not treated with Neurontin.
Tumorigenic Potential
In standard preclinical in vivo lifetime carcinogenicity studies, an unexpectedly high incidence of
pancreatic acinar adenocarcinomas was identified in male, but not female, rats. (See
PRECAUTIONS: Carcinogenesis, Mutagenesis, Impairment of Fertility.) The clinical
significance of this finding is unknown. Clinical experience during gabapentin’s premarketing
development provides no direct means to assess its potential for inducing tumors in humans.
In clinical studies in adjunctive therapy in epilepsy comprising 2085 patient-years of exposure in
patients >12 years of age, new tumors were reported in 10 patients (2 breast, 3 brain, 2 lung, 1
adrenal, 1 non-Hodgkin’s lymphoma, 1 endometrial carcinoma in situ), and preexisting tumors
worsened in 11 patients (9 brain, 1 breast, 1 prostate) during or up to 2 years following
discontinuation of Neurontin. Without knowledge of the background incidence and recurrence in
a similar population not treated with Neurontin, it is impossible to know whether the incidence
seen in this cohort is or is not affected by treatment.
Sudden and Unexplained Death in Patients With Epilepsy
During the course of premarketing development of Neurontin 8 sudden and unexplained deaths
were recorded among a cohort of 2203 patients treated (2103 patient-years of exposure).
Some of these could represent seizure-related deaths in which the seizure was not observed, e.g.,
at night. This represents an incidence of 0.0038 deaths per patient-year. Although this rate
exceeds that expected in a healthy population matched for age and sex, it is within the range of
estimates for the incidence of sudden unexplained deaths in patients with epilepsy not receiving
Neurontin (ranging from 0.0005 for the general population of epileptics to 0.003 for a clinical
trial population similar to that in the Neurontin program, to 0.005 for patients with refractory
epilepsy). Consequently, whether these figures are reassuring or raise further concern depends on
comparability of the populations reported upon to the Neurontin cohort and the accuracy of the
estimates provided.
PRECAUTIONS
Information for Patients
Inform patients of the availability of a Medication Guide, and instruct them to read the
Medication Guide prior to taking Neurontin. Instruct patients to take Neurontin only as
prescribed.
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Patients, their caregivers, and families should be counseled that AEDs, including Neurontin, may
increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert
for the emergence or worsening of symptoms of depression, any unusual changes in mood or
behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm.
Behaviors of concern should be reported immediately to healthcare providers.
Patients should be advised that Neurontin may cause dizziness, somnolence and other symptoms
and signs of CNS depression. Accordingly, they should be advised neither to drive a car nor to
operate other complex machinery until they have gained sufficient experience on Neurontin to
gauge whether or not it affects their mental and/or motor performance adversely.
Patients who require concomitant treatment with morphine may experience increases in
gabapentin concentrations. Patients should be carefully observed for signs of CNS depression,
such as somnolence, and the dose of Neurontin or morphine should be reduced appropriately (see
Drug Interactions).
Patients should be encouraged to enroll in the North American Antiepileptic Drug (NAAED)
Pregnancy Registry if they become pregnant. This registry is collecting information about the
safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll free number 1
888-233-2334 (see PRECAUTIONS, Pregnancy section).
Laboratory Tests
Clinical trials data do not indicate that routine monitoring of clinical laboratory parameters is
necessary for the safe use of Neurontin. The value of monitoring gabapentin blood
concentrations has not been established. Neurontin may be used in combination with other
antiepileptic drugs without concern for alteration of the blood concentrations of gabapentin or of
other antiepileptic drugs.
Drug Interactions
In vitro studies were conducted to investigate the potential of gabapentin to inhibit the major
cytochrome P450 enzymes (CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and
CYP3A4) that mediate drug and xenobiotic metabolism using isoform selective marker
substrates and human liver microsomal preparations. Only at the highest concentration tested
(171 μg/mL; 1 mM) was a slight degree of inhibition (14%-30%) of isoform CYP2A6 observed.
No inhibition of any of the other isoforms tested was observed at gabapentin concentrations up to
171 μg/mL (approximately 15 times the Cmax at 3600 mg/day).
Gabapentin is not appreciably metabolized nor does it interfere with the metabolism of
commonly coadministered antiepileptic drugs.
The drug interaction data described in this section were obtained from studies involving healthy
adults and adult patients with epilepsy.
Phenytoin: In a single (400 mg) and multiple dose (400 mg TID) study of Neurontin in epileptic
patients (N=8) maintained on phenytoin monotherapy for at least 2 months, gabapentin had no
effect on the steady-state trough plasma concentrations of phenytoin and phenytoin had no effect
on gabapentin pharmacokinetics.
Carbamazepine: Steady-state trough plasma carbamazepine and carbamazepine 10, 11 epoxide
concentrations were not affected by concomitant gabapentin (400 mg TID; N=12)
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administration. Likewise, gabapentin pharmacokinetics were unaltered by carbamazepine
administration.
Valproic Acid: The mean steady-state trough serum valproic acid concentrations prior to and
during concomitant gabapentin administration (400 mg TID; N=17) were not different and
neither were gabapentin pharmacokinetic parameters affected by valproic acid.
Phenobarbital: Estimates of steady-state pharmacokinetic parameters for phenobarbital or
gabapentin (300 mg TID; N=12) are identical whether the drugs are administered alone or
together.
Naproxen: Coadministration (N=18) of naproxen sodium capsules (250 mg) with Neurontin
(125 mg) appears to increase the amount of gabapentin absorbed by 12% to 15%. Gabapentin
had no effect on naproxen pharmacokinetic parameters. These doses are lower than the
therapeutic doses for both drugs. The magnitude of interaction within the recommended dose
ranges of either drug is not known.
Hydrocodone: Coadministration of Neurontin (125 to 500 mg; N=48) decreases hydrocodone
(10 mg; N=50) Cmax and AUC values in a dose-dependent manner relative to administration of
hydrocodone alone; Cmax and AUC values are 3% to 4% lower, respectively, after administration
of 125 mg Neurontin and 21% to 22% lower, respectively, after administration of 500 mg
Neurontin. The mechanism for this interaction is unknown. Hydrocodone increases gabapentin
AUC values by 14%. The magnitude of interaction at other doses is not known.
Morphine: A literature article reported that when a 60-mg controlled-release morphine capsule
was administered 2 hours prior to a 600-mg Neurontin capsule (N=12), mean gabapentin AUC
increased by 44% compared to gabapentin administered without morphine (see
PRECAUTIONS). Morphine pharmacokinetic parameter values were not affected by
administration of Neurontin 2 hours after morphine. The magnitude of interaction at other doses
is not known.
Cimetidine: In the presence of cimetidine at 300 mg QID (N=12) the mean apparent oral
clearance of gabapentin fell by 14% and creatinine clearance fell by 10%. Thus cimetidine
appeared to alter the renal excretion of both gabapentin and creatinine, an endogenous marker of
renal function. This small decrease in excretion of gabapentin by cimetidine is not expected to be
of clinical importance. The effect of gabapentin on cimetidine was not evaluated.
Oral Contraceptive: Based on AUC and half-life, multiple-dose pharmacokinetic profiles of
norethindrone and ethinyl estradiol following administration of tablets containing 2.5 mg of
norethindrone acetate and 50 mcg of ethinyl estradiol were similar with and without
coadministration of gabapentin (400 mg TID; N=13). The Cmax of norethindrone was 13%
higher when it was coadministered with gabapentin; this interaction is not expected to be of
clinical importance.
Antacid (Maalox®): Maalox reduced the bioavailability of gabapentin (N=16) by about 20%.
This decrease in bioavailability was about 5% when gabapentin was administered 2 hours after
Maalox. It is recommended that gabapentin be taken at least 2 hours following Maalox
administration.
Effect of Probenecid: Probenecid is a blocker of renal tubular secretion. Gabapentin
pharmacokinetic parameters without and with probenecid were comparable. This indicates that
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gabapentin does not undergo renal tubular secretion by the pathway that is blocked by
probenecid.
Drug/Laboratory Tests Interactions
Because false positive readings were reported with the Ames N-Multistix SG® dipstick test for
urinary protein when gabapentin was added to other antiepileptic drugs, the more specific
sulfosalicylic acid precipitation procedure is recommended to determine the presence of urine
protein.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Gabapentin was given in the diet to mice at 200, 600, and 2000 mg/kg/day and to rats at 250,
1000, and 2000 mg/kg/day for 2 years. A statistically significant increase in the incidence of
pancreatic acinar cell adenomas and carcinomas was found in male rats receiving the high dose;
the no-effect dose for the occurrence of carcinomas was 1000 mg/kg/day. Peak plasma
concentrations of gabapentin in rats receiving the high dose of 2000 mg/kg were 10 times higher
than plasma concentrations in humans receiving 3600 mg per day, and in rats receiving
1000 mg/kg/day peak plasma concentrations were 6.5 times higher than in humans receiving
3600 mg/day. The pancreatic acinar cell carcinomas did not affect survival, did not metastasize
and were not locally invasive. The relevance of this finding to carcinogenic risk in humans is
unclear.
Studies designed to investigate the mechanism of gabapentin-induced pancreatic carcinogenesis
in rats indicate that gabapentin stimulates DNA synthesis in rat pancreatic acinar cells in vitro
and, thus, may be acting as a tumor promoter by enhancing mitogenic activity. It is not known
whether gabapentin has the ability to increase cell proliferation in other cell types or in other
species, including humans.
Gabapentin did not demonstrate mutagenic or genotoxic potential in three in vitro and four in
vivo assays. It was negative in the Ames test and the in vitro HGPRT forward mutation assay in
Chinese hamster lung cells; it did not produce significant increases in chromosomal aberrations
in the in vitro Chinese hamster lung cell assay; it was negative in the in vivo chromosomal
aberration assay and in the in vivo micronucleus test in Chinese hamster bone marrow; it was
negative in the in vivo mouse micronucleus assay; and it did not induce unscheduled DNA
synthesis in hepatocytes from rats given gabapentin.
No adverse effects on fertility or reproduction were observed in rats at doses up to 2000 mg/kg
(approximately 5 times the maximum recommended human dose on a mg/m2 basis).
Pregnancy
Pregnancy Category C: Gabapentin has been shown to be fetotoxic in rodents, causing delayed
ossification of several bones in the skull, vertebrae, forelimbs, and hindlimbs. These effects
occurred when pregnant mice received oral doses of 1000 or 3000 mg/kg/day during the period
of organogenesis, or approximately 1 to 4 times the maximum dose of 3600 mg/day given to
epileptic patients on a mg/m2 basis. The no-effect level was 500 mg/kg/day or approximately ½
of the human dose on a mg/m2 basis.
When rats were dosed prior to and during mating, and throughout gestation, pups from all dose
groups (500, 1000 and 2000 mg/kg/day) were affected. These doses are equivalent to less than
approximately 1 to 5 times the maximum human dose on a mg/m2 basis. There was an increased
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incidence of hydroureter and/or hydronephrosis in rats in a study of fertility and general
reproductive performance at 2000 mg/kg/day with no effect at 1000 mg/kg/day, in a teratology
study at 1500 mg/kg/day with no effect at 300 mg/kg/day, and in a perinatal and postnatal study
at all doses studied (500, 1000 and 2000 mg/kg/day). The doses at which the effects occurred are
approximately 1 to 5 times the maximum human dose of 3600 mg/day on a mg/m2 basis; the no-
effect doses were approximately 3 times (Fertility and General Reproductive Performance study)
and approximately equal to (Teratogenicity study) the maximum human dose on a mg/m2 basis.
Other than hydroureter and hydronephrosis, the etiologies of which are unclear, the incidence of
malformations was not increased compared to controls in offspring of mice, rats, or rabbits given
doses up to 50 times (mice), 30 times (rats), and 25 times (rabbits) the human daily dose on a
mg/kg basis, or 4 times (mice), 5 times (rats), or 8 times (rabbits) the human daily dose on a
mg/m2 basis.
In a teratology study in rabbits, an increased incidence of postimplantation fetal loss occurred in
dams exposed to 60, 300, and 1500 mg/kg/day, or less than approximately ¼ to 8 times the
maximum human dose on a mg/m2 basis. There are no adequate and well-controlled studies in
pregnant women. This drug should be used during pregnancy only if the potential benefit
justifies the potential risk to the fetus.
To provide information regarding the effects of in utero exposure to Neurontin, physicians are
advised to recommend that pregnant patients taking Neurontin enroll in the North American
Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll free
number 1-888-233-2334, and must be done by patients themselves. Information on the registry
can also be found at the website http://www.aedpregnancyregistry.org/.
Use in Nursing Mothers
Gabapentin is secreted into human milk following oral administration. A nursed infant could be
exposed to a maximum dose of approximately 1 mg/kg/day of gabapentin. Because the effect on
the nursing infant is unknown, Neurontin should be used in women who are nursing only if the
benefits clearly outweigh the risks.
Pediatric Use
Safety and effectiveness of Neurontin (gabapentin) in the management of postherpetic neuralgia
in pediatric patients have not been established.
Effectiveness as adjunctive therapy in the treatment of partial seizures in pediatric patients below
the age of 3 years has not been established (see CLINICAL PHARMACOLOGY, Clinical
Studies).
Geriatric Use
The total number of patients treated with Neurontin in controlled clinical trials in patients with
postherpetic neuralgia was 336, of which 102 (30%) were 65 to 74 years of age, and 168 (50%)
were 75 years of age and older. There was a larger treatment effect in patients 75 years of age
and older compared with younger patients who received the same dosage. Since gabapentin is
almost exclusively eliminated by renal excretion, the larger treatment effect observed in patients
≥75 years may be a consequence of increased gabapentin exposure for a given dose that results
from an age-related decrease in renal function. However, other factors cannot be excluded. The
types and incidence of adverse events were similar across age groups except for peripheral
edema and ataxia, which tended to increase in incidence with age.
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Clinical studies of Neurontin in epilepsy did not include sufficient numbers of subjects aged 65
and over to determine whether they responded differently from younger subjects. Other reported
clinical experience has not identified differences in responses between the elderly and younger
patients. In general, dose selection for an elderly patient should be cautious, usually starting at
the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or
cardiac function, and of concomitant disease or other drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to
this drug may be greater in patients with impaired renal function. Because elderly patients are
more likely to have decreased renal function, care should be taken in dose selection, and dose
should be adjusted based on creatinine clearance values in these patients (see CLINICAL
PHARMACOLOGY, ADVERSE REACTIONS, and DOSAGE AND ADMINISTRATION
sections).
ADVERSE REACTIONS
Postherpetic Neuralgia
The most commonly observed adverse events associated with the use of Neurontin in adults, not
seen at an equivalent frequency among placebo-treated patients, were dizziness, somnolence, and
peripheral edema.
In the 2 controlled studies in postherpetic neuralgia, 16% of the 336 patients who received
Neurontin and 9% of the 227 patients who received placebo discontinued treatment because of an
adverse event. The adverse events that most frequently led to withdrawal in Neurontin®-treated
patients were dizziness, somnolence, and nausea.
Incidence in Controlled Clinical Trials
Table 3 lists treatment-emergent signs and symptoms that occurred in at least 1% of Neurontin
treated patients with postherpetic neuralgia participating in placebo-controlled trials and that
were numerically more frequent in the Neurontin group than in the placebo group. Adverse
events were usually mild to moderate in intensity.
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TABLE 3. Treatment-Emergent Adverse Event Incidence in
Controlled Trials in Postherpetic Neuralgia (Events
in at least 1% of Neurontin®-Treated Patients and
Numerically More Frequent Than in the Placebo
Group)
Body System/
Neurontin®
Placebo
Preferred Term
N=336
N=227
%
%
Body as a Whole
Asthenia
5.7
4.8
Infection
5.1
3.5
Headache
3.3
3.1
Accidental injury
3.3
1.3
Abdominal pain
2.7
2.6
Digestive System
Diarrhea
5.7
3.1
Dry mouth
4.8
1.3
Constipation
3.9
1.8
Nausea
3.9
3.1
Vomiting
3.3
1.8
Flatulence
2.1
1.8
Metabolic and Nutritional Disorders
Peripheral edema
8.3
2.2
Weight gain
1.8
0.0
Hyperglycemia
1.2
0.4
Nervous System
Dizziness
28.0
7.5
Somnolence
21.4
5.3
Ataxia
3.3
0.0
Thinking abnormal
2.7
0.0
Abnormal gait
1.5
0.0
Incoordination
1.5
0.0
Amnesia
1.2
0.9
Hypesthesia
1.2
0.9
Respiratory System
Pharyngitis
1.2
0.4
Skin and Appendages
Rash
1.2
0.9
Special Senses
Amblyopiaa
2.7
0.9
Conjunctivitis
1.2
0.0
Diplopia
1.2
0.0
Otitis media
1.2
0.0
a Reported as blurred vision
Other events in more than 1% of patients but equally or more frequent in the placebo group
included pain, tremor, neuralgia, back pain, dyspepsia, dyspnea, and flu syndrome.
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There were no clinically important differences between men and women in the types and
incidence of adverse events. Because there were few patients whose race was reported as other
than white, there are insufficient data to support a statement regarding the distribution of adverse
events by race.
Epilepsy
The most commonly observed adverse events associated with the use of Neurontin in
combination with other antiepileptic drugs in patients >12 years of age, not seen at an equivalent
frequency among placebo-treated patients, were somnolence, dizziness, ataxia, fatigue, and
nystagmus. The most commonly observed adverse events reported with the use of Neurontin in
combination with other antiepileptic drugs in pediatric patients 3 to 12 years of age, not seen at
an equal frequency among placebo-treated patients, were viral infection, fever, nausea and/or
vomiting, somnolence, and hostility (see WARNINGS, Neuropsychiatric Adverse Events).
Approximately 7% of the 2074 patients >12 years of age and approximately 7% of the 449
pediatric patients 3 to 12 years of age who received Neurontin in premarketing clinical trials
discontinued treatment because of an adverse event. The adverse events most commonly
associated with withdrawal in patients >12 years of age were somnolence (1.2%), ataxia (0.8%),
fatigue (0.6%), nausea and/or vomiting (0.6%), and dizziness (0.6%). The adverse events most
commonly associated with withdrawal in pediatric patients were emotional lability (1.6%),
hostility (1.3%), and hyperkinesia (1.1%).
Incidence in Controlled Clinical Trials
Table 4 lists treatment-emergent signs and symptoms that occurred in at least 1% of Neurontin
treated patients >12 years of age with epilepsy participating in placebo-controlled trials and were
numerically more common in the Neurontin group. In these studies, either Neurontin or placebo
was added to the patient’s current antiepileptic drug therapy. Adverse events were usually mild
to moderate in intensity.
The prescriber should be aware that these figures, obtained when Neurontin was added to
concurrent antiepileptic drug therapy, cannot be used to predict the frequency of adverse events
in the course of usual medical practice where patient characteristics and other factors may differ
from those prevailing during clinical studies. Similarly, the cited frequencies cannot be directly
compared with figures obtained from other clinical investigations involving different treatments,
uses, or investigators. An inspection of these frequencies, however, does provide the prescribing
physician with one basis to estimate the relative contribution of drug and nondrug factors to the
adverse event incidences in the population studied.
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TABLE 4.
Treatment-Emergent Adverse Event Incidence in Controlled Add-On
Trials In Patients >12 years of age (Events in at least 1% of Neurontin
patients and numerically more frequent than in the placebo group)
Body System/
Neurontina
Placeboa
Adverse Event
N=543
N=378
%
%
Body As A Whole
Fatigue
Weight Increase
Back Pain
Peripheral Edema
Cardiovascular
Vasodilatation
Digestive System
Dyspepsia
Mouth or Throat Dry
Constipation
Dental Abnormalities
Increased Appetite
Hematologic and Lymphatic Systems
Leukopenia
Musculoskeletal System
Myalgia
Fracture
Nervous System
Somnolence
Dizziness
Ataxia
Nystagmus
Tremor
Nervousness
Dysarthria
Amnesia
Depression
Thinking Abnormal
Twitching
Coordination Abnormal
Respiratory System
Rhinitis
Pharyngitis
Coughing
Skin and Appendages
Abrasion
Pruritus
11.0
2.9
1.8
1.7
1.1
2.2
1.7
1.5
1.5
1.1
1.1
2.0
1.1
19.3
17.1
12.5
8.3
6.8
2.4
2.4
2.2
1.8
1.7
1.3
1.1
4.1
2.8
1.8
1.3
1.3
5.0
1.6
0.5
0.5
0.3
0.5
0.5
0.8
0.3
0.8
0.5
1.9
0.8
8.7
6.9
5.6
4.0
3.2
1.9
0.5
0.0
1.1
1.3
0.5
0.3
3.7
1.6
1.3
0.0
0.5
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TABLE 4.
Treatment-Emergent Adverse Event Incidence in Controlled Add-On
Trials In Patients >12 years of age (Events in at least 1% of Neurontin
patients and numerically more frequent than in the placebo group)
Body System/
Neurontina
Placeboa
Adverse Event
N=543
N=378
%
%
Urogenital System
Impotence
1.5
1.1
Special Senses
Diplopia
Amblyopiab
5.9
4.2
1.9
1.1
Laboratory Deviations
WBC Decreased
1.1
0.5
a Plus background antiepileptic drug therapy
b Amblyopia was often described as blurred vision.
Other events in more than 1% of patients >12 years of age but equally or more frequent in the
placebo group included: headache, viral infection, fever, nausea and/or vomiting, abdominal
pain, diarrhea, convulsions, confusion, insomnia, emotional lability, rash, acne.
Among the treatment-emergent adverse events occurring at an incidence of at least 10% of
Neurontin-treated patients, somnolence and ataxia appeared to exhibit a positive dose-response
relationship.
The overall incidence of adverse events and the types of adverse events seen were similar among
men and women treated with Neurontin. The incidence of adverse events increased slightly with
increasing age in patients treated with either Neurontin or placebo. Because only 3% of patients
(28/921) in placebo-controlled studies were identified as nonwhite (black or other), there are
insufficient data to support a statement regarding the distribution of adverse events by race.
Table 5 lists treatment-emergent signs and symptoms that occurred in at least 2% of Neurontin
treated patients age 3 to 12 years of age with epilepsy participating in placebo-controlled trials
and were numerically more common in the Neurontin group. Adverse events were usually mild
to moderate in intensity.
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TABLE 5.
Treatment-Emergent Adverse Event Incidence in Pediatric Patients
Age 3 to 12 Years in a Controlled Add-On Trial (Events in at least
2% of Neurontin patients and numerically more frequent than in the
placebo group)
Body System/
Neurontina
Placeboa
Adverse Event
N=119
N=128
%
%
Body As A Whole
Viral Infection
10.9
3.1
Fever
10.1
3.1
Weight Increase
3.4
0.8
Fatigue
3.4
1.6
Digestive System
Nausea and/or Vomiting
8.4
7.0
Nervous System
Somnolence
8.4
4.7
Hostility
7.6
2.3
Emotional Lability
4.2
1.6
Dizziness
2.5
1.6
Hyperkinesia
2.5
0.8
Respiratory System
Bronchitis
3.4
0.8
Respiratory Infection
2.5
0.8
a
Plus background antiepileptic drug therapy
Other events in more than 2% of pediatric patients 3 to 12 years of age but equally or more
frequent in the placebo group included: pharyngitis, upper respiratory infection, headache,
rhinitis, convulsions, diarrhea, anorexia, coughing, and otitis media.
Other Adverse Events Observed During All Clinical Trials
Clinical Trials in Adults and Adolescents (Except Clinical Trials in Neuropathic Pain)
Neurontin has been administered to 4717 patients >12 years of age during all adjunctive therapy
clinical trials (except clinical trials in patients with neuropathic pain), only some of which were
placebo-controlled. During these trials, all adverse events were recorded by the clinical
investigators using terminology of their own choosing. To provide a meaningful estimate of the
proportion of individuals having adverse events, similar types of events were grouped into a
smaller number of standardized categories using modified COSTART dictionary terminology.
These categories are used in the listing below. The frequencies presented represent the
proportion of the 4717 patients >12 years of age exposed to Neurontin who experienced an event
of the type cited on at least one occasion while receiving Neurontin. All reported events are
included except those already listed in Table 4, those too general to be informative, and those not
reasonably associated with the use of the drug.
Events are further classified within body system categories and enumerated in order of
decreasing frequency using the following definitions: frequent adverse events are defined as
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those occurring in at least 1/100 patients; infrequent adverse events are those occurring in 1/100
to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients.
Body As A Whole: Frequent: asthenia, malaise, face edema; Infrequent: allergy, generalized
edema, weight decrease, chill; Rare: strange feelings, lassitude, alcohol intolerance, hangover
effect.
Cardiovascular System: Frequent: hypertension; Infrequent: hypotension, angina pectoris,
peripheral vascular disorder, palpitation, tachycardia, migraine, murmur; Rare: atrial fibrillation,
heart failure, thrombophlebitis, deep thrombophlebitis, myocardial infarction, cerebrovascular
accident, pulmonary thrombosis, ventricular extrasystoles, bradycardia, premature atrial
contraction, pericardial rub, heart block, pulmonary embolus, hyperlipidemia,
hypercholesterolemia, pericardial effusion, pericarditis.
Digestive System: Frequent: anorexia, flatulence, gingivitis; Infrequent: glossitis, gum
hemorrhage, thirst, stomatitis, increased salivation, gastroenteritis, hemorrhoids, bloody stools,
fecal incontinence, hepatomegaly; Rare: dysphagia, eructation, pancreatitis, peptic ulcer, colitis,
blisters in mouth, tooth discolor, perlèche, salivary gland enlarged, lip hemorrhage, esophagitis,
hiatal hernia, hematemesis, proctitis, irritable bowel syndrome, rectal hemorrhage, esophageal
spasm.
Endocrine System: Rare: hyperthyroid, hypothyroid, goiter, hypoestrogen, ovarian failure,
epididymitis, swollen testicle, cushingoid appearance.
Hematologic and Lymphatic System: Frequent: purpura most often described as bruises
resulting from physical trauma; Infrequent: anemia, thrombocytopenia, lymphadenopathy; Rare:
WBC count increased, lymphocytosis, non-Hodgkin’s lymphoma, bleeding time increased.
Musculoskeletal System: Frequent: arthralgia; Infrequent: tendinitis, arthritis, joint stiffness,
joint swelling, positive Romberg test; Rare: costochondritis, osteoporosis, bursitis, contracture.
Nervous System: Frequent: vertigo, hyperkinesia, paresthesia, decreased or absent reflexes,
increased reflexes, anxiety, hostility; Infrequent: CNS tumors, syncope, dreaming abnormal,
aphasia, hypesthesia, intracranial hemorrhage, hypotonia, dysesthesia, paresis, dystonia,
hemiplegia, facial paralysis, stupor, cerebellar dysfunction, positive Babinski sign, decreased
position sense, subdural hematoma, apathy, hallucination, decrease or loss of libido, agitation,
paranoia, depersonalization, euphoria, feeling high, doped-up sensation, psychosis; Rare:
choreoathetosis, orofacial dyskinesia, encephalopathy, nerve palsy, personality disorder,
increased libido, subdued temperament, apraxia, fine motor control disorder, meningismus, local
myoclonus, hyperesthesia, hypokinesia, mania, neurosis, hysteria, antisocial reaction.
Respiratory System: Frequent: pneumonia; Infrequent: epistaxis, dyspnea, apnea; Rare:
mucositis, aspiration pneumonia, hyperventilation, hiccup, laryngitis, nasal obstruction, snoring,
bronchospasm, hypoventilation, lung edema.
Dermatological: Infrequent: alopecia, eczema, dry skin, increased sweating, urticaria, hirsutism,
seborrhea, cyst, herpes simplex; Rare: herpes zoster, skin discolor, skin papules, photosensitive
reaction, leg ulcer, scalp seborrhea, psoriasis, desquamation, maceration, skin nodules,
subcutaneous nodule, melanosis, skin necrosis, local swelling.
Urogenital System: Infrequent: hematuria, dysuria, urination frequency, cystitis, urinary
retention, urinary incontinence, vaginal hemorrhage, amenorrhea, dysmenorrhea, menorrhagia,
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breast cancer, unable to climax, ejaculation abnormal; Rare: kidney pain, leukorrhea, pruritus
genital, renal stone, acute renal failure, anuria, glycosuria, nephrosis, nocturia, pyuria, urination
urgency, vaginal pain, breast pain, testicle pain.
Special Senses: Frequent: abnormal vision; Infrequent: cataract, conjunctivitis, eyes dry, eye
pain, visual field defect, photophobia, bilateral or unilateral ptosis, eye hemorrhage, hordeolum,
hearing loss, earache, tinnitus, inner ear infection, otitis, taste loss, unusual taste, eye twitching,
ear fullness; Rare: eye itching, abnormal accommodation, perforated ear drum, sensitivity to
noise, eye focusing problem, watery eyes, retinopathy, glaucoma, iritis, corneal disorders,
lacrimal dysfunction, degenerative eye changes, blindness, retinal degeneration, miosis,
chorioretinitis, strabismus, eustachian tube dysfunction, labyrinthitis, otitis externa, odd smell.
Clinical trials in Pediatric Patients With Epilepsy
Adverse events occurring during epilepsy clinical trials in 449 pediatric patients 3 to 12 years of
age treated with gabapentin that were not reported in adjunctive trials in adults are:
Body as a Whole: dehydration, infectious mononucleosis
Digestive System: hepatitis
Hemic and Lymphatic System: coagulation defect
Nervous System: aura disappeared, occipital neuralgia
Psychobiologic Function: sleepwalking
Respiratory System: pseudocroup, hoarseness
Clinical Trials in Adults With Neuropathic Pain of Various Etiologies
Safety information was obtained in 1173 patients during double-blind and open-label clinical
trials including neuropathic pain conditions for which efficacy has not been demonstrated.
Adverse events reported by investigators were grouped into standardized categories using
modified COSTART IV terminology. Listed below are all reported events except those already
listed in Table 3 and those not reasonably associated with the use of the drug.
Events are further classified within body system categories and enumerated in order of
decreasing frequency using the following definitions: frequent adverse events are defined as
those occurring in at least 1/100 patients; infrequent adverse events are those occurring in 1/100
to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients.
Body as a Whole: Infrequent: chest pain, cellulitis, malaise, neck pain, face edema, allergic
reaction, abscess, chills, chills and fever, mucous membrane disorder; Rare: body odor, cyst,
fever, hernia, abnormal BUN value, lump in neck, pelvic pain, sepsis, viral infection.
Cardiovascular System: Infrequent: hypertension, syncope, palpitation, migraine, hypotension,
peripheral vascular disorder, cardiovascular disorder, cerebrovascular accident, congestive heart
failure, myocardial infarction, vasodilatation; Rare: angina pectoris, heart failure, increased
capillary fragility, phlebitis, thrombophlebitis, varicose vein.
Digestive System: Infrequent: gastroenteritis, increased appetite, gastrointestinal disorder, oral
moniliasis, gastritis, tongue disorder, thirst, tooth disorder, abnormal stools, anorexia, liver
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function tests abnormal, periodontal abscess; Rare: cholecystitis, cholelithiasis, duodenal ulcer,
fecal incontinence, gamma glutamyl transpeptidase increased, gingivitis, intestinal obstruction,
intestinal ulcer, melena, mouth ulceration, rectal disorder, rectal hemorrhage, stomatitis.
Endocrine System: Infrequent: diabetes mellitus.
Hemic and Lymphatic System: Infrequent: ecchymosis, anemia; Rare: lymphadenopathy,
lymphoma-like reaction, prothrombin decreased.
Metabolic and Nutritional: Infrequent: edema, gout, hypoglycemia, weight loss; Rare: alkaline
phosphatase increased, diabetic ketoacidosis, lactic dehydrogenase increased.
Musculoskeletal: Infrequent: arthritis, arthralgia, myalgia, arthrosis, leg cramps, myasthenia;
Rare: shin bone pain, joint disorder, tendon disorder.
Nervous System: Frequent: confusion, depression; Infrequent: vertigo, nervousness,
paresthesia, insomnia, neuropathy, libido decreased, anxiety, depersonalization, reflexes
decreased, speech disorder, abnormal dreams, dysarthria, emotional lability, nystagmus, stupor,
circumoral paresthesia, euphoria, hyperesthesia, hypokinesia; Rare: agitation, hypertonia, libido
increased, movement disorder, myoclonus, vestibular disorder.
Respiratory System: Infrequent: cough increased, bronchitis, rhinitis, sinusitis, pneumonia,
asthma, lung disorder, epistaxis; Rare: hemoptysis, voice alteration.
Skin and Appendages: Infrequent: pruritus, skin ulcer, dry skin, herpes zoster, skin disorder,
fungal dermatitis, furunculosis, herpes simplex, psoriasis, sweating, urticaria, vesiculobullous
rash; Rare: acne, hair disorder, maculopapular rash, nail disorder, skin carcinoma, skin
discoloration, skin hypertrophy.
Special Senses: Infrequent: abnormal vision, ear pain, eye disorder, taste perversion, deafness;
Rare: conjunctival hyperemia, diabetic retinopathy, eye pain, fundi with microhemorrhage,
retinal vein thrombosis, taste loss.
Urogenital System: Infrequent: urinary tract infection, dysuria, impotence, urinary
incontinence, vaginal moniliasis, breast pain, menstrual disorder, polyuria, urinary retention;
Rare: cystitis, ejaculation abnormal, swollen penis, gynecomastia, nocturia, pyelonephritis,
swollen scrotum, urinary frequency, urinary urgency, urine abnormality.
Postmarketing and Other Experience
In addition to the adverse experiences reported during clinical testing of Neurontin, the following
adverse experiences have been reported in patients receiving marketed Neurontin. These adverse
experiences have not been listed above and data are insufficient to support an estimate of their
incidence or to establish causation. The listing is alphabetized: angioedema, blood glucose
fluctuation, breast hypertrophy, erythema multiforme, elevated liver function tests, fever,
hyponatremia, jaundice, movement disorder, Stevens-Johnson syndrome.
Adverse events following the abrupt discontinuation of gabapentin have also been reported. The
most frequently reported events were anxiety, insomnia, nausea, pain and sweating.
DRUG ABUSE AND DEPENDENCE
The abuse and dependence potential of Neurontin has not been evaluated in human studies.
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OVERDOSAGE
A lethal dose of gabapentin was not identified in mice and rats receiving single oral doses as
high as 8000 mg/kg. Signs of acute toxicity in animals included ataxia, labored breathing, ptosis,
sedation, hypoactivity, or excitation.
Acute oral overdoses of Neurontin up to 49 grams have been reported. In these cases, double
vision, slurred speech, drowsiness, lethargy and diarrhea were observed. All patients recovered
with supportive care.
Gabapentin can be removed by hemodialysis. Although hemodialysis has not been performed in
the few overdose cases reported, it may be indicated by the patient’s clinical state or in patients
with significant renal impairment.
DOSAGE AND ADMlNlSTRATION
Neurontin is given orally with or without food. Patients should be informed that, should they
break the scored 600 or 800 mg tablet in order to administer a half-tablet, they should take the
unused half-tablet as the next dose. Half-tablets not used within several days of breaking the
scored tablet should be discarded.
If Neurontin dose is reduced, discontinued or substituted with an alternative medication, this
should be done gradually over a minimum of 1 week (a longer period may be needed at the
discretion of the prescriber).
Postherpetic Neuralgia
In adults with postherpetic neuralgia, Neurontin therapy may be initiated as a single 300-mg dose
on Day 1, 600 mg/day on Day 2 (divided BID), and 900 mg/day on Day 3 (divided TID). The
dose can subsequently be titrated up as needed for pain relief to a daily dose of 1800 mg (divided
TID). In clinical studies, efficacy was demonstrated over a range of doses from 1800 mg/day to
3600 mg/day with comparable effects across the dose range. Additional benefit of using doses
greater than 1800 mg/day was not demonstrated.
Epilepsy
Neurontin is recommended for add-on therapy in patients 3 years of age and older. Effectiveness
in pediatric patients below the age of 3 years has not been established.
Patients >12 years of age: The effective dose of Neurontin is 900 to 1800 mg/day and given in
divided doses (three times a day) using 300 or 400 mg capsules, or 600 or 800 mg tablets. The
starting dose is 300 mg three times a day. If necessary, the dose may be increased using 300 or
400 mg capsules, or 600 or 800 mg tablets three times a day up to 1800 mg/day. Dosages up to
2400 mg/day have been well tolerated in long-term clinical studies. Doses of 3600 mg/day have
also been administered to a small number of patients for a relatively short duration, and have
been well tolerated. The maximum time between doses in the TID schedule should not exceed 12
hours.
Pediatric Patients Age 3–12 years: The starting dose should range from 10-15 mg/kg/day in
3 divided doses, and the effective dose reached by upward titration over a period of
approximately 3 days. The effective dose of Neurontin in patients 5 years of age and older is
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25–35 mg/kg/day and given in divided doses (three times a day). The effective dose in pediatric
patients ages 3 and 4 years is 40 mg/kg/day and given in divided doses (three times a day) (see
CLINICAL PHARMACOLOGY, Pediatrics.) Neurontin® may be administered as the oral
solution, capsule, or tablet, or using combinations of these formulations. Dosages up to
50 mg/kg/day have been well-tolerated in a long-term clinical study. The maximum time interval
between doses should not exceed 12 hours.
It is not necessary to monitor gabapentin plasma concentrations to optimize Neurontin therapy.
Further, because there are no significant pharmacokinetic interactions among Neurontin and
other commonly used antiepileptic drugs, the addition of Neurontin does not alter the plasma
levels of these drugs appreciably.
If Neurontin is discontinued and/or an alternate anticonvulsant medication is added to the
therapy, this should be done gradually over a minimum of 1 week.
Dosage in Renal Impairment
Creatinine clearance is difficult to measure in outpatients. In patients with stable renal function,
creatinine clearance (CCr) can be reasonably well estimated using the equation of Cockcroft and
Gault:
for females CCr=(0.85)(140-age)(weight)/[(72)(SCr)]
for males CCr=(140-age)(weight)/[(72)(SCr)]
where age is in years, weight is in kilograms and SCr is serum creatinine in mg/dL.
Dosage adjustment in patients ≥12 years of age with compromised renal function or undergoing
hemodialysis is recommended as follows (see dosing recommendations above for effective doses
in each indication).
TABLE 6. Neurontin® Dosage Based on Renal Function
Renal Function
Total Daily
Dose Regimen
Creatinine Clearance
Dose Range
(mg)
(mL/min)
(mg/day)
≥60
900-3600
300 TID
400 TID
600 TID
800 TID 1200 TID
>30-59
400-1400
200 BID 300 BID 400 BID
500 BID
700 BID
>15-29
200-700
200 QD
300 QD
400 QD
500 QD
700 QD
15a
100-300
100 QD
125 QD
150 QD
200 QD
300 QD
Post-Hemodialysis Supplemental Dose (mg)b
Hemodialysis
125b
150b
200b
250b
350b
a
For patients with creatinine clearance <15 mL/min, reduce daily dose in proportion to creatinine clearance
(e.g., patients with a creatinine clearance of 7.5 mL/min should receive one-half the daily dose that patients
with a creatinine clearance of 15 mL/min receive).
b
Patients on hemodialysis should receive maintenance doses based on estimates of creatinine clearance as
indicated in the upper portion of the table and a supplemental post-hemodialysis dose administered after each
4 hours of hemodialysis as indicated in the lower portion of the table.
The use of Neurontin in patients <12 years of age with compromised renal function has not been
studied.
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Dosage in Elderly
Because elderly patients are more likely to have decreased renal function, care should be taken in
dose selection, and dose should be adjusted based on creatinine clearance values in these
patients.
HOW SUPPLIED
Neurontin (gabapentin) capsules, tablets and oral solution are supplied as follows:
100 mg capsules;
White hard gelatin capsules printed with “PD” on one side and “Neurontin/100 mg” on
the other; available in:
Bottles of 100: N 0071-0803-24
Unit dose 50’s: N 0071-0803-40
300 mg capsules;
Yellow hard gelatin capsules printed with “PD” on one side and “Neurontin/300 mg” on
the other; available in:
Bottles of 100: N 0071-0805-24
Unit dose 50’s: N 0071-0805-40
400 mg capsules;
Orange hard gelatin capsules printed with “PD” on one side and “Neurontin/400 mg” on
the other; available in:
Bottles of 100: N 0071-0806-24
Unit dose 50’s: N 0071-0806-40
600 mg tablets;
White elliptical film-coated scored tablets debossed with “NT” and “16” on one side;
available in:
Bottles of 100: N 0071-0513-24
800 mg tablets;
White elliptical film-coated scored tablets debossed with “NT” and “26” on one side;
available in:
Bottles of 100: N 0071-0401-24
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250 mg/5 mL oral solution;
Clear colorless to slightly yellow solution; each 5 mL of oral solution contains 250 mg of
gabapentin; available in:
Bottles containing 470 mL: N0071-2012-23
Storage (Capsules)
Store at 25°C (77°F); excursions permitted to 15° - 30°C (59° - 86°F) [see USP Controlled
Room Temperature].
Storage (Tablets)
Store at 25°C (77°F); excursions permitted to 15° - 30°C (59° - 86°F) [see USP Controlled
Room Temperature].
Storage (Oral Solution)
Store refrigerated, 2°-8°C (36°-46°F)
Rx only
Distributed by:
Α Parke-Davis
Division of Pfizer Inc, NY, NY 10017
LAB-0106-11.0
Revised July 2010
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MEDICATION GUIDE
NEURONTIN (Neu rŏn' tĭn)
(Gabapentin)
Capsules, Tablets, and Oral Solution
Read the Medication Guide before you start taking NEURONTIN and each time you get a refill.
There may be new information. This information does not take the place of talking to your
healthcare provider about your medical condition or treatment.
What is the most important information I should know about NEURONTIN?
Do not stop taking NEURONTIN without first talking to your healthcare provider.
Stopping NEURONTIN suddenly can cause serious problems.
NEURONTIN can cause serious side effects including:
1. Like other antiepileptic drugs, NEURONTIN may cause suicidal thoughts or actions
in a very small number of people, about 1 in 500.
Call a healthcare provider right away if you have any of these symptoms, especially if
they are new, worse, or worry you:
• thoughts about suicide or dying
• attempts to commit suicide
• new or worse depression
• new or worse anxiety
• feeling agitated or restless
• panic attacks
• trouble sleeping (insomnia)
• new or worse irritability
• acting aggressive, being angry, or violent
• acting on dangerous impulses
•
an extreme increase in activity and talking (mania)
•
other unusual changes in behavior or mood
How can I watch for early symptoms of suicidal thoughts and actions?
• Pay attention to any changes, especially sudden changes, in mood, behaviors,
thoughts, or feelings.
• Keep all follow-up visits with your healthcare provider as scheduled.
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Call your healthcare provider between visits as needed, especially if you are worried
about symptoms.
Do not stop taking NEURONTIN without first talking to a healthcare provider.
• Stopping NEURONTIN suddenly can cause serious problems. Stopping a seizure
medicine suddenly in a patient who has epilepsy can cause seizures that will not
stop (status epilepticus).
Suicidal thoughts or actions can be caused by things other than medicines. If you have
suicidal thoughts or actions, your healthcare provider may check for other causes.
2. Changes in behavior and thinking - Using NEURONTIN in children 3 to 12 years of
age can cause emotional changes, aggressive behavior, problems with concentration,
restlessness, changes in school performance, and hyperactivity.
What is NEURONTIN?
NEURONTIN is a prescription medicine used to treat:
• Pain from damaged nerves (postherpetic pain) that follows healing of shingles (a painful
rash that comes after a herpes zoster infection) in adults.
• Partial seizures when taken together with other medicines in adults and children
3 years of age and older.
Who should not take NEURONTIN?
Do not take NEURONTIN if you are allergic to gabapentin or any of the other ingredients in
NEURONTIN. See the end of this Medication Guide for a complete list of ingredients in
NEURONTIN.
What should I tell my healthcare provider before taking NEURONTIN?
Before taking NEURONTIN, tell your healthcare provider if you:
• have or have had kidney problems or are on hemodialysis
• have or have had depression, mood problems, or suicidal thoughts or behavior
• are pregnant or plan to become pregnant. It is not known if NEURONTIN can harm your
unborn baby. Tell your healthcare provider right away if you become pregnant while
taking NEURONTIN. You and your healthcare provider will decide if you should take
NEURONTIN while you are pregnant.
o If you become pregnant while taking NEURONTIN, talk to your healthcare
provider about registering with the North American Antiepileptic Drug
(NAAED) Pregnancy Registry. The purpose of this registry is to collect
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information about the safety of antiepileptic drugs during pregnancy. You can
enroll in this registry by calling 1-888-233-2334.
• are breast-feeding or plan to breast-feed. NEURONTIN can pass into breast milk. You
and your healthcare provider should decide how you will feed your baby while you take
NEURONTIN.
Tell your healthcare provider about all the medicines you take, including prescription and
non-prescription medicines, vitamins, and herbal supplements.
Taking NEURONTIN with certain other medicines can cause side effects or affect how well they
work. Do not start or stop other medicines without talking to your healthcare provider.
Know the medicines you take. Keep a list of them and show it to your healthcare provider and
pharmacist when you get a new medicine.
How should I take NEURONTIN?
• Take NEURONTIN exactly as prescribed. Your healthcare provider will tell you how
much NEURONTIN to take.
o Do not change your dose of NEURONTIN without talking to your healthcare
provider. If you break a tablet in half the unused half of the tablet should be
taken at your next scheduled dose. Half tablets not used within several days of
breaking should be thrown away. If taking capsules, always swallow them
whole with plenty of water.
• NEURONTIN can be taken with or without food. If you take an antacid containing
aluminum and magnesium, such as Maalox®, Mylanta®, Gelusil®, Gaviscon®, or Di-Gel®,
you should wait at least 2 hours before taking your next dose of NEURONTIN.
• If you take too much NEURONTIN, call your healthcare provider or your local Poison
Control Center right away.
What should I avoid while taking NEURONTIN?
• Do not drink alcohol or take other medicines that make you sleepy or dizzy while taking
NEURONTIN without first talking with your healthcare provider. Taking NEURONTIN
with alcohol or drugs that cause sleepiness or dizziness may make your sleepiness or
dizziness worse.
• Do not drive, operate heavy machinery, or do other dangerous activities until you know
how NEURONTIN affects you. NEURONTIN can slow your thinking and motor skills.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
What are the possible side effects of NEURONTIN?
•
See “What is the most important information I should know about NEURONTIN?”
•
The most common side effects of NEURONTIN include:
•
dizziness
• difficulty with speaking
• lack of coordination
•
temporary loss of memory
(amnesia)
•
viral infection
•
tremor
•
feeling drowsy
•
difficulty with coordination
•
feeling tired
•
double vision
•
fever
•
unusual eye movement
•
jerky movements
Tell your healthcare provider if you have any side effect that bothers you or that does not go
away.
These are not all the possible side effects of NEURONTIN. For more information, ask your
healthcare provider or pharmacist.
Call your doctor for medical advice about side effects. You may report side effects to FDA
at 1-800-FDA-1088.
How should I store NEURONTIN?
• Store NEURONTIN Capsules between 59°F to 86°F (15°C to 30°C).
• Store NEURONTIN Tablets between 59°F to 86°F (15°C to 30°C).
• Store NEURONTIN Oral Solution in the refrigerator between 36°F to 46°F (2°C to 8°C).
Keep NEURONTIN and all medicines out of the reach of children.
General information about the safe and effective use of NEURONTIN
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide.
Do not use NEURONTIN for a condition for which it was not prescribed. Do not give
NEURONTIN to other people, even if they have the same symptoms that you have. It may harm
them.
This Medication Guide summarizes the most important information about NEURONTIN. If you
would like more information, talk with your healthcare provider. You can ask your healthcare
provider or pharmacist for information about NEURONTIN that was written for healthcare
professionals.
For more information about NEURONTIN, go to http://www.pfizer.com. For medical inquiries
or to report side effects regarding Neurontin, please call 1-800-438-1985.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
What are the ingredients in NEURONTIN?
Active ingredient: gabapentin
Inactive ingredients in the capsules: lactose, cornstarch, and talc.
The 100-mg capsule shell also contains: gelatin and titanium dioxide.
The 300-mg capsule shell also contains: gelatin, titanium dioxide, and yellow iron oxide.
The 400-mg capsule shell also contains: gelatin, red iron oxide, titanium dioxide, and yellow iron
oxide. The imprinting ink contains FD&C Blue No. 2 and titanium dioxide.
Inactive ingredients in the tablets: poloxamer 407, copolyvidonum, cornstarch, magnesium
stearate, hydroxypropyl cellulose, talc, candelilla wax, and purified water.
Inactive ingredients in the oral solution: glycerin, xylitol, purified water, and artificial flavor.
This Medication Guide has been approved by the U.S. Food and Drug Administration. Pfizer
LAB-0397-1.0
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:47:09.360180
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020235s043lbl.pdf', 'application_number': 20235, 'submission_type': 'SUPPL ', 'submission_number': 43}
|
12,347
|
NDA 020235/S-054, S-055, S-056
NDA 020882/S-038, S-039, S-040
NDA 021129/S-035, S-036, S-037
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Page 1 of 37
Neurontin® (gabapentin) Capsules
Neurontin® (gabapentin) Tablets
Neurontin® (gabapentin) Oral Solution
DESCRIPTION
Neurontin® (gabapentin) Capsules, Neurontin (gabapentin) Tablets, and Neurontin (gabapentin)
Oral Solution are supplied as imprinted hard shell capsules containing 100 mg,
300 mg, and 400 mg of gabapentin, elliptical film-coated tablets containing 600 mg and 800 mg
of gabapentin or an oral solution containing 250 mg/5 mL of gabapentin.
The inactive ingredients for the capsules are lactose, cornstarch, and talc. The 100 mg capsule
shell contains gelatin and titanium dioxide. The 300 mg capsule shell contains gelatin, titanium
dioxide, and yellow iron oxide. The 400 mg capsule shell contains gelatin, red iron oxide,
titanium dioxide, and yellow iron oxide. The imprinting ink contains FD&C Blue No. 2 and
titanium dioxide.
The inactive ingredients for the tablets are poloxamer 407, copolyvidonum, cornstarch,
magnesium stearate, hydroxypropyl cellulose, talc, candelilla wax, and purified water.
The inactive ingredients for the oral solution are glycerin, xylitol, purified water, and artificial
cool strawberry anise flavor.
Gabapentin is described as 1-(aminomethyl) cyclohexaneacetic acid with a molecular formula of
C9H17NO2 and a molecular weight of 171.24. The structural formula of gabapentin is: structural formula
Gabapentin is a white to off-white crystalline solid with a pKa1 of 3.7 and a pKa2 of 10.7. It is
freely soluble in water and both basic and acidic aqueous solutions. The log of the partition
coefficient (n-octanol/0.05M phosphate buffer) at pH 7.4 is –1.25.
CLINICAL PHARMACOLOGY
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NDA 021129/S-035, S-036, S-037
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Mechanism of Action
The mechanism by which gabapentin exerts its analgesic action is unknown, but in animal
models of analgesia, gabapentin prevents allodynia (pain-related behavior in response to a
normally innocuous stimulus) and hyperalgesia (exaggerated response to painful stimuli). In
particular, gabapentin prevents pain-related responses in several models of neuropathic pain in
rats or mice (e.g., spinal nerve ligation models, streptozocin-induced diabetes model, spinal cord
injury model, acute herpes zoster infection model). Gabapentin also decreases pain-related
responses after peripheral inflammation (carrageenan footpad test, late phase of formalin test).
Gabapentin did not alter immediate pain-related behaviors (rat tail flick test, formalin footpad
acute phase, acetic acid abdominal constriction test, footpad heat irradiation test). The relevance
of these models to human pain is not known.
The mechanism by which gabapentin exerts its anticonvulsant action is unknown, but in animal
test systems designed to detect anticonvulsant activity, gabapentin prevents seizures as do other
marketed anticonvulsants. Gabapentin exhibits antiseizure activity in mice and rats in both the
maximal electroshock and pentylenetetrazole seizure models and other preclinical models (e.g.,
strains with genetic epilepsy, etc.). The relevance of these models to human epilepsy is not
known.
Gabapentin is structurally related to the neurotransmitter GABA (gamma-aminobutyric acid) but
it does not modify GABAA or GABAB radioligand binding, it is not converted metabolically into
GABA or a GABA agonist, and it is not an inhibitor of GABA uptake or degradation.
Gabapentin was tested in radioligand binding assays at concentrations up to 100 µM and did not
exhibit affinity for a number of other common receptor sites, including benzodiazepine,
glutamate, N-methyl-D-aspartate (NMDA), quisqualate, kainate, strychnine-insensitive or
strychnine-sensitive glycine, alpha 1, alpha 2, or beta adrenergic, adenosine A1 or A2,
cholinergic muscarinic or nicotinic, dopamine D1 or D2, histamine H1, serotonin S1 or S2,
opiate mu, delta or kappa, cannabinoid 1, voltage-sensitive calcium channel sites labeled with
nitrendipine or diltiazem, or at voltage-sensitive sodium channel sites labeled with
batrachotoxinin A 20-alpha-benzoate. Furthermore, gabapentin did not alter the cellular uptake
of dopamine, noradrenaline, or serotonin.
In vitro studies with radiolabeled gabapentin have revealed a gabapentin binding site in areas of
rat brain including neocortex and hippocampus. A high-affinity binding protein in animal brain
tissue has been identified as an auxiliary subunit of voltage-activated calcium channels.
However, functional correlates of gabapentin binding, if any, remain to be elucidated.
Pharmacokinetics and Drug Metabolism
All pharmacological actions following gabapentin administration are due to the activity of the
parent compound; gabapentin is not appreciably metabolized in humans.
Oral Bioavailability: Gabapentin bioavailability is not dose proportional; i.e., as dose is
increased, bioavailability decreases. Bioavailability of gabapentin is approximately 60%, 47%,
34%, 33%, and 27% following 900, 1200, 2400, 3600, and 4800 mg/day given in 3 divided
Reference ID: 3301312
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NDA 020235/S-054, S-055, S-056
NDA 020882/S-038, S-039, S-040
NDA 021129/S-035, S-036, S-037
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doses, respectively. Food has only a slight effect on the rate and extent of absorption of
gabapentin (14% increase in AUC and Cmax).
Distribution: Less than 3% of gabapentin circulates bound to plasma protein. The apparent
volume of distribution of gabapentin after 150 mg intravenous administration is 58±6 L (mean
±SD). In patients with epilepsy, steady-state predose (Cmin) concentrations of gabapentin in
cerebrospinal fluid were approximately 20% of the corresponding plasma concentrations.
Elimination: Gabapentin is eliminated from the systemic circulation by renal excretion as
unchanged drug. Gabapentin is not appreciably metabolized in humans.
Gabapentin elimination half-life is 5 to 7 hours and is unaltered by dose or following multiple
dosing. Gabapentin elimination rate constant, plasma clearance, and renal clearance are directly
proportional to creatinine clearance (see CLINICAL PHARMACOLOGY, Special
Populations: Adult Patients With Renal Insufficiency, below). In elderly patients, and in patients
with impaired renal function, gabapentin plasma clearance is reduced. Gabapentin can be
removed from plasma by hemodialysis.
Dosage adjustment in patients with compromised renal function or undergoing hemodialysis is
recommended (see DOSAGE AND ADMINISTRATION, Table 6).
Special Populations: Adult Patients With Renal Insufficiency: Subjects (N=60) with renal
insufficiency (mean creatinine clearance ranging from 13-114 mL/min) were administered single
400 mg oral doses of gabapentin. The mean gabapentin half-life ranged from about 6.5 hours
(patients with creatinine clearance >60 mL/min) to 52 hours (creatinine clearance <30 mL/min)
and gabapentin renal clearance from about 90 mL/min (>60 mL/min group) to about 10 mL/min
(<30 mL/min). Mean plasma clearance (CL/F) decreased from approximately 190 mL/min to
20 mL/min.
Dosage adjustment in adult patients with compromised renal function is necessary (see
DOSAGE AND ADMINISTRATION). Pediatric patients with renal insufficiency have not
been studied.
Hemodialysis: In a study in anuric adult subjects (N=11), the apparent elimination half-life of
gabapentin on nondialysis days was about 132 hours; during dialysis the apparent half-life of
gabapentin was reduced to 3.8 hours. Hemodialysis thus has a significant effect on gabapentin
elimination in anuric subjects.
Dosage adjustment in patients undergoing hemodialysis is necessary (see DOSAGE AND
ADMINISTRATION).
Hepatic Disease: Because gabapentin is not metabolized, no study was performed in patients
with hepatic impairment.
Age: The effect of age was studied in subjects 20-80 years of age. Apparent oral clearance
(CL/F) of gabapentin decreased as age increased, from about 225 mL/min in those under 30
years of age to about 125 mL/min in those over 70 years of age. Renal clearance (CLr) and CLr
adjusted for body surface area also declined with age; however, the decline in the renal clearance
of gabapentin with age can largely be explained by the decline in renal function. Reduction of
Reference ID: 3301312
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NDA 021129/S-035, S-036, S-037
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gabapentin dose may be required in patients who have age related compromised renal function.
(See PRECAUTIONS, Geriatric Use, and DOSAGE AND ADMINISTRATION.)
Pediatric: Gabapentin pharmacokinetics were determined in 48 pediatric subjects between the
ages of 1 month and 12 years following a dose of approximately 10 mg/kg. Peak plasma
concentrations were similar across the entire age group and occurred 2 to 3 hours postdose. In
general, pediatric subjects between 1 month and <5 years of age achieved approximately 30%
lower exposure (AUC) than that observed in those 5 years of age and older. Accordingly, oral
clearance normalized per body weight was higher in the younger children. Apparent oral
clearance of gabapentin was directly proportional to creatinine clearance. Gabapentin elimination
half-life averaged 4.7 hours and was similar across the age groups studied.
A population pharmacokinetic analysis was performed in 253 pediatric subjects between 1 month
and 13 years of age. Patients received 10 to 65 mg/kg/day given TID. Apparent oral clearance
(CL/F) was directly proportional to creatinine clearance and this relationship was similar
following a single dose and at steady state. Higher oral clearance values were observed in
children <5 years of age compared to those observed in children 5 years of age and older, when
normalized per body weight. The clearance was highly variable in infants <1 year of age. The
normalized CL/F values observed in pediatric patients 5 years of age and older were consistent
with values observed in adults after a single dose. The oral volume of distribution normalized per
body weight was constant across the age range.
These pharmacokinetic data indicate that the effective daily dose in pediatric patients with
epilepsy ages 3 and 4 years should be 40 mg/kg/day to achieve average plasma concentrations
similar to those achieved in patients 5 years of age and older receiving gabapentin at 30
mg/kg/day (see DOSAGE AND ADMINISTRATION).
Gender: Although no formal study has been conducted to compare the pharmacokinetics of
gabapentin in men and women, it appears that the pharmacokinetic parameters for males and
females are similar and there are no significant gender differences.
Race: Pharmacokinetic differences due to race have not been studied. Because gabapentin is
primarily renally excreted and there are no important racial differences in creatinine clearance,
pharmacokinetic differences due to race are not expected.
Clinical Studies
Postherpetic Neuralgia
Neurontin was evaluated for the management of postherpetic neuralgia (PHN) in 2 randomized,
double-blind, placebo-controlled, multicenter studies; N=563 patients in the intent-to-treat (ITT)
population (Table 1). Patients were enrolled if they continued to have pain for more than 3
months after healing of the herpes zoster skin rash.
TABLE 1. Controlled PHN Studies: Duration, Dosages, and
Number of Patients
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Study
Study
Duration
Gabapentin
(mg/day)a
Target Dose
Patients
Receiving
Gabapentin
Patients
Receiving
Placebo
1
8 weeks
3600
113
116
2
7 weeks
1800, 2400
223
111
Total
336
227
aGiven in 3 divided doses (TID)
Each study included a 1-week baseline during which patients were screened for eligibility and a
7- or 8-week double-blind phase (3 or 4 weeks of titration and 4 weeks of fixed dose). Patients
initiated treatment with titration to a maximum of 900 mg/day gabapentin over 3 days. Dosages
were then to be titrated in 600 to 1200 mg/day increments at 3- to 7-day intervals to target dose
over 3 to 4 weeks. In Study 1, patients were continued on lower doses if not able to achieve the
target dose. During baseline and treatment, patients recorded their pain in a daily diary using an
11-point numeric pain rating scale ranging from 0 (no pain) to 10 (worst possible pain). A mean
pain score during baseline of at least 4 was required for randomization (baseline mean pain score
for Studies 1 and 2 combined was 6.4). Analyses were conducted using the ITT population (all
randomized patients who received at least one dose of study medication).
Both studies showed significant differences from placebo at all doses tested.
A significant reduction in weekly mean pain scores was seen by Week 1 in both studies, and
significant differences were maintained to the end of treatment. Comparable treatment effects
were observed in all active treatment arms. Pharmacokinetic/pharmacodynamic modeling
provided confirmatory evidence of efficacy across all doses. Figures 1 and 2 show these changes
for Studies 1 and 2.
Reference ID: 3301312
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g
r
a
p
h
g
r
a
p
h
NDA 020235/S-054, S-055, S-056
NDA 020882/S-038, S-039, S-040
NDA 021129/S-035, S-036, S-037
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Figure 1. Weekly Mean Pain Scores (Observed Cases in ITT Population): Study 1
Figure 2. Weekly Mean Pain Scores (Observed Cases in ITT Population): Study 2
Reference ID: 3301312
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gr
aph
NDA 020235/S-054, S-055, S-056
NDA 020882/S-038, S-039, S-040
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FDA Approved Labeling Text dated 05/01/2013
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The proportion of responders (those patients reporting at least 50% improvement in endpoint
pain score compared with baseline) was calculated for each study (Figure 3).
3600
1800
2400
Study 1
Study 2
Figure 3. Proportion of Responders (patients with ≥50% reduction in pain score) at
Endpoint: Controlled PHN Studies
Epilepsy
The effectiveness of Neurontin as adjunctive therapy (added to other antiepileptic drugs) was
established in multicenter placebo-controlled, double-blind, parallel-group clinical trials in adult
and pediatric patients (3 years and older) with refractory partial seizures.
Evidence of effectiveness was obtained in three trials conducted in 705 patients (age 12 years
and above) and one trial conducted in 247 pediatric patients (3 to 12 years of age). The patients
enrolled had a history of at least 4 partial seizures per month in spite of receiving one or more
antiepileptic drugs at therapeutic levels and were observed on their established antiepileptic drug
regimen during a 12-week baseline period (6 weeks in the study of pediatric patients). In patients
continuing to have at least 2 (or 4 in some studies) seizures per month, Neurontin or placebo was
then added on to the existing therapy during a 12-week treatment period. Effectiveness was
assessed primarily on the basis of the percent of patients with a 50% or greater reduction in
seizure frequency from baseline to treatment (the “responder rate”) and a derived measure called
Reference ID: 3301312
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NDA 021129/S-035, S-036, S-037
FDA Approved Labeling Text dated 05/01/2013
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response ratio, a measure of change defined as (T - B)/(T + B), in which B is the patient’s
baseline seizure frequency and T is the patient’s seizure frequency during treatment. Response
ratio is distributed within the range -1 to +1. A zero value indicates no change while complete
elimination of seizures would give a value of -1; increased seizure rates would give positive
values. A response ratio of -0.33 corresponds to a 50% reduction in seizure frequency. The
results given below are for all partial seizures in the intent-to-treat (all patients who received any
doses of treatment) population in each study, unless otherwise indicated.
One study compared Neurontin 1200 mg/day divided TID with placebo. Responder rate was
23% (14/61) in the Neurontin group and 9% (6/66) in the placebo group; the difference between
groups was statistically significant. Response ratio was also better in the Neurontin group
(-0.199) than in the placebo group (-0.044), a difference that also achieved statistical
significance.
A second study compared primarily 1200 mg/day divided TID Neurontin (N=101) with placebo
(N=98). Additional smaller Neurontin dosage groups (600 mg/day, N=53; 1800 mg/day, N=54)
were also studied for information regarding dose response. Responder rate was higher in the
Neurontin 1200 mg/day group (16%) than in the placebo group (8%), but the difference was not
statistically significant. The responder rate at 600 mg (17%) was also not significantly higher
than in the placebo, but the responder rate in the 1800 mg group (26%) was statistically
significantly superior to the placebo rate. Response ratio was better in the Neurontin
1200 mg/day group (-0.103) than in the placebo group (-0.022); but this difference was also not
statistically significant (p = 0.224). A better response was seen in the Neurontin 600 mg/day
group (-0.105) and 1800 mg/day group (-0.222) than in the 1200 mg/day group, with the
1800 mg/day group achieving statistical significance compared to the placebo group.
A third study compared Neurontin 900 mg/day divided TID (N=111) and placebo (N=109). An
additional Neurontin 1200 mg/day dosage group (N=52) provided dose-response data. A
statistically significant difference in responder rate was seen in the Neurontin 900 mg/day group
(22%) compared to that in the placebo group (10%). Response ratio was also statistically
significantly superior in the Neurontin 900 mg/day group (-0.119) compared to that in the
placebo group (-0.027), as was response ratio in 1200 mg/day Neurontin (-0.184) compared to
placebo.
Analyses were also performed in each study to examine the effect of Neurontin on preventing
secondarily generalized tonic-clonic seizures. Patients who experienced a secondarily
generalized tonic-clonic seizure in either the baseline or in the treatment period in all three
placebo-controlled studies were included in these analyses. There were several response ratio
comparisons that showed a statistically significant advantage for Neurontin compared to placebo
and favorable trends for almost all comparisons.
Analysis of responder rate using combined data from all three studies and all doses (N=162,
Neurontin; N=89, placebo) also showed a significant advantage for Neurontin over placebo in
reducing the frequency of secondarily generalized tonic-clonic seizures.
Reference ID: 3301312
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NDA 021129/S-035, S-036, S-037
FDA Approved Labeling Text dated 05/01/2013
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In two of the three controlled studies, more than one dose of Neurontin was used. Within each
study, the results did not show a consistently increased response to dose. However, looking
across studies, a trend toward increasing efficacy with increasing dose is evident (see Figure 4). graph
Figure 4. Responder Rate in Patients Receiving Neurontin Expressed as a Difference from
Placebo by Dose and Study: Adjunctive Therapy Studies in Patients ≥12 Years of
Age with Partial Seizures
In the figure, treatment effect magnitude, measured on the Y axis in terms of the difference in the
proportion of gabapentin and placebo-assigned patients attaining a 50% or greater reduction in
seizure frequency from baseline, is plotted against the daily dose of gabapentin administered
(X axis).
Although no formal analysis by gender has been performed, estimates of response (Response
Ratio) derived from clinical trials (398 men, 307 women) indicate no important gender
differences exist. There was no consistent pattern indicating that age had any effect on the
response to Neurontin. There were insufficient numbers of patients of races other than Caucasian
to permit a comparison of efficacy among racial groups.
A fourth study in pediatric patients age 3 to 12 years compared 25 - 35 mg/kg/day Neurontin
(N=118) with placebo (N=127). For all partial seizures in the intent-to-treat population, the
response ratio was statistically significantly better for the Neurontin group (-0.146) than for the
placebo group (-0.079). For the same population, the responder rate for Neurontin (21%) was not
significantly different from placebo (18%).
A study in pediatric patients age 1 month to 3 years compared 40 mg/kg/day Neurontin (N=38)
with placebo (N=38) in patients who were receiving at least one marketed antiepileptic drug and
had at least one partial seizure during the screening period (within 2 weeks prior to baseline).
Patients had up to 48 hours of baseline and up to 72 hours of double-blind video EEG monitoring
Reference ID: 3301312
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NDA 021129/S-035, S-036, S-037
FDA Approved Labeling Text dated 05/01/2013
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to record and count the occurrence of seizures. There were no statistically significant differences
between treatments in either the response ratio or responder rate.
INDICATIONS AND USAGE
Postherpetic Neuralgia
Neurontin (gabapentin) is indicated for the management of postherpetic neuralgia in adults.
Epilepsy
Neurontin (gabapentin) is indicated as adjunctive therapy in the treatment of partial seizures with
and without secondary generalization in patients over 12 years of age with epilepsy. Neurontin is
also indicated as adjunctive therapy in the treatment of partial seizures in pediatric patients age 3
– 12 years.
CONTRAINDICATIONS
Neurontin is contraindicated in patients who have demonstrated hypersensitivity to the drug or
its ingredients.
WARNINGS
Suicidal Behavior and Ideation
Antiepileptic drugs (AEDs), including Neurontin, increase the risk of suicidal thoughts or
behavior in patients taking these drugs for any indication. Patients treated with any AED for any
indication should be monitored for the emergence or worsening of depression, suicidal thoughts
or behavior, and/or any unusual changes in mood or behavior.
Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11
different AEDs showed that patients randomized to one of the AEDs had approximately twice
the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared
to patients randomized to placebo. In these trials, which had a median treatment duration of 12
weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated
patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an
increase of approximately one case of suicidal thinking or behavior for every 530 patients
treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated
patients, but the number is too small to allow any conclusion about drug effect on suicide.
The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one
week after starting drug treatment with AEDs and persisted for the duration of treatment
assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk
of suicidal thoughts or behavior beyond 24 weeks could not be assessed.
Reference ID: 3301312
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NDA 021129/S-035, S-036, S-037
FDA Approved Labeling Text dated 05/01/2013
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The risk of suicidal thoughts or behavior was generally consistent among drugs in the data
analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a
range of indications suggests that the risk applies to all AEDs used for any indication. The risk
did not vary substantially by age (5-100 years) in the clinical trials analyzed. Table 2 shows
absolute and relative risk by indication for all evaluated AEDs.
Table 2
Risk by indication for antiepileptic drugs in the pooled analysis
Indication
Placebo Patients Drug Patients
Relative Risk:
Risk Difference:
with Events Per
with Events Per
Incidence of Events in
Additional Drug
1000 Patients
1000 Patients
Drug
Patients with
Patients/Incidence in
Events Per 1000
Placebo Patients
Patients
Epilepsy
1.0
3.4
3.5
2.4
Psychiatric
5.7
8.5
1.5
2.9
Other
1.0
1.8
1.9
0.9
Total
2.4
4.3
1.8
1.9
The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in
clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for
the epilepsy and psychiatric indications.
Anyone considering prescribing Neurontin or any other AED must balance the risk of suicidal
thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for
which AEDs are prescribed are themselves associated with morbidity and mortality and an
increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge
during treatment, the prescriber needs to consider whether the emergence of these symptoms in
any given patient may be related to the illness being treated.
Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal
thoughts and behavior and should be advised of the need to be alert for the emergence or
worsening of the signs and symptoms of depression, any unusual changes in mood or behavior,
or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of
concern should be reported immediately to healthcare providers.
Neuropsychiatric Adverse Events-Pediatric Patients 3-12 years of age
Gabapentin use in pediatric patients with epilepsy 3-12 years of age is associated with the
occurrence of central nervous system related adverse events. The most significant of these can be
classified into the following categories: 1) emotional lability (primarily behavioral problems),
2) hostility, including aggressive behaviors, 3) thought disorder, including concentration
problems and change in school performance, and 4) hyperkinesia (primarily restlessness and
hyperactivity). Among the gabapentin-treated patients, most of the events were mild to moderate
in intensity.
Reference ID: 3301312
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FDA Approved Labeling Text dated 05/01/2013
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In controlled trials in pediatric patients 3–12 years of age, the incidence of these adverse events
was: emotional lability 6% (gabapentin-treated patients) vs. 1.3% (placebo-treated patients);
hostility 5.2% vs. 1.3%; hyperkinesia 4.7% vs. 2.9%; and thought disorder 1.7% vs. 0%. One of
these events, a report of hostility, was considered serious. Discontinuation of gabapentin
treatment occurred in 1.3% of patients reporting emotional lability and hyperkinesia and 0.9% of
gabapentin-treated patients reporting hostility and thought disorder. One placebo-treated patient
(0.4%) withdrew due to emotional lability.
Withdrawal Precipitated Seizure, Status Epilepticus
Antiepileptic drugs should not be abruptly discontinued because of the possibility of increasing
seizure frequency.
In the placebo-controlled studies in patients >12 years of age, the incidence of status epilepticus
in patients receiving Neurontin was 0.6% (3 of 543) vs. 0.5% in patients receiving placebo (2 of
378). Among the 2074 patients >12 years of age treated with Neurontin across all studies
(controlled and uncontrolled), 31 (1.5%) had status epilepticus. Of these, 14 patients had no prior
history of status epilepticus either before treatment or while on other medications. Because
adequate historical data are not available, it is impossible to say whether or not treatment with
Neurontin is associated with a higher or lower rate of status epilepticus than would be expected
to occur in a similar population not treated with Neurontin.
Tumorigenic Potential
In standard preclinical in vivo lifetime carcinogenicity studies, an unexpectedly high incidence of
pancreatic acinar adenocarcinomas was identified in male, but not female, rats. (See
PRECAUTIONS, Carcinogenesis, Mutagenesis, Impairment of Fertility.) The clinical
significance of this finding is unknown. Clinical experience during gabapentin’s premarketing
development provides no direct means to assess its potential for inducing tumors in humans.
In clinical studies in adjunctive therapy in epilepsy comprising 2085 patient-years of exposure in
patients >12 years of age, new tumors were reported in 10 patients (2 breast, 3 brain, 2 lung, 1
adrenal, 1 non-Hodgkin’s lymphoma, 1 endometrial carcinoma in situ), and preexisting tumors
worsened in 11 patients (9 brain, 1 breast, 1 prostate) during or up to 2 years following
discontinuation of Neurontin. Without knowledge of the background incidence and recurrence in
a similar population not treated with Neurontin, it is impossible to know whether the incidence
seen in this cohort is or is not affected by treatment.
Sudden and Unexplained Death in Patients With Epilepsy
During the course of premarketing development of Neurontin, 8 sudden and unexplained deaths
were recorded among a cohort of 2203 patients treated (2103 patient-years of exposure).
Some of these could represent seizure-related deaths in which the seizure was not observed, e.g.,
at night. This represents an incidence of 0.0038 deaths per patient-year. Although this rate
exceeds that expected in a healthy population matched for age and sex, it is within the range of
estimates for the incidence of sudden unexplained deaths in patients with epilepsy not receiving
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FDA Approved Labeling Text dated 05/01/2013
Page 13 of 37
Neurontin (ranging from 0.0005 for the general population of epileptics to 0.003 for a clinical
trial population similar to that in the Neurontin program, to 0.005 for patients with refractory
epilepsy). Consequently, whether these figures are reassuring or raise further concern depends on
comparability of the populations reported upon to the Neurontin cohort and the accuracy of the
estimates provided.
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan
hypersensitivity
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as Multiorgan
hypersensitivity, has been reported in patients taking antiepileptic drugs, including Neurontin.
Some of these events have been fatal or life-threatening. DRESS typically, although not
exclusively, presents with fever, rash, and/or lymphadenopathy, in association with other organ
system involvement, such as hepatitis, nephritis, hematological abnormalities, myocarditis, or
myositis sometimes resembling an acute viral infection. Eosinophilia is often present. Because
this disorder is variable in its expression, other organ systems not noted here may be involved.
It is important to note that early manifestations of hypersensitivity, such as fever or
lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are
present, the patient should be evaluated immediately. Neurontin should be discontinued if an
alternative etiology for the signs or symptoms cannot be established.
PRECAUTIONS
Information for Patients
Inform patients of the availability of a Medication Guide, and instruct them to read the
Medication Guide prior to taking Neurontin. Instruct patients to take Neurontin only as
prescribed.
Patients, their caregivers, and families should be counseled that AEDs, including Neurontin, may
increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert
for the emergence or worsening of symptoms of depression, any unusual changes in mood or
behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm.
Behaviors of concern should be reported immediately to healthcare providers.
Patients should be advised that Neurontin may cause dizziness, somnolence, and other symptoms
and signs of CNS depression. Accordingly, they should be advised neither to drive a car nor to
operate other complex machinery until they have gained sufficient experience on Neurontin to
gauge whether or not it affects their mental and/or motor performance adversely.
Patients who require concomitant treatment with morphine may experience increases in
gabapentin concentrations. Patients should be carefully observed for signs of CNS depression,
such as somnolence, and the dose of Neurontin or morphine should be reduced appropriately (see
PRECAUTIONS, Drug Interactions).
Patients should be encouraged to enroll in the North American Antiepileptic Drug (NAAED)
Pregnancy Registry if they become pregnant. This registry is collecting information about the
Reference ID: 3301312
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NDA 020235/S-054, S-055, S-056
NDA 020882/S-038, S-039, S-040
NDA 021129/S-035, S-036, S-037
FDA Approved Labeling Text dated 05/01/2013
Page 14 of 37
safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll free number 1
888-233-2334 (see PRECAUTIONS, Pregnancy).
Prior to initiation of treatment with Neurontin, the patient should be instructed that a rash or
other signs or symptoms of hypersensitivity (such as fever or lymphadenopathy) may herald a
serious medical event and that the patient should report any such occurrence to a physician
immediately.
Laboratory Tests
Clinical trials data do not indicate that routine monitoring of clinical laboratory parameters is
necessary for the safe use of Neurontin. The value of monitoring gabapentin blood
concentrations has not been established. Neurontin may be used in combination with other
antiepileptic drugs without concern for alteration of the blood concentrations of gabapentin or of
other antiepileptic drugs.
Drug Interactions
In vitro studies were conducted to investigate the potential of gabapentin to inhibit the major
cytochrome P450 enzymes (CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and
CYP3A4) that mediate drug and xenobiotic metabolism using isoform selective marker
substrates and human liver microsomal preparations. Only at the highest concentration tested
(171 μg/mL; 1 mM) was a slight degree of inhibition (14%-30%) of isoform CYP2A6 observed.
No inhibition of any of the other isoforms tested was observed at gabapentin concentrations up to
171 μg/mL (approximately 15 times the Cmax at 3600 mg/day).
Gabapentin is not appreciably metabolized nor does it interfere with the metabolism of
commonly coadministered antiepileptic drugs.
The drug interaction data described in this section were obtained from studies involving healthy
adults and adult patients with epilepsy.
Phenytoin: In a single (400 mg) and multiple dose (400 mg TID) study of Neurontin in epileptic
patients (N=8) maintained on phenytoin monotherapy for at least 2 months, gabapentin had no
effect on the steady-state trough plasma concentrations of phenytoin and phenytoin had no effect
on gabapentin pharmacokinetics.
Carbamazepine: Steady-state trough plasma carbamazepine and carbamazepine 10, 11 epoxide
concentrations were not affected by concomitant gabapentin (400 mg TID; N=12)
administration. Likewise, gabapentin pharmacokinetics were unaltered by carbamazepine
administration.
Valproic Acid: The mean steady-state trough serum valproic acid concentrations prior to and
during concomitant gabapentin administration (400 mg TID; N=17) were not different and
neither were gabapentin pharmacokinetic parameters affected by valproic acid.
Phenobarbital: Estimates of steady-state pharmacokinetic parameters for phenobarbital or
gabapentin (300 mg TID; N=12) are identical whether the drugs are administered alone or
together.
Reference ID: 3301312
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NDA 021129/S-035, S-036, S-037
FDA Approved Labeling Text dated 05/01/2013
Page 15 of 37
Naproxen: Coadministration (N=18) of naproxen sodium capsules (250 mg) with Neurontin
(125 mg) appears to increase the amount of gabapentin absorbed by 12% to 15%. Gabapentin
had no effect on naproxen pharmacokinetic parameters. These doses are lower than the
therapeutic doses for both drugs. The magnitude of interaction within the recommended dose
ranges of either drug is not known.
Hydrocodone: Coadministration of Neurontin (125 to 500 mg; N=48) decreases hydrocodone
(10 mg; N=50) Cmax and AUC values in a dose-dependent manner relative to administration of
hydrocodone alone; Cmax and AUC values are 3% to 4% lower, respectively, after administration
of 125 mg Neurontin and 21% to 22% lower, respectively, after administration of 500 mg
Neurontin. The mechanism for this interaction is unknown. Hydrocodone increases gabapentin
AUC values by 14%. The magnitude of interaction at other doses is not known.
Morphine: A literature article reported that when a 60 mg controlled-release morphine capsule
was administered 2 hours prior to a 600 mg Neurontin capsule (N=12), mean gabapentin AUC
increased by 44% compared to gabapentin administered without morphine (see
PRECAUTIONS). Morphine pharmacokinetic parameter values were not affected by
administration of Neurontin 2 hours after morphine. The magnitude of interaction at other doses
is not known.
Cimetidine: In the presence of cimetidine at 300 mg QID (N=12), the mean apparent oral
clearance of gabapentin fell by 14% and creatinine clearance fell by 10%. Thus, cimetidine
appeared to alter the renal excretion of both gabapentin and creatinine, an endogenous marker of
renal function. This small decrease in excretion of gabapentin by cimetidine is not expected to be
of clinical importance. The effect of gabapentin on cimetidine was not evaluated.
Oral Contraceptive: Based on AUC and half-life, multiple-dose pharmacokinetic profiles of
norethindrone and ethinyl estradiol following administration of tablets containing 2.5 mg of
norethindrone acetate and 50 mcg of ethinyl estradiol were similar with and without
coadministration of gabapentin (400 mg TID; N=13). The Cmax of norethindrone was 13% higher
when it was coadministered with gabapentin; this interaction is not expected to be of clinical
importance.
Antacid (Maalox®): Maalox reduced the bioavailability of gabapentin (N=16) by about 20%.
This decrease in bioavailability was about 5% when gabapentin was administered 2 hours after
Maalox. It is recommended that gabapentin be taken at least 2 hours following Maalox
administration.
Effect of Probenecid: Probenecid is a blocker of renal tubular secretion. Gabapentin
pharmacokinetic parameters without and with probenecid were comparable. This indicates that
gabapentin does not undergo renal tubular secretion by the pathway that is blocked by
probenecid.
Drug/Laboratory Test Interactions
Because false positive readings were reported with the Ames N-Multistix SG® dipstick test for
urinary protein when gabapentin was added to other antiepileptic drugs, the more specific
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FDA Approved Labeling Text dated 05/01/2013
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sulfosalicylic acid precipitation procedure is recommended to determine the presence of urine
protein.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Gabapentin was given in the diet to mice at 200, 600, and 2000 mg/kg/day and to rats at 250,
1000, and 2000 mg/kg/day for 2 years. A statistically significant increase in the incidence of
pancreatic acinar cell adenomas and carcinomas was found in male rats receiving the high dose;
the no-effect dose for the occurrence of carcinomas was 1000 mg/kg/day. Peak plasma
concentrations of gabapentin in rats receiving the high dose of 2000 mg/kg were 10 times higher
than plasma concentrations in humans receiving 3600 mg per day, and in rats receiving
1000 mg/kg/day, peak plasma concentrations were 6.5 times higher than in humans receiving
3600 mg/day. The pancreatic acinar cell carcinomas did not affect survival, did not metastasize,
and were not locally invasive. The relevance of this finding to carcinogenic risk in humans is
unclear.
Studies designed to investigate the mechanism of gabapentin-induced pancreatic carcinogenesis
in rats indicate that gabapentin stimulates DNA synthesis in rat pancreatic acinar cells in vitro
and, thus, may be acting as a tumor promoter by enhancing mitogenic activity. It is not known
whether gabapentin has the ability to increase cell proliferation in other cell types or in other
species, including humans.
Gabapentin did not demonstrate mutagenic or genotoxic potential in three in vitro and four in
vivo assays. It was negative in the Ames test and the in vitro HGPRT forward mutation assay in
Chinese hamster lung cells; it did not produce significant increases in chromosomal aberrations
in the in vitro Chinese hamster lung cell assay; it was negative in the in vivo chromosomal
aberration assay and in the in vivo micronucleus test in Chinese hamster bone marrow; it was
negative in the in vivo mouse micronucleus assay; and it did not induce unscheduled DNA
synthesis in hepatocytes from rats given gabapentin.
No adverse effects on fertility or reproduction were observed in rats at doses up to 2000 mg/kg
(approximately 5 times the maximum recommended human dose on a mg/m2 basis).
Pregnancy
Pregnancy Category C: Gabapentin has been shown to be fetotoxic in rodents, causing delayed
ossification of several bones in the skull, vertebrae, forelimbs, and hindlimbs. These effects
occurred when pregnant mice received oral doses of 1000 or 3000 mg/kg/day during the period
of organogenesis, or approximately 1 to 4 times the maximum dose of 3600 mg/day given to
epileptic patients on a mg/m2 basis. The no-effect level was 500 mg/kg/day or approximately ½
of the human dose on a mg/m2 basis.
When rats were dosed prior to and during mating, and throughout gestation, pups from all dose
groups (500, 1000, and 2000 mg/kg/day) were affected. These doses are equivalent to less than
approximately 1 to 5 times the maximum human dose on a mg/m2 basis. There was an increased
incidence of hydroureter and/or hydronephrosis in rats in a study of fertility and general
reproductive performance at 2000 mg/kg/day with no effect at 1000 mg/kg/day, in a teratology
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NDA 020882/S-038, S-039, S-040
NDA 021129/S-035, S-036, S-037
FDA Approved Labeling Text dated 05/01/2013
Page 17 of 37
study at 1500 mg/kg/day with no effect at 300 mg/kg/day, and in a perinatal and postnatal study
at all doses studied (500, 1000, and 2000 mg/kg/day). The doses at which the effects occurred
are approximately 1 to 5 times the maximum human dose of 3600 mg/day on a mg/m2 basis; the
no-effect doses were approximately 3 times (Fertility and General Reproductive Performance
study) and approximately equal to (Teratogenicity study) the maximum human dose on a mg/m2
basis. Other than hydroureter and hydronephrosis, the etiologies of which are unclear, the
incidence of malformations was not increased compared to controls in offspring of mice, rats, or
rabbits given doses up to 50 times (mice), 30 times (rats), and 25 times (rabbits) the human daily
dose on a mg/kg basis, or 4 times (mice), 5 times (rats), or 8 times (rabbits) the human daily dose
on a mg/m2 basis.
In a teratology study in rabbits, an increased incidence of postimplantation fetal loss occurred in
dams exposed to 60, 300, and 1500 mg/kg/day, or less than approximately ¼ to 8 times the
maximum human dose on a mg/m2 basis. There are no adequate and well-controlled studies in
pregnant women. This drug should be used during pregnancy only if the potential benefit
justifies the potential risk to the fetus.
To provide information regarding the effects of in utero exposure to Neurontin, physicians are
advised to recommend that pregnant patients taking Neurontin enroll in the North American
Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll free
number 1-888-233-2334, and must be done by patients themselves. Information on the registry
can also be found at the website http://www.aedpregnancyregistry.org/.
Use in Nursing Mothers
Gabapentin is secreted into human milk following oral administration. A nursed infant could be
exposed to a maximum dose of approximately 1 mg/kg/day of gabapentin. Because the effect on
the nursing infant is unknown, Neurontin should be used in women who are nursing only if the
benefits clearly outweigh the risks.
Pediatric Use
Safety and effectiveness of Neurontin (gabapentin) in the management of postherpetic neuralgia
in pediatric patients have not been established.
Effectiveness as adjunctive therapy in the treatment of partial seizures in pediatric patients below
the age of 3 years has not been established (see CLINICAL PHARMACOLOGY, Clinical
Studies).
Geriatric Use
The total number of patients treated with Neurontin in controlled clinical trials in patients with
postherpetic neuralgia was 336, of which 102 (30%) were 65 to 74 years of age, and 168 (50%)
were 75 years of age and older. There was a larger treatment effect in patients 75 years of age
and older compared with younger patients who received the same dosage. Since gabapentin is
almost exclusively eliminated by renal excretion, the larger treatment effect observed in patients
≥75 years may be a consequence of increased gabapentin exposure for a given dose that results
from an age-related decrease in renal function. However, other factors cannot be excluded. The
Reference ID: 3301312
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020235/S-054, S-055, S-056
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NDA 021129/S-035, S-036, S-037
FDA Approved Labeling Text dated 05/01/2013
Page 18 of 37
types and incidence of adverse events were similar across age groups except for peripheral
edema and ataxia, which tended to increase in incidence with age.
Clinical studies of Neurontin in epilepsy did not include sufficient numbers of subjects aged 65
and over to determine whether they responded differently from younger subjects. Other reported
clinical experience has not identified differences in responses between the elderly and younger
patients. In general, dose selection for an elderly patient should be cautious, usually starting at
the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or
cardiac function, and of concomitant disease or other drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to
this drug may be greater in patients with impaired renal function. Because elderly patients are
more likely to have decreased renal function, care should be taken in dose selection, and dose
should be adjusted based on creatinine clearance values in these patients (see CLINICAL
PHARMACOLOGY, ADVERSE REACTIONS, and DOSAGE AND
ADMINISTRATION).
ADVERSE REACTIONS
Postherpetic Neuralgia
The most commonly observed adverse events associated with the use of Neurontin in adults, not
seen at an equivalent frequency among placebo-treated patients, were dizziness, somnolence, and
peripheral edema.
In the 2 controlled studies in postherpetic neuralgia, 16% of the 336 patients who received
Neurontin and 9% of the 227 patients who received placebo discontinued treatment because of an
adverse event. The adverse events that most frequently led to withdrawal in Neurontin®-treated
patients were dizziness, somnolence, and nausea.
Incidence in Controlled Clinical Trials
Table 3 lists treatment-emergent signs and symptoms that occurred in at least 1% of Neurontin
treated patients with postherpetic neuralgia participating in placebo-controlled trials and that
were numerically more frequent in the Neurontin group than in the placebo group. Adverse
events were usually mild to moderate in intensity.
Reference ID: 3301312
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020235/S-054, S-055, S-056
NDA 020882/S-038, S-039, S-040
NDA 021129/S-035, S-036, S-037
FDA Approved Labeling Text dated 05/01/2013
Page 19 of 37
TABLE 3. Treatment-Emergent Adverse Event Incidence in
Controlled Trials in Postherpetic Neuralgia (Events
in at least 1% of Neurontin®-Treated Patients and
Numerically More Frequent Than in the Placebo
Group)
Body System/
Neurontin®
Placebo
Preferred Term
N=336
N=227
%
%
Body as a Whole
Asthenia
5.7
4.8
Infection
5.1
3.5
Headache
3.3
3.1
Accidental injury
3.3
1.3
Abdominal pain
2.7
2.6
Digestive System
Diarrhea
5.7
3.1
Dry mouth
4.8
1.3
Constipation
3.9
1.8
Nausea
3.9
3.1
Vomiting
3.3
1.8
Flatulence
2.1
1.8
Metabolic and Nutritional Disorders
Peripheral edema
8.3
2.2
Weight gain
1.8
0.0
Hyperglycemia
1.2
0.4
Nervous System
Dizziness
28.0
7.5
Somnolence
21.4
5.3
Ataxia
3.3
0.0
Thinking abnormal
2.7
0.0
Abnormal gait
1.5
0.0
Incoordination
1.5
0.0
Amnesia
1.2
0.9
Hypesthesia
1.2
0.9
Respiratory System
Pharyngitis
1.2
0.4
Skin and Appendages
Rash
1.2
0.9
Special Senses
Amblyopiaa
2.7
0.9
Conjunctivitis
1.2
0.0
Diplopia
1.2
0.0
Otitis media
1.2
0.0
Reference ID: 3301312
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FDA Approved Labeling Text dated 05/01/2013
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a Reported as blurred vision
Other events in more than 1% of patients but equally or more frequent in the placebo group
included pain, tremor, neuralgia, back pain, dyspepsia, dyspnea, and flu syndrome.
There were no clinically important differences between men and women in the types and
incidence of adverse events. Because there were few patients whose race was reported as other
than white, there are insufficient data to support a statement regarding the distribution of adverse
events by race.
Epilepsy
The most commonly observed adverse events associated with the use of Neurontin in
combination with other antiepileptic drugs in patients >12 years of age, not seen at an equivalent
frequency among placebo-treated patients, were somnolence, dizziness, ataxia, fatigue, and
nystagmus. The most commonly observed adverse events reported with the use of Neurontin in
combination with other antiepileptic drugs in pediatric patients 3 to 12 years of age, not seen at
an equal frequency among placebo-treated patients, were viral infection, fever, nausea and/or
vomiting, somnolence, and hostility (see WARNINGS, Neuropsychiatric Adverse Events-
Pediatric Patients 3-12 years of age).
Approximately 7% of the 2074 patients >12 years of age and approximately 7% of the 449
pediatric patients 3 to 12 years of age who received Neurontin in premarketing clinical trials
discontinued treatment because of an adverse event. The adverse events most commonly
associated with withdrawal in patients >12 years of age were somnolence (1.2%), ataxia (0.8%),
fatigue (0.6%), nausea and/or vomiting (0.6%), and dizziness (0.6%). The adverse events most
commonly associated with withdrawal in pediatric patients were emotional lability (1.6%),
hostility (1.3%), and hyperkinesia (1.1%).
Incidence in Controlled Clinical Trials
Table 4 lists treatment-emergent signs and symptoms that occurred in at least 1% of Neurontin
treated patients >12 years of age with epilepsy participating in placebo-controlled trials and were
numerically more common in the Neurontin group. In these studies, either Neurontin or placebo
was added to the patient’s current antiepileptic drug therapy. Adverse events were usually mild
to moderate in intensity.
The prescriber should be aware that these figures, obtained when Neurontin was added to
concurrent antiepileptic drug therapy, cannot be used to predict the frequency of adverse events
in the course of usual medical practice where patient characteristics and other factors may differ
from those prevailing during clinical studies. Similarly, the cited frequencies cannot be directly
compared with figures obtained from other clinical investigations involving different treatments,
uses, or investigators. An inspection of these frequencies, however, does provide the prescribing
physician with one basis to estimate the relative contribution of drug and nondrug factors to the
adverse event incidences in the population studied.
Reference ID: 3301312
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NDA 020882/S-038, S-039, S-040
NDA 021129/S-035, S-036, S-037
FDA Approved Labeling Text dated 05/01/2013
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TABLE 4.
Treatment-Emergent Adverse Event Incidence in Controlled Add-On
Trials In Patients >12 years of age (Events in at least 1% of Neurontin
patients and numerically more frequent than in the placebo group)
Body System/
Neurontina
Placeboa
Adverse Event
N=543
N=378
%
%
Body As A Whole
Fatigue
Weight Increase
Back Pain
Peripheral Edema
Cardiovascular
Vasodilatation
Digestive System
Dyspepsia
Mouth or Throat Dry
Constipation
Dental Abnormalities
Increased Appetite
Hematologic and Lymphatic Systems
Leukopenia
Musculoskeletal System
Myalgia
Fracture
Nervous System
Somnolence
Dizziness
Ataxia
Nystagmus
Tremor
Nervousness
Dysarthria
Amnesia
Depression
Thinking Abnormal
Twitching
Coordination Abnormal
Respiratory System
Rhinitis
Pharyngitis
Coughing
11.0
2.9
1.8
1.7
1.1
2.2
1.7
1.5
1.5
1.1
1.1
2.0
1.1
19.3
17.1
12.5
8.3
6.8
2.4
2.4
2.2
1.8
1.7
1.3
1.1
4.1
2.8
1.8
5.0
1.6
0.5
0.5
0.3
0.5
0.5
0.8
0.3
0.8
0.5
1.9
0.8
8.7
6.9
5.6
4.0
3.2
1.9
0.5
0.0
1.1
1.3
0.5
0.3
3.7
1.6
1.3
Reference ID: 3301312
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020235/S-054, S-055, S-056
NDA 020882/S-038, S-039, S-040
NDA 021129/S-035, S-036, S-037
FDA Approved Labeling Text dated 05/01/2013
Page 22 of 37
TABLE 4.
Treatment-Emergent Adverse Event Incidence in Controlled Add-On
Trials In Patients >12 years of age (Events in at least 1% of Neurontin
patients and numerically more frequent than in the placebo group)
Body System/
Neurontina
Placeboa
Adverse Event
N=543
N=378
%
%
Skin and Appendages
Abrasion
1.3
0.0
Pruritus
1.3
0.5
Urogenital System
Impotence
1.5
1.1
Special Senses
Diplopia
5.9
1.9
Amblyopiab
4.2
1.1
Laboratory Deviations
WBC Decreased
1.1
0.5
a Plus background antiepileptic drug therapy
b Amblyopia was often described as blurred vision.
Other events in more than 1% of patients >12 years of age but equally or more frequent in the
placebo group included: headache, viral infection, fever, nausea and/or vomiting, abdominal
pain, diarrhea, convulsions, confusion, insomnia, emotional lability, rash, acne.
Among the treatment-emergent adverse events occurring at an incidence of at least 10% in
Neurontin-treated patients, somnolence and ataxia appeared to exhibit a positive dose-response
relationship.
The overall incidence of adverse events and the types of adverse events seen were similar among
men and women treated with Neurontin. The incidence of adverse events increased slightly with
increasing age in patients treated with either Neurontin or placebo. Because only 3% of patients
(28/921) in placebo-controlled studies were identified as nonwhite (black or other), there are
insufficient data to support a statement regarding the distribution of adverse events by race.
Table 5 lists treatment-emergent signs and symptoms that occurred in at least 2% of Neurontin
treated patients age 3 to 12 years of age with epilepsy participating in placebo-controlled trials
and were numerically more common in the Neurontin group. Adverse events were usually mild
to moderate in intensity.
Reference ID: 3301312
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020235/S-054, S-055, S-056
NDA 020882/S-038, S-039, S-040
NDA 021129/S-035, S-036, S-037
FDA Approved Labeling Text dated 05/01/2013
Page 23 of 37
TABLE 5.
Treatment-Emergent Adverse Event Incidence in Pediatric Patients
Age 3 to 12 Years in a Controlled Add-On Trial (Events in at least
2% of Neurontin patients and numerically more frequent than in the
placebo group)
Body System/
Neurontina
Placeboa
Adverse Event
N=119
N=128
%
%
Body As A Whole
Viral Infection
10.9
3.1
Fever
10.1
3.1
Weight Increase
3.4
0.8
Fatigue
3.4
1.6
Digestive System
Nausea and/or Vomiting
8.4
7.0
Nervous System
Somnolence
8.4
4.7
Hostility
7.6
2.3
Emotional Lability
4.2
1.6
Dizziness
2.5
1.6
Hyperkinesia
2.5
0.8
Respiratory System
Bronchitis
3.4
0.8
Respiratory Infection
2.5
0.8
a Plus background antiepileptic drug therapy
Other events in more than 2% of pediatric patients 3 to 12 years of age but equally or more
frequent in the placebo group included: pharyngitis, upper respiratory infection, headache,
rhinitis, convulsions, diarrhea, anorexia, coughing, and otitis media.
Other Adverse Events Observed During All Clinical Trials
Clinical Trials in Adults and Adolescents (Except Clinical Trials in Neuropathic Pain)
Neurontin has been administered to 4717 patients >12 years of age during all adjunctive therapy
clinical trials (except clinical trials in patients with neuropathic pain), only some of which were
placebo-controlled. During these trials, all adverse events were recorded by the clinical
investigators using terminology of their own choosing. To provide a meaningful estimate of the
proportion of individuals having adverse events, similar types of events were grouped into a
smaller number of standardized categories using modified COSTART dictionary terminology.
These categories are used in the listing below. The frequencies presented represent the
proportion of the 4717 patients >12 years of age exposed to Neurontin who experienced an event
of the type cited on at least one occasion while receiving Neurontin. All reported events are
included except those already listed in Table 4, those too general to be informative, and those not
reasonably associated with the use of the drug.
Reference ID: 3301312
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020235/S-054, S-055, S-056
NDA 020882/S-038, S-039, S-040
NDA 021129/S-035, S-036, S-037
FDA Approved Labeling Text dated 05/01/2013
Page 24 of 37
Events are further classified within body system categories and enumerated in order of
decreasing frequency using the following definitions: frequent adverse events are defined as
those occurring in at least 1/100 patients; infrequent adverse events are those occurring in 1/100
to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients.
Body As A Whole: Frequent: asthenia, malaise, face edema; Infrequent: allergy, generalized
edema, weight decrease, chill; Rare: strange feelings, lassitude, alcohol intolerance, hangover
effect.
Cardiovascular System: Frequent: hypertension; Infrequent: hypotension, angina pectoris,
peripheral vascular disorder, palpitation, tachycardia, migraine, murmur; Rare: atrial fibrillation,
heart failure, thrombophlebitis, deep thrombophlebitis, myocardial infarction, cerebrovascular
accident, pulmonary thrombosis, ventricular extrasystoles, bradycardia, premature atrial
contraction, pericardial rub, heart block, pulmonary embolus, hyperlipidemia,
hypercholesterolemia, pericardial effusion, pericarditis.
Digestive System: Frequent: anorexia, flatulence, gingivitis; Infrequent: glossitis, gum
hemorrhage, thirst, stomatitis, increased salivation, gastroenteritis, hemorrhoids, bloody stools,
fecal incontinence, hepatomegaly; Rare: dysphagia, eructation, pancreatitis, peptic ulcer, colitis,
blisters in mouth, tooth discolor, perlèche, salivary gland enlarged, lip hemorrhage, esophagitis,
hiatal hernia, hematemesis, proctitis, irritable bowel syndrome, rectal hemorrhage, esophageal
spasm.
Endocrine System: Rare: hyperthyroid, hypothyroid, goiter, hypoestrogen, ovarian failure,
epididymitis, swollen testicle, cushingoid appearance.
Hematologic and Lymphatic Systems: Frequent: purpura most often described as bruises
resulting from physical trauma; Infrequent: anemia, thrombocytopenia, lymphadenopathy; Rare:
WBC count increased, lymphocytosis, non-Hodgkin’s lymphoma, bleeding time increased.
Musculoskeletal System: Frequent: arthralgia; Infrequent: tendinitis, arthritis, joint stiffness,
joint swelling, positive Romberg test; Rare: costochondritis, osteoporosis, bursitis, contracture.
Nervous System: Frequent: vertigo, hyperkinesia, paresthesia, decreased or absent reflexes,
increased reflexes, anxiety, hostility; Infrequent: CNS tumors, syncope, dreaming abnormal,
aphasia, hypesthesia, intracranial hemorrhage, hypotonia, dysesthesia, paresis, dystonia,
hemiplegia, facial paralysis, stupor, cerebellar dysfunction, positive Babinski sign, decreased
position sense, subdural hematoma, apathy, hallucination, decrease or loss of libido, agitation,
paranoia, depersonalization, euphoria, feeling high, doped-up sensation, psychosis; Rare:
choreoathetosis, orofacial dyskinesia, encephalopathy, nerve palsy, personality disorder,
increased libido, subdued temperament, apraxia, fine motor control disorder, meningismus, local
myoclonus, hyperesthesia, hypokinesia, mania, neurosis, hysteria, antisocial reaction.
Respiratory System: Frequent: pneumonia; Infrequent: epistaxis, dyspnea, apnea; Rare:
mucositis, aspiration pneumonia, hyperventilation, hiccup, laryngitis, nasal obstruction, snoring,
bronchospasm, hypoventilation, lung edema.
Dermatological: Infrequent: alopecia, eczema, dry skin, increased sweating, urticaria, hirsutism,
seborrhea, cyst, herpes simplex; Rare: herpes zoster, skin discolor, skin papules, photosensitive
Reference ID: 3301312
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020235/S-054, S-055, S-056
NDA 020882/S-038, S-039, S-040
NDA 021129/S-035, S-036, S-037
FDA Approved Labeling Text dated 05/01/2013
Page 25 of 37
reaction, leg ulcer, scalp seborrhea, psoriasis, desquamation, maceration, skin nodules,
subcutaneous nodule, melanosis, skin necrosis, local swelling.
Urogenital System: Infrequent: hematuria, dysuria, urination frequency, cystitis, urinary
retention, urinary incontinence, vaginal hemorrhage, amenorrhea, dysmenorrhea, menorrhagia,
breast cancer, unable to climax, ejaculation abnormal; Rare: kidney pain, leukorrhea, pruritus
genital, renal stone, acute renal failure, anuria, glycosuria, nephrosis, nocturia, pyuria, urination
urgency, vaginal pain, breast pain, testicle pain.
Special Senses: Frequent: abnormal vision; Infrequent: cataract, conjunctivitis, eyes dry, eye
pain, visual field defect, photophobia, bilateral or unilateral ptosis, eye hemorrhage, hordeolum,
hearing loss, earache, tinnitus, inner ear infection, otitis, taste loss, unusual taste, eye twitching,
ear fullness; Rare: eye itching, abnormal accommodation, perforated ear drum, sensitivity to
noise, eye focusing problem, watery eyes, retinopathy, glaucoma, iritis, corneal disorders,
lacrimal dysfunction, degenerative eye changes, blindness, retinal degeneration, miosis,
chorioretinitis, strabismus, eustachian tube dysfunction, labyrinthitis, otitis externa, odd smell.
Clinical Trials in Pediatric Patients With Epilepsy
Adverse events occurring during epilepsy clinical trials in 449 pediatric patients 3 to 12 years of
age treated with gabapentin that were not reported in adjunctive trials in adults are:
Body as a Whole: dehydration, infectious mononucleosis
Digestive System: hepatitis
Hematologic and Lymphatic Systems: coagulation defect
Nervous System: aura disappeared, occipital neuralgia
Psychobiologic Function: sleepwalking
Respiratory System: pseudocroup, hoarseness
Clinical Trials in Adults with Neuropathic Pain of Various Etiologies
Safety information was obtained in 1173 patients during double-blind and open-label clinical
trials including neuropathic pain conditions for which efficacy has not been demonstrated.
Adverse events reported by investigators were grouped into standardized categories using
modified COSTART IV terminology. Listed below are all reported events except those already
listed in Table 3 and those not reasonably associated with the use of the drug.
Events are further classified within body system categories and enumerated in order of
decreasing frequency using the following definitions: frequent adverse events are defined as
those occurring in at least 1/100 patients; infrequent adverse events are those occurring in 1/100
to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients.
Reference ID: 3301312
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020235/S-054, S-055, S-056
NDA 020882/S-038, S-039, S-040
NDA 021129/S-035, S-036, S-037
FDA Approved Labeling Text dated 05/01/2013
Page 26 of 37
Body as a Whole: Infrequent: chest pain, cellulitis, malaise, neck pain, face edema, allergic
reaction, abscess, chills, chills and fever, mucous membrane disorder; Rare: body odor, cyst,
fever, hernia, abnormal BUN value, lump in neck, pelvic pain, sepsis, viral infection.
Cardiovascular System: Infrequent: hypertension, syncope, palpitation, migraine, hypotension,
peripheral vascular disorder, cardiovascular disorder, cerebrovascular accident, congestive heart
failure, myocardial infarction, vasodilatation; Rare: angina pectoris, heart failure, increased
capillary fragility, phlebitis, thrombophlebitis, varicose vein.
Digestive System: Infrequent: gastroenteritis, increased appetite, gastrointestinal disorder, oral
moniliasis, gastritis, tongue disorder, thirst, tooth disorder, abnormal stools, anorexia, liver
function tests abnormal, periodontal abscess; Rare: cholecystitis, cholelithiasis, duodenal ulcer,
fecal incontinence, gamma glutamyl transpeptidase increased, gingivitis, intestinal obstruction,
intestinal ulcer, melena, mouth ulceration, rectal disorder, rectal hemorrhage, stomatitis.
Endocrine System: Infrequent: diabetes mellitus.
Hematologic and Lymphatic Systems: Infrequent: ecchymosis, anemia; Rare:
lymphadenopathy, lymphoma-like reaction, prothrombin decreased.
Metabolic and Nutritional: Infrequent: edema, gout, hypoglycemia, weight loss; Rare: alkaline
phosphatase increased, diabetic ketoacidosis, lactic dehydrogenase increased.
Musculoskeletal: Infrequent: arthritis, arthralgia, myalgia, arthrosis, leg cramps, myasthenia;
Rare: shin bone pain, joint disorder, tendon disorder.
Nervous System: Frequent: confusion, depression; Infrequent: vertigo, nervousness,
paresthesia, insomnia, neuropathy, libido decreased, anxiety, depersonalization, reflexes
decreased, speech disorder, abnormal dreams, dysarthria, emotional lability, nystagmus, stupor,
circumoral paresthesia, euphoria, hyperesthesia, hypokinesia; Rare: agitation, hypertonia, libido
increased, movement disorder, myoclonus, vestibular disorder.
Respiratory System: Infrequent: cough increased, bronchitis, rhinitis, sinusitis, pneumonia,
asthma, lung disorder, epistaxis; Rare: hemoptysis, voice alteration.
Skin and Appendages: Infrequent: pruritus, skin ulcer, dry skin, herpes zoster, skin disorder,
fungal dermatitis, furunculosis, herpes simplex, psoriasis, sweating, urticaria, vesiculobullous
rash; Rare: acne, hair disorder, maculopapular rash, nail disorder, skin carcinoma, skin
discoloration, skin hypertrophy.
Special Senses: Infrequent: abnormal vision, ear pain, eye disorder, taste perversion, deafness;
Rare: conjunctival hyperemia, diabetic retinopathy, eye pain, fundi with microhemorrhage,
retinal vein thrombosis, taste loss.
Urogenital System: Infrequent: urinary tract infection, dysuria, impotence, urinary
incontinence, vaginal moniliasis, breast pain, menstrual disorder, polyuria, urinary retention;
Rare: cystitis, ejaculation abnormal, swollen penis, gynecomastia, nocturia, pyelonephritis,
swollen scrotum, urinary frequency, urinary urgency, urine abnormality.
Reference ID: 3301312
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020235/S-054, S-055, S-056
NDA 020882/S-038, S-039, S-040
NDA 021129/S-035, S-036, S-037
FDA Approved Labeling Text dated 05/01/2013
Page 27 of 37
Postmarketing and Other Experience
In addition to the adverse experiences reported during clinical testing of Neurontin, the following
adverse experiences have been reported in patients receiving marketed Neurontin. These adverse
experiences have not been listed above and data are insufficient to support an estimate of their
incidence or to establish causation. The listing is alphabetized: angioedema, blood glucose
fluctuation, breast enlargement, elevated creatine kinase, elevated liver function tests, erythema
multiforme, fever, hyponatremia, jaundice, movement disorder, rhabdomyolysis, Stevens-
Johnson syndrome.
Adverse events following the abrupt discontinuation of gabapentin have also been reported. The
most frequently reported events were anxiety, insomnia, nausea, pain, and sweating.
DRUG ABUSE AND DEPENDENCE
Controlled Substance
Gabapentin is not a scheduled drug.
Abuse
Gabapentin does not exhibit affinity for benzodiazepine, opiate (mu, delta or kappa), or
cannabinoid 1 receptor sites. A small number of postmarketing cases report gabapentin misuse
and abuse. These individuals were taking higher than recommended doses of gabapentin for
unapproved uses. Most of the individuals described in these reports had a history of poly-
substance abuse or used gabapentin to relieve symptoms of withdrawal from other substances.
When prescribing gabapentin carefully evaluate patients for a history of drug abuse and observe
them for signs and symptoms of gabapentin misuse or abuse (e.g. development of tolerance, self-
dose escalation, and drug-seeking behavior).
Dependence
There are rare postmarketing reports of individuals experiencing withdrawal symptoms shortly
after discontinuing higher than recommended doses of gabapentin used to treat illnesses for
which the drug is not approved. Such symptoms included agitation, disorientation and confusion
after suddenly discontinuing gabapentin that resolved after restarting gabapentin. Most of these
individuals had a history of poly-substance abuse or used gabapentin to relieve symptoms of
withdrawal from other substances. The dependence and abuse potential of gabapentin has not
been evaluated in human studies.
OVERDOSAGE
A lethal dose of gabapentin was not identified in mice and rats receiving single oral doses as
high as 8000 mg/kg. Signs of acute toxicity in animals included ataxia, labored breathing, ptosis,
sedation, hypoactivity, or excitation.
Acute oral overdoses of Neurontin up to 49 grams have been reported. In these cases, double
vision, slurred speech, drowsiness, lethargy and diarrhea, were observed. All patients recovered
with supportive care.
Reference ID: 3301312
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020235/S-054, S-055, S-056
NDA 020882/S-038, S-039, S-040
NDA 021129/S-035, S-036, S-037
FDA Approved Labeling Text dated 05/01/2013
Page 28 of 37
Gabapentin can be removed by hemodialysis. Although hemodialysis has not been performed in
the few overdose cases reported, it may be indicated by the patient’s clinical state or in patients
with significant renal impairment.
DOSAGE AND ADMlNlSTRATION
Neurontin is given orally with or without food. Patients should be informed that, should they
break the scored 600 or 800 mg tablet in order to administer a half-tablet, they should take the
unused half-tablet as the next dose. Half-tablets not used within several days of breaking the
scored tablet should be discarded.
If Neurontin dose is reduced, discontinued, or substituted with an alternative medication, this
should be done gradually over a minimum of 1 week (a longer period may be needed at the
discretion of the prescriber).
Postherpetic Neuralgia
In adults with postherpetic neuralgia, Neurontin therapy may be initiated as a single 300-mg dose
on Day 1, 600 mg/day on Day 2 (divided BID), and 900 mg/day on Day 3 (divided TID). The
dose can subsequently be titrated up as needed for pain relief to a daily dose of 1800 mg (divided
TID). In clinical studies, efficacy was demonstrated over a range of doses from 1800 mg/day to
3600 mg/day with comparable effects across the dose range. Additional benefit of using doses
greater than 1800 mg/day was not demonstrated.
Epilepsy
Neurontin is recommended for add-on therapy in patients 3 years of age and older. Effectiveness
in pediatric patients below the age of 3 years has not been established.
Patients >12 years of age: The effective dose of Neurontin is 900 to 1800 mg/day and given in
divided doses (three times a day) using 300 or 400 mg capsules, or 600 or 800 mg tablets. The
starting dose is 300 mg three times a day. If necessary, the dose may be increased using 300 or
400 mg capsules, or 600 or 800 mg tablets three times a day up to 1800 mg/day. Dosages up to
2400 mg/day have been well tolerated in long-term clinical studies. Doses of 3600 mg/day have
also been administered to a small number of patients for a relatively short duration, and have
been well tolerated. The maximum time between doses in the TID schedule should not exceed
12 hours.
Pediatric Patients Age 3-12 years: The starting dose should range from 10-15 mg/kg/day in
3 divided doses, and the effective dose reached by upward titration over a period of
approximately 3 days. The effective dose of Neurontin in patients 5 years of age and older is
25–35 mg/kg/day and given in divided doses (three times a day). The effective dose in pediatric
patients ages 3 and 4 years is 40 mg/kg/day and given in divided doses (three times a day) (see
CLINICAL PHARMACOLOGY, Pediatric). Neurontin® may be administered as the oral
solution, capsule, or tablet, or using combinations of these formulations. Dosages up to
50 mg/kg/day have been well tolerated in a long-term clinical study. The maximum time interval
between doses should not exceed 12 hours.
Reference ID: 3301312
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020235/S-054, S-055, S-056
NDA 020882/S-038, S-039, S-040
NDA 021129/S-035, S-036, S-037
FDA Approved Labeling Text dated 05/01/2013
Page 29 of 37
It is not necessary to monitor gabapentin plasma concentrations to optimize Neurontin therapy.
Further, because there are no significant pharmacokinetic interactions among Neurontin and
other commonly used antiepileptic drugs, the addition of Neurontin does not alter the plasma
levels of these drugs appreciably.
If Neurontin is discontinued and/or an alternate anticonvulsant medication is added to the
therapy, this should be done gradually over a minimum of 1 week.
Dosage in Renal Impairment
Creatinine clearance is difficult to measure in outpatients. In patients with stable renal function,
creatinine clearance (CCr) can be reasonably well estimated using the equation of Cockcroft and
Gault:
for females CCr=(0.85)(140-age)(weight)/[(72)(SCr)]
for males CCr=(140-age)(weight)/[(72)(SCr)]
in which age is in years, weight is in kilograms, and SCr is serum creatinine in mg/dL.
Dosage adjustment in patients ≥12 years of age with compromised renal function or undergoing
hemodialysis is recommended as follows (see dosing recommendations above for effective doses
in each indication).
TABLE 6. Neurontin® Dosage Based on Renal Function
Renal Function
Total Daily
Dose Regimen
Creatinine Clearance
Dose Range
(mg)
(mL/min)
(mg/day)
≥60
900-3600
300 TID
400 TID
600 TID
800 TID 1200 TID
>30-59
400-1400
200 BID 300 BID 400 BID
500 BID
700 BID
>15-29
200-700
200 QD
300 QD
400 QD
500 QD
700 QD
15a
100-300
100 QD
125 QD
150 QD
200 QD
300 QD
Post-Hemodialysis Supplemental Dose (mg)b
Hemodialysis
125b
150b
200b
250b
350b
a
For patients with creatinine clearance <15 mL/min, reduce daily dose in proportion to creatinine clearance
(e.g., patients with a creatinine clearance of 7.5 mL/min should receive one-half the daily dose that patients
with a creatinine clearance of 15 mL/min receive).
b
Patients on hemodialysis should receive maintenance doses based on estimates of creatinine clearance as
indicated in the upper portion of the table and a supplemental post-hemodialysis dose administered after each
4 hours of hemodialysis as indicated in the lower portion of the table.
The use of Neurontin in patients <12 years of age with compromised renal function has not been
studied.
Dosage in Elderly
Reference ID: 3301312
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020235/S-054, S-055, S-056
NDA 020882/S-038, S-039, S-040
NDA 021129/S-035, S-036, S-037
FDA Approved Labeling Text dated 05/01/2013
Page 30 of 37
Because elderly patients are more likely to have decreased renal function, care should be taken in
dose selection, and dose should be adjusted based on creatinine clearance values in these
patients.
HOW SUPPLIED
Neurontin (gabapentin) capsules, tablets, and oral solution are supplied as follows:
100 mg capsules:
White hard gelatin capsules printed with “PD” on one side and “Neurontin/100 mg” on
the other; available in:
Bottles of 100: NDC 0071-0803-24
300 mg capsules:
Yellow hard gelatin capsules printed with “PD” on one side and “Neurontin/300 mg” on
the other; available in:
Bottles of 100: NDC 0071-0805-24
Unit dose 50’s: NDC 0071-0805-40
400 mg capsules:
Orange hard gelatin capsules printed with “PD” on one side and “Neurontin/400 mg” on
the other; available in:
Bottles of 100: NDC 0071-0806-24
Unit dose 50’s: NDC 0071-0806-40
600 mg tablets:
White elliptical film-coated scored tablets debossed with “NT” and “16” on one side;
available in:
Bottles of 100: NDC 0071-0513-24
800 mg tablets:
White elliptical film-coated scored tablets debossed with “NT” and “26” on one side;
available in:
Bottles of 100: NDC 0071-0401-24
250 mg/5 mL oral solution:
Clear colorless to slightly yellow solution; each 5 mL of oral solution contains 250 mg of
gabapentin; available in:
Reference ID: 3301312
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020235/S-054, S-055, S-056
NDA 020882/S-038, S-039, S-040
NDA 021129/S-035, S-036, S-037
FDA Approved Labeling Text dated 05/01/2013
Page 31 of 37
Bottles containing 470 mL: NDC 0071-2012-23
Storage (Capsules)
Store at 25°C (77°F); excursions permitted to 15° - 30°C (59° - 86°F) [see USP Controlled
Room Temperature].
Storage (Tablets)
Store at 25°C (77°F); excursions permitted to 15° - 30°C (59° - 86°F) [see USP Controlled
Room Temperature].
Storage (Oral Solution)
Store refrigerated, 2°-8°C (36°-46°F) company logo
LAB-0106-15.0
Revised May 2013
Reference ID: 3301312
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020235/S-054, S-055, S-056
NDA 020882/S-038, S-039, S-040
NDA 021129/S-035, S-036, S-037
FDA Approved Labeling Text dated 05/01/2013
Page 32 of 37
MEDICATION GUIDE
NEURONTIN (Neu rŏn' tĭn)
(Gabapentin)
Capsules, Tablets, and Oral Solution
Read the Medication Guide before you start taking NEURONTIN and each time you get
a refill. There may be new information. This information does not take the place of
talking to your healthcare provider about your medical condition or treatment.
What is the most important information I should know about NEURONTIN?
Do not stop taking NEURONTIN without first talking to your healthcare
provider.
Stopping NEURONTIN suddenly can cause serious problems.
NEURONTIN can cause serious side effects including:
1. Like other antiepileptic drugs, NEURONTIN may cause suicidal
thoughts or actions in a very small number of people, about 1 in 500.
Call a healthcare provider right away if you have any of these symptoms,
especially if they are new, worse, or worry you:
•
thoughts about suicide or dying
•
attempts to commit suicide
•
new or worse depression
•
new or worse anxiety
•
feeling agitated or restless
•
panic attacks
•
trouble sleeping (insomnia)
•
new or worse irritability
•
acting aggressive, being angry, or violent
•
acting on dangerous impulses
•
an extreme increase in activity and talking (mania)
•
other unusual changes in behavior or mood
How can I watch for early symptoms of suicidal thoughts and actions?
Reference ID: 3301312
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020235/S-054, S-055, S-056
NDA 020882/S-038, S-039, S-040
NDA 021129/S-035, S-036, S-037
FDA Approved Labeling Text dated 05/01/2013
Page 33 of 37
• Pay attention to any changes, especially sudden changes, in mood,
behaviors, thoughts, or feelings.
• Keep all follow-up visits with your healthcare provider as scheduled.
Call your healthcare provider between visits as needed, especially if you are
worried about symptoms.
Do not stop taking NEURONTIN without first talking to a healthcare
provider.
• Stopping NEURONTIN suddenly can cause serious problems. Stopping a
seizure medicine suddenly in a patient who has epilepsy can cause
seizures that will not stop (status epilepticus).
Suicidal thoughts or actions can be caused by things other than medicines. If you
have suicidal thoughts or actions, your healthcare provider may check for other
causes.
2. Changes in behavior and thinking - Using NEURONTIN in children 3 to 12
years of age can cause emotional changes, aggressive behavior, problems with
concentration, restlessness, changes in school performance, and hyperactivity.
3. NEURONTIN may cause a serious or life-threatening allergic reaction
that may affect your skin or other parts of your body such as your liver or blood
cells. You may or may not have rash when you get this type of reaction. It may
cause you to be hospitalized or to stop NEURONTIN. Call a healthcare provider right
away if you have any of the following symptoms:
• skin rash
• hives
• fever
• swollen glands that do not go away
• swelling of your lip and tongue
• yellowing of your skin or of the whites of the eyes
• unusual bruising or bleeding
• severe fatigue or weakness
• unexpected muscle pain
• frequent infections
Reference ID: 3301312
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020235/S-054, S-055, S-056
NDA 020882/S-038, S-039, S-040
NDA 021129/S-035, S-036, S-037
FDA Approved Labeling Text dated 05/01/2013
Page 34 of 37
These symptoms may be the first signs of a serious reaction. A healthcare
provider should examine you to decide if you should continue taking
NEURONTIN.
What is NEURONTIN?
NEURONTIN is a prescription medicine used to treat:
• Pain from damaged nerves (postherpetic pain) that follows healing of shingles (a
painful rash that comes after a herpes zoster infection) in adults.
• Partial seizures when taken together with other medicines in adults and children
3 years of age and older.
Who should not take NEURONTIN?
Do not take NEURONTIN if you are allergic to gabapentin or any of the other
ingredients in NEURONTIN. See the end of this Medication Guide for a complete list of
ingredients in NEURONTIN.
What should I tell my healthcare provider before taking NEURONTIN?
Before taking NEURONTIN, tell your healthcare provider if you:
• have or have had kidney problems or are on hemodialysis
• have or have had depression, mood problems, or suicidal thoughts or behavior
• are pregnant or plan to become pregnant. It is not known if NEURONTIN can
harm your unborn baby. Tell your healthcare provider right away if you become
pregnant while taking NEURONTIN. You and your healthcare provider will decide
if you should take NEURONTIN while you are pregnant.
o If you become pregnant while taking NEURONTIN, talk to your
healthcare provider about registering with the North American
Antiepileptic Drug (NAAED) Pregnancy Registry. The purpose of this
registry is to collect information about the safety of antiepileptic drugs
during pregnancy. You can enroll in this registry by calling 1-888-233
2334.
• are breast-feeding or plan to breast-feed. NEURONTIN can pass into breast milk.
You and your healthcare provider should decide how you will feed your baby
while you take NEURONTIN.
Reference ID: 3301312
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020235/S-054, S-055, S-056
NDA 020882/S-038, S-039, S-040
NDA 021129/S-035, S-036, S-037
FDA Approved Labeling Text dated 05/01/2013
Page 35 of 37
Tell your healthcare provider about all the medicines you take, including
prescription and non-prescription medicines, vitamins, and herbal supplements.
Taking NEURONTIN with certain other medicines can cause side effects or affect how
well they work. Do not start or stop other medicines without talking to your healthcare
provider.
Know the medicines you take. Keep a list of them and show it to your healthcare
provider and pharmacist when you get a new medicine.
How should I take NEURONTIN?
• Take NEURONTIN exactly as prescribed. Your healthcare provider will tell you
how much NEURONTIN to take.
o Do not change your dose of NEURONTIN without talking to your
healthcare provider. If you break a tablet in half, the unused half of
the tablet should be taken at your next scheduled dose. Half tablets
not used within several days of breaking should be thrown away. If
taking capsules, always swallow them whole with plenty of water.
• NEURONTIN can be taken with or without food. If you take an antacid containing
aluminum and magnesium, such as Maalox®, Mylanta®, Gelusil®, Gaviscon®, or
Di-Gel®, you should wait at least 2 hours before taking your next dose of
NEURONTIN.
• If you take too much NEURONTIN, call your healthcare provider or your local
Poison Control Center right away.
What should I avoid while taking NEURONTIN?
• Do not drink alcohol or take other medicines that make you sleepy or dizzy while
taking NEURONTIN without first talking with your healthcare provider. Taking
NEURONTIN with alcohol or drugs that cause sleepiness or dizziness may make
your sleepiness or dizziness worse.
• Do not drive, operate heavy machinery, or do other dangerous activities until you
know how NEURONTIN affects you. NEURONTIN can slow your thinking and
motor skills.
What are the possible side effects of NEURONTIN?
• See “What is the most important information I should know about NEURONTIN?”
• The most common side effects of NEURONTIN include:
Reference ID: 3301312
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020235/S-054, S-055, S-056
NDA 020882/S-038, S-039, S-040
NDA 021129/S-035, S-036, S-037
FDA Approved Labeling Text dated 05/01/2013
Page 36 of 37
• difficulty with speaking
• dizziness
• temporary loss of memory
• lack of coordination
(amnesia)
• viral infection
• tremor
• feeling drowsy
• difficulty with coordination
• feeling tired
• double vision
• fever
• unusual eye movement
• jerky movements
Tell your healthcare provider if you have any side effect that bothers you or that does
not go away.
These are not all the possible side effects of NEURONTIN. For more information, ask
your healthcare provider or pharmacist.
Call your doctor for medical advice about side effects. You may report side
effects to FDA at 1-800-FDA-1088.
How should I store NEURONTIN?
• Store NEURONTIN Capsules between 59°F to 86°F (15°C to 30°C).
• Store NEURONTIN Tablets between 59°F to 86°F (15°C to 30°C).
• Store NEURONTIN Oral Solution in the refrigerator between 36°F to 46°F (2°C to
8°C).
Keep NEURONTIN and all medicines out of the reach of children.
General information about the safe and effective use of NEURONTIN
Medicines are sometimes prescribed for purposes other than those listed in a
Medication Guide. Do not use NEURONTIN for a condition for which it was not
prescribed. Do not give NEURONTIN to other people, even if they have the same
symptoms that you have. It may harm them.
This Medication Guide summarizes the most important information about NEURONTIN.
If you would like more information, talk with your healthcare provider. You can ask your
healthcare provider or pharmacist for information about NEURONTIN that was written
for healthcare professionals.
For more information about NEURONTIN, go to http://www.pfizer.com. For medical
inquiries or to report side effects regarding NEURONTIN, please call 1-800-438-1985.
Reference ID: 3301312
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020235/S-054, S-055, S-056
NDA 020882/S-038, S-039, S-040
NDA 021129/S-035, S-036, S-037
FDA Approved Labeling Text dated 05/01/2013
Page 37 of 37
What are the ingredients in NEURONTIN?
Active ingredient: gabapentin
Inactive ingredients in the capsules: lactose, cornstarch, and talc.
The 100-mg capsule shell also contains: gelatin and titanium dioxide.
The 300-mg capsule shell also contains: gelatin, titanium dioxide, and yellow iron oxide.
The 400-mg capsule shell also contains: gelatin, red iron oxide, titanium dioxide, and
yellow iron oxide. The imprinting ink contains FD&C Blue No. 2 and titanium dioxide.
Inactive ingredients in the tablets: poloxamer 407, copolyvidonum, cornstarch,
magnesium stearate, hydroxypropyl cellulose, talc, candelilla wax, and purified water.
Inactive ingredients in the oral solution: glycerin, xylitol, purified water, and
artificial flavor.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
This product’s label may have been updated. For current full prescribing information,
please visit www.pfizer.com company logo
LAB-0397-4.0
Revised May 2013
Reference ID: 3301312
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:47:09.586971
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020235s054s055s056,020882s038s039s040,021129s035s036s037lbl.pdf', 'application_number': 20235, 'submission_type': 'SUPPL ', 'submission_number': 56}
|
12,345
|
NDA 020235/S-036; NDA 020882/S-022; NDA 021129/S-022
FDA Approved Labeling Text dated 03/01/2011
Page 1
Neurontin® (gabapentin) Capsules
Neurontin® (gabapentin) Tablets
Neurontin® (gabapentin) Oral Solution
DESCRIPTION
Neurontin® (gabapentin) Capsules, Neurontin (gabapentin) Tablets, and Neurontin (gabapentin)
Oral Solution are supplied as imprinted hard shell capsules containing 100 mg,
300 mg, and 400 mg of gabapentin, elliptical film-coated tablets containing 600 mg and 800 mg
of gabapentin or an oral solution containing 250 mg/5 mL of gabapentin.
The inactive ingredients for the capsules are lactose, cornstarch, and talc. The 100 mg capsule
shell contains gelatin and titanium dioxide. The 300 mg capsule shell contains gelatin, titanium
dioxide, and yellow iron oxide. The 400 mg capsule shell contains gelatin, red iron oxide,
titanium dioxide, and yellow iron oxide. The imprinting ink contains FD&C Blue No. 2 and
titanium dioxide.
The inactive ingredients for the tablets are poloxamer 407, copolyvidonum, cornstarch,
magnesium stearate, hydroxypropyl cellulose, talc, candelilla wax and purified water.
The inactive ingredients for the oral solution are glycerin, xylitol, purified water and artificial
cool strawberry anise flavor.
Gabapentin is described as 1-(aminomethyl) cyclohexaneacetic acid with a molecular formula of
C9H17NO2 and a molecular weight of 171.24. The structural formula of gabapentin is: structural formula
Gabapentin is a white to off-white crystalline solid with a pKa1 of 3.7 and a pKa2 of 10.7. It is
freely soluble in water and both basic and acidic aqueous solutions. The log of the partition
coefficient (n-octanol/0.05M phosphate buffer) at pH 7.4 is –1.25.
CLINICAL PHARMACOLOGY
Mechanism of Action
The mechanism by which gabapentin exerts its analgesic action is unknown, but in animal
models of analgesia, gabapentin prevents allodynia (pain-related behavior in response to a
normally innocuous stimulus) and hyperalgesia (exaggerated response to painful stimuli). In
Reference ID: 2911805
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020235/S-036; NDA 020882/S-022; NDA 021129/S-022
FDA Approved Labeling Text dated 03/01/2011
Page 2
particular, gabapentin prevents pain-related responses in several models of neuropathic pain in
rats or mice (e.g. spinal nerve ligation models, streptozocin-induced diabetes model, spinal cord
injury model, acute herpes zoster infection model). Gabapentin also decreases pain-related
responses after peripheral inflammation (carrageenan footpad test, late phase of formalin test).
Gabapentin did not alter immediate pain-related behaviors (rat tail flick test, formalin footpad
acute phase, acetic acid abdominal constriction test, footpad heat irradiation test). The relevance
of these models to human pain is not known.
The mechanism by which gabapentin exerts its anticonvulsant action is unknown, but in animal
test systems designed to detect anticonvulsant activity, gabapentin prevents seizures as do other
marketed anticonvulsants. Gabapentin exhibits antiseizure activity in mice and rats in both the
maximal electroshock and pentylenetetrazole seizure models and other preclinical models (e.g.,
strains with genetic epilepsy, etc.). The relevance of these models to human epilepsy is not
known.
Gabapentin is structurally related to the neurotransmitter GABA (gamma-aminobutyric acid) but
it does not modify GABAA or GABAB radioligand binding, it is not converted metabolically into
GABA or a GABA agonist, and it is not an inhibitor of GABA uptake or degradation.
Gabapentin was tested in radioligand binding assays at concentrations up to 100 µM and did not
exhibit affinity for a number of other common receptor sites, including benzodiazepine,
glutamate, N-methyl-D-aspartate (NMDA), quisqualate, kainate, strychnine-insensitive or
strychnine-sensitive glycine, alpha 1, alpha 2, or beta adrenergic, adenosine A1 or A2,
cholinergic muscarinic or nicotinic, dopamine D1 or D2, histamine H1, serotonin S1 or S2,
opiate mu, delta or kappa, cannabinoid 1, voltage-sensitive calcium channel sites labeled with
nitrendipine or diltiazem, or at voltage-sensitive sodium channel sites labeled with
batrachotoxinin A 20-alpha-benzoate. Furthermore, gabapentin did not alter the cellular uptake
of dopamine, noradrenaline, or serotonin.
In vitro studies with radiolabeled gabapentin have revealed a gabapentin binding site in areas of
rat brain including neocortex and hippocampus. A high-affinity binding protein in animal brain
tissue has been identified as an auxiliary subunit of voltage-activated calcium channels.
However, functional correlates of gabapentin binding, if any, remain to be elucidated.
Pharmacokinetics and Drug Metabolism
All pharmacological actions following gabapentin administration are due to the activity of the
parent compound; gabapentin is not appreciably metabolized in humans.
Oral Bioavailability: Gabapentin bioavailability is not dose proportional; i.e., as dose is
increased, bioavailability decreases. Bioavailability of gabapentin is approximately 60%, 47%,
34%, 33%, and 27% following 900, 1200, 2400, 3600, and 4800 mg/day given in 3 divided
doses, respectively. Food has only a slight effect on the rate and extent of absorption of
gabapentin (14% increase in AUC and Cmax).
Distribution: Less than 3% of gabapentin circulates bound to plasma protein. The apparent
volume of distribution of gabapentin after 150 mg intravenous administration is 58±6 L (Mean
±SD). In patients with epilepsy, steady-state predose (Cmin) concentrations of gabapentin in
cerebrospinal fluid were approximately 20% of the corresponding plasma concentrations.
Reference ID: 2911805
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020235/S-036; NDA 020882/S-022; NDA 021129/S-022
FDA Approved Labeling Text dated 03/01/2011
Page 3
Elimination: Gabapentin is eliminated from the systemic circulation by renal excretion as
unchanged drug. Gabapentin is not appreciably metabolized in humans.
Gabapentin elimination half-life is 5 to 7 hours and is unaltered by dose or following multiple
dosing. Gabapentin elimination rate constant, plasma clearance, and renal clearance are directly
proportional to creatinine clearance (see Special Populations: Patients With Renal Insufficiency,
below). In elderly patients, and in patients with impaired renal function, gabapentin plasma
clearance is reduced. Gabapentin can be removed from plasma by hemodialysis.
Dosage adjustment in patients with compromised renal function or undergoing hemodialysis is
recommended (see DOSAGE AND ADMINISTRATION, Table 6).
Special Populations: Adult Patients With Renal Insufficiency: Subjects (N=60) with renal
insufficiency (mean creatinine clearance ranging from 13-114 mL/min) were administered single
400 mg oral doses of gabapentin. The mean gabapentin half-life ranged from about 6.5 hours
(patients with creatinine clearance >60 mL/min) to 52 hours (creatinine clearance <30 mL/min)
and gabapentin renal clearance from about 90 mL/min (>60 mL/min group) to about 10 mL/min
(<30 mL/min). Mean plasma clearance (CL/F) decreased from approximately 190 mL/min to
20 mL/min.
Dosage adjustment in adult patients with compromised renal function is necessary (see
DOSAGE AND ADMINISTRATION). Pediatric patients with renal insufficiency have not been
studied.
Hemodialysis: In a study in anuric adult subjects (N=11), the apparent elimination half-life of
gabapentin on nondialysis days was about 132 hours; during dialysis the apparent half-life of
gabapentin was reduced to 3.8 hours. Hemodialysis thus has a significant effect on gabapentin
elimination in anuric subjects.
Dosage adjustment in patients undergoing hemodialysis is necessary (see DOSAGE AND
ADMINISTRATION).
Hepatic Disease: Because gabapentin is not metabolized, no study was performed in patients
with hepatic impairment.
Age: The effect of age was studied in subjects 20-80 years of age. Apparent oral clearance
(CL/F) of gabapentin decreased as age increased, from about 225 mL/min in those under 30
years of age to about 125 mL/min in those over 70 years of age. Renal clearance (CLr) and CLr
adjusted for body surface area also declined with age; however, the decline in the renal clearance
of gabapentin with age can largely be explained by the decline in renal function. Reduction of
gabapentin dose may be required in patients who have age related compromised renal function.
(See PRECAUTIONS, Geriatric Use, and DOSAGE AND ADMINISTRATION.)
Pediatric: Gabapentin pharmacokinetics were determined in 48 pediatric subjects between the
ages of 1 month and 12 years following a dose of approximately 10 mg/kg. Peak plasma
concentrations were similar across the entire age group and occurred 2 to 3 hours postdose. In
general, pediatric subjects between 1 month and <5 years of age achieved approximately 30%
lower exposure (AUC) than that observed in those 5 years of age and older. Accordingly, oral
clearance normalized per body weight was higher in the younger children. Apparent oral
clearance of gabapentin was directly proportional to creatinine clearance. Gabapentin elimination
half-life averaged 4.7 hours and was similar across the age groups studied.
Reference ID: 2911805
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020235/S-036; NDA 020882/S-022; NDA 021129/S-022
FDA Approved Labeling Text dated 03/01/2011
Page 4
A population pharmacokinetic analysis was performed in 253 pediatric subjects between 1 month
and 13 years of age. Patients received 10 to 65 mg/kg/day given TID. Apparent oral clearance
(CL/F) was directly proportional to creatinine clearance and this relationship was similar
following a single dose and at steady state. Higher oral clearance values were observed in
children <5 years of age compared to those observed in children 5 years of age and older, when
normalized per body weight. The clearance was highly variable in infants <1 year of age. The
normalized CL/F values observed in pediatric patients 5 years of age and older were consistent
with values observed in adults after a single dose. The oral volume of distribution normalized per
body weight was constant across the age range.
These pharmacokinetic data indicate that the effective daily dose in pediatric patients with
epilepsy ages 3 and 4 years should be 40 mg/kg/day to achieve average plasma concentrations
similar to those achieved in patients 5 years of age and older receiving gabapentin at 30
mg/kg/day (see DOSAGE AND ADMINISTRATION).
Gender: Although no formal study has been conducted to compare the pharmacokinetics of
gabapentin in men and women, it appears that the pharmacokinetic parameters for males and
females are similar and there are no significant gender differences.
Race: Pharmacokinetic differences due to race have not been studied. Because gabapentin is
primarily renally excreted and there are no important racial differences in creatinine clearance,
pharmacokinetic differences due to race are not expected.
Clinical Studies
Postherpetic Neuralgia
Neurontin was evaluated for the management of postherpetic neuralgia (PHN) in 2 randomized,
double-blind, placebo-controlled, multicenter studies; N=563 patients in the intent-to-treat (ITT)
population (Table 1). Patients were enrolled if they continued to have pain for more than 3
months after healing of the herpes zoster skin rash.
TABLE 1. Controlled PHN Studies: Duration, Dosages, and
Number of Patients
Study
Study
Duration
Gabapentin
(mg/day)a
Target Dose
Patients
Receiving
Gabapentin
Patients
Receiving
Placebo
1
8 weeks
3600
113
116
2
7 weeks
1800, 2400
223
111
Total
336
227
a
Given in 3 divided doses (TID)
Each study included a 1-week baseline during which patients were screened for eligibility and a
7- or 8-week double-blind phase (3 or 4 weeks of titration and 4 weeks of fixed dose). Patients
initiated treatment with titration to a maximum of 900 mg/day gabapentin over 3 days. Dosages
were then to be titrated in 600 to 1200 mg/day increments at 3- to 7-day intervals to target dose
over 3 to 4 weeks. In Study 1, patients were continued on lower doses if not able to achieve the
Reference ID: 2911805
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020235/S-036; NDA 020882/S-022; NDA 021129/S-022
FDA Approved Labeling Text dated 03/01/2011
Page 5
target dose. During baseline and treatment, patients recorded their pain in a daily diary using an
11-point numeric pain rating scale ranging from 0 (no pain) to 10 (worst possible pain). A mean
pain score during baseline of at least 4 was required for randomization (baseline mean pain score
for Studies 1 and 2 combined was 6.4). Analyses were conducted using the ITT population (all
randomized patients who received at least one dose of study medication).
Both studies showed significant differences from placebo at all doses tested.
A significant reduction in weekly mean pain scores was seen by Week 1 in both studies, and
significant differences were maintained to the end of treatment. Comparable treatment effects
were observed in all active treatment arms. Pharmacokinetic/pharmacodynamic modeling
provided confirmatory evidence of efficacy across all doses. Figures 1 and 2 show these changes
for Studies 1 and 2.
gr
ap
h
Baseline
1
2
3
4
5
6
7
8
Weeks
Figure 1. Weekly Mean Pain Scores (Observed Cases in ITT Population): Study 1
Reference ID: 2911805
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
g
r
a
p
h
NDA 020235/S-036; NDA 020882/S-022; NDA 021129/S-022
FDA Approved Labeling Text dated 03/01/2011
Page 6
Figure 2. Weekly Mean Pain Scores (Observed Cases in ITT Population): Study 2
The proportion of responders (those patients reporting at least 50% improvement in endpoint
pain score compared with baseline) was calculated for each study (Figure 3).
Reference ID: 2911805
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
grap
h
NDA 020235/S-036; NDA 020882/S-022; NDA 021129/S-022
FDA Approved Labeling Text dated 03/01/2011
Page 7
Figure 3.
Proportion of Responders (patients with ≥50% reduction in pain score) at
Endpoint: Controlled PHN Studies
Epilepsy
The effectiveness of Neurontin as adjunctive therapy (added to other antiepileptic drugs) was
established in multicenter placebo-controlled, double-blind, parallel-group clinical trials in adult
and pediatric patients (3 years and older) with refractory partial seizures.
Evidence of effectiveness was obtained in three trials conducted in 705 patients (age 12 years
and above) and one trial conducted in 247 pediatric patients (3 to 12 years of age). The patients
enrolled had a history of at least 4 partial seizures per month in spite of receiving one or more
antiepileptic drugs at therapeutic levels and were observed on their established antiepileptic drug
regimen during a 12-week baseline period (6 weeks in the study of pediatric patients). In patients
continuing to have at least 2 (or 4 in some studies) seizures per month, Neurontin or placebo was
then added on to the existing therapy during a 12-week treatment period. Effectiveness was
assessed primarily on the basis of the percent of patients with a 50% or greater reduction in
seizure frequency from baseline to treatment (the “responder rate”) and a derived measure called
response ratio, a measure of change defined as (T - B)/(T + B), where B is the patient’s baseline
seizure frequency and T is the patient’s seizure frequency during treatment. Response ratio is
distributed within the range -1 to +1. A zero value indicates no change while complete
elimination of seizures would give a value of -1; increased seizure rates would give positive
values. A response ratio of -0.33 corresponds to a 50% reduction in seizure frequency. The
Reference ID: 2911805
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020235/S-036; NDA 020882/S-022; NDA 021129/S-022
FDA Approved Labeling Text dated 03/01/2011
Page 8
results given below are for all partial seizures in the intent-to-treat (all patients who received any
doses of treatment) population in each study, unless otherwise indicated.
One study compared Neurontin 1200 mg/day divided TID with placebo. Responder rate was
23% (14/61) in the Neurontin group and 9% (6/66) in the placebo group; the difference between
groups was statistically significant. Response ratio was also better in the Neurontin group
(-0.199) than in the placebo group (-0.044), a difference that also achieved statistical
significance.
A second study compared primarily 1200 mg/day divided TID Neurontin (N=101) with placebo
(N=98). Additional smaller Neurontin dosage groups (600 mg/day, N=53; 1800 mg/day, N=54)
were also studied for information regarding dose response. Responder rate was higher in the
Neurontin 1200 mg/day group (16%) than in the placebo group (8%), but the difference was not
statistically significant. The responder rate at 600 mg (17%) was also not significantly higher
than in the placebo, but the responder rate in the 1800 mg group (26%) was statistically
significantly superior to the placebo rate. Response ratio was better in the Neurontin
1200 mg/day group (-0.103) than in the placebo group (-0.022); but this difference was also not
statistically significant (p = 0.224). A better response was seen in the Neurontin 600 mg/day
group (-0.105) and 1800 mg/day group (-0.222) than in the 1200 mg/day group, with the
1800 mg/day group achieving statistical significance compared to the placebo group.
A third study compared Neurontin 900 mg/day divided TID (N=111) and placebo (N=109). An
additional Neurontin 1200 mg/day dosage group (N=52) provided dose-response data. A
statistically significant difference in responder rate was seen in the Neurontin 900 mg/day group
(22%) compared to that in the placebo group (10%). Response ratio was also statistically
significantly superior in the Neurontin 900 mg/day group (-0.119) compared to that in the
placebo group (-0.027), as was response ratio in 1200 mg/day Neurontin (-0.184) compared to
placebo.
Analyses were also performed in each study to examine the effect of Neurontin on preventing
secondarily generalized tonic-clonic seizures. Patients who experienced a secondarily
generalized tonic-clonic seizure in either the baseline or in the treatment period in all three
placebo-controlled studies were included in these analyses. There were several response ratio
comparisons that showed a statistically significant advantage for Neurontin compared to placebo
and favorable trends for almost all comparisons.
Analysis of responder rate using combined data from all three studies and all doses (N=162,
Neurontin; N=89, placebo) also showed a significant advantage for Neurontin over placebo in
reducing the frequency of secondarily generalized tonic-clonic seizures.
In two of the three controlled studies, more than one dose of Neurontin was used. Within each
study the results did not show a consistently increased response to dose. However, looking across
studies, a trend toward increasing efficacy with increasing dose is evident (see Figure 4).
Reference ID: 2911805
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020235/S-036; NDA 020882/S-022; NDA 021129/S-022
FDA Approved Labeling Text dated 03/01/2011
graph
Figure 4. Responder Rate in Patients Receiving Neurontin Expressed as a Difference
from Placebo by Dose and Study: Adjunctive Therapy Studies in Patients ≥12
Years of Age with Partial Seizures
In the figure, treatment effect magnitude, measured on the Y axis in terms of the difference in the
proportion of gabapentin and placebo assigned patients attaining a 50% or greater reduction in
seizure frequency from baseline, is plotted against the daily dose of gabapentin administered
(X axis).
Although no formal analysis by gender has been performed, estimates of response (Response
Ratio) derived from clinical trials (398 men, 307 women) indicate no important gender
differences exist. There was no consistent pattern indicating that age had any effect on the
response to Neurontin. There were insufficient numbers of patients of races other than Caucasian
to permit a comparison of efficacy among racial groups.
A fourth study in pediatric patients age 3 to 12 years compared 25 – 35 mg/kg/day Neurontin
(N=118) with placebo (N=127). For all partial seizures in the intent-to-treat population, the
response ratio was statistically significantly better for the Neurontin group (-0.146) than for the
placebo group (-0.079). For the same population, the responder rate for Neurontin (21%) was not
significantly different from placebo (18%).
A study in pediatric patients age 1 month to 3 years compared 40 mg/kg/day Neurontin (N=38)
with placebo (N=38) in patients who were receiving at least one marketed antiepileptic drug and
had at least one partial seizure during the screening period (within 2 weeks prior to baseline).
Patients had up to 48 hours of baseline and up to 72 hours of double-blind video EEG monitoring
to record and count the occurrence of seizures. There were no statistically significant differences
between treatments in either the response ratio or responder rate.
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INDICATIONS AND USAGE
Postherpetic Neuralgia
Neurontin (gabapentin) is indicated for the management of postherpetic neuralgia in adults.
Epilepsy
Neurontin (gabapentin) is indicated as adjunctive therapy in the treatment of partial seizures with
and without secondary generalization in patients over 12 years of age with epilepsy. Neurontin is
also indicated as adjunctive therapy in the treatment of partial seizures in pediatric patients age 3
– 12 years.
CONTRAINDICATIONS
Neurontin is contraindicated in patients who have demonstrated hypersensitivity to the drug or
its ingredients.
WARNINGS
Suicidal Behavior and Ideation
Antiepileptic drugs (AEDs), including Neurontin, increase the risk of suicidal thoughts or
behavior in patients taking these drugs for any indication. Patients treated with any AED for any
indication should be monitored for the emergence or worsening of depression, suicidal thoughts
or behavior, and/or any unusual changes in mood or behavior.
Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11
different AEDs showed that patients randomized to one of the AEDs had approximately twice
the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared
to patients randomized to placebo. In these trials, which had a median treatment duration of 12
weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated
patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an
increase of approximately one case of suicidal thinking or behavior for every 530 patients
treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated
patients, but the number is too small to allow any conclusion about drug effect on suicide.
The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one
week after starting drug treatment with AEDs and persisted for the duration of treatment
assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk
of suicidal thoughts or behavior beyond 24 weeks could not be assessed.
The risk of suicidal thoughts or behavior was generally consistent among drugs in the data
analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a
range of indications suggests that the risk applies to all AEDs used for any indication. The risk
did not vary substantially by age (5-100 years) in the clinical trials analyzed.
Table 2 shows absolute and relative risk by indication for all evaluated AEDs.
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Table 2
Risk by indication for antiepileptic drugs in the pooled analysis
Indication
Placebo Patients Drug Patients
Relative Risk:
Risk Difference:
with Events Per
with Events Per
Incidence of Events in
Additional Drug
1000 Patients
1000 Patients
Drug
Patients with
Patients/Incidence in
Events Per 1000
Placebo Patients
Patients
Epilepsy
1.0
3.4
3.5
2.4
Psychiatric
5.7
8.5
1.5
2.9
Other
1.0
1.8
1.9
0.9
Total
2.4
4.3
1.8
1.9
The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in
clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for
the epilepsy and psychiatric indications.
Anyone considering prescribing Neurontin or any other AED must balance the risk of suicidal
thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for
which AEDs are prescribed are themselves associated with morbidity and mortality and an
increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge
during treatment, the prescriber needs to consider whether the emergence of these symptoms in
any given patient may be related to the illness being treated.
Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal
thoughts and behavior and should be advised of the need to be alert for the emergence or
worsening of the signs and symptoms of depression, any unusual changes in mood or behavior,
or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of
concern should be reported immediately to healthcare providers.
Neuropsychiatric Adverse Events—Pediatric Patients 3-12 years of age
Gabapentin use in pediatric patients with epilepsy 3–12 years of age is associated with the
occurrence of central nervous system related adverse events. The most significant of these can be
classified into the following categories: 1) emotional lability (primarily behavioral problems),
2) hostility, including aggressive behaviors, 3) thought disorder, including concentration
problems and change in school performance, and 4) hyperkinesia (primarily restlessness and
hyperactivity). Among the gabapentin-treated patients, most of the events were mild to moderate
in intensity.
In controlled trials in pediatric patients 3–12 years of age the incidence of these adverse events
was: emotional lability 6% (gabapentin-treated patients) vs 1.3% (placebo-treated patients);
hostility 5.2% vs 1.3%; hyperkinesia 4.7% vs 2.9%; and thought disorder 1.7% vs 0%. One of
these events, a report of hostility, was considered serious. Discontinuation of gabapentin
treatment occurred in 1.3% of patients reporting emotional lability and hyperkinesia and 0.9% of
gabapentin-treated patients reporting hostility and thought disorder. One placebo-treated patient
(0.4%) withdrew due to emotional lability.
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Withdrawal Precipitated Seizure, Status Epilepticus
Antiepileptic drugs should not be abruptly discontinued because of the possibility of increasing
seizure frequency.
In the placebo-controlled studies in patients >12 years of age, the incidence of status epilepticus
in patients receiving Neurontin was 0.6% (3 of 543) versus 0.5% in patients receiving placebo (2
of 378). Among the 2074 patients >12 years of age treated with Neurontin across all studies
(controlled and uncontrolled) 31 (1.5%) had status epilepticus. Of these, 14 patients had no prior
history of status epilepticus either before treatment or while on other medications. Because
adequate historical data are not available, it is impossible to say whether or not treatment with
Neurontin is associated with a higher or lower rate of status epilepticus than would be expected
to occur in a similar population not treated with Neurontin.
Tumorigenic Potential
In standard preclinical in vivo lifetime carcinogenicity studies, an unexpectedly high incidence of
pancreatic acinar adenocarcinomas was identified in male, but not female, rats. (See
PRECAUTIONS: Carcinogenesis, Mutagenesis, Impairment of Fertility.) The clinical
significance of this finding is unknown. Clinical experience during gabapentin’s premarketing
development provides no direct means to assess its potential for inducing tumors in humans.
In clinical studies in adjunctive therapy in epilepsy comprising 2085 patient-years of exposure in
patients >12 years of age, new tumors were reported in 10 patients (2 breast, 3 brain, 2 lung, 1
adrenal, 1 non-Hodgkin’s lymphoma, 1 endometrial carcinoma in situ), and preexisting tumors
worsened in 11 patients (9 brain, 1 breast, 1 prostate) during or up to 2 years following
discontinuation of Neurontin. Without knowledge of the background incidence and recurrence in
a similar population not treated with Neurontin, it is impossible to know whether the incidence
seen in this cohort is or is not affected by treatment.
Sudden and Unexplained Death in Patients With Epilepsy
During the course of premarketing development of Neurontin 8 sudden and unexplained deaths
were recorded among a cohort of 2203 patients treated (2103 patient-years of exposure).
Some of these could represent seizure-related deaths in which the seizure was not observed, e.g.,
at night. This represents an incidence of 0.0038 deaths per patient-year. Although this rate
exceeds that expected in a healthy population matched for age and sex, it is within the range of
estimates for the incidence of sudden unexplained deaths in patients with epilepsy not receiving
Neurontin (ranging from 0.0005 for the general population of epileptics to 0.003 for a clinical
trial population similar to that in the Neurontin program, to 0.005 for patients with refractory
epilepsy). Consequently, whether these figures are reassuring or raise further concern depends on
comparability of the populations reported upon to the Neurontin cohort and the accuracy of the
estimates provided.
PRECAUTIONS
Information for Patients
Inform patients of the availability of a Medication Guide, and instruct them to read the
Medication Guide prior to taking Neurontin. Instruct patients to take Neurontin only as
prescribed.
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Patients, their caregivers, and families should be counseled that AEDs, including Neurontin, may
increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert
for the emergence or worsening of symptoms of depression, any unusual changes in mood or
behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm.
Behaviors of concern should be reported immediately to healthcare providers.
Patients should be advised that Neurontin may cause dizziness, somnolence and other symptoms
and signs of CNS depression. Accordingly, they should be advised neither to drive a car nor to
operate other complex machinery until they have gained sufficient experience on Neurontin to
gauge whether or not it affects their mental and/or motor performance adversely.
Patients who require concomitant treatment with morphine may experience increases in
gabapentin concentrations. Patients should be carefully observed for signs of CNS depression,
such as somnolence, and the dose of Neurontin or morphine should be reduced appropriately (see
Drug Interactions).
Patients should be encouraged to enroll in the North American Antiepileptic Drug (NAAED)
Pregnancy Registry if they become pregnant. This registry is collecting information about the
safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll free number 1
888-233-2334 (see PRECAUTIONS, Pregnancy section).
Laboratory Tests
Clinical trials data do not indicate that routine monitoring of clinical laboratory parameters is
necessary for the safe use of Neurontin. The value of monitoring gabapentin blood
concentrations has not been established. Neurontin may be used in combination with other
antiepileptic drugs without concern for alteration of the blood concentrations of gabapentin or of
other antiepileptic drugs.
Drug Interactions
In vitro studies were conducted to investigate the potential of gabapentin to inhibit the major
cytochrome P450 enzymes (CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and
CYP3A4) that mediate drug and xenobiotic metabolism using isoform selective marker
substrates and human liver microsomal preparations. Only at the highest concentration tested
(171 μg/mL; 1 mM) was a slight degree of inhibition (14%-30%) of isoform CYP2A6 observed.
No inhibition of any of the other isoforms tested was observed at gabapentin concentrations up to
171 μg/mL (approximately 15 times the Cmax at 3600 mg/day).
Gabapentin is not appreciably metabolized nor does it interfere with the metabolism of
commonly coadministered antiepileptic drugs.
The drug interaction data described in this section were obtained from studies involving healthy
adults and adult patients with epilepsy.
Phenytoin: In a single (400 mg) and multiple dose (400 mg TID) study of Neurontin in epileptic
patients (N=8) maintained on phenytoin monotherapy for at least 2 months, gabapentin had no
effect on the steady-state trough plasma concentrations of phenytoin and phenytoin had no effect
on gabapentin pharmacokinetics.
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Carbamazepine: Steady-state trough plasma carbamazepine and carbamazepine 10, 11 epoxide
concentrations were not affected by concomitant gabapentin (400 mg TID; N=12)
administration. Likewise, gabapentin pharmacokinetics were unaltered by carbamazepine
administration.
Valproic Acid: The mean steady-state trough serum valproic acid concentrations prior to and
during concomitant gabapentin administration (400 mg TID; N=17) were not different and
neither were gabapentin pharmacokinetic parameters affected by valproic acid.
Phenobarbital: Estimates of steady-state pharmacokinetic parameters for phenobarbital or
gabapentin (300 mg TID; N=12) are identical whether the drugs are administered alone or
together.
Naproxen: Coadministration (N=18) of naproxen sodium capsules (250 mg) with Neurontin
(125 mg) appears to increase the amount of gabapentin absorbed by 12% to 15%. Gabapentin
had no effect on naproxen pharmacokinetic parameters. These doses are lower than the
therapeutic doses for both drugs. The magnitude of interaction within the recommended dose
ranges of either drug is not known.
Hydrocodone: Coadministration of Neurontin (125 to 500 mg; N=48) decreases hydrocodone
(10 mg; N=50) Cmax and AUC values in a dose-dependent manner relative to administration of
hydrocodone alone; Cmax and AUC values are 3% to 4% lower, respectively, after administration
of 125 mg Neurontin and 21% to 22% lower, respectively, after administration of 500 mg
Neurontin. The mechanism for this interaction is unknown. Hydrocodone increases gabapentin
AUC values by 14%. The magnitude of interaction at other doses is not known.
Morphine: A literature article reported that when a 60-mg controlled-release morphine capsule
was administered 2 hours prior to a 600-mg Neurontin capsule (N=12), mean gabapentin AUC
increased by 44% compared to gabapentin administered without morphine (see
PRECAUTIONS). Morphine pharmacokinetic parameter values were not affected by
administration of Neurontin 2 hours after morphine. The magnitude of interaction at other doses
is not known.
Cimetidine: In the presence of cimetidine at 300 mg QID (N=12) the mean apparent oral
clearance of gabapentin fell by 14% and creatinine clearance fell by 10%. Thus cimetidine
appeared to alter the renal excretion of both gabapentin and creatinine, an endogenous marker of
renal function. This small decrease in excretion of gabapentin by cimetidine is not expected to be
of clinical importance. The effect of gabapentin on cimetidine was not evaluated.
Oral Contraceptive: Based on AUC and half-life, multiple-dose pharmacokinetic profiles of
norethindrone and ethinyl estradiol following administration of tablets containing 2.5 mg of
norethindrone acetate and 50 mcg of ethinyl estradiol were similar with and without
coadministration of gabapentin (400 mg TID; N=13). The Cmax of norethindrone was 13%
higher when it was coadministered with gabapentin; this interaction is not expected to be of
clinical importance.
Antacid (Maalox®): Maalox reduced the bioavailability of gabapentin (N=16) by about 20%.
This decrease in bioavailability was about 5% when gabapentin was administered 2 hours after
Maalox. It is recommended that gabapentin be taken at least 2 hours following Maalox
administration.
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Effect of Probenecid: Probenecid is a blocker of renal tubular secretion. Gabapentin
pharmacokinetic parameters without and with probenecid were comparable. This indicates that
gabapentin does not undergo renal tubular secretion by the pathway that is blocked by
probenecid.
Drug/Laboratory Tests Interactions
Because false positive readings were reported with the Ames N-Multistix SG® dipstick test for
urinary protein when gabapentin was added to other antiepileptic drugs, the more specific
sulfosalicylic acid precipitation procedure is recommended to determine the presence of urine
protein.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Gabapentin was given in the diet to mice at 200, 600, and 2000 mg/kg/day and to rats at 250,
1000, and 2000 mg/kg/day for 2 years. A statistically significant increase in the incidence of
pancreatic acinar cell adenomas and carcinomas was found in male rats receiving the high dose;
the no-effect dose for the occurrence of carcinomas was 1000 mg/kg/day. Peak plasma
concentrations of gabapentin in rats receiving the high dose of 2000 mg/kg were 10 times higher
than plasma concentrations in humans receiving 3600 mg per day, and in rats receiving
1000 mg/kg/day peak plasma concentrations were 6.5 times higher than in humans receiving
3600 mg/day. The pancreatic acinar cell carcinomas did not affect survival, did not metastasize
and were not locally invasive. The relevance of this finding to carcinogenic risk in humans is
unclear.
Studies designed to investigate the mechanism of gabapentin-induced pancreatic carcinogenesis
in rats indicate that gabapentin stimulates DNA synthesis in rat pancreatic acinar cells in vitro
and, thus, may be acting as a tumor promoter by enhancing mitogenic activity. It is not known
whether gabapentin has the ability to increase cell proliferation in other cell types or in other
species, including humans.
Gabapentin did not demonstrate mutagenic or genotoxic potential in three in vitro and four in
vivo assays. It was negative in the Ames test and the in vitro HGPRT forward mutation assay in
Chinese hamster lung cells; it did not produce significant increases in chromosomal aberrations
in the in vitro Chinese hamster lung cell assay; it was negative in the in vivo chromosomal
aberration assay and in the in vivo micronucleus test in Chinese hamster bone marrow; it was
negative in the in vivo mouse micronucleus assay; and it did not induce unscheduled DNA
synthesis in hepatocytes from rats given gabapentin.
No adverse effects on fertility or reproduction were observed in rats at doses up to 2000 mg/kg
(approximately 5 times the maximum recommended human dose on a mg/m2 basis).
Pregnancy
Pregnancy Category C: Gabapentin has been shown to be fetotoxic in rodents, causing delayed
ossification of several bones in the skull, vertebrae, forelimbs, and hindlimbs. These effects
occurred when pregnant mice received oral doses of 1000 or 3000 mg/kg/day during the period
of organogenesis, or approximately 1 to 4 times the maximum dose of 3600 mg/day given to
epileptic patients on a mg/m2 basis. The no-effect level was 500 mg/kg/day or approximately ½
of the human dose on a mg/m2 basis.
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When rats were dosed prior to and during mating, and throughout gestation, pups from all dose
groups (500, 1000 and 2000 mg/kg/day) were affected. These doses are equivalent to less than
approximately 1 to 5 times the maximum human dose on a mg/m2 basis. There was an increased
incidence of hydroureter and/or hydronephrosis in rats in a study of fertility and general
reproductive performance at 2000 mg/kg/day with no effect at 1000 mg/kg/day, in a teratology
study at 1500 mg/kg/day with no effect at 300 mg/kg/day, and in a perinatal and postnatal study
at all doses studied (500, 1000 and 2000 mg/kg/day). The doses at which the effects occurred are
approximately 1 to 5 times the maximum human dose of 3600 mg/day on a mg/m2 basis; the no-
effect doses were approximately 3 times (Fertility and General Reproductive Performance study)
and approximately equal to (Teratogenicity study) the maximum human dose on a mg/m2 basis.
Other than hydroureter and hydronephrosis, the etiologies of which are unclear, the incidence of
malformations was not increased compared to controls in offspring of mice, rats, or rabbits given
doses up to 50 times (mice), 30 times (rats), and 25 times (rabbits) the human daily dose on a
mg/kg basis, or 4 times (mice), 5 times (rats), or 8 times (rabbits) the human daily dose on a
mg/m2 basis.
In a teratology study in rabbits, an increased incidence of postimplantation fetal loss occurred in
dams exposed to 60, 300, and 1500 mg/kg/day, or less than approximately ¼ to 8 times the
maximum human dose on a mg/m2 basis. There are no adequate and well-controlled studies in
pregnant women. This drug should be used during pregnancy only if the potential benefit
justifies the potential risk to the fetus.
To provide information regarding the effects of in utero exposure to Neurontin, physicians are
advised to recommend that pregnant patients taking Neurontin enroll in the North American
Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll free
number 1-888-233-2334, and must be done by patients themselves. Information on the registry
can also be found at the website http://www.aedpregnancyregistry.org/.
Use in Nursing Mothers
Gabapentin is secreted into human milk following oral administration. A nursed infant could be
exposed to a maximum dose of approximately 1 mg/kg/day of gabapentin. Because the effect on
the nursing infant is unknown, Neurontin should be used in women who are nursing only if the
benefits clearly outweigh the risks.
Pediatric Use
Safety and effectiveness of Neurontin (gabapentin) in the management of postherpetic neuralgia
in pediatric patients have not been established.
Effectiveness as adjunctive therapy in the treatment of partial seizures in pediatric patients below
the age of 3 years has not been established (see CLINICAL PHARMACOLOGY, Clinical
Studies).
Geriatric Use
The total number of patients treated with Neurontin in controlled clinical trials in patients with
postherpetic neuralgia was 336, of which 102 (30%) were 65 to 74 years of age, and 168 (50%)
were 75 years of age and older. There was a larger treatment effect in patients 75 years of age
and older compared with younger patients who received the same dosage. Since gabapentin is
almost exclusively eliminated by renal excretion, the larger treatment effect observed in patients
≥75 years may be a consequence of increased gabapentin exposure for a given dose that results
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from an age-related decrease in renal function. However, other factors cannot be excluded. The
types and incidence of adverse events were similar across age groups except for peripheral
edema and ataxia, which tended to increase in incidence with age.
Clinical studies of Neurontin in epilepsy did not include sufficient numbers of subjects aged 65
and over to determine whether they responded differently from younger subjects. Other reported
clinical experience has not identified differences in responses between the elderly and younger
patients. In general, dose selection for an elderly patient should be cautious, usually starting at
the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or
cardiac function, and of concomitant disease or other drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to
this drug may be greater in patients with impaired renal function. Because elderly patients are
more likely to have decreased renal function, care should be taken in dose selection, and dose
should be adjusted based on creatinine clearance values in these patients (see CLINICAL
PHARMACOLOGY, ADVERSE REACTIONS, and DOSAGE AND ADMINISTRATION
sections).
ADVERSE REACTIONS
Postherpetic Neuralgia
The most commonly observed adverse events associated with the use of Neurontin in adults, not
seen at an equivalent frequency among placebo-treated patients, were dizziness, somnolence, and
peripheral edema.
In the 2 controlled studies in postherpetic neuralgia, 16% of the 336 patients who received
Neurontin and 9% of the 227 patients who received placebo discontinued treatment because of an
adverse event. The adverse events that most frequently led to withdrawal in Neurontin®-treated
patients were dizziness, somnolence, and nausea.
Incidence in Controlled Clinical Trials
Table 3 lists treatment-emergent signs and symptoms that occurred in at least 1% of Neurontin
treated patients with postherpetic neuralgia participating in placebo-controlled trials and that
were numerically more frequent in the Neurontin group than in the placebo group. Adverse
events were usually mild to moderate in intensity.
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TABLE 3. Treatment-Emergent Adverse Event Incidence in
Controlled Trials in Postherpetic Neuralgia (Events
in at least 1% of Neurontin®-Treated Patients and
Numerically More Frequent Than in the Placebo
Group)
Body System/
Neurontin®
Placebo
Preferred Term
N=336
N=227
%
%
Body as a Whole
Asthenia
5.7
4.8
Infection
5.1
3.5
Headache
3.3
3.1
Accidental injury
3.3
1.3
Abdominal pain
2.7
2.6
Digestive System
Diarrhea
5.7
3.1
Dry mouth
4.8
1.3
Constipation
3.9
1.8
Nausea
3.9
3.1
Vomiting
3.3
1.8
Flatulence
2.1
1.8
Metabolic and Nutritional Disorders
Peripheral edema
8.3
2.2
Weight gain
1.8
0.0
Hyperglycemia
1.2
0.4
Nervous System
Dizziness
28.0
7.5
Somnolence
21.4
5.3
Ataxia
3.3
0.0
Thinking abnormal
2.7
0.0
Abnormal gait
1.5
0.0
Incoordination
1.5
0.0
Amnesia
1.2
0.9
Hypesthesia
1.2
0.9
Respiratory System
Pharyngitis
1.2
0.4
Skin and Appendages
Rash
1.2
0.9
Special Senses
Amblyopiaa
2.7
0.9
Conjunctivitis
1.2
0.0
Diplopia
1.2
0.0
Otitis media
1.2
0.0
a Reported as blurred vision
Other events in more than 1% of patients but equally or more frequent in the placebo group
included pain, tremor, neuralgia, back pain, dyspepsia, dyspnea, and flu syndrome.
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There were no clinically important differences between men and women in the types and
incidence of adverse events. Because there were few patients whose race was reported as other
than white, there are insufficient data to support a statement regarding the distribution of adverse
events by race.
Epilepsy
The most commonly observed adverse events associated with the use of Neurontin in
combination with other antiepileptic drugs in patients >12 years of age, not seen at an equivalent
frequency among placebo-treated patients, were somnolence, dizziness, ataxia, fatigue, and
nystagmus. The most commonly observed adverse events reported with the use of Neurontin in
combination with other antiepileptic drugs in pediatric patients 3 to 12 years of age, not seen at
an equal frequency among placebo-treated patients, were viral infection, fever, nausea and/or
vomiting, somnolence, and hostility (see WARNINGS, Neuropsychiatric Adverse Events).
Approximately 7% of the 2074 patients >12 years of age and approximately 7% of the 449
pediatric patients 3 to 12 years of age who received Neurontin in premarketing clinical trials
discontinued treatment because of an adverse event. The adverse events most commonly
associated with withdrawal in patients >12 years of age were somnolence (1.2%), ataxia (0.8%),
fatigue (0.6%), nausea and/or vomiting (0.6%), and dizziness (0.6%). The adverse events most
commonly associated with withdrawal in pediatric patients were emotional lability (1.6%),
hostility (1.3%), and hyperkinesia (1.1%).
Incidence in Controlled Clinical Trials
Table 4 lists treatment-emergent signs and symptoms that occurred in at least 1% of Neurontin
treated patients >12 years of age with epilepsy participating in placebo-controlled trials and were
numerically more common in the Neurontin group. In these studies, either Neurontin or placebo
was added to the patient’s current antiepileptic drug therapy. Adverse events were usually mild
to moderate in intensity.
The prescriber should be aware that these figures, obtained when Neurontin was added to
concurrent antiepileptic drug therapy, cannot be used to predict the frequency of adverse events
in the course of usual medical practice where patient characteristics and other factors may differ
from those prevailing during clinical studies. Similarly, the cited frequencies cannot be directly
compared with figures obtained from other clinical investigations involving different treatments,
uses, or investigators. An inspection of these frequencies, however, does provide the prescribing
physician with one basis to estimate the relative contribution of drug and nondrug factors to the
adverse event incidences in the population studied.
Reference ID: 2911805
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020235/S-036; NDA 020882/S-022; NDA 021129/S-022
FDA Approved Labeling Text dated 03/01/2011
Page 20
TABLE 4.
Treatment-Emergent Adverse Event Incidence in Controlled Add-On
Trials In Patients >12 years of age (Events in at least 1% of Neurontin
patients and numerically more frequent than in the placebo group)
Body System/
Neurontina
Placeboa
Adverse Event
N=543
N=378
%
%
Body As A Whole
Fatigue
Weight Increase
Back Pain
Peripheral Edema
Cardiovascular
Vasodilatation
Digestive System
Dyspepsia
Mouth or Throat Dry
Constipation
Dental Abnormalities
Increased Appetite
Hematologic and Lymphatic Systems
Leukopenia
Musculoskeletal System
Myalgia
Fracture
Nervous System
Somnolence
Dizziness
Ataxia
Nystagmus
Tremor
Nervousness
Dysarthria
Amnesia
Depression
Thinking Abnormal
Twitching
Coordination Abnormal
Respiratory System
Rhinitis
Pharyngitis
Coughing
Skin and Appendages
Abrasion
Pruritus
11.0
2.9
1.8
1.7
1.1
2.2
1.7
1.5
1.5
1.1
1.1
2.0
1.1
19.3
17.1
12.5
8.3
6.8
2.4
2.4
2.2
1.8
1.7
1.3
1.1
4.1
2.8
1.8
1.3
1.3
5.0
1.6
0.5
0.5
0.3
0.5
0.5
0.8
0.3
0.8
0.5
1.9
0.8
8.7
6.9
5.6
4.0
3.2
1.9
0.5
0.0
1.1
1.3
0.5
0.3
3.7
1.6
1.3
0.0
0.5
Reference ID: 2911805
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For current labeling information, please visit https://www.fda.gov/drugsatfda
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FDA Approved Labeling Text dated 03/01/2011
Page 21
TABLE 4.
Treatment-Emergent Adverse Event Incidence in Controlled Add-On
Trials In Patients >12 years of age (Events in at least 1% of Neurontin
patients and numerically more frequent than in the placebo group)
Body System/
Neurontina
Placeboa
Adverse Event
N=543
N=378
%
%
Urogenital System
Impotence
1.5
1.1
Special Senses
Diplopia
Amblyopiab
5.9
4.2
1.9
1.1
Laboratory Deviations
WBC Decreased
1.1
0.5
a Plus background antiepileptic drug therapy
b Amblyopia was often described as blurred vision.
Other events in more than 1% of patients >12 years of age but equally or more frequent in the
placebo group included: headache, viral infection, fever, nausea and/or vomiting, abdominal
pain, diarrhea, convulsions, confusion, insomnia, emotional lability, rash, acne.
Among the treatment-emergent adverse events occurring at an incidence of at least 10% of
Neurontin-treated patients, somnolence and ataxia appeared to exhibit a positive dose-response
relationship.
The overall incidence of adverse events and the types of adverse events seen were similar among
men and women treated with Neurontin. The incidence of adverse events increased slightly with
increasing age in patients treated with either Neurontin or placebo. Because only 3% of patients
(28/921) in placebo-controlled studies were identified as nonwhite (black or other), there are
insufficient data to support a statement regarding the distribution of adverse events by race.
Table 5 lists treatment-emergent signs and symptoms that occurred in at least 2% of Neurontin
treated patients age 3 to 12 years of age with epilepsy participating in placebo-controlled trials
and were numerically more common in the Neurontin group. Adverse events were usually mild
to moderate in intensity.
Reference ID: 2911805
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Page 22
TABLE 5.
Treatment-Emergent Adverse Event Incidence in Pediatric Patients
Age 3 to 12 Years in a Controlled Add-On Trial (Events in at least
2% of Neurontin patients and numerically more frequent than in the
placebo group)
Body System/
Neurontina
Placeboa
Adverse Event
N=119
N=128
%
%
Body As A Whole
Viral Infection
10.9
3.1
Fever
10.1
3.1
Weight Increase
3.4
0.8
Fatigue
3.4
1.6
Digestive System
Nausea and/or Vomiting
8.4
7.0
Nervous System
Somnolence
8.4
4.7
Hostility
7.6
2.3
Emotional Lability
4.2
1.6
Dizziness
2.5
1.6
Hyperkinesia
2.5
0.8
Respiratory System
Bronchitis
3.4
0.8
Respiratory Infection
2.5
0.8
a
Plus background antiepileptic drug therapy
Other events in more than 2% of pediatric patients 3 to 12 years of age but equally or more
frequent in the placebo group included: pharyngitis, upper respiratory infection, headache,
rhinitis, convulsions, diarrhea, anorexia, coughing, and otitis media.
Other Adverse Events Observed During All Clinical Trials
Clinical Trials in Adults and Adolescents (Except Clinical Trials in Neuropathic Pain)
Neurontin has been administered to 4717 patients >12 years of age during all adjunctive therapy
clinical trials (except clinical trials in patients with neuropathic pain), only some of which were
placebo-controlled. During these trials, all adverse events were recorded by the clinical
investigators using terminology of their own choosing. To provide a meaningful estimate of the
proportion of individuals having adverse events, similar types of events were grouped into a
smaller number of standardized categories using modified COSTART dictionary terminology.
These categories are used in the listing below. The frequencies presented represent the
proportion of the 4717 patients >12 years of age exposed to Neurontin who experienced an event
of the type cited on at least one occasion while receiving Neurontin. All reported events are
included except those already listed in Table 4, those too general to be informative, and those not
reasonably associated with the use of the drug.
Events are further classified within body system categories and enumerated in order of
decreasing frequency using the following definitions: frequent adverse events are defined as
Reference ID: 2911805
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Page 23
those occurring in at least 1/100 patients; infrequent adverse events are those occurring in 1/100
to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients.
Body As A Whole: Frequent: asthenia, malaise, face edema; Infrequent: allergy, generalized
edema, weight decrease, chill; Rare: strange feelings, lassitude, alcohol intolerance, hangover
effect.
Cardiovascular System: Frequent: hypertension; Infrequent: hypotension, angina pectoris,
peripheral vascular disorder, palpitation, tachycardia, migraine, murmur; Rare: atrial fibrillation,
heart failure, thrombophlebitis, deep thrombophlebitis, myocardial infarction, cerebrovascular
accident, pulmonary thrombosis, ventricular extrasystoles, bradycardia, premature atrial
contraction, pericardial rub, heart block, pulmonary embolus, hyperlipidemia,
hypercholesterolemia, pericardial effusion, pericarditis.
Digestive System: Frequent: anorexia, flatulence, gingivitis; Infrequent: glossitis, gum
hemorrhage, thirst, stomatitis, increased salivation, gastroenteritis, hemorrhoids, bloody stools,
fecal incontinence, hepatomegaly; Rare: dysphagia, eructation, pancreatitis, peptic ulcer, colitis,
blisters in mouth, tooth discolor, perlèche, salivary gland enlarged, lip hemorrhage, esophagitis,
hiatal hernia, hematemesis, proctitis, irritable bowel syndrome, rectal hemorrhage, esophageal
spasm.
Endocrine System: Rare: hyperthyroid, hypothyroid, goiter, hypoestrogen, ovarian failure,
epididymitis, swollen testicle, cushingoid appearance.
Hematologic and Lymphatic System: Frequent: purpura most often described as bruises
resulting from physical trauma; Infrequent: anemia, thrombocytopenia, lymphadenopathy; Rare:
WBC count increased, lymphocytosis, non-Hodgkin’s lymphoma, bleeding time increased.
Musculoskeletal System: Frequent: arthralgia; Infrequent: tendinitis, arthritis, joint stiffness,
joint swelling, positive Romberg test; Rare: costochondritis, osteoporosis, bursitis, contracture.
Nervous System: Frequent: vertigo, hyperkinesia, paresthesia, decreased or absent reflexes,
increased reflexes, anxiety, hostility; Infrequent: CNS tumors, syncope, dreaming abnormal,
aphasia, hypesthesia, intracranial hemorrhage, hypotonia, dysesthesia, paresis, dystonia,
hemiplegia, facial paralysis, stupor, cerebellar dysfunction, positive Babinski sign, decreased
position sense, subdural hematoma, apathy, hallucination, decrease or loss of libido, agitation,
paranoia, depersonalization, euphoria, feeling high, doped-up sensation, psychosis; Rare:
choreoathetosis, orofacial dyskinesia, encephalopathy, nerve palsy, personality disorder,
increased libido, subdued temperament, apraxia, fine motor control disorder, meningismus, local
myoclonus, hyperesthesia, hypokinesia, mania, neurosis, hysteria, antisocial reaction.
Respiratory System: Frequent: pneumonia; Infrequent: epistaxis, dyspnea, apnea; Rare:
mucositis, aspiration pneumonia, hyperventilation, hiccup, laryngitis, nasal obstruction, snoring,
bronchospasm, hypoventilation, lung edema.
Dermatological: Infrequent: alopecia, eczema, dry skin, increased sweating, urticaria, hirsutism,
seborrhea, cyst, herpes simplex; Rare: herpes zoster, skin discolor, skin papules, photosensitive
reaction, leg ulcer, scalp seborrhea, psoriasis, desquamation, maceration, skin nodules,
subcutaneous nodule, melanosis, skin necrosis, local swelling.
Urogenital System: Infrequent: hematuria, dysuria, urination frequency, cystitis, urinary
retention, urinary incontinence, vaginal hemorrhage, amenorrhea, dysmenorrhea, menorrhagia,
Reference ID: 2911805
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Page 24
breast cancer, unable to climax, ejaculation abnormal; Rare: kidney pain, leukorrhea, pruritus
genital, renal stone, acute renal failure, anuria, glycosuria, nephrosis, nocturia, pyuria, urination
urgency, vaginal pain, breast pain, testicle pain.
Special Senses: Frequent: abnormal vision; Infrequent: cataract, conjunctivitis, eyes dry, eye
pain, visual field defect, photophobia, bilateral or unilateral ptosis, eye hemorrhage, hordeolum,
hearing loss, earache, tinnitus, inner ear infection, otitis, taste loss, unusual taste, eye twitching,
ear fullness; Rare: eye itching, abnormal accommodation, perforated ear drum, sensitivity to
noise, eye focusing problem, watery eyes, retinopathy, glaucoma, iritis, corneal disorders,
lacrimal dysfunction, degenerative eye changes, blindness, retinal degeneration, miosis,
chorioretinitis, strabismus, eustachian tube dysfunction, labyrinthitis, otitis externa, odd smell.
Clinical trials in Pediatric Patients With Epilepsy
Adverse events occurring during epilepsy clinical trials in 449 pediatric patients 3 to 12 years of
age treated with gabapentin that were not reported in adjunctive trials in adults are:
Body as a Whole: dehydration, infectious mononucleosis
Digestive System: hepatitis
Hemic and Lymphatic System: coagulation defect
Nervous System: aura disappeared, occipital neuralgia
Psychobiologic Function: sleepwalking
Respiratory System: pseudocroup, hoarseness
Clinical Trials in Adults With Neuropathic Pain of Various Etiologies
Safety information was obtained in 1173 patients during double-blind and open-label clinical
trials including neuropathic pain conditions for which efficacy has not been demonstrated.
Adverse events reported by investigators were grouped into standardized categories using
modified COSTART IV terminology. Listed below are all reported events except those already
listed in Table 3 and those not reasonably associated with the use of the drug.
Events are further classified within body system categories and enumerated in order of
decreasing frequency using the following definitions: frequent adverse events are defined as
those occurring in at least 1/100 patients; infrequent adverse events are those occurring in 1/100
to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients.
Body as a Whole: Infrequent: chest pain, cellulitis, malaise, neck pain, face edema, allergic
reaction, abscess, chills, chills and fever, mucous membrane disorder; Rare: body odor, cyst,
fever, hernia, abnormal BUN value, lump in neck, pelvic pain, sepsis, viral infection.
Cardiovascular System: Infrequent: hypertension, syncope, palpitation, migraine, hypotension,
peripheral vascular disorder, cardiovascular disorder, cerebrovascular accident, congestive heart
failure, myocardial infarction, vasodilatation; Rare: angina pectoris, heart failure, increased
capillary fragility, phlebitis, thrombophlebitis, varicose vein.
Digestive System: Infrequent: gastroenteritis, increased appetite, gastrointestinal disorder, oral
moniliasis, gastritis, tongue disorder, thirst, tooth disorder, abnormal stools, anorexia, liver
Reference ID: 2911805
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For current labeling information, please visit https://www.fda.gov/drugsatfda
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Page 25
function tests abnormal, periodontal abscess; Rare: cholecystitis, cholelithiasis, duodenal ulcer,
fecal incontinence, gamma glutamyl transpeptidase increased, gingivitis, intestinal obstruction,
intestinal ulcer, melena, mouth ulceration, rectal disorder, rectal hemorrhage, stomatitis.
Endocrine System: Infrequent: diabetes mellitus.
Hemic and Lymphatic System: Infrequent: ecchymosis, anemia; Rare: lymphadenopathy,
lymphoma-like reaction, prothrombin decreased.
Metabolic and Nutritional: Infrequent: edema, gout, hypoglycemia, weight loss; Rare: alkaline
phosphatase increased, diabetic ketoacidosis, lactic dehydrogenase increased.
Musculoskeletal: Infrequent: arthritis, arthralgia, myalgia, arthrosis, leg cramps, myasthenia;
Rare: shin bone pain, joint disorder, tendon disorder.
Nervous System: Frequent: confusion, depression; Infrequent: vertigo, nervousness,
paresthesia, insomnia, neuropathy, libido decreased, anxiety, depersonalization, reflexes
decreased, speech disorder, abnormal dreams, dysarthria, emotional lability, nystagmus, stupor,
circumoral paresthesia, euphoria, hyperesthesia, hypokinesia; Rare: agitation, hypertonia, libido
increased, movement disorder, myoclonus, vestibular disorder.
Respiratory System: Infrequent: cough increased, bronchitis, rhinitis, sinusitis, pneumonia,
asthma, lung disorder, epistaxis; Rare: hemoptysis, voice alteration.
Skin and Appendages: Infrequent: pruritus, skin ulcer, dry skin, herpes zoster, skin disorder,
fungal dermatitis, furunculosis, herpes simplex, psoriasis, sweating, urticaria, vesiculobullous
rash; Rare: acne, hair disorder, maculopapular rash, nail disorder, skin carcinoma, skin
discoloration, skin hypertrophy.
Special Senses: Infrequent: abnormal vision, ear pain, eye disorder, taste perversion, deafness;
Rare: conjunctival hyperemia, diabetic retinopathy, eye pain, fundi with microhemorrhage,
retinal vein thrombosis, taste loss.
Urogenital System: Infrequent: urinary tract infection, dysuria, impotence, urinary
incontinence, vaginal moniliasis, breast pain, menstrual disorder, polyuria, urinary retention;
Rare: cystitis, ejaculation abnormal, swollen penis, gynecomastia, nocturia, pyelonephritis,
swollen scrotum, urinary frequency, urinary urgency, urine abnormality.
Postmarketing and Other Experience
In addition to the adverse experiences reported during clinical testing of Neurontin, the following
adverse experiences have been reported in patients receiving marketed Neurontin. These adverse
experiences have not been listed above and data are insufficient to support an estimate of their
incidence or to establish causation. The listing is alphabetized: angioedema, blood glucose
fluctuation, breast enlargement, erythema multiforme, elevated liver function tests, fever,
hyponatremia, jaundice, movement disorder, Stevens-Johnson syndrome.
Adverse events following the abrupt discontinuation of gabapentin have also been reported. The
most frequently reported events were anxiety, insomnia, nausea, pain and sweating.
DRUG ABUSE AND DEPENDENCE
The abuse and dependence potential of Neurontin has not been evaluated in human studies.
Reference ID: 2911805
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Page 26
OVERDOSAGE
A lethal dose of gabapentin was not identified in mice and rats receiving single oral doses as
high as 8000 mg/kg. Signs of acute toxicity in animals included ataxia, labored breathing, ptosis,
sedation, hypoactivity, or excitation.
Acute oral overdoses of Neurontin up to 49 grams have been reported. In these cases, double
vision, slurred speech, drowsiness, lethargy and diarrhea were observed. All patients recovered
with supportive care.
Gabapentin can be removed by hemodialysis. Although hemodialysis has not been performed in
the few overdose cases reported, it may be indicated by the patient’s clinical state or in patients
with significant renal impairment.
DOSAGE AND ADMlNlSTRATION
Neurontin is given orally with or without food. Patients should be informed that, should they
break the scored 600 or 800 mg tablet in order to administer a half-tablet, they should take the
unused half-tablet as the next dose. Half-tablets not used within several days of breaking the
scored tablet should be discarded.
If Neurontin dose is reduced, discontinued or substituted with an alternative medication, this
should be done gradually over a minimum of 1 week (a longer period may be needed at the
discretion of the prescriber).
Postherpetic Neuralgia
In adults with postherpetic neuralgia, Neurontin therapy may be initiated as a single 300-mg dose
on Day 1, 600 mg/day on Day 2 (divided BID), and 900 mg/day on Day 3 (divided TID). The
dose can subsequently be titrated up as needed for pain relief to a daily dose of 1800 mg (divided
TID). In clinical studies, efficacy was demonstrated over a range of doses from 1800 mg/day to
3600 mg/day with comparable effects across the dose range. Additional benefit of using doses
greater than 1800 mg/day was not demonstrated.
Epilepsy
Neurontin is recommended for add-on therapy in patients 3 years of age and older. Effectiveness
in pediatric patients below the age of 3 years has not been established.
Patients >12 years of age: The effective dose of Neurontin is 900 to 1800 mg/day and given in
divided doses (three times a day) using 300 or 400 mg capsules, or 600 or 800 mg tablets. The
starting dose is 300 mg three times a day. If necessary, the dose may be increased using 300 or
400 mg capsules, or 600 or 800 mg tablets three times a day up to 1800 mg/day. Dosages up to
2400 mg/day have been well tolerated in long-term clinical studies. Doses of 3600 mg/day have
also been administered to a small number of patients for a relatively short duration, and have
been well tolerated. The maximum time between doses in the TID schedule should not exceed 12
hours.
Pediatric Patients Age 3–12 years: The starting dose should range from 10-15 mg/kg/day in
3 divided doses, and the effective dose reached by upward titration over a period of
approximately 3 days. The effective dose of Neurontin in patients 5 years of age and older is
Reference ID: 2911805
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Page 27
25–35 mg/kg/day and given in divided doses (three times a day). The effective dose in pediatric
patients ages 3 and 4 years is 40 mg/kg/day and given in divided doses (three times a day) (see
CLINICAL PHARMACOLOGY, Pediatrics.) Neurontin® may be administered as the oral
solution, capsule, or tablet, or using combinations of these formulations. Dosages up to
50 mg/kg/day have been well-tolerated in a long-term clinical study. The maximum time interval
between doses should not exceed 12 hours.
It is not necessary to monitor gabapentin plasma concentrations to optimize Neurontin therapy.
Further, because there are no significant pharmacokinetic interactions among Neurontin and
other commonly used antiepileptic drugs, the addition of Neurontin does not alter the plasma
levels of these drugs appreciably.
If Neurontin is discontinued and/or an alternate anticonvulsant medication is added to the
therapy, this should be done gradually over a minimum of 1 week.
Dosage in Renal Impairment
Creatinine clearance is difficult to measure in outpatients. In patients with stable renal function,
creatinine clearance (CCr) can be reasonably well estimated using the equation of Cockcroft and
Gault:
for females CCr=(0.85)(140-age)(weight)/[(72)(SCr)]
for males CCr=(140-age)(weight)/[(72)(SCr)]
where age is in years, weight is in kilograms and SCr is serum creatinine in mg/dL.
Dosage adjustment in patients ≥12 years of age with compromised renal function or undergoing
hemodialysis is recommended as follows (see dosing recommendations above for effective doses
in each indication).
TABLE 6. Neurontin® Dosage Based on Renal Function
Renal Function
Total Daily
Dose Regimen
Creatinine Clearance
Dose Range
(mg)
(mL/min)
(mg/day)
≥60
900-3600
300 TID
400 TID
600 TID
800 TID 1200 TID
>30-59
400-1400
200 BID 300 BID 400 BID
500 BID
700 BID
>15-29
200-700
200 QD
300 QD
400 QD
500 QD
700 QD
15a
100-300
100 QD
125 QD
150 QD
200 QD
300 QD
Post-Hemodialysis Supplemental Dose (mg)b
Hemodialysis
125b
150b
200b
250b
350b
a
For patients with creatinine clearance <15 mL/min, reduce daily dose in proportion to creatinine clearance
(e.g., patients with a creatinine clearance of 7.5 mL/min should receive one-half the daily dose that patients
with a creatinine clearance of 15 mL/min receive).
b
Patients on hemodialysis should receive maintenance doses based on estimates of creatinine clearance as
indicated in the upper portion of the table and a supplemental post-hemodialysis dose administered after each
4 hours of hemodialysis as indicated in the lower portion of the table.
Reference ID: 2911805
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020235/S-036; NDA 020882/S-022; NDA 021129/S-022
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Page 28
The use of Neurontin in patients <12 years of age with compromised renal function has not been
studied.
Dosage in Elderly
Because elderly patients are more likely to have decreased renal function, care should be taken in
dose selection, and dose should be adjusted based on creatinine clearance values in these
patients.
HOW SUPPLIED
Neurontin (gabapentin) capsules, tablets and oral solution are supplied as follows:
100 mg capsules;
White hard gelatin capsules printed with “PD” on one side and “Neurontin/100 mg” on
the other; available in:
Bottles of 100: N 0071-0803-24
Unit dose 50’s: N 0071-0803-40
300 mg capsules;
Yellow hard gelatin capsules printed with “PD” on one side and “Neurontin/300 mg” on
the other; available in:
Bottles of 100: N 0071-0805-24
Unit dose 50’s: N 0071-0805-40
400 mg capsules;
Orange hard gelatin capsules printed with “PD” on one side and “Neurontin/400 mg” on
the other; available in:
Bottles of 100: N 0071-0806-24
Unit dose 50’s: N 0071-0806-40
600 mg tablets;
White elliptical film-coated scored tablets debossed with “NT” and “16” on one side;
available in:
Bottles of 100: N 0071-0513-24
800 mg tablets;
White elliptical film-coated scored tablets debossed with “NT” and “26” on one side;
available in:
Bottles of 100: N 0071-0401-24
Reference ID: 2911805
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020235/S-036; NDA 020882/S-022; NDA 021129/S-022
FDA Approved Labeling Text dated 03/01/2011
Page 29
250 mg/5 mL oral solution;
Clear colorless to slightly yellow solution; each 5 mL of oral solution contains 250 mg of
gabapentin; available in:
Bottles containing 470 mL: N0071-2012-23
Storage (Capsules)
Store at 25°C (77°F); excursions permitted to 15° - 30°C (59° - 86°F) [see USP Controlled
Room Temperature].
Storage (Tablets)
Store at 25°C (77°F); excursions permitted to 15° - 30°C (59° - 86°F) [see USP Controlled
Room Temperature].
Storage (Oral Solution)
Store refrigerated, 2°-8°C (36°-46°F)
Rx only
Distributed by:
Α Parke-Davis
Division of Pfizer Inc, NY, NY 10017
LAB-0106-11.0
Revised July 2010
Reference ID: 2911805
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For current labeling information, please visit https://www.fda.gov/drugsatfda
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FDA Approved Labeling Text dated 03/01/2011
Page 30
MEDICATION GUIDE
NEURONTIN (Neu rŏn' tĭn)
(Gabapentin)
Capsules, Tablets, and Oral Solution
Read the Medication Guide before you start taking NEURONTIN and each time you get a refill.
There may be new information. This information does not take the place of talking to your
healthcare provider about your medical condition or treatment.
What is the most important information I should know about NEURONTIN?
Do not stop taking NEURONTIN without first talking to your healthcare provider.
Stopping NEURONTIN suddenly can cause serious problems.
NEURONTIN can cause serious side effects including:
1. Like other antiepileptic drugs, NEURONTIN may cause suicidal thoughts or actions
in a very small number of people, about 1 in 500.
Call a healthcare provider right away if you have any of these symptoms, especially if
they are new, worse, or worry you:
• thoughts about suicide or dying
• attempts to commit suicide
• new or worse depression
• new or worse anxiety
• feeling agitated or restless
• panic attacks
• trouble sleeping (insomnia)
• new or worse irritability
• acting aggressive, being angry, or violent
• acting on dangerous impulses
•
an extreme increase in activity and talking (mania)
•
other unusual changes in behavior or mood
How can I watch for early symptoms of suicidal thoughts and actions?
• Pay attention to any changes, especially sudden changes, in mood, behaviors,
thoughts, or feelings.
• Keep all follow-up visits with your healthcare provider as scheduled.
Reference ID: 2911805
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020235/S-036; NDA 020882/S-022; NDA 021129/S-022
FDA Approved Labeling Text dated 03/01/2011
Page 31
Call your healthcare provider between visits as needed, especially if you are worried
about symptoms.
Do not stop taking NEURONTIN without first talking to a healthcare provider.
• Stopping NEURONTIN suddenly can cause serious problems. Stopping a seizure
medicine suddenly in a patient who has epilepsy can cause seizures that will not
stop (status epilepticus).
Suicidal thoughts or actions can be caused by things other than medicines. If you have
suicidal thoughts or actions, your healthcare provider may check for other causes.
2. Changes in behavior and thinking - Using NEURONTIN in children 3 to 12 years of
age can cause emotional changes, aggressive behavior, problems with concentration,
restlessness, changes in school performance, and hyperactivity.
What is NEURONTIN?
NEURONTIN is a prescription medicine used to treat:
• Pain from damaged nerves (postherpetic pain) that follows healing of shingles (a painful
rash that comes after a herpes zoster infection) in adults.
• Partial seizures when taken together with other medicines in adults and children
3 years of age and older.
Who should not take NEURONTIN?
Do not take NEURONTIN if you are allergic to gabapentin or any of the other ingredients in
NEURONTIN. See the end of this Medication Guide for a complete list of ingredients in
NEURONTIN.
What should I tell my healthcare provider before taking NEURONTIN?
Before taking NEURONTIN, tell your healthcare provider if you:
• have or have had kidney problems or are on hemodialysis
• have or have had depression, mood problems, or suicidal thoughts or behavior
• are pregnant or plan to become pregnant. It is not known if NEURONTIN can harm your
unborn baby. Tell your healthcare provider right away if you become pregnant while
taking NEURONTIN. You and your healthcare provider will decide if you should take
NEURONTIN while you are pregnant.
o If you become pregnant while taking NEURONTIN, talk to your healthcare
provider about registering with the North American Antiepileptic Drug
(NAAED) Pregnancy Registry. The purpose of this registry is to collect
Reference ID: 2911805
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020235/S-036; NDA 020882/S-022; NDA 021129/S-022
FDA Approved Labeling Text dated 03/01/2011
Page 32
information about the safety of antiepileptic drugs during pregnancy. You can
enroll in this registry by calling 1-888-233-2334.
• are breast-feeding or plan to breast-feed. NEURONTIN can pass into breast milk. You
and your healthcare provider should decide how you will feed your baby while you take
NEURONTIN.
Tell your healthcare provider about all the medicines you take, including prescription and
non-prescription medicines, vitamins, and herbal supplements.
Taking NEURONTIN with certain other medicines can cause side effects or affect how well they
work. Do not start or stop other medicines without talking to your healthcare provider.
Know the medicines you take. Keep a list of them and show it to your healthcare provider and
pharmacist when you get a new medicine.
How should I take NEURONTIN?
• Take NEURONTIN exactly as prescribed. Your healthcare provider will tell you how
much NEURONTIN to take.
o Do not change your dose of NEURONTIN without talking to your healthcare
provider. If you break a tablet in half the unused half of the tablet should be
taken at your next scheduled dose. Half tablets not used within several days of
breaking should be thrown away. If taking capsules, always swallow them
whole with plenty of water.
• NEURONTIN can be taken with or without food. If you take an antacid containing
aluminum and magnesium, such as Maalox®, Mylanta®, Gelusil®, Gaviscon®, or Di-Gel®,
you should wait at least 2 hours before taking your next dose of NEURONTIN.
• If you take too much NEURONTIN, call your healthcare provider or your local Poison
Control Center right away.
What should I avoid while taking NEURONTIN?
• Do not drink alcohol or take other medicines that make you sleepy or dizzy while taking
NEURONTIN without first talking with your healthcare provider. Taking NEURONTIN
with alcohol or drugs that cause sleepiness or dizziness may make your sleepiness or
dizziness worse.
• Do not drive, operate heavy machinery, or do other dangerous activities until you know
how NEURONTIN affects you. NEURONTIN can slow your thinking and motor skills.
Reference ID: 2911805
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020235/S-036; NDA 020882/S-022; NDA 021129/S-022
FDA Approved Labeling Text dated 03/01/2011
Page 33
What are the possible side effects of NEURONTIN?
•
See “What is the most important information I should know about NEURONTIN?”
•
The most common side effects of NEURONTIN include:
•
dizziness
• difficulty with speaking
• lack of coordination
•
temporary loss of memory
(amnesia)
•
viral infection
•
tremor
•
feeling drowsy
•
difficulty with coordination
•
feeling tired
•
double vision
•
fever
•
unusual eye movement
•
jerky movements
Tell your healthcare provider if you have any side effect that bothers you or that does not go
away.
These are not all the possible side effects of NEURONTIN. For more information, ask your
healthcare provider or pharmacist.
Call your doctor for medical advice about side effects. You may report side effects to FDA
at 1-800-FDA-1088.
How should I store NEURONTIN?
• Store NEURONTIN Capsules between 59°F to 86°F (15°C to 30°C).
• Store NEURONTIN Tablets between 59°F to 86°F (15°C to 30°C).
• Store NEURONTIN Oral Solution in the refrigerator between 36°F to 46°F (2°C to 8°C).
Keep NEURONTIN and all medicines out of the reach of children.
General information about the safe and effective use of NEURONTIN
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide.
Do not use NEURONTIN for a condition for which it was not prescribed. Do not give
NEURONTIN to other people, even if they have the same symptoms that you have. It may harm
them.
This Medication Guide summarizes the most important information about NEURONTIN. If you
would like more information, talk with your healthcare provider. You can ask your healthcare
provider or pharmacist for information about NEURONTIN that was written for healthcare
professionals.
For more information about NEURONTIN, go to http://www.pfizer.com. For medical inquiries
or to report side effects regarding Neurontin, please call 1-800-438-1985.
Reference ID: 2911805
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020235/S-036; NDA 020882/S-022; NDA 021129/S-022
FDA Approved Labeling Text dated 03/01/2011
Page 34
What are the ingredients in NEURONTIN?
Active ingredient: gabapentin
Inactive ingredients in the capsules: lactose, cornstarch, and talc.
The 100-mg capsule shell also contains: gelatin and titanium dioxide.
The 300-mg capsule shell also contains: gelatin, titanium dioxide, and yellow iron oxide.
The 400-mg capsule shell also contains: gelatin, red iron oxide, titanium dioxide, and yellow iron
oxide. The imprinting ink contains FD&C Blue No. 2 and titanium dioxide.
Inactive ingredients in the tablets: poloxamer 407, copolyvidonum, cornstarch, magnesium
stearate, hydroxypropyl cellulose, talc, candelilla wax, and purified water.
Inactive ingredients in the oral solution: glycerin, xylitol, purified water, and artificial flavor.
This Medication Guide has been approved by the U.S. Food and Drug Administration. company logo
LAB-0397-1.0
Reference ID: 2911805
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:47:09.590244
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020235s036,020882s022,021129s022lbl.pdf', 'application_number': 20235, 'submission_type': 'SUPPL ', 'submission_number': 36}
|
12,348
|
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
NEURONTIN safely and effectively. See full prescribing information for
NEURONTIN.
NEURONTIN® (gabapentin) capsules, for oral use
NEURONTIN® (gabapentin) tablets, for oral use
NEURONTIN® (gabapentin) oral solution
Initial U.S. Approval: 1993
-------------------------RECENT MAJOR CHANGES----------------------------
Warnings and Precautions: Anaphylaxis and Angioedema: discontinue
NEURONTIN and evaluate patient immediately (5.2)
9/2015
--------------------------- INDICATIONS AND USAGE ----------------------------
NEURONTIN is indicated for:
Postherpetic neuralgia in adults (1)
Adjunctive therapy in the treatment of partial onset seizures, with and
without secondary generalization, in adults and pediatric patients 3 years
and older with epilepsy (1)
----------------------- DOSAGE AND ADMINISTRATION -----------------------
Postherpetic Neuralgia (2.1)
o Dose can be titrated up as needed to a dose of 1800 mg/day
o Day 1: Single 300 mg dose
o Day 2: 600 mg/day (i.e., 300 mg two times a day)
o Day 3: 900 mg/day (i.e., 300 mg three times a day)
Epilepsy with Partial Onset Seizures (2.2)
o Patients 12 years of age and older: starting dose is 300 mg three times
daily; may be titrated up to 600 mg three times daily
o Patients 3 to 11 years of age: starting dose range is 10 to 15 mg/kg/day,
given in three divided doses; recommended dose in patients 3 to 4
years of age is 40 mg/kg/day, given in three divided doses; the
recommended dose in patients 5 to 11 years of age is 25 to
35 mg/kg/day, given in three divided doses. The recommended dose is
reached by upward titration over a period of approximately 3 days
Dose should be adjusted in patients with reduced renal function (2.3, 2.4)
--------------------- DOSAGE FORMS AND STRENGTHS----------------------
Capsules: 100 mg, 300 mg, and 400 mg (3)
Tablets: 600 mg, and 800 mg (3)
Oral Solution: 250 mg/5mL (3)
------------------------------ CONTRAINDICATIONS ------------------------------
Known hypersensitivity to gabapentin or its ingredients (4)
----------------------- WARNINGS AND PRECAUTIONS -----------------------
Drug Reaction with Eosinophilia and Systemic Symptoms (Multiorgan
hypersensitivity): discontinue NEURONTIN if an alternative etiology
cannot be established (5.1)
Anaphylaxis and Angioedema: discontinue NEURONTIN and evaluate
patient immediately (5.2)
Driving impairment: warn patients not to drive until they have gained
sufficient experience with NEURONTIN to assess whether it will impair
their ability to drive (5.3)
Somnolence/Sedation and Dizziness: NEURONTIN may impair the
patient’s ability to operate complex machinery (5.4)
Increased seizure frequency may occur in patients with seizure disorders if
NEURONTIN is abruptly discontinued (5.5)
Suicidal Behavior and Ideation: monitor for suicidal thoughts and behavior
(5.6)
Neuropsychiatric Adverse Reactions in Children 3-12 Years of Age:
monitor for such events (5.7)
------------------------------ ADVERSE REACTIONS ------------------------------
Most common adverse reactions (incidence ≥8% and at least twice that for
placebo) were:
Postherpetic neuralgia: dizziness, somnolence, and peripheral edema (6.1)
Epilepsy in patients >12 years of age: somnolence, dizziness, ataxia,
fatigue, and nystagmus (6.1)
Epilepsy in patients 3 to 12 years of age: viral infection, fever, nausea
and/or vomiting, somnolence, and hostility (6.1)
----------------------------DRUG INTERACTIONS--------------------------------
Morphine increases gabapentin concentrations; dose adjustment may be
needed (5.4, 7.2)
To report SUSPECTED ADVERSE REACTIONS, contact Pfizer, Inc. at
1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
----------------------- USE IN SPECIFIC POPULATIONS------------------------
Pregnancy: based on animal data, may cause fetal harm. (8.1 )
Pediatric Use: effectiveness as adjunctive therapy in treatment of partial
seizures in pediatric patients below the age of 3 years has not been
established (8.4)
See 17 for PATIENT COUNSELING INFORMATION and Medication
Guide.
Revised: 9/2015
FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
2
DOSAGE AND ADMINISTRATION
2.1 Dosage for Postherpetic Neuralgia
2.2 Dosage for Epilepsy with Partial Onset Seizures
2.3 Dosage Adjustment in Patients with Renal Impairment
2.4 Dosage in Elderly
2.5 Administration Information
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1 Drug Reaction with Eosinophilia and Systemic Symptoms
(DRESS)/Multiorgan Hypersensitivity
5.2 Anaphylaxis and Angioedema
5.3 Effects on Driving and Operating Heavy Machinery
5.4 Somnolence/Sedation and Dizziness
5.5 Withdrawal Precipitated Seizure, Status Epilepticus
5.6 Suicidal Behavior and Ideation
5.7 Neuropsychiatric Adverse Reactions (Pediatric Patients 3-12 Years
of Age)
5.8 Tumorigenic Potential
5.9 Sudden and Unexplained Death in Patients with Epilepsy
6
ADVERSE REACTIONS
6.1 Clinical Trials Experience
6.2 Postmarketing Experience
7
DRUG INTERACTIONS
7.1 Other Antiepileptic Drugs
7.2 Opioids
7.3 Maalox® (aluminum hydroxide, magnesium hydroxide)
7.4 Drug/Laboratory Test Interactions
8
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Renal Impairment
9
DRUG ABUSE AND DEPENDENCE
9.1 Controlled Substance
9.2 Abuse
9.3 Dependence
10
OVERDOSAGE
11
DESCRIPTION
12
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.3 Pharmacokinetics
13
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14
CLINICAL STUDIES
14.1 Postherpetic Neuralgia
14.2 Epilepsy for Partial Onset Seizures (Adjunctive Therapy)
16
HOW SUPPLIED/STORAGE AND HANDLING
17
PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information are not
listed.
Reference ID: 3818812
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
_______________________________________________________________________________________________________________________________________
FULL PRESCRIBING INFORMATION
1 INDICATIONS AND USAGE
NEURONTIN® is indicated for:
Management of postherpetic neuralgia in adults
Adjunctive therapy in the treatment of partial onset seizures, with and without secondary
generalization, in adults and pediatric patients 3 years and older with epilepsy
2 DOSAGE AND ADMINISTRATION
2.1
Dosage for Postherpetic Neuralgia
In adults with postherpetic neuralgia, NEURONTIN may be initiated on Day 1 as a single
300 mg dose, on Day 2 as 600 mg/day (300 mg two times a day), and on Day 3 as 900 mg/day
(300 mg three times a day). The dose can subsequently be titrated up as needed for pain relief to
a dose of 1800 mg/day (600 mg three times a day). In clinical studies, efficacy was demonstrated
over a range of doses from 1800 mg/day to 3600 mg/day with comparable effects across the dose
range; however, in these clinical studies, the additional benefit of using doses greater than
1800 mg/day was not demonstrated.
2.2
Dosage for Epilepsy with Partial Onset Seizures
Patients 12 years of age and above
The starting dose is 300 mg three times a day. The recommended maintenance dose of
NEURONTIN is 300 mg to 600 mg three times a day. Dosages up to 2400 mg/day have been
well tolerated in long-term clinical studies. Doses of 3600 mg/day have also been administered
to a small number of patients for a relatively short duration, and have been well tolerated.
Administer NEURONTIN three times a day using 300 mg or 400 mg capsules, or 600 mg or
800 mg tablets. The maximum time between doses should not exceed 12 hours.
Pediatric Patients Age 3 to 11 years
The starting dose range is 10 mg/kg/day to 15 mg/kg/day, given in three divided doses, and the
recommended maintenance dose reached by upward titration over a period of approximately
3 days. The recommended maintenance dose of NEURONTIN in patients 3 to 4 years of age is
40 mg/kg/day, given in three divided doses. The recommended maintenance dose of
NEURONTIN in patients 5 to 11 years of age is 25 mg/kg/day to 35 mg/kg/day, given in three
divided doses. NEURONTIN may be administered as the oral solution, capsule, or tablet, or
using combinations of these formulations. Dosages up to 50 mg/kg/day have been well tolerated
in a long-term clinical study. The maximum time interval between doses should not exceed
12 hours.
Reference ID: 3818812
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2.3
Dosage Adjustment in Patients with Renal Impairment
Dosage adjustment in patients 12 years of age and older with renal impairment or undergoing
hemodialysis is recommended, as follows (see dosing recommendations above for effective
doses in each indication):
TABLE 1.
NEURONTIN Dosage Based on Renal Function
Renal Function
Total Daily
Dose Regimen
Creatinine Clearance Dose Range
(mg)
(mL/min)
(mg/day)
60
900 to 3600
300 TID
400 TID
600 TID
800 TID
1200 TID
>30 to 59
400 to 1400
200 BID
300 BID
400 BID
500 BID
700 BID
>15 to 29
200 to 700
200 QD
300 QD
400 QD
500 QD
700 QD
15a
100 to 300
100 QD
125 QD
150 QD
200 QD
300 QD
Post-Hemodialysis Supplemental Dose (mg)b
Hemodialysis
125b
150b
200b
250b
350b
TID = Three times a day; BID = Two times a day; QD = Single daily dose
a
For patients with creatinine clearance <15 mL/min, reduce daily dose in proportion to creatinine clearance
(e.g., patients with a creatinine clearance of 7.5 mL/min should receive one-half the daily dose that patients with a
creatinine clearance of 15 mL/min receive).
b
Patients on hemodialysis should receive maintenance doses based on estimates of creatinine clearance as
indicated in the upper portion of the table and a supplemental post-hemodialysis dose administered after each
4 hours of hemodialysis as indicated in the lower portion of the table.
Creatinine clearance (CLCr) is difficult to measure in outpatients. In patients with stable renal
function, creatinine clearance can be reasonably well estimated using the equation of Cockcroft
and Gault: structural formula
The use of NEURONTIN in patients less than 12 years of age with compromised renal function
has not been studied.
2.4
Dosage in Elderly
Because elderly patients are more likely to have decreased renal function, care should be taken in
dose selection, and dose should be adjusted based on creatinine clearance values in these
patients.
Reference ID: 3818812
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2.5
Administration Information
Administer NEURONTIN orally with or without food.
NEURONTIN capsules should be swallowed whole with water.
Inform patients that, should they divide the scored 600 mg or 800 mg NEURONTIN tablet in
order to administer a half-tablet, they should take the unused half-tablet as the next dose. Half-
tablets not used within 28 days of dividing the scored tablet should be discarded.
If the NEURONTIN dose is reduced, discontinued, or substituted with an alternative medication,
this should be done gradually over a minimum of 1 week (a longer period may be needed at the
discretion of the prescriber).
3 DOSAGE FORMS AND STRENGTHS
Capsules:
100 mg: white hard gelatin capsules printed with “PD” on the body and
“Neurontin/100 mg” on the cap
300 mg: yellow hard gelatin capsules printed with “PD” on the body and
“Neurontin/300 mg” on the cap
400 mg: orange hard gelatin capsules printed with “PD” on the body and
“Neurontin/400 mg” on the cap
Tablets:
600 mg: white elliptical film-coated scored tablets debossed with “NT” and “16” on one
side
800 mg: white elliptical film-coated scored tablets debossed with “NT” and “26” on one
side
Oral solution: 250 mg per 5 mL (50 mg per mL), clear colorless to slightly yellow solution
4 CONTRAINDICATIONS
NEURONTIN is contraindicated in patients who have demonstrated hypersensitivity to the drug
or its ingredients.
5 WARNINGS AND PRECAUTIONS
5.1
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan
Hypersensitivity
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as multiorgan
hypersensitivity, has occurred with NEURONTIN. Some of these reactions have been fatal or
life-threatening. DRESS typically, although not exclusively, presents with fever, rash, and/or
lymphadenopathy, in association with other organ system involvement, such as hepatitis,
Reference ID: 3818812
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
nephritis, hematological abnormalities, myocarditis, or myositis sometimes resembling an acute
viral infection. Eosinophilia is often present. This disorder is variable in its expression, and other
organ systems not noted here may be involved.
It is important to note that early manifestations of hypersensitivity, such as fever or
lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are
present, the patient should be evaluated immediately. NEURONTIN should be discontinued if an
alternative etiology for the signs or symptoms cannot be established.
5.2
Anaphylaxis and Angioedema
NEURONTIN can cause anaphylaxis and angioedema after the first dose or at any time during
treatment. Signs and symptoms in reported cases have included difficulty breathing, swelling of
the lips, throat, and tongue, and hypotension requiring emergency treatment. Patients should be
instructed to discontinue NEURONTIN and seek immediate medical care should they experience
signs or symptoms of anaphylaxis or angioedema.
5.3
Effects on Driving and Operating Heavy Machinery
Patients taking NEURONTIN should not drive until they have gained sufficient experience to
assess whether NEURONTIN impairs their ability to drive. Driving performance studies
conducted with a prodrug of gabapentin (gabapentin enacarbil tablet, extended release) indicate
that gabapentin may cause significant driving impairment. Prescribers and patients should be
aware that patients’ ability to assess their own driving competence, as well as their ability to
assess the degree of somnolence caused by NEURONTIN, can be imperfect. The duration of
driving impairment after starting therapy with NEURONTIN is unknown. Whether the
impairment is related to somnolence [see Warnings and Precautions (5.4)] or other effects of
NEURONTIN is unknown.
Moreover, because NEURONTIN causes somnolence and dizziness [see Warnings and
Precautions (5.4)], patients should be advised not to operate complex machinery until they have
gained sufficient experience on NEURONTIN to assess whether NEURONTIN impairs their
ability to perform such tasks.
5.4
Somnolence/Sedation and Dizziness
During the controlled epilepsy trials in patients older than 12 years of age receiving doses of
NEURONTIN up to 1800 mg daily, somnolence, dizziness, and ataxia were reported at a greater
rate in patients receiving NEURONTIN compared to placebo: i.e., 19% in drug versus 9% in
placebo for somnolence, 17% in drug versus 7% in placebo for dizziness, and 13% in drug
versus 6% in placebo for ataxia. In these trials somnolence, ataxia and fatigue were common
adverse reactions leading to discontinuation of NEURONTIN in patients older than 12 years of
age, with 1.2%, 0.8% and 0.6% discontinuing for these events, respectively.
During the controlled trials in patients with post-herpetic neuralgia, somnolence and dizziness
were reported at a greater rate compared to placebo in patients receiving NEURONTIN, in
Reference ID: 3818812
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
dosages up to 3600 mg per day: i.e., 21% in NEURONTIN-treated patients versus 5% in
placebo-treated patients for somnolence and 28% in NEURONTIN-treated patients versus 8% in
placebo-treated patients for dizziness. Dizziness and somnolence were among the most common
adverse reactions leading to discontinuation of NEURONTIN.
Patients should be carefully observed for signs of central nervous system (CNS) depression, such
as somnolence and sedation, when NEURONTIN is used with other drugs with sedative
properties because of potential synergy. In addition, patients who require concomitant treatment
with morphine may experience increases in gabapentin concentrations and may require dose
adjustment [see Drug Interactions (7.2)].
5.5
Withdrawal Precipitated Seizure, Status Epilepticus
Antiepileptic drugs should not be abruptly discontinued because of the possibility of increasing
seizure frequency.
In the placebo-controlled epilepsy studies in patients >12 years of age, the incidence of status
epilepticus in patients receiving NEURONTIN was 0.6% (3 of 543) vs. 0.5% in patients
receiving placebo (2 of 378). Among the 2074 patients >12 years of age treated with
NEURONTIN across all epilepsy studies (controlled and uncontrolled), 31 (1.5%) had status
epilepticus. Of these, 14 patients had no prior history of status epilepticus either before treatment
or while on other medications. Because adequate historical data are not available, it is impossible
to say whether or not treatment with NEURONTIN is associated with a higher or lower rate of
status epilepticus than would be expected to occur in a similar population not treated with
NEURONTIN.
5.6
Suicidal Behavior and Ideation
Antiepileptic drugs (AEDs), including NEURONTIN, increase the risk of suicidal thoughts or
behavior in patients taking these drugs for any indication. Patients treated with any AED for any
indication should be monitored for the emergence or worsening of depression, suicidal thoughts
or behavior, and/or any unusual changes in mood or behavior.
Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of
11 different AEDs showed that patients randomized to one of the AEDs had approximately twice
the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared
to patients randomized to placebo. In these trials, which had a median treatment duration of
12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-
treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients,
representing an increase of approximately one case of suicidal thinking or behavior for every
530 patients treated. There were four suicides in drug-treated patients in the trials and none in
placebo-treated patients, but the number is too small to allow any conclusion about drug effect
on suicide.
The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one
week after starting drug treatment with AEDs and persisted for the duration of treatment
Reference ID: 3818812
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk
of suicidal thoughts or behavior beyond 24 weeks could not be assessed.
The risk of suicidal thoughts or behavior was generally consistent among drugs in the data
analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a
range of indications suggests that the risk applies to all AEDs used for any indication. The risk
did not vary substantially by age (5-100 years) in the clinical trials analyzed. Table 2 shows
absolute and relative risk by indication for all evaluated AEDs.
TABLE 2 Risk by Indication for Antiepileptic Drugs in the Pooled Analysis
Indication
Placebo Patients Drug Patients
Relative Risk:
Risk Difference:
with Events Per
with Events Per
Incidence of Events in
Additional Drug
1000 Patients
1000 Patients
Drug
Patients with
Patients/Incidence in
Events Per 1000
Placebo Patients
Patients
Epilepsy
1.0
3.4
3.5
2.4
Psychiatric
5.7
8.5
1.5
2.9
Other
1.0
1.8
1.9
0.9
Total
2.4
4.3
1.8
1.9
The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in
clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for
the epilepsy and psychiatric indications.
Anyone considering prescribing NEURONTIN or any other AED must balance the risk of
suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses
for which AEDs are prescribed are themselves associated with morbidity and mortality and an
increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge
during treatment, the prescriber needs to consider whether the emergence of these symptoms in
any given patient may be related to the illness being treated.
Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal
thoughts and behavior and should be advised of the need to be alert for the emergence or
worsening of the signs and symptoms of depression, any unusual changes in mood or behavior,
or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of
concern should be reported immediately to healthcare providers.
5.7
Neuropsychiatric Adverse Reactions (Pediatric Patients 3-12 Years of Age)
Gabapentin use in pediatric patients with epilepsy 3-12 years of age is associated with the
occurrence of central nervous system related adverse reactions. The most significant of these can
be classified into the following categories: 1) emotional lability (primarily behavioral problems),
2) hostility, including aggressive behaviors, 3) thought disorder, including concentration
problems and change in school performance, and 4) hyperkinesia (primarily restlessness and
hyperactivity). Among the gabapentin-treated patients, most of the reactions were mild to
moderate in intensity.
Reference ID: 3818812
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
In controlled clinical epilepsy trials in pediatric patients 3–12 years of age, the incidence of these
adverse reactions was: emotional lability 6% (gabapentin-treated patients) vs. 1.3% (placebo
treated patients); hostility 5.2% vs. 1.3%; hyperkinesia 4.7% vs. 2.9%; and thought disorder
1.7% vs. 0%. One of these reactions, a report of hostility, was considered serious.
Discontinuation of gabapentin treatment occurred in 1.3% of patients reporting emotional lability
and hyperkinesia and 0.9% of gabapentin-treated patients reporting hostility and thought
disorder. One placebo-treated patient (0.4%) withdrew due to emotional lability.
5.8
Tumorigenic Potential
In an oral carcinogenicity study, gabapentin increased the incidence of pancreatic acinar cell
tumors in rats [see Nonclinical Toxicology (13.1)]. The clinical significance of this finding is
unknown. Clinical experience during gabapentin’s premarketing development provides no direct
means to assess its potential for inducing tumors in humans.
In clinical studies in adjunctive therapy in epilepsy comprising 2085 patient-years of exposure in
patients >12 years of age, new tumors were reported in 10 patients (2 breast, 3 brain, 2 lung,
1 adrenal, 1 non-Hodgkin’s lymphoma, 1 endometrial carcinoma in situ), and preexisting tumors
worsened in 11 patients (9 brain, 1 breast, 1 prostate) during or up to 2 years following
discontinuation of NEURONTIN. Without knowledge of the background incidence and
recurrence in a similar population not treated with NEURONTIN, it is impossible to know
whether the incidence seen in this cohort is or is not affected by treatment.
5.9
Sudden and Unexplained Death in Patients with Epilepsy
During the course of premarketing development of NEURONTIN, 8 sudden and unexplained
deaths were recorded among a cohort of 2203 epilepsy patients treated (2103 patient-years of
exposure) with NEURONTIN.
Some of these could represent seizure-related deaths in which the seizure was not observed, e.g.,
at night. This represents an incidence of 0.0038 deaths per patient-year. Although this rate
exceeds that expected in a healthy population matched for age and sex, it is within the range of
estimates for the incidence of sudden unexplained deaths in patients with epilepsy not receiving
NEURONTIN (ranging from 0.0005 for the general population of epileptics to 0.003 for a
clinical trial population similar to that in the NEURONTIN program, to 0.005 for patients with
refractory epilepsy). Consequently, whether these figures are reassuring or raise further concern
depends on comparability of the populations reported upon to the NEURONTIN cohort and the
accuracy of the estimates provided.
6 ADVERSE REACTIONS
The following serious adverse reactions are discussed in greater detail in other sections:
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan
Hypersensitivity [see Warnings and Precautions (5.1)]
Anaphylaxis and Angioedema [see Warnings and Precautions (5.2)]
Reference ID: 3818812
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Somnolence/Sedation and Dizziness [see Warnings and Precautions (5.4)]
Withdrawal Precipitated Seizure, Status Epilepticus [see Warnings and Precautions
(5.5)]
Suicidal Behavior and Ideation [see Warnings and Precautions (5.6)]
Neuropsychiatric Adverse Reactions (Pediatric Patients 3-12 Years of Age) [see
Warnings and Precautions (5.7)]
Sudden and Unexplained Death in Patients with Epilepsy [see Warnings and Precautions
(5.9)]
6.1
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates
observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials
of another drug and may not reflect the rates observed in practice.
Postherpetic Neuralgia
The most common adverse reactions associated with the use of NEURONTIN in adults, not seen
at an equivalent frequency among placebo-treated patients, were dizziness, somnolence, and
peripheral edema.
In the 2 controlled trials in postherpetic neuralgia, 16% of the 336 patients who received
NEURONTIN and 9% of the 227 patients who received placebo discontinued treatment because
of an adverse reaction. The adverse reactions that most frequently led to withdrawal in
NEURONTIN-treated patients were dizziness, somnolence, and nausea.
Table 3 lists adverse reactions that occurred in at least 1% of NEURONTIN-treated patients with
postherpetic neuralgia participating in placebo-controlled trials and that were numerically more
frequent in the NEURONTIN group than in the placebo group.
Reference ID: 3818812
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
TABLE 3. Adverse Reactions in Pooled Placebo-Controlled
Trials in Postherpetic Neuralgia
NEURONTIN
Placebo
N=336
N=227
%
%
Body as a Whole
Asthenia
6
5
Infection
5
4
Accidental injury
3
1
Digestive System
Diarrhea
6
3
Dry mouth
5
1
Constipation
4
2
Nausea
4
3
Vomiting
3
2
Metabolic and Nutritional Disorders
Peripheral edema
8
2
Weight gain
2
0
Hyperglycemia
1
0
Nervous System
Dizziness
28
8
Somnolence
21
5
Ataxia
3
0
Abnormal thinking
3
0
Abnormal gait
2
0
Incoordination
2
0
Respiratory System
Pharyngitis
1
0
Special Senses
Amblyopiaa
3
1
Conjunctivitis
1
0
Diplopia
1
0
Otitis media
1
0
a
Reported as blurred vision
Other reactions in more than 1% of patients but equally or more frequent in the placebo group
included pain, tremor, neuralgia, back pain, dyspepsia, dyspnea, and flu syndrome.
There were no clinically important differences between men and women in the types and
incidence of adverse reactions. Because there were few patients whose race was reported as other
than white, there are insufficient data to support a statement regarding the distribution of adverse
reactions by race.
Reference ID: 3818812
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Epilepsy with Partial Onset Seizures (Adjunctive Therapy)
The most common adverse reactions with NEURONTIN in combination with other antiepileptic
drugs in patients >12 years of age, not seen at an equivalent frequency among placebo-treated
patients, were somnolence, dizziness, ataxia, fatigue, and nystagmus.
The most common adverse reactions with NEURONTIN in combination with other antiepileptic
drugs in pediatric patients 3 to 12 years of age, not seen at an equal frequency among placebo-
treated patients, were viral infection, fever, nausea and/or vomiting, somnolence, and hostility
[see Warnings and Precautions (5.5)].
Approximately 7% of the 2074 patients >12 years of age and approximately 7% of the
449 pediatric patients 3 to 12 years of age who received NEURONTIN in premarketing clinical
trials discontinued treatment because of an adverse reaction. The adverse reactions most
commonly associated with withdrawal in patients >12 years of age were somnolence (1.2%),
ataxia (0.8%), fatigue (0.6%), nausea and/or vomiting (0.6%), and dizziness (0.6%). The adverse
reactions most commonly associated with withdrawal in pediatric patients were emotional
lability (1.6%), hostility (1.3%), and hyperkinesia (1.1%).
Table 4 lists adverse reactions that occurred in at least 1% of NEURONTIN-treated patients
>12 years of age with epilepsy participating in placebo-controlled trials and were numerically
more common in the NEURONTIN group. In these studies, either NEURONTIN or placebo was
added to the patient’s current antiepileptic drug therapy.
TABLE 4.
Adverse Reactions in Pooled Placebo-Controlled Add-On Trials In
Epilepsy Patients >12 years of age
NEURONTINa
Placeboa
N=543
N=378
%
%
Body As A Whole
Fatigue
Increased Weight
Back Pain
Peripheral Edema
Cardiovascular
Vasodilatation
Digestive System
Dyspepsia
Dry Mouth or Throat
Constipation
Dental Abnormalities
11
3
2
2
5
2
1
1
1
0
2
2
2
2
1
1
1
0
Reference ID: 3818812
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For current labeling information, please visit https://www.fda.gov/drugsatfda
TABLE 4.
Adverse Reactions in Pooled Placebo-Controlled Add-On Trials In
Epilepsy Patients >12 years of age
NEURONTINa
Placeboa
N=543
N=378
%
%
Nervous System
Somnolence
19
9
Dizziness
17
7
Ataxia
13
6
Nystagmus
8
4
Tremor
7
3
Dysarthria
2
1
Amnesia
2
0
Depression
2
1
Abnormal thinking
2
1
Abnormal coordination
1
0
Respiratory System
Pharyngitis
3
2
Coughing
2
1
Skin and Appendages
Abrasion
1
0
Urogenital System
Impotence
2
1
Special Senses
Diplopia
Amblyopiab
6
4
2
1
a Plus background antiepileptic drug therapy
b Amblyopia was often described as blurred vision.
Among the adverse reactions occurring at an incidence of at least 10% in NEURONTIN-treated
patients, somnolence and ataxia appeared to exhibit a positive dose-response relationship.
The overall incidence of adverse reactions and the types of adverse reactions seen were similar
among men and women treated with NEURONTIN. The incidence of adverse reactions
increased slightly with increasing age in patients treated with either NEURONTIN or placebo.
Because only 3% of patients (28/921) in placebo-controlled studies were identified as nonwhite
(black or other), there are insufficient data to support a statement regarding the distribution of
adverse reactions by race.
Table 5 lists adverse reactions that occurred in at least 2% of NEURONTIN-treated patients, age
3 to 12 years of age with epilepsy participating in placebo-controlled trials, and which were
numerically more common in the NEURONTIN group.
Reference ID: 3818812
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
TABLE 5.
Adverse Reactions in a Placebo-Controlled Add-On Trial in
Pediatric Epilepsy Patients Age 3 to 12 Years
NEURONTINa
Placeboa
N=119
N=128
%
%
Body As A Whole
Viral Infection
11
3
Fever
10
3
Increased Weight
3
1
Fatigue
3
2
Digestive System
Nausea and/or Vomiting
8
7
Nervous System
Somnolence
8
5
Hostility
8
2
Emotional Lability
4
2
Dizziness
3
2
Hyperkinesia
3
1
Respiratory System
Bronchitis
3
1
Respiratory Infection
3
1
a Plus background antiepileptic drug therapy
Other reactions in more than 2% of pediatric patients 3 to 12 years of age but equally or more
frequent in the placebo group included: pharyngitis, upper respiratory infection, headache,
rhinitis, convulsions, diarrhea, anorexia, coughing, and otitis media.
6.2
Postmarketing Experience
The following adverse reactions have been identified during postmarketing use of
NEURONTIN. Because these reactions are reported voluntarily from a population of uncertain
size, it is not always possible to reliably estimate their frequency or establish a causal
relationship to drug exposure.
Hepatobiliary disorders: jaundice
Investigations: elevated creatine kinase, elevated liver function tests
Metabolism and nutrition disorders: hyponatremia
Musculoskeletal and connective tissue disorder: rhabdomyolysis
Nervous system disorders: movement disorder
Reproductive system and breast disorders: breast enlargement, changes in libido, ejaculation
disorders and anorgasmia
Skin and subcutaneous tissue disorders: angioedema [see Warnings and Precautions (5.2)],
erythema multiforme, Stevens-Johnson syndrome.
Adverse reactions following the abrupt discontinuation of gabapentin have also been reported.
The most frequently reported reactions were anxiety, insomnia, nausea, pain, and sweating.
Reference ID: 3818812
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For current labeling information, please visit https://www.fda.gov/drugsatfda
7 DRUG INTERACTIONS
7.1
Other Antiepileptic Drugs
Gabapentin is not appreciably metabolized nor does it interfere with the metabolism of
commonly coadministered antiepileptic drugs [see Clinical Pharmacology (12.3)].
7.2
Opioids
Hydrocodone
Coadministration of NEURONTIN with hydrocodone decreases hydrocodone exposure [see
Clinical Pharmacology (12.3)]. The potential for alteration in hydrocodone exposure and effect
should be considered when NEURONTIN is started or discontinued in a patient taking
hydrocodone.
Morphine
When gabapentin is administered with morphine, patients should be observed for signs of central
nervous system (CNS) depression, such as somnolence, sedation and respiratory depression [see
Clinical Pharmacology (12.3)].
7.3
Maalox® (aluminum hydroxide, magnesium hydroxide)
The mean bioavailability of gabapentin was reduced by about 20% with concomitant use of an
antacid (Maalox®) containing magnesium and aluminum hydroxides. It is recommended that
gabapentin be taken at least 2 hours following Maalox administration [see Clinical
Pharmacology (12.3)].
7.4
Drug/Laboratory Test Interactions
Because false positive readings were reported with the Ames N-Multistix SG® dipstick test for
urinary protein when gabapentin was added to other antiepileptic drugs, the more specific
sulfosalicylic acid precipitation procedure is recommended to determine the presence of urine
protein.
8 USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Pregnancy Category C: There are no adequate and well-controlled studies in pregnant women. In
nonclinical studies in mice, rats, and rabbits, gabapentin was developmentally toxic when
administered to pregnant animals at doses similar to or lower than those used clinically.
NEURONTIN should be used during pregnancy only if the potential benefit justifies the
potential risk to the fetus.
Reference ID: 3818812
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
When pregnant mice received oral doses of gabapentin (500, 1000, or 3000 mg/kg/day) during
the period of organogenesis, embryo-fetal toxicity (increased incidences of skeletal variations)
was observed at the two highest doses. The no-effect dose for embryo-fetal developmental
toxicity in mice was 500 mg/kg/day or approximately ½ of the maximum recommended human
dose (MRHD) of 3600 mg/kg on a body surface area (mg/m2) basis.
In studies in which rats received oral doses of gabapentin (500 to 2000 mg/kg/day), during
pregnancy, adverse effect on offspring development (increased incidences of hydroureter and/or
hydronephrosis) were observed at all doses. The lowest effect dose for developmental toxicity in
rats is approximately equal to the MRHD on a mg/m2 basis.
When pregnant rabbits were treated with gabapentin during the period of organogenesis, an
increase in embryo-fetal mortality was observed at all doses tested (60, 300, or 1500 mg/kg). The
lowest effect dose for embryo-fetal developmental toxicity in rabbits is less than the MRHD on a
mg/m2 basis.
In a published study, gabapentin (400 mg/kg/day) was administered by intraperitoneal injection
to neonatal mice during the first postnatal week, a period of synaptogenesis in rodents
(corresponding to the last trimester of pregnancy in humans). Gabapentin caused a marked
decrease in neuronal synapse formation in brains of intact mice and abnormal neuronal synapse
formation in a mouse model of synaptic repair. Gabapentin has been shown in vitro to interfere
with activity of the α2δ subunit of voltage-activated calcium channels, a receptor involved in
neuronal synaptogenesis. The clinical significance of these findings is unknown.
To provide information regarding the effects of in utero exposure to NEURONTIN, physicians
are advised to recommend that pregnant patients taking NEURONTIN enroll in the North
American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll
free number 1-888-233-2334, and must be done by patients themselves. Information on the
registry can also be found at the website http://www.aedpregnancyregistry.org/.
8.3
Nursing Mothers
Gabapentin is secreted into human milk following oral administration. A nursed infant could be
exposed to a maximum dose of approximately 1 mg/kg/day of gabapentin. Because the effect on
the nursing infant is unknown, NEURONTIN should be used in women who are nursing only if
the benefits clearly outweigh the risks.
8.4
Pediatric Use
Safety and effectiveness of NEURONTIN in the management of postherpetic neuralgia in
pediatric patients have not been established.
Effectiveness as adjunctive therapy in the treatment of partial seizures in pediatric patients below
the age of 3 years has not been established [see Clinical Studies (14.2)].
Reference ID: 3818812
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
8.5
Geriatric Use
The total number of patients treated with NEURONTIN in controlled clinical trials in patients
with postherpetic neuralgia was 336, of which 102 (30%) were 65 to 74 years of age, and
168 (50%) were 75 years of age and older. There was a larger treatment effect in patients
75 years of age and older compared with younger patients who received the same dosage. Since
gabapentin is almost exclusively eliminated by renal excretion, the larger treatment effect
observed in patients 75 years may be a consequence of increased gabapentin exposure for a
given dose that results from an age-related decrease in renal function. However, other factors
cannot be excluded. The types and incidence of adverse reactions were similar across age groups
except for peripheral edema and ataxia, which tended to increase in incidence with age.
Clinical studies of NEURONTIN in epilepsy did not include sufficient numbers of subjects aged
65 and over to determine whether they responded differently from younger subjects. Other
reported clinical experience has not identified differences in responses between the elderly and
younger patients. In general, dose selection for an elderly patient should be cautious, usually
starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic,
renal, or cardiac function, and of concomitant disease or other drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to
this drug may be greater in patients with impaired renal function. Because elderly patients are
more likely to have decreased renal function, care should be taken in dose selection, and dose
should be adjusted based on creatinine clearance values in these patients [see Dosage and
Administration (2.4), Adverse Reactions (6), and Clinical Pharmacology (12.3)].
8.6
Renal Impairment
Dosage adjustment in adult patients with compromised renal function is necessary [see Dosage
and Administration (2.3) and Clinical Pharmacology (12.3)]. Pediatric patients with renal
insufficiency have not been studied.
Dosage adjustment in patients undergoing hemodialysis is necessary [see Dosage and
Administration (2.3) and Clinical Pharmacology (12.3)].
9 DRUG ABUSE AND DEPENDENCE
9.1
Controlled Substance
Gabapentin is not a scheduled drug.
9.2
Abuse
Gabapentin does not exhibit affinity for benzodiazepine, opiate (mu, delta or kappa), or
cannabinoid 1 receptor sites. A small number of postmarketing cases report gabapentin misuse
and abuse. These individuals were taking higher than recommended doses of gabapentin for
unapproved uses. Most of the individuals described in these reports had a history of poly-
substance abuse or used gabapentin to relieve symptoms of withdrawal from other substances.
Reference ID: 3818812
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For current labeling information, please visit https://www.fda.gov/drugsatfda
When prescribing gabapentin carefully evaluate patients for a history of drug abuse and observe
them for signs and symptoms of gabapentin misuse or abuse (e.g., development of tolerance,
self-dose escalation, and drug-seeking behavior).
9.3
Dependence
There are rare postmarketing reports of individuals experiencing withdrawal symptoms shortly
after discontinuing higher than recommended doses of gabapentin used to treat illnesses for
which the drug is not approved. Such symptoms included agitation, disorientation and confusion
after suddenly discontinuing gabapentin that resolved after restarting gabapentin. Most of these
individuals had a history of poly-substance abuse or used gabapentin to relieve symptoms of
withdrawal from other substances. The dependence and abuse potential of gabapentin has not
been evaluated in human studies.
10 OVERDOSAGE
A lethal dose of gabapentin was not identified in mice and rats receiving single oral doses as
high as 8000 mg/kg. Signs of acute toxicity in animals included ataxia, labored breathing, ptosis,
sedation, hypoactivity, or excitation.
Acute oral overdoses of NEURONTIN up to 49 grams have been reported. In these cases, double
vision, slurred speech, drowsiness, lethargy, and diarrhea were observed. All patients recovered
with supportive care. Coma, resolving with dialysis, has been reported in patients with chronic
renal failure who were treated with NEURONTIN.
Gabapentin can be removed by hemodialysis. Although hemodialysis has not been performed in
the few overdose cases reported, it may be indicated by the patient’s clinical state or in patients
with significant renal impairment.
If overexposure occurs, call your poison control center at 1-800-222-1222.
11 DESCRIPTION
The active ingredient in NEURONTIN capsules, tablets, and oral solution is gabapentin,which
has the chemical name 1-(aminomethyl)cyclohexaneacetic acid.
The molecular formula of gabapentin is C9H17NO2 and the molecular weight is 171.24. The
structural formula of gabapentin is: structural formula
Reference ID: 3818812
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Gabapentin is a white to off-white crystalline solid with a pKa1 of 3.7 and a pKa2 of 10.7. It is
freely soluble in water and both basic and acidic aqueous solutions. The log of the partition
coefficient (n-octanol/0.05M phosphate buffer) at pH 7.4 is –1.25.
Each Neurontin capsule contains 100 mg, 300 mg, or 400 mg of gabapentin and the following
inactive ingredients: lactose, cornstarch, talc, gelatin, titanium dioxide, FD&C Blue No. 2,
yellow iron oxide (300 mg and 400 mg only), and red iron oxide (400 mg only).
Each Neurontin tablet contains 600 mg or 800 mg of gabapentin and the following inactive
ingredients: poloxamer 407, copovidone, cornstarch, magnesium stearate, hydroxypropyl
cellulose, talc, and candelilla wax
Neurontin oral solution contains 250 mg of gabapentin per 5 mL (50 mg per mL) and the
following inactive ingredients: glycerin, xylitol, purified water, and artificial cool strawberry
anise flavor.
12 CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
The precise mechanisms by which gabapentin produces its analgesic and antiepileptic actions are
unknown. Gabapentin is structurally related to the neurotransmitter gamma-aminobutyric acid
(GABA) but has no effect on GABA binding, uptake, or degradation. In vitro studies have shown
that gabapentin binds with high-affinity to the α2δ subunit of voltage-activated calcium channels;
however, the relationship of this binding to the therapeutic effects of gabapentin is unknown.
12.3
Pharmacokinetics
All pharmacological actions following gabapentin administration are due to the activity of the
parent compound; gabapentin is not appreciably metabolized in humans.
Oral Bioavailability
Gabapentin bioavailability is not dose proportional; i.e., as dose is increased, bioavailability
decreases. Bioavailability of gabapentin is approximately 60%, 47%, 34%, 33%, and 27%
following 900, 1200, 2400, 3600, and 4800 mg/day given in 3 divided doses, respectively. Food
has only a slight effect on the rate and extent of absorption of gabapentin (14% increase in AUC
and Cmax).
Distribution
Less than 3% of gabapentin circulates bound to plasma protein. The apparent volume of
distribution of gabapentin after 150 mg intravenous administration is 58±6 L (mean ±SD). In
patients with epilepsy, steady-state predose (Cmin) concentrations of gabapentin in cerebrospinal
fluid were approximately 20% of the corresponding plasma concentrations.
Reference ID: 3818812
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Elimination
Gabapentin is eliminated from the systemic circulation by renal excretion as unchanged drug.
Gabapentin is not appreciably metabolized in humans.
Gabapentin elimination half-life is 5 to 7 hours and is unaltered by dose or following multiple
dosing. Gabapentin elimination rate constant, plasma clearance, and renal clearance are directly
proportional to creatinine clearance. In elderly patients, and in patients with impaired renal
function, gabapentin plasma clearance is reduced. Gabapentin can be removed from plasma by
hemodialysis.
Specific Populations
Age
The effect of age was studied in subjects 20-80 years of age. Apparent oral clearance (CL/F) of
gabapentin decreased as age increased, from about 225 mL/min in those under 30 years of age to
about 125 mL/min in those over 70 years of age. Renal clearance (CLr) and CLr adjusted for
body surface area also declined with age; however, the decline in the renal clearance of
gabapentin with age can largely be explained by the decline in renal function. [see Dosage and
Administration (2.4) and Use in Specific Populations (8.5)].
Gender
Although no formal study has been conducted to compare the pharmacokinetics of gabapentin in
men and women, it appears that the pharmacokinetic parameters for males and females are
similar and there are no significant gender differences.
Race
Pharmacokinetic differences due to race have not been studied. Because gabapentin is primarily
renally excreted and there are no important racial differences in creatinine clearance,
pharmacokinetic differences due to race are not expected.
Pediatric
Gabapentin pharmacokinetics were determined in 48 pediatric subjects between the ages of 1
month and 12 years following a dose of approximately 10 mg/kg. Peak plasma concentrations
were similar across the entire age group and occurred 2 to 3 hours postdose. In general, pediatric
subjects between 1 month and <5 years of age achieved approximately 30% lower exposure
(AUC) than that observed in those 5 years of age and older. Accordingly, oral clearance
normalized per body weight was higher in the younger children. Apparent oral clearance of
gabapentin was directly proportional to creatinine clearance. Gabapentin elimination half-life
averaged 4.7 hours and was similar across the age groups studied.
Reference ID: 3818812
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
A population pharmacokinetic analysis was performed in 253 pediatric subjects between 1 month
and 13 years of age. Patients received 10 to 65 mg/kg/day given three times a day. Apparent oral
clearance (CL/F) was directly proportional to creatinine clearance and this relationship was
similar following a single dose and at steady state. Higher oral clearance values were observed in
children <5 years of age compared to those observed in children 5 years of age and older, when
normalized per body weight. The clearance was highly variable in infants <1 year of age. The
normalized CL/F values observed in pediatric patients 5 years of age and older were consistent
with values observed in adults after a single dose. The oral volume of distribution normalized per
body weight was constant across the age range.
These pharmacokinetic data indicate that the effective daily dose in pediatric patients with
epilepsy ages 3 and 4 years should be 40 mg/kg/day to achieve average plasma concentrations
similar to those achieved in patients 5 years of age and older receiving gabapentin at 30
mg/kg/day [see Dosage and Administration (2.1)].
Adult Patients with Renal Impairment
Subjects (N=60) with renal impairment (mean creatinine clearance ranging from
13-114 mL/min) were administered single 400 mg oral doses of gabapentin. The mean
gabapentin half-life ranged from about 6.5 hours (patients with creatinine clearance
>60 mL/min) to 52 hours (creatinine clearance <30 mL/min) and gabapentin renal clearance
from about 90 mL/min (>60 mL/min group) to about 10 mL/min (<30 mL/min). Mean plasma
clearance (CL/F) decreased from approximately 190 mL/min to 20 mL/min [see Dosage and
Administration (2.3) and Use in Specific Populations (8.6)]. Pediatric patients with renal
insufficiency have not been studied.
Hemodialysis
In a study in anuric adult subjects (N=11), the apparent elimination half-life of gabapentin on
nondialysis days was about 132 hours; during dialysis the apparent half-life of gabapentin was
reduced to 3.8 hours. Hemodialysis thus has a significant effect on gabapentin elimination in
anuric subjects [see Dosage and Administration (2.3) and Use in Specific Populations (8.6)].
Hepatic Disease
Because gabapentin is not metabolized, no study was performed in patients with hepatic
impairment.
Drug Interactions
In Vitro Studies
In vitro studies were conducted to investigate the potential of gabapentin to inhibit the
major cytochrome P450 enzymes (CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6,
CYP2E1, and CYP3A4) that mediate drug and xenobiotic metabolism using isoform
selective marker substrates and human liver microsomal preparations. Only at the highest
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concentration tested (171 mcg/mL; 1 mM) was a slight degree of inhibition (14%-30%)
of isoform CYP2A6 observed. No inhibition of any of the other isoforms tested was
observed at gabapentin concentrations up to 171 mcg/mL (approximately 15 times the
Cmax at 3600 mg/day).
In Vivo Studies
The drug interaction data described in this section were obtained from studies involving
healthy adults and adult patients with epilepsy.
Phenytoin
In a single (400 mg) and multiple dose (400 mg three times a day) study of
NEURONTIN in epileptic patients (N=8) maintained on phenytoin monotherapy for at
least 2 months, gabapentin had no effect on the steady-state trough plasma concentrations
of phenytoin and phenytoin had no effect on gabapentin pharmacokinetics.
Carbamazepine
Steady-state trough plasma carbamazepine and carbamazepine 10, 11 epoxide
concentrations were not affected by concomitant gabapentin (400 mg three times a day;
N=12) administration. Likewise, gabapentin pharmacokinetics were unaltered by
carbamazepine administration.
Valproic Acid
The mean steady-state trough serum valproic acid concentrations prior to and during
concomitant gabapentin administration (400 mg three times a day; N=17) were not
different and neither were gabapentin pharmacokinetic parameters affected by valproic
acid.
Phenobarbital
Estimates of steady-state pharmacokinetic parameters for phenobarbital or gabapentin
(300 mg three times a day; N=12) are identical whether the drugs are administered alone
or together.
Naproxen
Coadministration (N=18) of naproxen sodium capsules (250 mg) with NEURONTIN
(125 mg) appears to increase the amount of gabapentin absorbed by 12% to 15%.
Gabapentin had no effect on naproxen pharmacokinetic parameters. These doses are
lower than the therapeutic doses for both drugs. The magnitude of interaction within the
recommended dose ranges of either drug is not known.
Hydrocodone
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Coadministration of NEURONTIN (125 to 500 mg; N=48) decreases hydrocodone
(10 mg; N=50) Cmax and AUC values in a dose-dependent manner relative to
administration of hydrocodone alone; Cmax and AUC values are 3% to 4% lower,
respectively, after administration of 125 mg NEURONTIN and 21% to 22% lower,
respectively, after administration of 500 mg NEURONTIN. The mechanism for this
interaction is unknown. Hydrocodone increases gabapentin AUC values by 14%. The
magnitude of interaction at other doses is not known.
Morphine
A literature article reported that when a 60 mg controlled-release morphine capsule was
administered 2 hours prior to a 600 mg NEURONTIN capsule (N=12), mean gabapentin
AUC increased by 44% compared to gabapentin administered without morphine.
Morphine pharmacokinetic parameter values were not affected by administration of
NEURONTIN 2 hours after morphine. The magnitude of interaction at other doses is not
known.
Cimetidine
In the presence of cimetidine at 300 mg QID (N=12), the mean apparent oral clearance of
gabapentin fell by 14% and creatinine clearance fell by 10%. Thus, cimetidine appeared
to alter the renal excretion of both gabapentin and creatinine, an endogenous marker of
renal function. This small decrease in excretion of gabapentin by cimetidine is not
expected to be of clinical importance. The effect of gabapentin on cimetidine was not
evaluated.
Oral Contraceptive
Based on AUC and half-life, multiple-dose pharmacokinetic profiles of norethindrone
and ethinyl estradiol following administration of tablets containing 2.5 mg of
norethindrone acetate and 50 mcg of ethinyl estradiol were similar with and without
coadministration of gabapentin (400 mg three times a day; N=13). The Cmax of
norethindrone was 13% higher when it was coadministered with gabapentin; this
interaction is not expected to be of clinical importance.
Antacid (Maalox®) (aluminum hydroxide, magnesium hydroxide)
Antacid (Maalox®) containing magnesium and aluminum hydroxides reduced the mean
bioavailability of gabapentin (N=16) by about 20%. This decrease in bioavailability was
about 10% when gabapentin was administered 2 hours after Maalox.
Probenecid
Probenecid is a blocker of renal tubular secretion. Gabapentin pharmacokinetic
parameters without and with probenecid were comparable. This indicates that gabapentin
does not undergo renal tubular secretion by the pathway that is blocked by probenecid.
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13 NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
Gabapentin was administered orally to mice and rats in 2-year carcinogenicity studies. No
evidence of drug-related carcinogenicity was observed in mice treated at doses up to
2000 mg/kg/day. At 2000 mg/kg, the plasma gabapentin exposure (AUC) in mice is
approximately 2 times that in humans at the MRHD of 3600 mg/day. In rats, increases in the
incidence of pancreatic acinar cell adenoma and carcinoma were found in male rats receiving the
highest dose (2000 mg/kg), but not at doses of 250 or 1000 mg/kg/day. At 1000 mg/kg, the
plasma gabapentin exposure (AUC) in rats is approximately 5 times that in humans at the
MRHD.
Studies designed to investigate the mechanism of gabapentin-induced pancreatic carcinogenesis
in rats indicate that gabapentin stimulates DNA synthesis in rat pancreatic acinar cells in vitro
and, thus, may be acting as a tumor promoter by enhancing mitogenic activity. It is not known
whether gabapentin has the ability to increase cell proliferation in other cell types or in other
species, including humans.
Gabapentin did not demonstrate mutagenic or genotoxic potential in three in vitro and four in
vivo assays. It was negative in the Ames test and the in vitro HGPRT forward mutation assay in
Chinese hamster lung cells; it did not produce significant increases in chromosomal aberrations
in the in vitro Chinese hamster lung cell assay; it was negative in the in vivo chromosomal
aberration assay and in the in vivo micronucleus test in Chinese hamster bone marrow; it was
negative in the in vivo mouse micronucleus assay; and it did not induce unscheduled DNA
synthesis in hepatocytes from rats given gabapentin.
No adverse effects on fertility or reproduction were observed in rats at doses up to 2000 mg/kg.
At 2000 mg/kg, the plasma gabapentin exposure (AUC) in rats is approximately 8 times that in
humans at the MRHD.
14 CLINICAL STUDIES
14.1
Postherpetic Neuralgia
NEURONTIN was evaluated for the management of postherpetic neuralgia (PHN) in two
randomized, double-blind, placebo-controlled, multicenter studies. The intent-to-treat (ITT)
population consisted of a total of 563 patients with pain for more than 3 months after healing of
the herpes zoster skin rash (Table 6).
TABLE 6. Controlled PHN Studies: Duration, Dosages, and
Number of Patients
Study
Study
Duration
Gabapentin
(mg/day)a
Target Dose
Patients
Receiving
Gabapentin
Patients
Receiving
Placebo
1
8 weeks
3600
113
116
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2
7 weeks
1800, 2400
223
111
Total
336
227
aGiven in 3 divided doses (TID)
Each study included a 7- or 8-week double-blind phase (3 or 4 weeks of titration and 4 weeks of
fixed dose). Patients initiated treatment with titration to a maximum of 900 mg/day gabapentin
over 3 days. Dosages were then to be titrated in 600 to 1200 mg/day increments at 3- to 7-day
intervals to the target dose over 3 to 4 weeks. Patients recorded their pain in a daily diary using
an 11-point numeric pain rating scale ranging from 0 (no pain) to 10 (worst possible pain). A
mean pain score during baseline of at least 4 was required for randomization. Analyses were
conducted using the ITT population (all randomized patients who received at least one dose of
study medication).
Both studies demonstrated efficacy compared to placebo at all doses tested.
The reduction in weekly mean pain scores was seen by Week 1 in both studies, and were
maintained to the end of treatment. Comparable treatment effects were observed in all active
treatment arms. Pharmacokinetic/pharmacodynamic modeling provided confirmatory evidence
of efficacy across all doses. Figures 1 and 2 show pain intensity scores over time for Studies 1
and 2.
gr
ap
h
2
1
0
Baseline
1
2
3
4
5
6
7
8
Weeks
Figure 1. Weekly Mean Pain Scores (Observed Cases in ITT Population): Study 1
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gr
ap
h
Figure 2. Weekly Mean Pain Scores (Observed Cases in ITT Population): Study 2
The proportion of responders (those patients reporting at least 50% improvement in endpoint
pain score compared with baseline) was calculated for each study (Figure 3).
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graph
Figure 3. Proportion of Responders (patients with 50% reduction in pain score) at Endpoint:
Controlled PHN Studies
14.2
Epilepsy for Partial Onset Seizures (Adjunctive Therapy)
The effectiveness of NEURONTIN as adjunctive therapy (added to other antiepileptic drugs)
was established in multicenter placebo-controlled, double-blind, parallel-group clinical trials in
adult and pediatric patients (3 years and older) with refractory partial seizures.
Evidence of effectiveness was obtained in three trials conducted in 705 patients (age 12 years
and above) and one trial conducted in 247 pediatric patients (3 to 12 years of age). The patients
enrolled had a history of at least 4 partial seizures per month in spite of receiving one or more
antiepileptic drugs at therapeutic levels and were observed on their established antiepileptic drug
regimen during a 12-week baseline period (6 weeks in the study of pediatric patients). In patients
continuing to have at least 2 (or 4 in some studies) seizures per month, NEURONTIN or placebo
was then added on to the existing therapy during a 12-week treatment period. Effectiveness was
assessed primarily on the basis of the percent of patients with a 50% or greater reduction in
seizure frequency from baseline to treatment (the “responder rate”) and a derived measure called
response ratio, a measure of change defined as (T - B)/(T + B), in which B is the patient’s
baseline seizure frequency and T is the patient’s seizure frequency during treatment. Response
ratio is distributed within the range -1 to +1. A zero value indicates no change while complete
elimination of seizures would give a value of -1; increased seizure rates would give positive
values. A response ratio of -0.33 corresponds to a 50% reduction in seizure frequency. The
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results given below are for all partial seizures in the intent-to-treat (all patients who received any
doses of treatment) population in each study, unless otherwise indicated.
One study compared NEURONTIN 1200 mg/day, in three divided doses with placebo.
Responder rate was 23% (14/61) in the NEURONTIN group and 9% (6/66) in the placebo group;
the difference between groups was statistically significant. Response ratio was also better in the
NEURONTIN group (-0.199) than in the placebo group (-0.044), a difference that also achieved
statistical significance.
A second study compared primarily NEURONTIN 1200 mg/day, in three divided doses
(N=101), with placebo (N=98). Additional smaller NEURONTIN dosage groups (600 mg/day,
N=53; 1800 mg/day, N=54) were also studied for information regarding dose response.
Responder rate was higher in the NEURONTIN 1200 mg/day group (16%) than in the placebo
group (8%), but the difference was not statistically significant. The responder rate at 600 mg
(17%) was also not significantly higher than in the placebo, but the responder rate in the
1800 mg group (26%) was statistically significantly superior to the placebo rate. Response ratio
was better in the NEURONTIN 1200 mg/day group (-0.103) than in the placebo group (-0.022);
but this difference was also not statistically significant (p = 0.224). A better response was seen in
the NEURONTIN 600 mg/day group (-0.105) and 1800 mg/day group (-0.222) than in the
1200 mg/day group, with the 1800 mg/day group achieving statistical significance compared to
the placebo group.
A third study compared NEURONTIN 900 mg/day, in three divided doses (N=111), and placebo
(N=109). An additional NEURONTIN 1200 mg/day dosage group (N=52) provided dose-
response data. A statistically significant difference in responder rate was seen in the
NEURONTIN 900 mg/day group (22%) compared to that in the placebo group (10%). Response
ratio was also statistically significantly superior in the NEURONTIN 900 mg/day group (-0.119)
compared to that in the placebo group (-0.027), as was response ratio in 1200 mg/day
NEURONTIN (-0.184) compared to placebo.
Analyses were also performed in each study to examine the effect of NEURONTIN on
preventing secondarily generalized tonic-clonic seizures. Patients who experienced a secondarily
generalized tonic-clonic seizure in either the baseline or in the treatment period in all three
placebo-controlled studies were included in these analyses. There were several response ratio
comparisons that showed a statistically significant advantage for NEURONTIN compared to
placebo and favorable trends for almost all comparisons.
Analysis of responder rate using combined data from all three studies and all doses (N=162,
NEURONTIN; N=89, placebo) also showed a significant advantage for NEURONTIN over
placebo in reducing the frequency of secondarily generalized tonic-clonic seizures.
In two of the three controlled studies, more than one dose of NEURONTIN was used. Within
each study, the results did not show a consistently increased response to dose. However, looking
across studies, a trend toward increasing efficacy with increasing dose is evident (see Figure 4).
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graph
Figure 4. Responder Rate in Patients Receiving NEURONTIN Expressed as a Difference from
Placebo by Dose and Study: Adjunctive Therapy Studies in Patients 12 Years of Age with
Partial Seizures
In the figure, treatment effect magnitude, measured on the Y axis in terms of the difference in the
proportion of gabapentin and placebo-assigned patients attaining a 50% or greater reduction in
seizure frequency from baseline, is plotted against the daily dose of gabapentin administered
(X axis).
Although no formal analysis by gender has been performed, estimates of response (Response
Ratio) derived from clinical trials (398 men, 307 women) indicate no important gender
differences exist. There was no consistent pattern indicating that age had any effect on the
response to NEURONTIN. There were insufficient numbers of patients of races other than
Caucasian to permit a comparison of efficacy among racial groups.
A fourth study in pediatric patients age 3 to 12 years compared 25 –35 mg/kg/day NEURONTIN
(N=118) with placebo (N=127). For all partial seizures in the intent-to-treat population, the
response ratio was statistically significantly better for the NEURONTIN group (-0.146) than for
the placebo group (-0.079). For the same population, the responder rate for NEURONTIN (21%)
was not significantly different from placebo (18%).
A study in pediatric patients age 1 month to 3 years compared 40 mg/kg/day NEURONTIN
(N=38) with placebo (N=38) in patients who were receiving at least one marketed antiepileptic
drug and had at least one partial seizure during the screening period (within 2 weeks prior to
baseline). Patients had up to 48 hours of baseline and up to 72 hours of double-blind video EEG
monitoring to record and count the occurrence of seizures. There were no statistically significant
differences between treatments in either the response ratio or responder rate.
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16
HOW SUPPLIED/STORAGE AND HANDLING
NEURONTIN (gabapentin) capsules, tablets, and oral solution are supplied as follows:
100 mg capsules:
White hard gelatin capsules printed with “PD” on the body and “Neurontin/100 mg” on
the cap; available in:
Bottles of 100: NDC 0071-0803-24
300 mg capsules:
Yellow hard gelatin capsules printed with “PD” on the body and “Neurontin/300 mg” on
the cap; available in:
Bottles of 100: NDC 0071-0805-24
Unit dose 50’s: NDC 0071-0805-40
400 mg capsules:
Orange hard gelatin capsules printed with “PD” on the body and “Neurontin/400 mg” on
the cap; available in:
Bottles of 100: NDC 0071-0806-24
Unit dose 50’s: NDC 0071-0806-40
600 mg tablets:
White elliptical film-coated scored tablets debossed with “NT” and “16” on one side;
available in:
Bottles of 100: NDC 0071-0513-24
800 mg tablets:
White elliptical film-coated scored tablets debossed with “NT” and “26” on one side;
available in:
Bottles of 100: NDC 0071-0401-24
250 mg per 5 mL oral solution:
Clear colorless to slightly yellow solution; each 5 mL of oral solution contains 250 mg of
gabapentin; available in:
Bottles containing 470 mL: NDC 0071-2012-23
Store NEURONTIN Tablets and Capsules at 25°C (77°F); excursions permitted between 15°C to
30°C (59°F to 86°F) [see USP Controlled Room Temperature].
Store NEURONTIN Oral Solution refrigerated, 2C to 8C (36F to 46F).
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17 PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Administration Information
Inform patients that NEURONTIN is taken orally with or without food. Inform patients that,
should they divide the scored 600 mg or 800 mg tablet in order to administer a half-tablet, they
should take the unused half-tablet as the next dose. Advise patients to discard half-tablets not
used within 28 days of dividing the scored tablet.
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity
Prior to initiation of treatment with NEURONTIN, instruct patients that a rash or other signs or
symptoms of hypersensitivity (such as fever or lymphadenopathy) may herald a serious medical
event and that the patient should report any such occurrence to a physician immediately [see
Warnings and Precautions (5.1)].
Anaphylaxis and Angioedema
Advise patients to discontinue NEURONTIN and seek medical care if they develop signs or
symptoms of anaphylaxis or angioedema [see Warnings and Precautions (5.2)].
Dizziness and Somnolence and Effects on Driving and Operating Heavy Machinery
Advise patients that NEURONTIN may cause dizziness, somnolence, and other symptoms and
signs of CNS depression. Other drugs with sedative properties may increase these symptoms.
Accordingly, although patients’ ability to determine their level of impairment can be unreliable,
advise them neither to drive a car nor to operate other complex machinery until they have gained
sufficient experience on NEURONTIN to gauge whether or not it affects their mental and/or
motor performance adversely. Inform patients that it is not known how long this effect lasts [see
Warnings and Precautions (5.3) and Warnings and Precautions (5.4)].
Suicidal Thinking and Behavior
Counsel the patient, their caregivers, and families that AEDs, including NEURONTIN, may
increase the risk of suicidal thoughts and behavior. Advise patients of the need to be alert for the
emergence or worsening of symptoms of depression, any unusual changes in mood or behavior,
or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Instruct patients to
report behaviors of concern immediately to healthcare providers [see Warnings and Precautions
(5.6)].
Use in Pregnancy
Instruct patients to notify their physician if they become pregnant or intend to become pregnant
during therapy, and to notify their physician if they are breast feeding or intend to breast feed
during therapy [see Use in Specific Populations (8.1) and (8.3)].
Encourage patients to enroll in the NAAED Pregnancy Registry if they become pregnant. This
registry is collecting information about the safety of antiepileptic drugs during pregnancy. To
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enroll, patients can call the toll free number 1-888-233-2334 [see Use in Specific Populations
(8.1)].
This product’s label may have been updated. For full prescribing information, please visit
www.pfizer.com. company logo
LAB-0106-20.0
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MEDICATION GUIDE
NEURONTIN (Neu rŏn' tĭn)
(Gabapentin)
Capsules, Tablets, and Oral Solution
Read the Medication Guide before you start taking NEURONTIN and each time you get a refill.
There may be new information. This information does not take the place of talking to your
healthcare provider about your medical condition or treatment.
What is the most important information I should know about NEURONTIN?
Do not stop taking NEURONTIN without first talking to your healthcare provider.
Stopping NEURONTIN suddenly can cause serious problems.
NEURONTIN can cause serious side effects including:
1. Suicidal Thoughts. Like other antiepileptic drugs, NEURONTIN may cause suicidal
thoughts or actions in a very small number of people, about 1 in 500.
Call a healthcare provider right away if you have any of these symptoms, especially if
they are new, worse, or worry you:
thoughts about suicide or dying
attempts to commit suicide
new or worse depression
new or worse anxiety
feeling agitated or restless
panic attacks
trouble sleeping (insomnia)
new or worse irritability
acting aggressive, being angry, or violent
acting on dangerous impulses
an extreme increase in activity and talking (mania)
other unusual changes in behavior or mood
How can I watch for early symptoms of suicidal thoughts and actions?
Pay attention to any changes, especially sudden changes, in mood, behaviors,
thoughts, or feelings.
Keep all follow-up visits with your healthcare provider as scheduled.
Call your healthcare provider between visits as needed, especially if you are worried
about symptoms.
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Do not stop taking NEURONTIN without first talking to a healthcare provider.
Stopping NEURONTIN suddenly can cause serious problems. Stopping a seizure
medicine suddenly in a patient who has epilepsy can cause seizures that will not
stop (status epilepticus).
Suicidal thoughts or actions can be caused by things other than medicines. If you
have suicidal thoughts or actions, your healthcare provider may check for other
causes.
2. Changes in behavior and thinking - Using NEURONTIN in children 3 to 12 years of
age can cause emotional changes, aggressive behavior, problems with concentration,
restlessness, changes in school performance, and hyperactivity.
3. NEURONTIN may cause serious or life-threatening allergic reactions that may affect
your skin or other parts of your body such as your liver or blood cells. This may cause you to
be hospitalized or to stop NEURONTIN. You may or may not have a rash with an allergic
reaction caused by NEURONTIN. Call a healthcare provider right away if you have any of
the following symptoms:
skin rash
hives
difficulty breathing
fever
swollen glands that do not go away
swelling of your face, lips, throat, or tongue
yellowing of your skin or of the whites of the eyes
unusual bruising or bleeding
severe fatigue or weakness
unexpected muscle pain
frequent infections
These symptoms may be the first signs of a serious reaction. A healthcare provider
should examine you to decide if you should continue taking NEURONTIN.
What is NEURONTIN?
NEURONTIN is a prescription medicine used to treat:
Pain from damaged nerves (postherpetic pain) that follows healing of shingles (a painful
rash that comes after a herpes zoster infection) in adults.
Partial seizures when taken together with other medicines in adults and children
3 years of age and older with seizures.
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Who should not take NEURONTIN?
Do not take NEURONTIN if you are allergic to gabapentin or any of the other ingredients in
NEURONTIN. See the end of this Medication Guide for a complete list of ingredients in
NEURONTIN.
What should I tell my healthcare provider before taking NEURONTIN?
Before taking NEURONTIN, tell your healthcare provider if you:
have or have had kidney problems or are on hemodialysis
have or have had depression, mood problems, or suicidal thoughts or behavior
have diabetes
are pregnant or plan to become pregnant. It is not known if NEURONTIN can harm your
unborn baby. Tell your healthcare provider right away if you become pregnant while
taking NEURONTIN. You and your healthcare provider will decide if you should take
NEURONTIN while you are pregnant.
o If you become pregnant while taking NEURONTIN, talk to your healthcare
provider about registering with the North American Antiepileptic Drug
(NAAED) Pregnancy Registry. The purpose of this registry is to collect
information about the safety of antiepileptic drugs during pregnancy. You can
enroll in this registry by calling 1-888-233-2334.
are breast-feeding or plan to breast-feed. NEURONTIN can pass into breast milk. You
and your healthcare provider should decide how you will feed your baby while you take
NEURONTIN.
Tell your healthcare provider about all the medicines you take, including prescription and
over-the-counter medicines, vitamins, and herbal supplements.
Taking NEURONTIN with certain other medicines can cause side effects or affect how well they
work. Do not start or stop other medicines without talking to your healthcare provider.
Know the medicines you take. Keep a list of them and show it to your healthcare provider and
pharmacist when you get a new medicine.
How should I take NEURONTIN?
Take NEURONTIN exactly as prescribed. Your healthcare provider will tell you how
much NEURONTIN to take.
o Do not change your dose of NEURONTIN without talking to your healthcare
provider.
o If you take NEURONTIN tablets and break a tablet in half, the unused half of
the tablet should be taken at your next scheduled dose. Half tablets not used
within 28 days of breaking should be thrown away.
o Take NEURONTIN capsules with water.
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NEURONTIN tablets can be taken with or without food. If you take an antacid
containing aluminum and magnesium, such as Maalox®, Mylanta®, Gelusil®, Gaviscon® ,
or Di-Gel®, you should wait at least 2 hours before taking your next dose of
NEURONTIN.
If you take too much NEURONTIN, call your healthcare provider or your local Poison
Control Center right away at 1-800-222-1222.
What should I avoid while taking NEURONTIN?
Do not drink alcohol or take other medicines that make you sleepy or dizzy while taking
NEURONTIN without first talking with your healthcare provider. Taking NEURONTIN
with alcohol or drugs that cause sleepiness or dizziness may make your sleepiness or
dizziness worse.
Do not drive, operate heavy machinery, or do other dangerous activities until you know
how NEURONTIN affects you. NEURONTIN can slow your thinking and motor skills.
What are the possible side effects of NEURONTIN?
NEURONTIN may cause serious side effects including:
See “What is the most important information I should know about NEURONTIN?”
problems driving while using NEURONTIN. See “What I should avoid while taking
Neurontin?”
sleepiness and dizziness, which could increase the occurrence of accidental injury,
including falls
The most common side effects of NEURONTIN include:
lack of coordination
feeling tired
viral infection
fever
feeling drowsy
jerky movements
nausea and vomiting
difficulty with coordination
difficulty with speaking
double vision
tremor
unusual eye movement
swelling, usually of legs and feet
Tell your healthcare provider if you have any side effect that bothers you or that does not go
away.
These are not all the possible side effects of NEURONTIN. For more information, ask your
healthcare provider or pharmacist.
Call your doctor for medical advice about side effects. You may report side effects to FDA
at 1-800-FDA-1088.
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How should I store NEURONTIN?
Store NEURONTIN Capsules and Tablets between 68°F to 77°F (20°C to 25°C).
Store NEURONTIN Oral Solution in the refrigerator between 36°F to 46°F (2°C to 8°C).
Keep NEURONTIN and all medicines out of the reach of children.
General information about the safe and effective use of NEURONTIN
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide.
Do not use NEURONTIN for a condition for which it was not prescribed. Do not give
NEURONTIN to other people, even if they have the same symptoms that you have. It may harm
them.
This Medication Guide summarizes the most important information about NEURONTIN. If you
would like more information, talk with your healthcare provider. You can ask your healthcare
provider or pharmacist for information about NEURONTIN that was written for healthcare
professionals.
For more information go to http://www.pfizer.com or call 1-800-438-1985.
What are the ingredients in NEURONTIN?
Active ingredient: gabapentin
Inactive ingredients in the capsules: lactose, cornstarch, talc, gelatin, titanium dioxide and
FD&C Blue No. 2.
The 300-mg capsule shell also contains: yellow iron oxide.
The 400-mg capsule shell also contains: red iron oxide, and yellow iron oxide.
Inactive ingredients in the tablets: poloxamer 407, copovidone, cornstarch, magnesium
stearate, hydroxypropyl cellulose, talc, and candelilla wax
Inactive ingredients in the oral solution: glycerin, xylitol, purified water, and artificial flavor.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
This product’s label may have been updated. For current full prescribing information, please visit
www.pfizer.com. company logo
LAB-0397-8.0
Revised September 2015
Reference ID: 3818812
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020235s060,020882s043,021129s042lbl.pdf', 'application_number': 20235, 'submission_type': 'SUPPL ', 'submission_number': 60}
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1
PRODUCT INFORMATION
SEREVENT®
(salmeterol xinafoate)
Inhalation Aerosol
Bronchodilator Aerosol
For Oral Inhalation Only
WARNING: Data from a large placebo-controlled US study that compared the safety of
salmeterol (SEREVENT Inhalation Aerosol) or placebo added to usual asthma therapy showed a
small but significant increase in asthma-related deaths in patients receiving salmeterol (13 deaths
out of 13,174 patients treated for 28 weeks) versus those on placebo (4 of 13,179). Subgroup
analyses suggest the risk may be greater in African-American patients compared to Caucasians
(see WARNINGS and CLINICAL PHARMACOLOGY: Clinical Trials: Asthma: Salmeterol
Multi-center Asthma Research Trial).
DESCRIPTION: SEREVENT (salmeterol xinafoate) Inhalation Aerosol contains salmeterol
xinafoate as the racemic form of the 1-hydroxy-2-naphthoic acid salt of salmeterol. The active
component of the formulation is salmeterol base, a highly selective beta2-adrenergic
bronchodilator. The chemical name of salmeterol xinafoate is 4-hydroxy-α1-[[[6-(4-
phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol, 1-hydroxy-2-
naphthalenecarboxylate. Salmeterol xinafoate has the following chemical structure:
The molecular weight of salmeterol xinafoate is 603.8, and the empirical formula is
C25H37NO4C11H8O3. Salmeterol xinafoate is a white to off-white powder. It is freely soluble in
methanol; slightly soluble in ethanol, chloroform, and isopropanol; and sparingly soluble in
water.
SEREVENT Inhalation Aerosol is a pressurized, metered-dose aerosol unit for oral inhalation.
It contains a microcrystalline suspension of salmeterol xinafoate in a mixture of 2
chlorofluorocarbon propellants (trichlorofluoromethane and dichlorodifluoromethane) with soya
lecithin. 36.25 mcg of salmeterol xinafoate is equivalent to 25 mcg of salmeterol base. Each
actuation delivers 25 mcg of salmeterol base (as salmeterol xinafoate) from the valve and 21 mcg
of salmeterol base (as salmeterol xinafoate) from the actuator. Each 6.5-g canister provides
60 inhalations and each 13-g canister provides 120 inhalations.
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2
CLINICAL PHARMACOLOGY:
Mechanism of Action: Salmeterol is a long-acting beta-adrenergic agonist. In vitro studies
and in vivo pharmacologic studies demonstrate that salmeterol is selective for
beta2-adrenoceptors compared with isoproterenol, which has approximately equal agonist
activity on beta1- and beta2-adrenoceptors. In vitro studies show salmeterol to be at least 50 times
more selective for beta2-adrenoceptors than albuterol. Although beta2-adrenoceptors are the
predominant adrenergic receptors in bronchial smooth muscle and beta1-adrenoceptors are the
predominant receptors in the heart, there are also beta2-adrenoceptors in the human heart
comprising 10% to 50% of the total beta-adrenoceptors. The precise function of these is not yet
established, but they raise the possibility that even highly selective beta2-agonists may have
cardiac effects.
The pharmacologic effects of beta2-adrenoceptor agonist drugs, including salmeterol, are at
least in part attributable to stimulation of intracellular adenyl cyclase, the enzyme that catalyzes
the conversion of adenosine triphosphate (ATP) to cyclic-3′,5′-adenosine monophosphate (cyclic
AMP). Increased cyclic AMP levels cause relaxation of bronchial smooth muscle and inhibition
of release of mediators of immediate hypersensitivity from cells, especially from mast cells.
In vitro tests show that salmeterol is a potent and long-lasting inhibitor of the release of mast
cell mediators, such as histamine, leukotrienes, and prostaglandin D2, from human lung.
Salmeterol inhibits histamine-induced plasma protein extravasation and inhibits platelet
activating factor-induced eosinophil accumulation in the lungs of guinea pigs when administered
by the inhaled route. In humans, single doses of salmeterol attenuate allergen-induced bronchial
hyper-responsiveness.
Pharmacokinetics: Salmeterol xinafoate, an ionic salt, dissociates in solution so that the
salmeterol and 1-hydroxy-2-naphthoic acid (xinafoate) moieties are absorbed, distributed,
metabolized, and excreted independently. Salmeterol acts locally in the lung; therefore, plasma
levels do not predict therapeutic effect.
Absorption: Because of the small therapeutic dose, systemic levels of salmeterol are low or
undetectable after inhalation of recommended doses (42 mcg of salmeterol inhalation aerosol
twice daily). Following chronic administration of an inhaled dose of 42 mcg twice daily,
salmeterol was detected in plasma within 5 to 10 minutes in 6 asthmatic patients; plasma
concentrations were very low, with peak concentrations of 150 pg/mL and no accumulation with
repeated doses. Larger inhaled doses gave approximately proportionally increased blood levels.
In these patients, a second peak concentration of 115 pg/mL occurred at about 45 minutes,
probably due to absorption of the swallowed portion of the dose (most of the dose delivered by a
metered-dose inhaler is swallowed).
Distribution: Binding of salmeterol to human plasma proteins averages 96% in vitro over
the concentration range of 8 to 7722 ng of salmeterol base per milliliter, much higher than those
achieved following therapeutic doses of salmeterol.
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3
Metabolism: Salmeterol base is extensively metabolized by hydroxylation, with subsequent
elimination predominantly in the feces. No significant amount of unchanged salmeterol base was
detected in either urine or feces.
Excretion: In 2 healthy subjects who received 1 mg of radiolabeled salmeterol (as salmeterol
xinafoate) orally, approximately 25% and 60% of the radiolabeled salmeterol was eliminated in
urine and feces, respectively, over a period of 7 days. The terminal elimination half-life was
about 5.5 hours (1 volunteer only).
The xinafoate moiety has no apparent pharmacologic activity. The xinafoate moiety is highly
protein bound (>99%) and has a long elimination half-life of 11 days.
Special Populations: The pharmacokinetics of salmeterol base has not been studied in
elderly patients or in patients with hepatic or renal impairment. Since salmeterol is
predominantly cleared by hepatic metabolism, liver function impairment may lead to
accumulation of salmeterol in plasma. Therefore, patients with hepatic disease should be closely
monitored.
Pharmacodynamics: Inhaled salmeterol, like other beta-adrenergic agonist drugs, can in
some patients produce dose-related cardiovascular effects and effects on blood glucose and/or
serum potassium (see PRECAUTIONS). The cardiovascular effects (heart rate, blood pressure)
associated with salmeterol occur with similar frequency, and are of similar type and severity, as
those noted following albuterol administration.
The effects of rising doses of salmeterol and standard inhaled doses of albuterol were studied
in volunteers and in patients with asthma. Salmeterol doses up to 84 mcg administered as
inhalation aerosol resulted in heart rate increases of 3 to 16 beats/min, about the same as
albuterol dosed at 180 mcg by inhalation aerosol (4 to 10 beats/min). In 2 double-blind asthma
studies, patients receiving either 42 mcg of salmeterol inhalation aerosol twice daily (n = 81) or
180 mcg of albuterol inhalation aerosol 4 times daily (n = 80) underwent continuous
electrocardiographic monitoring during four 24-hour periods; no clinically significant
dysrhythmias were noted. Continuous electrocardiographic monitoring was also performed in 2
double-blind studies in COPD patients (see ADVERSE REACTIONS).
Studies in laboratory animals (minipigs, rodents, and dogs) have demonstrated the occurrence
of cardiac arrhythmias and sudden death (with histologic evidence of myocardial necrosis) when
beta-agonists and methylxanthines are administered concurrently. The clinical significance of
these findings is unknown.
Clinical Trials: Asthma: In placebo- and albuterol-controlled, single-dose clinical trials with
SEREVENT Inhalation Aerosol, the time to onset of effective bronchodilatation (>15%
improvement in forced expiratory volume in 1 second [FEV1]) was 10 to 20 minutes after a
42-mcg dose. Maximum improvement in FEV1 generally occurred within 180 minutes, and
clinically significant improvement continued for 12 hours in most patients.
In 2 large, randomized, double-blind studies, SEREVENT Inhalation Aerosol was compared
with albuterol and placebo in patients with mild-to-moderate asthma, including both patients
who did and who did not receive concomitant inhaled corticosteroids. The efficacy of
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4
SEREVENT Inhalation Aerosol was demonstrated over the 12-week period with no change in
effectiveness over this period of time. There were no gender-related differences in safety or
efficacy. No development of tachyphylaxis to the bronchodilator effect has been noted in these
studies. FEV1 measurements (percent of predicted) from these two 12-week trials are shown
below for both the first and last treatment days.
Figure 1: FEV1, as Percent of Predicted,
From 2 Large 12-Week Clinical Trials
First Treatment Day
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Last Treatment Day (Week 12)
During daily treatment with SEREVENT Inhalation Aerosol for 12 weeks in patients with
asthma, the following treatment effects were seen:
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6
Table 1: Daily Efficacy Measurements in 2 Large 12-Week Clinical Trials
(Combined Data)
Parameter
Time
Placebo
SEREVENT
Inhalation
Aerosol
Albuterol
Inhalation
Aerosol
No. of randomized subjects
187
184
185
Mean AM peak expiratory
flow rate (L/min)
baseline
12 weeks
412
414
409
438*
398
390
Mean % days with no
asthma symptoms
baseline
12 weeks
11
17
11
35*
14
24
Mean % nights with no
awakenings
baseline
12 weeks
67
74
67
87*
65
74
Rescue medications (mean
no. of inhalations per day)
baseline
12 weeks
4.4
3.3
4.1
1.3†‡
4.0
1.9
Asthma exacerbations
17%
11%
14%
*P<0.001 versus albuterol and placebo.
†P<0.05 versus albuterol.
‡P<0.001 versus placebo.
Safe usage with maintenance of efficacy for periods up to 1 year has been documented.
Effects in Patients With Asthma on Concomitant Inhaled Corticosteroids: In 4
clinical trials in adult and adolescent patients with asthma (n = 1922), the effect of adding
salmeterol to inhaled corticosteroid therapy was evaluated. The studies utilized the inhalation
aerosol formulation of salmeterol xinafoate for a treatment period of 6 months. They compared
the addition of salmeterol therapy to an increase (at least doubling) of the inhaled corticosteroid
dose.
Two randomized, double-blind, parallel group clinical trials (n = 997) enrolled patients (ages
18-82 years) with persistent asthma who were previously maintained but not adequately
controlled on inhaled corticosteroid therapy. During the 2-week run-in period, all patients were
switched to beclomethasone dipropionate 168 mcg twice daily. Patients still not adequately
controlled were randomized to either the addition of salmeterol inhalation aerosol 42 mcg twice
daily or an increase of beclomethasone dipropionate to 336 mcg twice daily. As compared to the
doubled dose of beclomethasone dipropionate, the addition of salmeterol resulted in statistically
significantly greater improvements in pulmonary function and asthma symptoms, and
statistically significantly greater reduction in supplemental albuterol use. The percent of patients
who experienced asthma exacerbations overall was not different between groups (i.e., 16.2% in
the salmeterol group versus 17.9% in the higher dose beclomethasone dipropionate group).
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Two randomized, double-blind, parallel group clinical trials (n = 925) enrolled patients (ages
12-78 years) with persistent asthma who were previously maintained but not adequately
controlled on prior therapy. During the 2- to 4-week run-in period, all patients were switched to
fluticasone propionate 88 mcg twice daily. Patients still not adequately controlled were
randomized to either the addition of salmeterol inhalation aerosol 42 mcg twice daily or an
increase of fluticasone propionate to 220 mcg twice daily. As compared to the increased
(2.5 times) dose of fluticasone propionate, the addition of salmeterol resulted in statistically
significantly greater improvements in pulmonary function and asthma symptoms, and
statistically significantly greater reduction in supplemental albuterol use. Fewer patients
receiving salmeterol experienced asthma exacerbations than those receiving the higher dose of
fluticasone propionate (8.8% versus 13.8%).
Salmeterol Multi-center Asthma Research Trial: The Salmeterol Multi-center
Asthma Research Trial (SMART) enrolled long-acting beta2-agonist–naive patients with asthma
(average age of 39 years, 71% Caucasian, 18% African-American, 8% Hispanic) to assess the
safety of salmeterol (SEREVENT Inhalation Aerosol, 42 mcg twice daily over 28 weeks)
compared to placebo when added to usual asthma therapy. The primary endpoint was the
combined number of respiratory-related deaths or respiratory-related life-threatening experiences
(intubation and mechanical ventilation). Other endpoints included combined asthma-related
deaths or life-threatening experiences and asthma-related deaths. A planned interim analysis was
conducted when approximately half of the intended number of patients had been enrolled
(N = 26,353).
Due to the low rate of primary events in the study, the findings of the planned interim analysis
were not conclusive. The analysis showed no significant difference for the primary endpoint for
the total population. However, a higher number of asthma-related deaths or life-threatening
experiences (36 vs. 23) and a higher number of asthma-related deaths (13 vs. 4) occurred in the
patients treated with salmeterol. Post hoc subgroup analyses revealed no significant increase in
respiratory- or asthma-related episodes, including deaths, in Caucasian patients. In
African-Americans, the study showed a small, though statistically significantly greater, number
of primary events (20 vs. 7), asthma-related deaths or life-threatening experiences (19 vs. 4), and
asthma-related deaths (8 vs. 1) in patients taking salmeterol compared to those taking placebo.
The numbers of patients from other ethnic groups were too small to draw any conclusions in
these populations. Even though SMART did not reach predetermined stopping criteria for the
total population, the study was stopped due to the findings in African-American patients and
difficulties in enrollment.
Exercise-Induced Bronchospasm: Protection against exercise-induced bronchospasm
was examined in 3 controlled studies. Based on median values, patients who received
SEREVENT Inhalation Aerosol had consistently less exercise-induced fall in FEV1 than patients
who received placebo, and they were protected for a longer period of time than patients who
received albuterol (see Table 2). There were, however, some patients who were not protected
from exercise-induced bronchospasm after SEREVENT administration and others in whom
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8
protection against exercise-induced bronchospasm decreased with continued administration over
a period of 4 weeks.
Table 2: Exercise-Induced Bronchospasm Mean Percentage Fall in Postexercise FEV1
Treatment
Clinical Trials/Time After Dose
Placebo
SEREVENT
Inhalation Aerosol
Albuterol
Inhalation Aerosol
Study A: 1st Dose
6 hours
12 hours
37
27
9*
16*
Study A: 4th Week
6 hours
12 hours
30
24
19
12
Study B:
1 hour
6 hours
12 hours
37
37
34
0*
5*†
6*†
2*
27
33
Study C:
0.5 hour
2.5 hours
4.5 hours
6.0 hours
43
33
--
--
16*
12*†
12†
19†
8*
30
36
41
*Statistically superior to placebo (P≤0.05).
†Statistically superior to albuterol (P≤0.05).
Chronic Obstructive Pulmonary Disease (COPD): In 2 large randomized,
double-blind studies, SEREVENT Inhalation Aerosol administered twice daily was compared
with placebo and ipratropium bromide inhalation aerosol administered 4 times daily in patients
with COPD (emphysema and chronic bronchitis), including patients who were reversible (≥12%
and ≥200 mL increase in baseline FEV1 after albuterol treatment) and nonreversible to albuterol.
After a single 42-mcg dose of SEREVENT, significant improvement in pulmonary function
(mean FEV1 increase of 12% or more) occurred within 30 minutes, reached a peak within
4 hours on average, and persisted for 12 hours with no loss in effectiveness observed over a
12-week treatment period. Serial 12-hour measurements of FEV1 from these two 12-week trials
are shown below for both the first and last treatment days.
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9
Figure 2: FEV1 From 2 Large 12-Week Clinical Trials
First Treatment Day
* Ipratropium inhalation aerosol (or matching placebo) administered
immediately following hour 6 assessment.
Last Treatment Day (Week 12)
* Ipratropium inhalation aerosol (or matching placebo) administered
immediately following hour 6 assessment.
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INDICATIONS AND USAGE:
Asthma: SEREVENT Inhalation Aerosol is indicated for long-term, twice-daily (morning and
evening) administration in the maintenance treatment of asthma and in the prevention of
bronchospasm in patients 12 years of age and older with reversible obstructive airway disease,
including patients with symptoms of nocturnal asthma, who require regular treatment with
inhaled, short-acting beta2-agonists. It should not be used in patients whose asthma can be
managed by occasional use of inhaled, short-acting beta2-agonists.
SEREVENT Inhalation Aerosol may be used alone or in combination with inhaled or
systemic corticosteroid therapy.
SEREVENT Inhalation Aerosol is also indicated for prevention of exercise-induced
bronchospasm in patients 12 years of age and older.
COPD: SEREVENT Inhalation Aerosol is indicated for long-term, twice daily (morning and
evening) administration in the maintenance treatment of bronchospasm associated with COPD
(including emphysema and chronic bronchitis).
CONTRAINDICATIONS: SEREVENT Inhalation Aerosol is contraindicated in patients with a
history of hypersensitivity to salmeterol or any other component of the drug product (see
DESCRIPTION).
WARNINGS: DATA FROM A LARGE PLACEBO-CONTROLLED SAFETY STUDY
THAT WAS STOPPED EARLY SUGGEST THAT SALMETEROL MAY BE ASSOCIATED
WITH RARE SERIOUS ASTHMA EPISODES OR ASTHMA-RELATED DEATHS. Data
from this study, called the Salmeterol Multi-center Asthma Research Trial (SMART), further
suggest that the risk might be greater in African-American patients, in whom the increased risk
was statistically significant at the time of the interim analysis. These results led to stopping the
study prematurely (see CLINICAL PHARMACOLOGY: Clinical Trials: Asthma: Salmeterol
Multi-center Asthma Research Trial). The data from the SMART study are not adequate to
determine whether concurrent use of inhaled corticosteroids provides protection from this risk.
Given the similar basic mechanisms of action of beta2-agonists, it is possible that the findings
seen in the SMART study may be consistent with a class effect. Findings similar to the SMART
study findings were reported in a prior 16-week clinical study performed in the United
Kingdom, the Salmeterol Nationwide Surveillance (SNS) study. In the SNS study, the incidence
of asthma-related death was numerically, though not statistically, greater in patients with asthma
treated with salmeterol (42 mcg twice daily) versus albuterol (180 mcg 4 times daily) added to
usual asthma therapy.
SEREVENT INHALATION AEROSOL SHOULD NOT BE INITIATED IN
PATIENTS WITH SIGNIFICANTLY WORSENING OR ACUTELY DETERIORATING
ASTHMA, WHICH MAY BE A LIFE-THREATENING CONDITION. Serious acute
respiratory events, including fatalities, have been reported, both in the United States and
worldwide, when SEREVENT Inhalation Aerosol has been initiated in this situation.
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Although it is not possible from these reports to determine whether SEREVENT
Inhalation Aerosol contributed to these adverse events or simply failed to relieve the
deteriorating asthma, the use of SEREVENT Inhalation Aerosol in this setting is
inappropriate.
SEREVENT INHALATION AEROSOL SHOULD NOT BE USED TO TREAT
ACUTE SYMPTOMS. It is crucial to inform patients of this and prescribe an inhaled,
short-acting beta2-agonist for this purpose as well as warn them that increasing inhaled
beta2-agonist use is a signal of deteriorating asthma.
SEREVENT INHALATION AEROSOL IS NOT A SUBSTITUTE FOR INHALED OR
ORAL CORTICOSTEROIDS. Corticosteroids should not be stopped or reduced when
SEREVENT Inhalation Aerosol is initiated.
(See PRECAUTIONS: Information for Patients and the accompanying PATIENT'S
INSTRUCTIONS FOR USE.)
1. Do Not Introduce SEREVENT Inhalation Aerosol as a Treatment for Acutely Deteriorating
Asthma: SEREVENT Inhalation Aerosol is intended for the maintenance treatment of asthma
(see INDICATIONS AND USAGE) and should not be introduced in acutely deteriorating
asthma, which is a potentially life-threatening condition. There are no data demonstrating that
SEREVENT Inhalation Aerosol provides greater efficacy than or additional efficacy to inhaled,
short-acting beta2-agonists in patients with worsening asthma. Serious acute respiratory events,
including fatalities, have been reported, both in the United States and worldwide, in patients
receiving SEREVENT Inhalation Aerosol. In most cases, these have occurred in patients with
severe asthma (e.g., patients with a history of corticosteroid dependence, low pulmonary
function, intubation, mechanical ventilation, frequent hospitalizations, or previous
life-threatening acute asthma exacerbations) and/or in some patients in whom asthma has been
acutely deteriorating (e.g., unresponsive to usual medications; increasing need for inhaled,
short-acting beta2-agonists; increasing need for systemic corticosteroids; significant increase in
symptoms; recent emergency room visits; sudden or progressive deterioration in pulmonary
function). However, they have occurred in a few patients with less severe asthma as well. It was
not possible from these reports to determine whether SEREVENT Inhalation Aerosol
contributed to these events or simply failed to relieve the deteriorating asthma.
2. Do Not Use SEREVENT Inhalation Aerosol to Treat Acute Symptoms: An inhaled,
short-acting beta2-agonist, not SEREVENT Inhalation Aerosol, should be used to relieve acute
asthma or COPD symptoms. When prescribing SEREVENT Inhalation Aerosol, the physician
must also provide the patient with an inhaled, short-acting beta2-agonist (e.g., albuterol) for
treatment of symptoms that occur acutely, despite regular twice-daily (morning and evening) use
of SEREVENT Inhalation Aerosol.
When beginning treatment with SEREVENT Inhalation Aerosol, patients who have been
taking inhaled, short-acting beta2-agonists on a regular basis (e.g., 4 times a day) should be
instructed to discontinue the regular use of these drugs and use them only for symptomatic relief
of acute asthma or COPD symptoms (see PRECAUTIONS: Information for Patients).
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3. Watch for Increasing Use of Inhaled, Short-Acting Beta2-Agonists, Which Is a Marker of
Deteriorating Asthma: Asthma may deteriorate acutely over a period of hours or chronically
over several days or longer. If the patient’s inhaled, short-acting beta2-agonist becomes less
effective or the patient needs more inhalations than usual, this may be a marker of
destabilization of asthma. In this setting, the patient requires immediate reevaluation with
reassessment of the treatment regimen, giving special consideration to the possible need for
corticosteroids. If the patient uses 4 or more inhalations per day of an inhaled, short-acting
beta2-agonist for 2 or more consecutive days, or if more than 1 canister (200 inhalations per
canister) of inhaled, short-acting beta2-agonist is used in an 8-week period in conjunction with
SEREVENT Inhalation Aerosol, then the patient should consult the physician for reevaluation.
Increasing the daily dosage of SEREVENT Inhalation Aerosol in this situation is not
appropriate. SEREVENT Inhalation Aerosol should not be used more frequently than
twice daily (morning and evening) at the recommended dose of 2 inhalations.
4. Do Not Use SEREVENT Inhalation Aerosol as a Substitute for Oral or Inhaled
Corticosteroids: The use of beta-adrenergic agonist bronchodilators alone may not be adequate
to control asthma in many patients. Early consideration should be given to adding
anti-inflammatory agents, e.g., corticosteroids. There are no data demonstrating that
SEREVENT Inhalation Aerosol has a clinical anti-inflammatory effect and could be expected to
take the place of corticosteroids. Patients who already require oral or inhaled corticosteroids for
treatment of asthma should be continued on this type of treatment even if they feel better as a
result of initiating SEREVENT Inhalation Aerosol. Any change in corticosteroid dosage should
be made ONLY after clinical evaluation (see PRECAUTIONS: Information for Patients).
5. Do Not Exceed Recommended Dosage: As with other inhaled beta2-adrenergic drugs,
SEREVENT Inhalation Aerosol should not be used more often or at higher doses than
recommended. Fatalities have been reported in association with excessive use of inhaled
sympathomimetic drugs. Large doses of inhaled or oral salmeterol (12 to 20 times the
recommended dose) have been associated with clinically significant prolongation of the QTc
interval, which has the potential for producing ventricular arrhythmias.
6. Paradoxical Bronchospasm: SEREVENT Inhalation Aerosol can produce paradoxical
bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs,
SEREVENT Inhalation Aerosol should be discontinued immediately and alternative therapy
instituted. It should be recognized that paradoxical bronchospasm, when associated with inhaled
formulations, frequently occurs with the first use of a new canister or vial.
7. Immediate Hypersensitivity Reactions: Immediate hypersensitivity reactions may occur after
administration of SEREVENT Inhalation Aerosol, as demonstrated by rare cases of urticaria,
angioedema, rash, and bronchospasm.
8. Upper Airway Symptoms: Symptoms of laryngeal spasm, irritation, or swelling, such as
stridor and choking, have been reported rarely in patients receiving SEREVENT Inhalation
Aerosol.
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13
SEREVENT Inhalation Aerosol, like all other beta-adrenergic agonists, can produce a
clinically significant cardiovascular effect in some patients as measured by pulse rate, blood
pressure, and/or symptoms. Although such effects are uncommon after administration of
SEREVENT Inhalation Aerosol at recommended doses, if they occur, the drug may need to be
discontinued. In addition, beta-agonists have been reported to produce electrocardiogram (ECG)
changes, such as flattening of the T wave, prolongation of the QTc interval, and ST segment
depression. The clinical significance of these findings is unknown. Therefore, SEREVENT
Inhalation Aerosol, like all sympathomimetic amines, should be used with caution in patients
with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and
hypertension.
PRECAUTIONS:
General: 1. Use With Spacer or Other Devices: The safety and effectiveness of SEREVENT
Inhalation Aerosol when used with a spacer or other devices have not been adequately studied.
2. Cardiovascular and Other Effects: No effect on the cardiovascular system is usually seen
after the administration of inhaled salmeterol in recommended doses, but the cardiovascular and
central nervous system effects seen with all sympathomimetic drugs (e.g., increased blood
pressure, heart rate, excitement) can occur after use of salmeterol and may require
discontinuation of the drug. Salmeterol, like all sympathomimetic amines, should be used with
caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac
arrhythmias, and hypertension; in patients with convulsive disorders or thyrotoxicosis; and in
patients who are unusually responsive to sympathomimetic amines.
As has been described with other beta-adrenergic agonist bronchodilators, clinically
significant changes in systolic and/or diastolic blood pressure, pulse rate, and electrocardiograms
have been seen infrequently in individual patients in controlled clinical studies with salmeterol.
3. Metabolic Effects: Doses of the related beta2-adrenoceptor agonist albuterol, when
administered intravenously, have been reported to aggravate preexisting diabetes mellitus and
ketoacidosis. No effects on glucose have been seen with SEREVENT Inhalation Aerosol at
recommended doses. Beta-adrenergic agonist medications may produce significant hypokalemia
in some patients, possibly through intracellular shunting, which has the potential to produce
adverse cardiovascular effects. The decrease is usually transient, not requiring supplementation.
Clinically significant changes in blood glucose and/or serum potassium were seen rarely
during clinical studies with long-term administration of SEREVENT Inhalation Aerosol at
recommended doses.
Information for Patients: See illustrated PATIENT’S INSTRUCTIONS FOR USE. SHAKE
WELL BEFORE USING.
It is important that patients understand how to use SEREVENT Inhalation Aerosol
appropriately and how it should be used in relation to other asthma or COPD medications they
are taking. Patients should be given the following information:
1. Shake well before using.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
14
2. The action of SEREVENT Inhalation Aerosol may last up to 12 hours or longer. The
recommended dosage (2 inhalations twice daily, morning and evening) should not be exceeded.
3. SEREVENT Inhalation Aerosol is not meant to relieve acute asthma or COPD symptoms and
extra doses should not be used for that purpose. Acute symptoms should be treated with an
inhaled, short-acting beta2-agonist such as albuterol (the physician should provide the patient
with such medication and instruct the patient in how it should be used).
4. Patients should not stop SEREVENT therapy for asthma or COPD without physician/provider
guidance since symptoms may recur after discontinuation.
5. The physician should be notified immediately if any of the following situations occur, which
may be a sign of seriously worsening asthma.
• Decreasing effectiveness of inhaled, short-acting beta2-agonists
• Need for more inhalations than usual of inhaled, short-acting beta2-agonists
• Use of 4 or more inhalations per day of a short-acting beta2-agonist for 2 or more days
consecutively
• Use of more than one 200-inhalation canister of an inhaled, short-acting beta2-agonist (e.g.,
albuterol) in an 8-week period
6. SEREVENT Inhalation Aerosol should not be used as a substitute for oral or inhaled
corticosteroids. The dosage of these medications should not be changed and they should not be
stopped without consulting the physician, even if the patient feels better after initiating treatment
with SEREVENT Inhalation Aerosol.
7. Patients should be cautioned regarding common adverse cardiovascular effects, such as
palpitations, chest pain, rapid heart rate, tremor, or nervousness.
8. In patients receiving SEREVENT Inhalation Aerosol, other inhaled medications should be
used only as directed by the physician.
9. When using SEREVENT Inhalation Aerosol to prevent exercise-induced bronchospasm,
patients should take the dose at least 30 to 60 minutes before exercise.
10. If you are pregnant or nursing, contact your physician about use of SEREVENT Inhalation
Aerosol.
11. Effective and safe use of SEREVENT Inhalation Aerosol includes an understanding of the
way that it should be administered.
Drug Interactions: Short-Acting Beta-Agonists: In the two 3-month, repetitive-dose
clinical asthma trials (n = 184), the mean daily need for additional beta2-agonist use was 1 to 1½
inhalations per day, but some patients used more. Eight percent of patients used at least 8
inhalations per day at least on 1 occasion. Six percent used 9 to 12 inhalations at least once.
There were 15 patients (8%) who averaged over 4 inhalations per day. Four of these used an
average of 8 to 11 inhalations per day. In these 15 patients there was no observed increase in
frequency of cardiovascular adverse events. The safety of concomitant use of more than 8
inhalations per day of short-acting beta2-agonists with SEREVENT Inhalation Aerosol has not
been established. In 15 patients who experienced worsening of asthma while receiving
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
15
SEREVENT Inhalation Aerosol, nebulized albuterol (1 dose in most) led to improvement in
FEV1 and no increase in occurrence of cardiovascular adverse events.
Monoamine Oxidase Inhibitors and Tricyclic Antidepressants: Salmeterol should
be administered with extreme caution to patients being treated with monoamine oxidase
inhibitors or tricyclic antidepressants, or within 2 weeks of discontinuation of such agents,
because the action of salmeterol on the vascular system may be potentiated by these agents.
Corticosteroids and Cromoglycate: In clinical trials, inhaled corticosteroids and/or
inhaled cromolyn sodium did not alter the safety profile of SEREVENT Inhalation Aerosol when
administered concurrently.
Methylxanthines: The concurrent use of intravenously or orally administered
methylxanthines (e.g., aminophylline, theophylline) by patients receiving SEREVENT Inhalation
Aerosol has not been completely evaluated. In 1 clinical asthma trial, 87 patients receiving
SEREVENT Inhalation Aerosol 42 mcg twice daily concurrently with a theophylline product had
adverse event rates similar to those in 71 patients receiving SEREVENT Inhalation Aerosol
without theophylline. Resting heart rates were slightly higher in the patients on theophylline but
were little affected by SEREVENT Inhalation Aerosol therapy.
Beta-adrenergic receptor blocking agents not only block the pulmonary effect of beta-agonists,
such as SEREVENT Inhalation Aerosol, but may also produce severe bronchospasm in asthmatic
patients. Therefore, patients with asthma should not normally be treated with beta-blockers.
However, under certain circumstances, e.g., as prophylaxis after myocardial infarction, there may
be no acceptable alternatives to the use of beta-adrenergic blocking agents in patients with
asthma. In this setting, cardioselective beta-blockers could be considered, although they should
be administered with caution.
The ECG changes and/or hypokalemia that may result from the administration of
nonpotassium-sparing diuretics (such as loop or thiazide diuretics) can be acutely worsened by
beta-agonists, especially when the recommended dose of the beta-agonist is exceeded. Although
the clinical significance of these effects is not known, caution is advised in the coadministration
of beta-agonists with nonpotassium-sparing diuretics.
Carcinogenesis, Mutagenesis, Impairment of Fertility: In an 18-month oral
carcinogenicity study in CD-mice, salmeterol xinafoate at oral doses of 1.4 mg/kg and above
(approximately 9 times the maximum recommended daily inhalation dose in adults based on
comparison of the areas under the plasma concentration versus time curves [AUCs]) caused
dose-related increases in the incidence of smooth muscle hyperplasia, cystic glandular
hyperplasia, leiomyomas of the uterus, and cysts in the ovaries. The incidence of
leiomyosarcomas was not statistically significant. No tumors were seen at 0.2 mg/kg
(comparable to the maximum recommended human daily inhalation dose in adults based on
comparison of the AUCs).
In a 24-month inhalation and oral carcinogenicity study in Sprague Dawley rats, salmeterol
caused dose-related increases in the incidence of mesovarian leiomyomas and ovarian cysts at
inhalation and oral doses of 0.68 mg/kg per day and above (approximately 55 times the
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
16
maximum recommended human daily inhalation dose in adults on a mg/m2 basis). No tumors
were seen at 0.21 mg/kg per day (approximately 15 times the maximum recommended human
daily inhalation dose in adults on a mg/m2 basis). These findings in rodents are similar to those
reported previously for other beta-adrenergic agonist drugs. The relevance of these findings to
human use is unknown.
Salmeterol xinafoate produced no detectable or reproducible increases in microbial and
mammalian gene mutation in vitro. No clastogenic activity occurred in vitro in human
lymphocytes or in vivo in a rat micronucleus test. No effects on fertility were identified in male
and female rats treated orally with salmeterol xinafoate at doses up to 2 mg/kg (approximately
160 times the maximum recommended human daily inhalation dose in adults on a mg/m2 basis).
Pregnancy: Teratogenic Effects: Pregnancy Category C. No teratogenic effects occurred in
the rat at oral doses up to 2 mg/kg (approximately 160 times the maximum recommended human
daily inhalation dose in adults on a mg/m2 basis). In pregnant Dutch rabbits administered oral
doses of 1 mg/kg and above (approximately 20 times the maximum recommended human daily
inhalation dose in adults based on the comparison of the AUCs), salmeterol xinafoate exhibited
fetal toxic effects characteristically resulting from beta-adrenoceptor stimulation; these included
precocious eyelid openings, cleft palate, sternebral fusion, limb and paw flexures, and delayed
ossification of the frontal cranial bones. No significant effects occurred at an oral dose of
0.6 mg/kg (approximately 10 times the maximum recommended human daily inhalation dose in
adults based on comparison of the AUCs).
New Zealand White rabbits were less sensitive since only delayed ossification of the frontal
cranial bones was seen at oral doses of 10 mg/kg (approximately 1600 times the maximum
recommended human daily inhalation dose on a mg/m2 basis). Extensive use of other
beta-agonists has provided no evidence that these class effects in animals are relevant to use in
humans. There are no adequate and well-controlled studies with SEREVENT Inhalation Aerosol
in pregnant women. SEREVENT Inhalation Aerosol should be used during pregnancy only if the
potential benefit justifies the potential risk to the fetus.
Use in Labor and Delivery: There are no well-controlled human studies that have
investigated effects of salmeterol on preterm labor or labor at term. Because of the potential for
beta-agonist interference with uterine contractility, use of SEREVENT Inhalation Aerosol for
prevention of bronchospasm during labor should be restricted to those patients in whom the
benefits clearly outweigh the risks.
Nursing Mothers: Plasma levels of salmeterol after inhaled therapeutic doses are very low. In
rats, salmeterol xinafoate is excreted in milk. However, since there is no experience with use of
SEREVENT Inhalation Aerosol by nursing mothers, a decision should be made whether to
discontinue nursing or to discontinue the drug, taking into account the importance of the drug to
the mother. Caution should be exercised when salmeterol xinafoate is administered to a nursing
woman.
Pediatric Use: The safety and effectiveness of SEREVENT Inhalation Aerosol in children
younger than 12 years of age have not been established.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
17
Geriatric Use: Of the total number of patients who received SEREVENT Inhalation Aerosol in
all asthma clinical studies, 241 were 65 years of age and older. Geriatric patients (65 years and
older) with reversible obstructive airway disease were evaluated in 4 well-controlled studies of 3
weeks’ to 3 months’ duration. Two placebo-controlled, crossover studies evaluated twice-daily
dosing with salmeterol for 21 to 28 days in 45 patients. An additional 75 geriatric patients were
treated with salmeterol for 3 months in 2 large parallel-group, multicenter studies. These 120
patients experienced increases in AM and PM peak expiratory flow rate and decreases in diurnal
variation in peak expiratory flow rate similar to responses seen in the total populations of the 2
latter studies. The adverse event type and frequency in geriatric patients were not different from
those of the total populations studied.
In 2 large, randomized, double-blind, placebo-controlled 3-month studies involving patients
with COPD, 133 patients using SEREVENT Inhalation Aerosol were 65 years and older. These
patients experienced similar improvements in FEV1 as observed for patients younger than 65.
No apparent differences in the efficacy and safety of SEREVENT Inhalation Aerosol were
observed when geriatric patients were compared with younger patients in asthma and COPD
clinical trials. As with other beta2-agonists, however, special caution should be observed when
using SEREVENT Inhalation Aerosol in geriatric patients who have concomitant cardiovascular
disease that could be adversely affected by this class of drug. Based on available data, no
adjustment of salmeterol dosage in geriatric patients is warranted.
ADVERSE REACTIONS: Adverse reactions to salmeterol are similar in nature to reactions to
other selective beta2-adrenoceptor agonists, i.e., tachycardia; palpitations; immediate
hypersensitivity reactions, including urticaria, angioedema, rash, bronchospasm (see
WARNINGS); headache; tremor; nervousness; and paradoxical bronchospasm (see
WARNINGS).
Asthma: Two multicenter, 12-week, controlled studies have evaluated twice-daily doses of
SEREVENT Inhalation Aerosol in patients 12 years of age and older with asthma. Table 3
reports the incidence of adverse events in these 2 studies.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
18
Table 3: Adverse Experience Incidence in 2 Large 12-Week Asthma Clinical Trials*
Percent of Patients
Adverse Event Type
Placebo
n = 187
SEREVENT
Inhalation
Aerosol
42 mcg
twice daily
n = 184
Albuterol
Inhalation
Aerosol
180 mcg
4 times daily
n = 185
Ear, nose, and throat
Upper respiratory tract infection
Nasopharyngitis
Disease of nasal cavity/sinus
Sinus headache
13
12
4
2
14
14
6
4
16*
11
1
<1
Gastrointestinal
Stomachache
0
4
0
Neurological
Headache
Tremor
23
2
28
4
27
3
Respiratory
Cough
Lower respiratory infection
6
2
7
4
3
2
* The only adverse experience classified as serious was 1 case of upper respiratory tract infection
in a patient treated with albuterol.
Table 3 includes all events (whether considered drug-related or nondrug-related by the
investigator) that occurred at a rate of over 3% in the SEREVENT Inhalation Aerosol treatment
group and were more common in the SEREVENT Inhalation Aerosol group than in the placebo
group.
Pharyngitis, allergic rhinitis, dizziness/giddiness, and influenza occurred at 3% or more but
were equally common on placebo. Other events occurring in the SEREVENT Inhalation Aerosol
treatment group at a frequency of 1% to 3% were as follows:
Cardiovascular: Tachycardia, palpitations.
Ear, Nose, and Throat: Rhinitis, laryngitis.
Gastrointestinal: Nausea, viral gastroenteritis, nausea and vomiting, diarrhea, abdominal
pain.
Hypersensitivity: Urticaria.
Mouth and Teeth: Dental pain.
Musculoskeletal: Pain in joint, back pain, muscle cramp/contraction, myalgia/myositis,
muscular soreness.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
19
Neurological: Nervousness, malaise/fatigue.
Respiratory: Tracheitis/bronchitis.
Skin: Rash/skin eruption.
Urogenital: Dysmenorrhea.
Data from small dose-response studies show an apparent dose relationship for tremor,
nervousness, and palpitations.
In clinical trials evaluating concurrent therapy of salmeterol with inhaled corticosteroids,
adverse events were consistent with those previously reported for salmeterol, or might otherwise
be expected with the use of inhaled corticosteroids.
COPD: Two multicenter, 12-week, controlled studies have evaluated twice-daily doses of
SEREVENT Inhalation Aerosol in patients with COPD. Table 4 reports the incidence of adverse
events in these 2 studies.
Table 4: Adverse Experience Incidence in 2 Large 12-Week COPD Clinical Trials
Percent of Patients
Adverse Event Type
Placebo
n = 278
SEREVENT
Inhalation
Aerosol
42 mcg
twice daily
n = 267
Ipratropium
Inhalation
Aerosol
36 mcg
4 times daily
n = 271
Ear, nose, and throat
Upper respiratory tract infection
7
9
9
Sore throat
3
8
6
Nasal sinus infection
1
4
2
Gastrointestinal
Diarrhea
3
5
4
Musculoskeletal
Back pain
3
4
3
Neurological
Headache
10
12
8
Respiratory
Chest congestion
3
4
3
Table 4 includes all events (whether considered drug-related or nondrug-related by the
investigator) that occurred at a rate of over 3% in the SEREVENT Inhalation Aerosol treatment
group and were more common in the SEREVENT Inhalation Aerosol group than in the placebo
group.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
20
Common cold, rhinorrhea, bronchitis, cough, exacerbation of chest congestion, chest pain, and
dizziness occurred at 3% or more but were equally common on placebo. Other events occurring
in the SEREVENT Inhalation Aerosol treatment group at a frequency of 1% to 3% were as
follows:
Ear, Nose, and Throat: Cold symptoms, earache, epistaxis, nasal congestion, nasal sinus
congestion, sneezing.
Gastrointestinal: Nausea, dyspepsia, gastric pain, gastric upset, abdominal pain,
constipation, heartburn, oral candidiasis, xerostomia, vomiting, surgical removal of tooth.
Musculoskeletal: Leg cramps, myalgia, neck pain, pain in arm, shoulder pain, muscle
injury of neck.
Neurological: Insomnia, sinus headache.
Non-Site Specific: Fatigue, fever, pain in body, discomfort in chest.
Respiratory: Acute bronchitis, dyspnea, influenza, lower respiratory tract infection,
pneumonia, respiratory tract infection, shortness of breath, wheezing.
Urogenital: Urinary tract infection.
Electrocardiographic Monitoring in Patients With COPD: Continuous
electrocardiographic (Holter) monitoring was performed on 284 patients in 2 large COPD
clinical trials during five 24-hour periods. No cases of sustained ventricular tachycardia were
observed. At baseline, non-sustained, asymptomatic ventricular tachycardia was recorded for 7
(7.1%), 8 (9.4%), and 3 (3.0%) patients in the placebo, SEREVENT, and ipratropium groups,
respectively. During treatment, nonsustained, asymptomatic ventricular tachycardia that
represented a clinically significant change from baseline was reported for 11 (11.6%), 15
(18.3%), and 20 (20.8%) patients receiving placebo, SEREVENT, and ipratropium, respectively.
Four of these cases of ventricular tachycardia were reported as adverse events (1 placebo, 3
SEREVENT) by 1 investigator based upon review of Holter data. One case of ventricular
tachycardia was observed during ECG evaluation of chest pain (ipratropium) and reported as an
adverse event.
Observed During Clinical Practice: In extensive US and worldwide postmarketing
experience, serious exacerbations of asthma, including some that have been fatal, have been
reported. In most cases, these have occurred in patients with severe asthma and/or in some
patients in whom asthma has been acutely deteriorating (see WARNINGS no. 1), but they have
occurred in a few patients with less severe asthma as well. It was not possible from these reports
to determine whether SEREVENT Inhalation Aerosol contributed to these events or simply
failed to relieve the deteriorating asthma.
The following events have also been identified during postapproval use of SEREVENT in
clinical practice. Because they are reported voluntarily from a population of unknown size,
estimates of frequency cannot be made. These events have been chosen for inclusion due to a
combination of their seriousness, frequency of reporting, or potential causal connection to
SEREVENT.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
21
Respiratory: Rare reports of upper airway symptoms of laryngeal spasm, irritation, or
swelling such as stridor or choking; oropharyngeal irritation.
Cardiovascular: Hypertension, arrhythmias (including atrial fibrillation, supraventricular
tachycardia, extrasystoles).
OVERDOSAGE: The expected signs and symptoms with overdosage are those of excessive
beta-adrenergic stimulation and/or occurrence or exaggeration of any of the symptoms listed
under ADVERSE REACTIONS, e.g., seizures, angina, hypertension or hypotension, tachycardia
with rates up to 200 beats/min, arrhythmias, nervousness, headache, tremor, muscle cramps, dry
mouth, palpitation, nausea, dizziness, fatigue, malaise, and insomnia. Overdosage with
salmeterol may be expected to result in exaggeration of the pharmacologic adverse effects
associated with beta-adrenoceptor agonists, including tachycardia and/or arrhythmia, tremor,
headache, and muscle cramps. Overdosage with salmeterol can lead to clinically significant
prolongation of the QTc interval, which can produce ventricular arrhythmias. Other signs of
overdosage may include hypokalemia and hyperglycemia.
As with all sympathomimetic aerosol medications, cardiac arrest and even death may be
associated with abuse of SEREVENT Inhalation Aerosol.
Treatment consists of discontinuation of SEREVENT Inhalation Aerosol together with
appropriate symptomatic therapy. The judicious use of a cardioselective beta-receptor blocker
may be considered, bearing in mind that such medication can produce bronchospasm. There is
insufficient evidence to determine if dialysis is beneficial for overdosage of SEREVENT
Inhalation Aerosol. Cardiac monitoring is recommended in cases of overdosage.
No deaths were seen in rats at inhalation doses of 2.9 mg/kg (approximately 240 times the
maximum recommended human daily inhalation dose on a mg/m2 basis) and in dogs at
0.7 mg/kg (approximately 190 times the maximum recommended human daily inhalation dose
on a mg/m2 basis). By the oral route, no deaths occurred in mice at 150 mg/kg (approximately
6100 times the maximum recommended human daily inhalation dose on a mg/m2 basis) and in
rats at 1000 mg/kg (approximately 81,000 times the maximum recommended human daily
inhalation dose on a mg/m2 basis).
DOSAGE AND ADMINISTRATION: SEREVENT Inhalation Aerosol should be administered
by the orally inhaled route only (see PATIENT’S INSTRUCTIONS FOR USE). It is
recommended to “test spray” SEREVENT Inhalation Aerosol into the air 4 times before using
for the first time and in cases where the aerosol has not been used for a prolonged period of time
(i.e., more than 4 weeks).
Asthma: For maintenance of bronchodilatation and prevention of symptoms of asthma,
including the symptoms of nocturnal asthma, the usual dosage for patients 12 years of age and
older is 2 inhalations (42 mcg) twice daily (morning and evening, approximately 12 hours apart).
Adverse effects are more likely to occur with higher doses of salmeterol, and more frequent
administration or administration of a larger number of inhalations is not recommended.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
22
To gain full therapeutic benefit, SEREVENT Inhalation Aerosol should be administered twice
daily (morning and evening) in the treatment of reversible airway obstruction.
If a previously effective dosage regimen fails to provide the usual response, medical advice
should be sought immediately as this is often a sign of destabilization of asthma. Under these
circumstances, the therapeutic regimen should be re-evaluated and additional therapeutic options,
such as inhaled or systemic corticosteroids, should be considered. If symptoms arise in the period
between doses, an inhaled, short-acting beta2-agonist should be taken for immediate relief.
COPD: For maintenance treatment of bronchospasm associated with COPD (including chronic
bronchitis and emphysema), the usual dosage for adults is 2 inhalations (42 mcg) twice daily
(morning and evening, approximately 12 hours apart).
Prevention of Exercise-Induced Bronchospasm: Two inhalations at least 30 to
60 minutes before exercise have been shown to protect against exercise-induced bronchospasm
in many patients for up to 12 hours. Additional doses of SEREVENT Inhalation Aerosol should
not be used for 12 hours after the administration of this drug. Patients who are receiving
SEREVENT Inhalation Aerosol twice daily (morning and evening) should not use additional
SEREVENT Inhalation Aerosol for prevention of exercise-induced bronchospasm. If this dose is
not effective, other appropriate therapy for exercise-induced bronchospasm should be
considered.
Geriatric Use: In studies where geriatric patients (65 years of age or older, see
PRECAUTIONS) have been treated with SEREVENT Inhalation Aerosol, efficacy and safety of
42 mcg given twice daily (morning and evening) did not differ from that in younger patients.
Consequently, no dosage adjustment is recommended.
HOW SUPPLIED: SEREVENT Inhalation Aerosol is supplied in 13-g canisters containing 120
metered actuations in boxes of 1. Each actuation delivers 25 mcg of salmeterol base (as
salmeterol xinafoate) from the valve and 21 mcg of salmeterol base (as salmeterol xinafoate)
from the actuator. Each canister is supplied with a green plastic actuator with a teal-colored
strapcap and patient's instructions (NDC 0173-0464-00). Also available, SEREVENT Inhalation
Aerosol Refill (NDC 0173-0465-00), a 13-g canister only with patient’s instructions.
SEREVENT Inhalation Aerosol is also supplied in a pack that consists of a 6.5-g canister
containing 60 metered actuations in boxes of 1. Each actuation delivers 25 mcg of salmeterol
base (as salmeterol xinafoate) from the valve and 21 mcg of salmeterol base from the actuator (as
salmeterol xinafoate). Each canister is supplied with a green plastic actuator with a teal-colored
strapcap and patient's instructions (NDC 0173-0467-00).
For use with SEREVENT Inhalation Aerosol actuator only. The green actuator with
SEREVENT Inhalation Aerosol should not be used with other aerosol medications, and actuators
from other aerosol medications should not be used with a SEREVENT Inhalation Aerosol
canister.
The correct amount of medication in each inhalation cannot be assured after 120 actuations
from the 13-g canister or 60 actuations from the 6.5-g canister even though the canister is not
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
23
completely empty. The canister should be discarded when the labeled number of actuations has
been used.
Store between 15º and 30ºC (59º and 86ºF). Store canister with nozzle end down. Protect from
freezing temperatures and direct sunlight.
Avoid spraying in eyes. Contents under pressure. Do not puncture or incinerate. Do not store
at temperatures above 120ºF. Keep out of reach of children. As with most inhaled medications in
aerosol canisters, the therapeutic effect of this medication may decrease when the canister is
cold; for best results, the canister should be at room temperature before use. Shake well before
using.
Note: The indented statement below is required by the Federal government’s Clean Air Act for
all products containing or manufactured with chlorofluorocarbons (CFCs).
WARNING: Contains trichlorofluoromethane and dichlorodifluoromethane,
substances which harm public health and environment by destroying ozone in the upper
atmosphere.
A notice similar to the above WARNING has been placed in the patient information leaflet of
this product pursuant to EPA regulations. The patient’s warning states that the patient should
consult his or her physician if there are questions about alternatives.
GlaxoSmithKline
Research Triangle Park, NC 27709
©2003, GlaxoSmithKline. All rights reserved.
August 2003
RL-2033
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:47:09.872563
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/20236slr028_serevent_lbl.pdf', 'application_number': 20236, 'submission_type': 'SUPPL ', 'submission_number': 28}
|
12,350
|
3
SALAGEN
®
Tablets
(pilocarpine hydrochloride)
DESCRIPTION: SALAGEN
®
Tablets contain pilocarpine hydrochloride, a cholinergic agonist for oral
use. Pilocarpine hydrochloride is a hygroscopic, odorless, bitter tasting white crystal or powder, which is
soluble in water and alcohol and virtually insoluble in most non-polar solvents. Pilocarpine hydrochloride,
with a chemical name of (3S-cis)-2(3H)-Furanone, 3-ethyldihydro-4-[(1-methyl-1H-imidazol-5-yl)methyl]
monohydrochloride, has a molecular weight of 244.72.
Each SALAGEN
®
Tablet for oral administration contains 5 mg of pilocarpine hydrochloride. Inactive
ingredients in the tablet, the tablet's film coating, polishing, and branding are: carnauba wax,
hydroxypropyl methylcellulose, iron oxide, microcrystalline cellulose, stearic acid, titanium dioxide and
other ingredients.
CLINICAL PHARMACOLOGY:
Pharmacodynamics: Pilocarpine is a cholinergic parasympathomimetic agent exerting a broad
spectrum of pharmacologic effects with predominant muscarinic action. Pilocarpine, in appropriate
dosage, can increase secretion by the exocrine glands. The sweat, salivary, lacrimal, gastric, pancreatic,
and intestinal glands and the mucous cells of the respiratory tract may be stimulated. When applied
topically to the eye as a single dose it causes miosis, spasm of accommodation, and may cause a
transitory rise in intraocular pressure followed by a more persistent fall. Dose-related smooth muscle
stimulation of the intestinal tract may cause increased tone, increased motility, spasm, and tenesmus.
Bronchial smooth muscle tone may increase. The tone and motility of urinary tract, gallbladder, and
biliary duct smooth muscle may be enhanced. Pilocarpine may have paradoxical effects on the
cardiovascular system. The expected effect of a muscarinic agonist is vasodepression, but
administration of pilocarpine may produce hypertension after a brief episode of hypotension. Bradycardia
and tachycardia have both been reported with use of pilocarpine.
In a study of 12 healthy male volunteers there was a dose-related increase in unstimulated salivary flow
following single 5 and 10 mg oral doses of SALAGEN
® Tablets. This effect of pilocarpine on salivary flow
was time-related with an onset at 20 minutes and a peak effect at 1 hour with a duration of 3 to 5 hours
(See Pharmacokinetics section).
Head & Neck Cancer Patients: In a 12 week randomized, double-blind, placebo-controlled study in 207
patients (placebo, N=65; 5 mg, N=73; 10 mg, N=69), increases from baseline (means 0.072 and 0.112
mL/min, ranges -0.690 to 0.728 and -0.380 to 1.689) of whole saliva flow for the 5 mg (63%) and 10 mg
(90%) tablet, respectively, were seen 1 hour after the first dose of SALAGEN
®
Tablets. Increases in
unstimulated parotid flow were seen following the first dose
(means 0.025 and 0.046 mL/min, ranges 0 to 0.414 and -0.070 to 1.002 mL/min for the 5 and 10 mg
dose, respectively). In this study, no correlation existed between the amount of increase in salivary flow
and the degree of symptomatic relief.
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4
Sjogren's Syndrome Patients: In two 12 week randomized, double-blind, placebo-controlled studies in
629 patients (placebo, n=253; 2.5 mg, n=121; 5 mg, n=255; 5-7.5 mg, n=114), the ability of SALAGEN
®
Tablets to stimulate saliva production was assessed. In these trials using varying doses of SALAGEN
®
Tablets (2.5-7.5 mg), the rate of saliva production was plotted against time. An Area Under the Curve
(AUC) representing the total amount of saliva produced during the observation interval was calculated.
Relative to placebo, an increase in the amount of saliva being produced was observed following the first
dose of SALAGEN
®
Tablets and was maintained throughout the duration (12 weeks) of the trials in an
approximate dose response fashion (See Clinical Studies section).
Pharmacokinetics: In a multiple-dose pharmacokinetic study in male volunteers following 2 days of 5 or
10 mg of oral pilocarpine hydrochloride tablets given at 8 a.m., noontime, and 6 p.m., the mean
elimination half-life was 0.76 hours for the 5 mg dose and 1.35 hours for the 10 mg dose. Tmax values
were 1.25 hours and 0.85 hours. Cmax values were 15 ng/mL and 41 ng/mL. The AUC trapezoidal
values were 33 h(ng/mL) and 108 h(ng/mL), respectively, for the 5 and 10 mg doses following the last 6
hour dose.
Pharmacokinetics in elderly male volunteers (n = 11) were comparable to those in younger men. In five
healthy elderly female volunteers, the mean Cmax and AUC were approximately twice that of elderly
males and young normal male volunteers.
When taken with a high fat meal by 12 healthy male volunteers, there was a decrease in the rate of
absorption of pilocarpine from SALAGEN
®
Tablets. Mean Tmax‘s were 1.47 and 0.87 hours, and mean
Cmax‘s were 51.8 and 59.2 ng/mL for fed and fasted, respectively.
Limited information is available about the metabolism and elimination of pilocarpine in humans.
Inactivation of pilocarpine is thought to occur at neuronal synapses and probably in plasma. Pilocarpine
and its minimally active or inactive degradation products, including pilocarpic acid, are excreted in the
urine. Pilocarpine does not bind to human or rat plasma proteins over a concentration range of 5 to
25,000 ng/mL. The effect of pilocarpine on plasma protein binding of other drugs has not been
evaluated.
In patients with mild to moderate hepatic impairment (n=12), administration of a single 5 mg dose
resulted in a 30% decrease in total plasma clearance and a doubling of exposure (as measured by AUC).
Peak plasma levels were also increased by about 30% and half-life was increased to 2.1 hrs.
There were no significant differences in the pharmacokinetics of oral pilocarpine in volunteer subjects
(n=8) with renal insufficiency (mean creatinine clearances 25.4 mL/min; range 9.8 – 40.8 mL/min)
compared to the pharmacokinetics previously observed in normal volunteers.
Clinical Studies: Head & Neck Cancer Patients: A 12 week randomized, double-blind, placebo-
controlled study in 207 patients (142 men, 65 women) was conducted in patients whose mean age was
58.5 years with a range of 19 to 77; the racial distribution was Caucasian 95%, Black 4%, and other 1%.
In this population, a statistically significant improvement in mouth dryness occurred in the 5 and 10 mg
SALAGEN
®
Tablet treated patients compared to placebo treated patients. The 5 and 10 mg treated
patients could not be distinguished. (See Pharmacodynamics section for flow study details.)
Another 12 week, double-blind, randomized, placebo-controlled study was conducted in 162 patients
whose mean age was 57.8 years with a range of 27 to 80; the racial distribution was Caucasian 88%,
Black 10%, and other 2%. The effects of placebo were compared to 2.5 mg three times a day of
SALAGEN
®
Tablets for 4 weeks followed by adjustment to 5 mg three times a day and 10 mg three times
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5
a day. Lowering of the dose was necessary because of adverse events in 3 of 67 patients treated with 5
mg of SALAGEN
®
Tablets and in 7 of 66 patients treated with 10 mg of SALAGEN
®
Tablets. After 4
weeks of treatment, 2.5 mg of SALAGEN
® Tablets three times a day was comparable to placebo in
relieving dryness. In patients treated with 5 mg and 10 mg of SALAGEN
®
Tablets, the greatest
improvement in dryness was noted in patients with no measurable salivary flow at baseline.
In both studies, some patients noted improvement in the global assessment of their dry mouth, speaking
without liquids, and a reduced need for supplemental oral comfort agents.
In the two placebo-controlled clinical trials, the most common adverse events related to drug, and
increasing in rate as dose increases, were sweating, nausea, rhinitis, diarrhea, chills, flushing, urinary
frequency, dizziness, and asthenia. The most common adverse experience causing withdrawal from
treatment was sweating (5 mg t.i.d. <1%; 10 mg t.i.d.=12%).
Sjogren's Syndrome Patients: Two separate studies were conducted in patients with primary or
secondary Sjogren's Syndrome. In both studies, the majority of patients best fit the European criteria for
having primary Sjogren's Syndrome. [“Criteria for the Classification of Sjogren's Syndrome” (Vitali C,
Bombardieri S, Moutsopoulos HM, et al: Preliminary criteria for the classification of Sjogren's syndrome.
Arthritis Rheum 36:340-347, 1993.)]
A 12-week, randomized, double-blind, parallel-group, placebo-controlled study was conducted in 256
patients (14 men, 242 women) whose mean age was 57 years with a range of 24 to 85 years. The racial
distribution was as follows: Caucasian 91%, Black 6%, and other 3%.
The effects of placebo were compared with those of SALAGEN
®
Tablets 5 mg four times a day (20
mg/day) for 6 weeks. At 6 weeks, the patients’ dosage was increased from 5 mg SALAGEN
®
Tablets
q.i.d. to 7.5 mg q.i.d. The data collected during the first 6 weeks of the trial were evaluated for safety and
efficacy, and the data of the second 6 weeks of the trial were used to provide additional evidence of
safety.
After 6 weeks of treatment, statistically significant global improvement of dry mouth was observed
compared to placebo. “Global improvement” is defined as a score of 55 mm or more on a 100 mm visual
analogue scale in response to the question, “Please rate your present condition of dry mouth
(xerostomia) compared with your condition at the start of this study. Consider the changes to your dry
mouth and other symptoms related to your dry mouth that have occurred since you have taken this
medication.” Patients’ assessments of specific dry mouth symptoms such as severity of dry mouth,
mouth discomfort, ability to speak without water, ability to sleep without drinking water, ability to swallow
food without drinking, and a decreased use of saliva substitutes were found to be consistent with the
significant global improvement described.
Another 12 week randomized, double-blind, parallel-group, placebo-controlled study was conducted in
373 patients (16 men, 357 women) whose mean age was 55 years with a range of 21 to 84. The racial
distribution was Caucasian 80%, Oriental 14%, Black 2%, and 4% of other origin. The treatment groups
were 2.5 mg pilocarpine tablets, 5 mg SALAGEN
®
Tablets, and placebo. All treatments were
administered on a four times a day regimen.
After 12 weeks of treatment, statistically significant global improvement of dry mouth was observed at a
dose of 5 mg compared with placebo. The 2.5 mg (10mg/day) group was not significantly different than
placebo. However, a subgroup of patients with rheumatoid arthritis tended to improve in global
assessments at both the 2.5 mg q.i.d. (9 patients) and 5 mg q.i.d. (16 patients) dose (10-20 mg/day).
The clinical significance of this finding is unknown.
Patients’ assessments of specific dry mouth symptoms such as severity of dry mouth, mouth discomfort,
ability to sleep without drinking water, and decreased use of saliva substitutes were also found to be
consistent with the significant global improvement described when measured after 6 weeks and 12
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6
weeks of SALAGEN
®
Tablets use.
INDICATIONS AND USAGE: SALAGEN
®
Tablets are indicated for 1) the treatment of symptoms of dry
mouth from salivary gland hypofunction caused by radiotherapy for cancer of the head and neck; and 2)
the treatment of symptoms of dry mouth in patients with Sjogren's syndrome.
CONTRAINDICATIONS: SALAGEN
®
Tablets are contraindicated in patients with uncontrolled asthma,
known hypersensitivity to pilocarpine, and when miosis is undesirable, e.g., in acute iritis and in narrow-
angle (angle closure) glaucoma.
WARNINGS:
Cardiovascular Disease: Patients with significant cardiovascular disease may be unable to compensate
for transient changes in hemodynamics or rhythm induced by pilocarpine. Pulmonary edema has been
reported as a complication of pilocarpine toxicity from high ocular doses given for acute angle-closure
glaucoma. Pilocarpine should be administered with caution in and under close medical supervision of
patients with significant cardiovascular disease.
Ocular: Ocular formulations of pilocarpine have been reported to cause visual blurring which may result
in decreased visual acuity, especially at night and in patients with central lens changes, and to cause
impairment of depth perception. Caution should be advised while driving at night or performing
hazardous activities in reduced lighting.
Pulmonary Disease: Pilocarpine has been reported to increase airway resistance, bronchial smooth
muscle tone, and bronchial secretions. Pilocarpine hydrochloride should be administered with caution to
and under close medical supervision in patients with controlled asthma, chronic bronchitis, or chronic
obstructive pulmonary disease requiring pharmacotherapy.
PRECAUTIONS:
General: Pilocarpine toxicity is characterized by an exaggeration of its parasympathomimetic effects.
These may include: headache, visual disturbance, lacrimation, sweating, respiratory distress,
gastrointestinal spasm, nausea, vomiting, diarrhea, atrioventricular block, tachycardia, bradycardia,
hypotension, hypertension, shock, mental confusion, cardiac arrhythmia, and tremors.
The dose-related cardiovascular pharmacologic effects of pilocarpine include hypotension, hypertension,
bradycardia, and tachycardia.
Pilocarpine should be administered with caution to patients with known or suspected cholelithiasis or
biliary tract disease. Contractions of the gallbladder or biliary smooth muscle could precipitate
complications including cholecystitis, cholangitis, and biliary obstruction.
Pilocarpine may increase ureteral smooth muscle tone and could theoretically precipitate renal colic (or
"ureteral reflux"), particularly in patients with nephrolithiasis.
Cholinergic agonists may have dose-related central nervous system effects. This should be considered
when treating patients with underlying cognitive or psychiatric disturbances.
Hepatic Insufficiency: Based on decreased plasma clearance observed in patients with moderate hepatic
impairment, the starting dose in these patients should be 5 mg twice daily, followed by adjustment based
on therapeutic response and tolerability. Patients with mild hepatic insufficiency (Child-Pugh score of 5-
6) do not require dosage reductions. To date, pharmacokinetic studies in subjects with severe hepatic
impairment (Child-Pugh score of 10-15) have not been carried out. The use of pilocarpine in these
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For current labeling information, please visit https://www.fda.gov/drugsatfda
7
patients is not recommended.
Child-Pugh scoring system for Hepatic impairment
Points Scored for Increasing Abnormality
Clinical and Biochemical Measurements
1
2
3
Encephalopathy (grade)*
None
1 and 2
3 and 4
Ascites
Absent
Slight
Moderate
Bilirubin (mg. Per 100 ml.)
1-2
2-3
>3
Albumin (g. per 100 ml.)
3-5
2.8-3.5
<2.8
Prothrombin time (sec. Prolonged)
1-4
4-6
>6
For primary biliary cirrhosis:-
Bilirubin (mg. per 100 ml.)
1-4
4-10
>10
* According to grading of Trey, Burns, and Saunders (1966)
Reference: Pugh, R.N.H., Murray-Lyon, I.M., Dawson, J.L. Pietroni, M.C., Williams, R. 1973, Transection
of the Oesophagus for Bleeding Oesophageal Varices, Brit. J. Surg., 60:646-9.
Information for Patients: Patients should be informed that pilocarpine may cause visual disturbances,
especially at night, that could impair their ability to drive safely.
If a patient sweats excessively while taking pilocarpine hydrochloride and cannot drink enough liquid, the
patient should consult a physician. Dehydration may develop.
Drug Interactions: Pilocarpine should be administered with caution to patients taking beta-adrenergic
antagonists because of the possibility of conduction disturbances. Drugs with parasympathomimetic
effects administered concurrently with pilocarpine would be expected to result in additive pharmacologic
effects.
Pilocarpine might antagonize the anticholinergic effects of drugs used concomitantly. These effects
should be considered when anticholinergic properties may be contributing to the therapeutic effect of
concomitant medication (e.g., atropine, inhaled ipratropium).
While no formal drug interaction studies have been performed, the following concomitant drugs were
used in at least 10% of patients in either or both Sjogren’s efficacy studies: acetylsalicylic acid, artificial
tears, calcium, conjugated estrogens, hydroxychloroquine sulfate, ibuprofen, levothyroxine sodium,
medroxyprogesterone acetate, methotrexate, multivitamins, naproxen, omeprazole, paracetamol, and
prednisone.
Carcinogenesis, mutagenesis, impairment of fertility: Lifetime oral carcinogenicity studies were
conducted in CD-1 mice and Sprague-Dawley rats. Pilocarpine did not induce tumors in mice at any
dosage studied (up to 30mg/kg/day, which yielded a systemic exposure approximately 50 times larger
than the maximum systemic exposure observed clinically). In rats, a dosage of 18mg/kg/day, which
yielded a systemic exposure approximately 100 times larger than the maximum systemic exposure
observed clinically, resulted in a statistically significant increase in the incidence of benign
pheochromocytomas in both males and females, and a statistically significant increase in the incidence of
hepatocellular adenomas in female rats. The tumorigenicity observed in rats was observed only at a
large multiple of the maximum labeled clinical dose, and may not be relevant to clinical use.
No evidence that pilocarpine has the potential to cause genetic toxicity was obtained in a series of
studies that included: 1) bacterial assays (Salmonella and E. coli) for reverse gene mutations; 2) an in
vitro chromosome aberration assay in a Chinese hamster ovary cell line; 3) an in vivo chromosome
aberration assay (micronucleus test) in mice; and 4) a primary DNA damage assay (unscheduled DNA
synthesis) in rat hepatocyte primary cultures.
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8
Oral administration of pilocarpine to male and female rats at a dosage of 18 mg/kg/day, which yielded a
systemic exposure approximately 100 times larger than the maximum systemic exposure observed
clinically, resulted in impaired reproductive function, including reduced fertility, decreased sperm motility,
and morphologic evidence of abnormal sperm. It is unclear whether the reduction in fertility was due to
effects on male animals, female animals, or both males and females. In dogs, exposure to pilocarpine at
a dosage of 3 mg/kg/day (approximately 3 times the maximum recommended human dose when
compared on the basis of body surface area (mg/m2) estimates) for six months resulted in evidence of
impaired spermatogenesis. The data obtained in these studies suggest that pilocarpine may impair the
fertility of male and female humans. SALAGEN® Tablets should be administered to individuals who are
attempting to conceive a child only if the potential benefit justifies potential impairment of fertility.
Pregnancy: Teratogenic effects
Pregnancy Category C: Pilocarpine was associated with a reduction in the mean fetal body weight and
an increase in the incidence of skeletal variations when given to pregnant rats at a dosage of 90
mg/kg/day (approximately 26 times the maximum recommended dose for a 50 kg human when
compared on the basis of body surface area (mg/m2 ) estimates). These effects may have been
secondary to maternal toxicity. In another study, oral administration of pilocarpine to female rats during
gestation and lactation at a dosage of 36 mg/kg/day (approximately 10 times the maximum
recommended dose for a 50 kg human when compared on the basis of body surface area (mg/m2)
estimates) resulted in an increased incidence of stillbirths; decreased neonatal survival and reduced
mean body weight of pups were observed at dosages of 18 mg/kg/day (approximately 5 times the
maximum recommended dose for a 50 kg human when compared on the basis of body surface area
(mg/m2 ) estimates) and above. There are no adequate and well-controlled studies in pregnant women.
SALAGEN
®
Tablets should be used during pregnancy only if the potential benefit justifies the potential
risk to the fetus.
Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are
excreted in human milk and because of the potential for serious adverse reactions in nursing infants from
SALAGEN
®
Tablets, a decision should be made whether to discontinue nursing or to discontinue the
drug, taking into account the importance of the drug to the mother.
Pediatric Use: Safety and effectiveness in pediatric patients have not been established.
Geriatric Use: Head and Neck Cancer Patients: In the placebo-controlled clinical trials (see Clinical
Studies section) the mean age of patients was approximately 58 years (range 19 to 80).
Of these patients, 97/369 (61/217 receiving pilocarpine) were over the age of 65 years. In the healthy
volunteer studies, 15/150 subjects were over the age of 65 years. In both study populations, the adverse
events reported by those over 65 years and those 65 years and younger were comparable. Of the 15
elderly volunteers (5 women, 10 men), the 5 women had higher Cmax's and AUC's than the men. (See
Pharmacokinetics section.)
Sjogren’s Syndrome Patients: In the placebo-controlled clinical trials (see Clinical Studies section), the
mean age of patients was approximately 55 years (range 21 to 85). The adverse events reported by
those over 65 years and those 65 years and younger were comparable except for notable trends for
urinary frequency, diarrhea, and dizziness (see ADVERSE REACTIONS section).
ADVERSE REACTIONS: Head & Neck Cancer Patients: In controlled studies, 217 patients received
pilocarpine, of whom 68% were men and 32% were women. Race distribution was 91% Caucasian, 8%
Black, and 1% of other origin. Mean age was approximately 58 years. The majority of patients were
between 50 and 64 years (51%), 33% were 65 years and older and 16% were younger than 50 years of
age.
The most frequent adverse experiences associated with SALAGEN
®
Tablets were a consequence of the
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
9
expected pharmacologic effects of pilocarpine.
Adverse Event
10 mg t.i.d.
5 mg t.i.d.
Placebo t.i.d.
(30mg/day)
(15mg/day)
n=121
n=141
n=152
Sweating
68%
29%
9%
Nausea
15
6
4
Rhinitis
14
5
7
Diarrhea
7
4
5
Chills
15
3
<1
Flushing
13
8
3
Urinary Frequency
12
9
7
Dizziness
12
5
4
Asthenia
12
6
3
In addition, the following adverse events (≥3% incidence) were reported at dosages of 15-30 mg/day in
the controlled clinical trials:
Adverse Event
Pilocarpine HCl
Placebo
5-10 mg t.i.d.
t.i.d.
(15-30 mg/day)
n=212
n=152
Headache
11%
8%
Dyspepsia
7
5
Lacrimation
6
8
Edema
5
4
Abdominal Pain
4
4
Amblyopia
4
2
Vomiting
4
1
Pharyngitis
3
8
Hypertension
3
1
The following events were reported with treated head and neck cancer patients at incidences of 1% to
2% at dosages of 7.5 to 30 mg/day: abnormal vision, conjunctivitis, dysphagia, epistaxis, myalgias,
pruritus, rash, sinusitis, tachycardia, taste perversion, tremor, voice alteration.
The following events were reported rarely in treated head and neck cancer patients (<1%): Causal
relation is unknown.
Body as a whole: body odor, hypothermia, mucous membrane abnormality
Cardiovascular: bradycardia, ECG abnormality, palpitations, syncope
Digestive: anorexia, increased appetite, esophagitis, gastrointestinal disorder, tongue disorder
Hematologic: leukopenia, lymphadenopathy
Nervous: anxiety, confusion, depression, abnormal dreams, hyperkinesia, hypesthesia, nervousness,
paresthesias, speech disorder, twitching
Respiratory: increased sputum, stridor, yawning
Skin: seborrhea
Special senses: deafness, eye pain, glaucoma
Urogenital: dysuria, metrorrhagia, urinary impairment
In long-term treatment were two patients with underlying cardiovascular disease of whom one
experienced a myocardial infarct and another an episode of syncope. The association with drug is
uncertain.
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10
Sjogren's Syndrome Patients: In controlled studies, 376 patients received pilocarpine, of whom 5% were
men and 95% were women. Race distribution was 84% Caucasian, 9% Oriental, 3% Black, and 4% of
other origin. Mean age was 55 years. The majority of patients were between 40 and 69 years (70%),
16% were 70 years and older and 14% were younger than 40 years of age. Of these patients, 161/629
(89/376 receiving pilocarpine) were over the age of 65 years. The adverse events reported by those over
65 years and those 65 years and younger were comparable except for notable trends for urinary
frequency, diarrhea, and dizziness. The incidences of urinary frequency and diarrhea in the elderly were
about double those in the non-elderly. The incidence of dizziness was about three times as high in the
elderly as in the non-elderly. These adverse experiences were not considered to be serious. In the 2
placebo-controlled studies, the most common adverse events related to drug use were sweating, urinary
frequency, chills, and vasodilatation (flushing). The most commonly reported reason for patient
discontinuation of treatment was sweating. Expected pharmacologic effects of pilocarpine include the
following adverse experiences associated with SALAGEN
®
Tablets:
Adverse Event
5 mg q.i.d.
Placebo q.i.d.
(20 mg/day)
n=255
n=253
Sweating
40%
7%
Urinary Frequency
10
4
Nausea
9
9
Flushing
9
2
Rhinitis
7
8
Diarrhea
6
7
Chills
4
2
Increased Salivation
3
0
Asthenia
2
2
In addition, the following adverse events (≥3% incidence) were reported at dosing of 20 mg/day in the
controlled clinical trials:
Adverse Event
Pilocarpine HCl
Placebo
5 mg q.i.d.
q.i.d.
(20 mg/day)
n=255
n=253
Headache
13%
19%
Flu Syndrome
9
9
Dyspepsia
7
7
Dizziness
6
7
Pain
4
2
Sinusitis
4
5
Abdominal Pain
3
4
Vomiting
3
1
Pharyngitis
2
5
Rash
2
3
Infection
2
6
The following events were reported in Sjogren's patients at incidences of 1% to 2% at dosing of 20
mg/day: accidental injury, allergic reaction, back pain, blurred vision, constipation, increased cough,
edema, epistaxis, face edema, fever, flatulence, glossitis, lab test abnormalities, including chemistry,
hematology, and urinalysis, myalgia, palpitation, pruritus, somnolence, stomatitis, tachycardia, tinnitus,
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11
urinary incontinence, urinary tract infection, vaginitis.
The following events were reported rarely in treated Sjogren's patients (<1%) at dosing of 10-30 mg/day:
Causal relation is unknown.
Body as a whole: chest pain, cyst, death, moniliasis, neck pain, neck rigidity, photosensitivity reaction
Cardiovascular: angina pectoris, arrhythmia, ECG abnormality, hypotension, hypertension, intracranial
hemorrhage, migraine, myocardial infarction
Digestive: anorexia, bilirubinemia, cholelithiasis, colitis, dry mouth, eructation, gastritis, gastroenteritis,
gastrointestinal disorder, gingivitis, hepatitis, abnormal liver function tests, melena, nausea &
vomiting, pancreatitis, parotid gland enlargement, salivary gland enlargement, sputum increased,
taste loss, tongue disorder, tooth disorder
Hematologic: hematuria, lymphadenopathy, abnormal platelets, thrombocythemia, thrombocytopenia,
thrombosis, abnormal WBC
Metabolic and Nutritional: peripheral edema, hypoglycemia
Musculoskeletal: arthralgia, arthritis, bone disorder, spontaneous bone fracture, pathological fracture,
myasthenia, tendon disorder, tenosynovitis
Nervous: aphasia, confusion, depression, abnormal dreams, emotional lability, hyperkinesia,
hypesthesia, insomnia, leg cramps, nervousness, paresthesias, abnormal thinking, tremor
Respiratory: bronchitis, dyspnea, hiccup, laryngismus, laryngitis, pneumonia, viral infection, voice
alteration
Skin: alopecia, contact dermatitis, dry skin, eczema, erythema nodosum, exfoliative dermatitis, herpes
simplex, skin ulcer, vesiculobullous rash
Special senses: cataract, conjunctivitis, dry eyes, ear disorder, ear pain, eye disorder, eye hemorrhage,
glaucoma, lacrimation disorder, retinal disorder, taste perversion, abnormal vision
Urogenital: breast pain, dysuria, mastitis, menorrhagia, metrorrhagia, ovarian disorder, pyuria,
salpingitis, urethral pain, urinary urgency, vaginal hemorrhage, vaginal moniliasis
The following adverse experiences have been reported rarely with ocular pilocarpine: A-V block,
agitation, ciliary congestion, confusion, delusion, depression, dermatitis, middle ear disturbance, eyelid
twitching, malignant glaucoma, iris cysts, macular hole, shock, and visual hallucination.
MANAGEMENT OF OVERDOSE: Fatal overdosage with pilocarpine has been reported in the scientific
literature at doses presumed to be greater than 100 mg in two hospitalized patients. 100 mg of
pilocarpine is considered potentially fatal. Overdosage should be treated with atropine titration (0.5 mg to
1.0 mg given subcutaneously or intravenously) and supportive measures to maintain respiration and
circulation. Epinephrine (0.3 mg to 1.0 mg, subcutaneously or intramuscularly) may also be of value in
the presence of severe cardiovascular depression or bronchoconstriction. It is not known if pilocarpine is
dialyzable.
DOSAGE AND ADMINISTRATION:
Regardless of the indication, the starting dose in patients with moderate hepatic impairment should be 5
mg twice daily, followed by adjustment based on therapeutic response and tolerability. Patients with mild
hepatic insufficiency do not require dosage reductions. The use of pilocarpine in patients with severe
hepatic insufficiency is not recommended. If needed, refer to the Hepatic Insufficiency subsection of the
Precautions section of this label for definitions of mild, moderate and severe hepatic impairment.
Head & Neck Cancer Patients:
The recommended initial dose of SALAGEN
®
Tablets is one tablet (5 mg) taken three times a day.
Dosage should be adjusted according to therapeutic response and tolerability. The usual dosage range
is 3-6 tablets or 15-30 mg per day. (Not to exceed 2 tablets per dose.) Although early improvement may
be realized, at least 12 weeks of uninterrupted therapy with SALAGEN
®
Tablets may be necessary to
This label may not be the latest approved by FDA.
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12
assess whether a beneficial response will be achieved. The incidence of the most common adverse
events increases with dose. The lowest dose that is tolerated and effective should be used for
maintenance.
Sjogren's Syndrome Patients:
The recommended dose of SALAGEN
®
Tablets is one tablet (5 mg) taken four times a day. Efficacy was
established by 6 weeks of use.
HOW SUPPLIED:
SALAGEN
®
Tablets, 5 mg, are white, film coated, round tablets, coded MGI 705. Each tablet contains 5
mg pilocarpine hydrochloride. They are supplied as follows:
NDC 58063-705-10 bottles of 100
Store at Controlled Room Temperature 15°-30°C (59°-86°F).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
---------------------------------------------------------------------------------------------------------------------
This is a representation of an electronic record that was signed electronically and
this page is the manifestation of the electronic signature.
---------------------------------------------------------------------------------------------------------------------
/s/
---------------------
Markham Luke
6/10/02 09:09:18 AM
Acting for Dr. Jonathan Wilkin
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For current labeling information, please visit https://www.fda.gov/drugsatfda
|
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2025-02-12T13:47:10.062316
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2002/20237s8s9lbl.pdf', 'application_number': 20237, 'submission_type': 'SUPPL ', 'submission_number': 9}
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NDA 20-237/S012
Page 3
SALAGEN
®
Tablets
(pilocarpine hydrochloride)
DESCRIPTION: SALAGEN
®
Tablets contain pilocarpine hydrochloride, a cholinergic agonist for
oral use. Pilocarpine hydrochloride is a hygroscopic, odorless, bitter tasting white crystal or
powder which is soluble in water and alcohol and virtually insoluble in most non-polar solvents.
Pilocarpine hydrochloride, with a chemical name of (3S-cis)-2(3H)-Furanone, 3-ethyldihydro-4-
[(1-methyl-1H-imidazol-5-yl)methyl] monohydrochloride, has a molecular weight of 244.72.
Each 5 mg SALAGEN
®
Tablet for oral administration contains 5 mg of pilocarpine hydrochloride.
Inactive ingredients in the tablet, the tablet's film coating, and polishing are: carnauba wax,
hydroxypropyl methylcellulose, microcrystalline cellulose, stearic acid, titanium dioxide and other
ingredients.
Each 7.5 mg SALAGEN
®
Tablet for oral administration contains 7.5 mg of pilocarpine
hydrochloride. Inactive ingredients in the tablet, the tablet's film coating, and polishing are:
carnauba wax, hydroxypropyl methylcellulose, microcrystalline cellulose, stearic acid, titanium
dioxide, FD&C blue # 2 aluminum lake, and other ingredients.
CLINICAL PHARMACOLOGY:
Pharmacodynamics: Pilocarpine is a cholinergic parasympathomimetic agent exerting a broad
spectrum of pharmacologic effects with predominant muscarinic action. Pilocarpine, in
appropriate dosage, can increase secretion by the exocrine glands. The sweat, salivary, lacrimal,
gastric, pancreatic, and intestinal glands and the mucous cells of the respiratory tract may be
stimulated. When applied topically to the eye as a single dose it causes miosis, spasm of
accommodation, and may cause a transitory rise in intraocular pressure followed by a more
persistent fall. Dose-related smooth muscle stimulation of the intestinal tract may cause
increased tone, increased motility, spasm, and tenesmus. Bronchial smooth muscle tone may
increase. The tone and motility of urinary tract, gallbladder, and biliary duct smooth muscle may
be enhanced. Pilocarpine may have paradoxical effects on the cardiovascular system. The
expected effect of a muscarinic agonist is vasodepression, but administration of pilocarpine may
produce hypertension after a brief episode of hypotension. Bradycardia and tachycardia have
both been reported with use of pilocarpine.
In a study of 12 healthy male volunteers there was a dose-related increase in unstimulated
salivary flow following single 5 and 10 mg oral doses of SALAGEN
® Tablets. This effect of
pilocarpine on salivary flow was time-related with an onset at 20 minutes and a peak effect at 1
hour with a duration of 3 to 5 hours (See Pharmacokinetics section).
Head & Neck Cancer Patients: In a 12 week randomized, double-blind, placebo-controlled study
in 207 patients (placebo, N=65; 5 mg, N=73; 10 mg, N=69), increases from baseline (means
0.072 and 0.112 mL/min, ranges -0.690 to 0.728 and -0.380 to 1.689) of whole saliva flow for the
5 mg (63%) and 10 mg (90%) tablet, respectively, were seen 1 hour after the first dose of
SALAGEN
®
Tablets. Increases in unstimulated parotid flow were seen following the first dose
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NDA 20-237/S012
Page 4
(means 0.025 and 0.046 mL/min, ranges 0 to 0.414 and -0.070 to 1.002 mL/min for the 5 and 10
mg dose, respectively). In this study, no correlation existed between the amount of increase in
salivary flow and the degree of symptomatic relief.
Sjogren's Syndrome Patients: In two 12 week randomized, double-blind, placebo-controlled
studies in 629 patients (placebo, n=253; 2.5 mg, n=121; 5 mg, n=255; 5-7.5 mg, n=114), the
ability of SALAGEN
®
Tablets to stimulate saliva production was assessed. In these trials using
varying doses of SALAGEN
®
Tablets (2.5-7.5 mg), the rate of saliva production was plotted
against time. An Area Under the Curve (AUC) representing the total amount of saliva produced
during the observation interval was calculated. Relative to placebo, an increase in the amount of
saliva being produced was observed following the first dose of SALAGEN
®
Tablets and was
maintained throughout the duration (12 weeks) of the trials in an approximate dose response
fashion (See Clinical Studies section).
Pharmacokinetics: In a multiple-dose pharmacokinetic study in male volunteers following 2
days of 5 or 10 mg of oral pilocarpine hydrochloride tablets given at 8 a.m., noontime, and 6 p.m.,
the mean elimination half-life was 0.76 hours for the 5 mg dose and 1.35 hours for the 10 mg
dose. Tmax values were 1.25 hours and 0.85 hours. Cmax values were 15 ng/mL and 41
ng/mL. The AUC trapezoidal values were 33 h(ng/mL) and 108 h(ng/mL), respectively, for the 5
and 10 mg doses following the last 6 hour dose.
Pharmacokinetics in elderly male volunteers (n = 11) were comparable to those in younger men.
In five healthy elderly female volunteers, the mean Cmax and AUC were approximately twice that
of elderly males and young normal male volunteers.
When taken with a high fat meal by 12 healthy male volunteers, there was a decrease in the rate
of absorption of pilocarpine from SALAGEN
®
Tablets. Mean Tmax's were 1.47 and 0.87 hours,
and mean Cmax's were 51.8 and 59.2 ng/mL for fed and fasted, respectively.
Limited information is available about the metabolism and elimination of pilocarpine in humans.
Inactivation of pilocarpine is thought to occur at neuronal synapses and probably in plasma.
Pilocarpine and its minimally active or inactive degradation products, including pilocarpic acid, are
excreted in the urine. Pilocarpine does not bind to human or rat plasma proteins over a
concentration range of 5 to 25,000 ng/mL. The effect of pilocarpine on plasma protein binding of
other drugs has not been evaluated.
In patients with mild to moderate hepatic impairment (n=12), administration of a single 5 mg dose
resulted in a 30% decrease in total plasma clearance and a doubling of exposure (as measured
by AUC). Peak plasma levels were also increased by about 30% and half-life was increased to
2.1 hrs.
There were no significant differences in the pharmacokinetics of oral pilocarpine in volunteer
subjects (n=8) with renal insufficiency (mean creatinine clearances 25.4 mL/min; range 9.8 – 40.8
mL/min) compared to the pharmacokinetics previously observed in normal volunteers.
Clinical Studies: Head & Neck Cancer Patients: A 12 week randomized, double-blind, placebo-
controlled study in 207 patients (142 men, 65 women) was conducted in patients whose mean
age was 58.5 years with a range of 19 to 77; the racial distribution was Caucasian 95%, Black
4%, and other 1%. In this population, a statistically significant improvement in mouth dryness
occurred in the 5 and 10 mg SALAGEN
®
Tablet treated patients compared to placebo treated
patients. The 5 and 10 mg treated patients could not be distinguished. (See Pharmacodynamics
section for flow study details.)
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NDA 20-237/S012
Page 5
Another 12 week, double-blind, randomized, placebo-controlled study was conducted in 162
patients whose mean age was 57.8 years with a range of 27 to 80; the racial distribution was
Caucasian 88%, Black 10%, and other 2%. The effects of placebo were compared to 2.5 mg
three times a day of SALAGEN
®
Tablets for 4 weeks followed by adjustment to 5 mg three times
a day and 10 mg three times a day. Lowering of the dose was necessary because of adverse
events in 3 of 67 patients treated with 5 mg of SALAGEN
®
Tablets and in 7 of 66 patients treated
with 10 mg of SALAGEN
®
Tablets. After 4 weeks of treatment, 2.5 mg of SALAGEN
® Tablets
three times a day was comparable to placebo in relieving dryness. In patients treated with 5 mg
and 10 mg of SALAGEN
®
Tablets, the greatest improvement in dryness was noted in patients
with no measurable salivary flow at baseline.
In both studies, some patients noted improvement in the global assessment of their dry mouth,
speaking without liquids, and a reduced need for supplemental oral comfort agents.
In the two placebo-controlled clinical trials, the most common adverse events related to drug, and
increasing in rate as dose increases, were sweating, nausea, rhinitis, diarrhea, chills, flushing,
urinary frequency, dizziness, and asthenia. The most common adverse experience causing
withdrawal from treatment was sweating (5 mg t.i.d. <1%; 10 mg t.i.d.=12%).
Sjogren's Syndrome Patients: Two separate studies were conducted in patients with primary or
secondary Sjogren's Syndrome. In both studies, the majority of patients best fit the European
criteria for having primary Sjogren's Syndrome. [“Criteria for the Classification of Sjogren's
Syndrome” (Vitali C, Bombardieri S, Moutsopoulos HM, et al: Preliminary criteria for the
classification of Sjogren's syndrome. Arthritis Rheum 36:340-347, 1993.)]
A 12-week, randomized, double-blind, parallel-group, placebo-controlled study was conducted in
256 patients (14 men, 242 women) whose mean age was 57 years with a range of 24 to 85
years. The racial distribution was as follows: Caucasian 91%, Black 6%, and other 3%.
The effects of placebo were compared with those of SALAGEN
®
Tablets 5 mg four times a day
(20 mg/day) for 6 weeks. At 6 weeks, the patients’ dosage was increased from 5 mg SALAGEN
®
Tablets q.i.d. to 7.5 mg q.i.d. The data collected during the first 6 weeks of the trial were
evaluated for safety and efficacy, and the data of the second 6 weeks of the trial were used to
provide additional evidence of safety.
After 6 weeks of treatment, statistically significant global improvement of dry mouth was observed
compared to placebo. “Global improvement” is defined as a score of 55 mm or more on a 100
mm visual analogue scale in response to the question, “Please rate your present condition of dry
mouth (xerostomia) compared with your condition at the start of this study. Consider the changes
to your dry mouth and other symptoms related to your dry mouth that have occurred since you
have taken this medication.” Patients’ assessments of specific dry mouth symptoms such as
severity of dry mouth, mouth discomfort, ability to speak without water, ability to sleep without
drinking water, ability to swallow food without drinking, and a decreased use of saliva substitutes
were found to be consistent with the significant global improvement described.
Another 12 week randomized, double-blind, parallel-group, placebo-controlled study was
conducted in 373 patients (16 men, 357 women) whose mean age was 55 years with a range of
21 to 84. The racial distribution was Caucasian 80%, Oriental 14%, Black 2%, and 4% of other
origin. The treatment groups were 2.5 mg pilocarpine tablets, 5 mg SALAGEN
®
Tablets, and
placebo. All treatments were administered on a four times a day regimen.
After 12 weeks of treatment, statistically significant global improvement of dry mouth was
observed at a dose of 5 mg compared with placebo. The 2.5 mg (10mg/day) group was not
significantly different than placebo. However, a subgroup of patients with rheumatoid arthritis
tended to improve in global assessments at both the 2.5 mg q.i.d. (9 patients) and 5 mg q.i.d. (16
patients) dose (10-20 mg/day). The clinical significance of this finding is unknown.
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NDA 20-237/S012
Page 6
Patients’ assessments of specific dry mouth symptoms such as severity of dry mouth, mouth
discomfort, ability to sleep without drinking water, and decreased use of saliva substitutes were
also found to be consistent with the significant global improvement described when measured
after 6 weeks and 12 weeks of SALAGEN
®
Tablets use.
INDICATIONS AND USAGE: SALAGEN
®
Tablets are indicated for 1) the treatment of symptoms
of dry mouth from salivary gland hypofunction caused by radiotherapy for cancer of the head and
neck; and 2) the treatment of symptoms of dry mouth in patients with Sjogren's syndrome.
CONTRAINDICATIONS: SALAGEN
®
Tablets are contraindicated in patients with uncontrolled
asthma, known hypersensitivity to pilocarpine, and when miosis is undesirable, e.g., in acute iritis
and in narrow-angle (angle closure) glaucoma.
WARNINGS:
Cardiovascular Disease: Patients with significant cardiovascular disease may be unable to
compensate for transient changes in hemodynamics or rhythm induced by pilocarpine.
Pulmonary edema has been reported as a complication of pilocarpine toxicity from high ocular
doses given for acute angle-closure glaucoma. Pilocarpine should be administered with caution
in and under close medical supervision of patients with significant cardiovascular disease.
Ocular: Ocular formulations of pilocarpine have been reported to cause visual blurring which
may result in decreased visual acuity, especially at night and in patients with central lens
changes, and to cause impairment of depth perception. Caution should be advised while driving
at night or performing hazardous activities in reduced lighting.
Pulmonary Disease: Pilocarpine has been reported to increase airway resistance, bronchial
smooth muscle tone, and bronchial secretions. Pilocarpine hydrochloride should be administered
with caution to and under close medical supervision in patients with controlled asthma, chronic
bronchitis, or chronic obstructive pulmonary disease requiring pharmacotherapy.
PRECAUTIONS:
General: Pilocarpine toxicity is characterized by an exaggeration of its parasympathomimetic
effects. These may include: headache, visual disturbance, lacrimation, sweating, respiratory
distress, gastrointestinal spasm, nausea, vomiting, diarrhea, atrioventricular block, tachycardia,
bradycardia, hypotension, hypertension, shock, mental confusion, cardiac arrhythmia, and
tremors.
The dose-related cardiovascular pharmacologic effects of pilocarpine include hypotension,
hypertension, bradycardia, and tachycardia.
Pilocarpine should be administered with caution to patients with known or suspected cholelithiasis
or biliary tract disease. Contractions of the gallbladder or biliary smooth muscle could precipitate
complications including cholecystitis, cholangitis, and biliary obstruction.
Pilocarpine may increase ureteral smooth muscle tone and could theoretically precipitate renal
colic (or "ureteral reflux"), particularly in patients with nephrolithiasis.
Cholinergic agonists may have dose-related central nervous system effects. This should be
considered when treating patients with underlying cognitive or psychiatric disturbances.
Hepatic Insufficiency: Based on decreased plasma clearance observed in patients with moderate
hepatic impairment, the starting dose in these patients should be 5 mg twice daily, followed by
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NDA 20-237/S012
Page 7
adjustment based on therapeutic response and tolerability. Patients with mild hepatic
insufficiency (Child-Pugh score of 5-6) do not require dosage reductions. To date,
pharmacokinetic studies in subjects with severe hepatic impairment (Child-Pugh score of 10-15)
have not been carried out. The use of pilocarpine in these patients is not recommended.
Child-Pugh scoring system for Hepatic impairment
Points Scored for Increasing Abnormality
Clinical and Biochemical Measurements
1
2
3
Encephalopathy (grade)*
None
1 and 2
3 and 4
Ascites
Absent
Slight
Moderate
Bilirubin (mg. Per 100 ml.)
1-2
2-3
>3
Albumin (g. per 100 ml.)
3-5
2.8-3.5
<2.8
Prothrombin time (sec. Prolonged)
1-4
4-6
>6
For primary biliary cirrhosis:-
Bilirubin (mg. per 100 ml.)
1-4
4-10
>10
*According to grading of Trey, Burns, and Saunders (1966)
Reference: Pugh, R.N.H., Murray-Lyon, I.M., Dawson, J.L. Pietroni, M.C., Williams, R. 1973,
Transection of the Oesophagus for Bleeding Oesophageal Varices, Brit. J. Surg., 60:646-9.
Information for Patients: Patients should be informed that pilocarpine may cause visual
disturbances, especially at night, that could impair their ability to drive safely.
If a patient sweats excessively while taking pilocarpine hydrochloride and cannot drink enough
liquid, the patient should consult a physician. Dehydration may develop.
Drug Interactions: Pilocarpine should be administered with caution to patients taking beta
adrenergic antagonists because of the possibility of conduction disturbances. Drugs with
parasympathomimetic effects administered concurrently with pilocarpine would be expected to
result in additive pharmacologic effects. Pilocarpine might antagonize the anticholinergic effects
of drugs used concomitantly. These effects should be considered when anticholinergic properties
may be contributing to the therapeutic effect of concomitant medication (e.g., atropine, inhaled
ipratropium).
While no formal drug interaction studies have been performed, the following concomitant drugs
were used in at least 10% of patients in either or both Sjogren’s efficacy studies: acetylsalicylic
acid, artificial tears, calcium, conjugated estrogens, hydroxychloroquine sulfate, ibuprofen,
levothyroxine sodium, medroxyprogesterone acetate, methotrexate, multivitamins, naproxen,
omeprazole, paracetamol, and prednisone.
Carcinogenesis, mutagenesis, impairment of fertility: Lifetime oral carcinogenicity studies
were conducted in CD-1 mice and Sprague-Dawley rats. Pilocarpine did not induce tumors in
mice at any dosage studied (up to 30mg/kg/day, which yielded a systemic exposure
approximately 50 times larger than the maximum systemic exposure observed clinically). In rats,
a dosage of 18mg/kg/day, which yielded a systemic exposure approximately 100 times larger
than the maximum systemic exposure observed clinically, resulted in a statistically significant
increase in the incidence of benign pheochromocytomas in both males and females, and a
statistically significant increase in the incidence of hepatocellular adenomas in female rats. The
tumorigenicity observed in rats was observed only at a large multiple of the maximum labeled
clinical dose, and may not be relevant to clinical use.
No evidence that pilocarpine has the potential to cause genetic toxicity was obtained in a series
of studies that included: 1) bacterial assays (Salmonella and E. coli) for reverse gene mutations;
2) an in vitro chromosome aberration assay in a Chinese hamster ovary cell line; 3) an in vivo
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NDA 20-237/S012
Page 8
chromosome aberration assay (micronucleus test) in mice; and 4) a primary DNA damage assay
(unscheduled DNA synthesis) in rat hepatocyte primary cultures.
Oral administration of pilocarpine to male and female rats at a dosage of 18 mg/kg/day, which
yielded a systemic exposure approximately 100 times larger than the maximum systemic
exposure observed clinically, resulted in impaired reproductive function, including reduced fertility,
decreased sperm motility, and morphologic evidence of abnormal sperm. It is unclear whether
the reduction in fertility was due to effects on male animals, female animals, or both males and
females. In dogs, exposure to pilocarpine at a dosage of 3 mg/kg/day (approximately 3 times the
maximum recommended human dose when compared on the basis of body surface area (mg/m2)
estimates) for six months resulted in evidence of impaired spermatogenesis. The data obtained
in these studies suggest that pilocarpine may impair the fertility of male and female humans.
SALAGEN® Tablets should be administered to individuals who are attempting to conceive a child
only if the potential benefit justifies potential impairment of fertility.
Pregnancy: Teratogenic effects
Pregnancy Category C: Pilocarpine was associated with a reduction in the mean fetal body
weight and an increase in the incidence of skeletal variations when given to pregnant rats at a
dosage of 90 mg/kg/day (approximately 26 times the maximum recommended dose for a 50 kg
human when compared on the basis of body surface area (mg/m2 ) estimates). These effects
may have been secondary to maternal toxicity. In another study, oral administration of pilocarpine
to female rats during gestation and lactation at a dosage of 36 mg/kg/day (approximately 10 times
the maximum recommended dose for a 50 kg human when compared on the basis of body
surface area (mg/m2 ) estimates) resulted in an increased incidence of stillbirths; decreased
neonatal survival and reduced mean body weight of pups were observed at dosages of 18
mg/kg/day (approximately 5 times the maximum recommended dose for a 50 kg human when
compared on the basis of body surface area (mg/m2 ) estimates) and above. There are no
adequate and well-controlled studies in pregnant women. SALAGEN
®
Tablets should be used
during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many
drugs are excreted in human milk and because of the potential for serious adverse reactions in
nursing infants from SALAGEN
®
Tablets, a decision should be made whether to discontinue
nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use: Safety and effectiveness in pediatric patients have not been established.
Geriatric Use: Head and Neck Cancer Patients: In the placebo-controlled clinical trials (see
Clinical Studies section) the mean age of patients was approximately 58 years (range 19 to 80).
Of these patients, 97/369 (61/217 receiving pilocarpine) were over the age of 65 years. In the
healthy volunteer studies, 15/150 subjects were over the age of 65 years. In both study
populations, the adverse events reported by those over 65 years and those 65 years and younger
were comparable. Of the 15 elderly volunteers (5 women, 10 men), the 5 women had higher
Cmax's and AUC's than the men. (See Pharmacokinetics section.)
Sjogren’s Syndrome Patients: In the placebo-controlled clinical trials (see Clinical Studies
section), the mean age of patients was approximately 55 years (range 21 to 85 ). The adverse
events reported by those over 65 years and those 65 years and younger were comparable except
for notable trends for urinary frequency, diarrhea, and dizziness (see ADVERSE REACTIONS
section).
ADVERSE REACTIONS: Head & Neck Cancer Patients: In controlled studies, 217 patients
received pilocarpine, of whom 68% were men and 32% were women. Race distribution was 91%
Caucasian, 8% Black, and 1% of other origin. Mean age was approximately 58 years. The
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NDA 20-237/S012
Page 9
majority of patients were between 50 and 64 years (51%), 33% were 65 years and older and 16%
were younger than 50 years of age.
The most frequent adverse experiences associated with SALAGEN
®
Tablets were a
consequence of the expected pharmacologic effects of pilocarpine.
Adverse Event
10 mg t.i.d.
5 mg t.i.d.
Placebo
(30mg/day)
(15mg/day)
(t.i.d.)
n=121
n=141
n=152
Sweating
68%
29%
9%
Nausea
15
6
4
Rhinitis
14
5
7
Diarrhea
7
4
5
Chills
15
3
<1
Flushing
13
8
3
Urinary Frequency
12
9
7
Dizziness
12
5
4
Asthenia
12
6
3
In addition, the following adverse events (≥3% incidence) were reported at dosages of 15-30
mg/day in the controlled clinical trials:
Adverse Event
Pilocarpine HCl
Placebo
5-10 mg t.i.d.
(15-30 mg/day)
(t.i.d.)
n=212
n=152
Headache
11%
8%
Dyspepsia
7
5
Lacrimation
6
8
Edema
5
4
Abdominal Pain
4
4
Amblyopia
4
2
Vomiting
4
1
Pharyngitis
3
8
Hypertension
3
1
The following events were reported with treated head and neck cancer patients at incidences of
1% to 2% at dosages of 7.5 to 30 mg/day: abnormal vision, conjunctivitis, dysphagia, epistaxis,
myalgias, pruritus, rash, sinusitis, tachycardia, taste perversion, tremor, voice alteration.
The following events were reported rarely in treated head and neck cancer patients (<1%):
Causal relation is unknown.
Body as a whole: body odor, hypothermia, mucous membrane abnormality
Cardiovascular: bradycardia, ECG abnormality, palpitations, syncope
Digestive: anorexia, increased appetite, esophagitis, gastrointestinal disorder, tongue disorder
Hematologic: leukopenia, lymphadenopathy
Nervous: anxiety, confusion, depression, abnormal dreams, hyperkinesia, hypesthesia,
nervousness, paresthesias, speech disorder, twitching
Respiratory: increased sputum, stridor, yawning
Skin: seborrhea
Special senses: deafness, eye pain, glaucoma
Urogenital: dysuria, metrorrhagia, urinary impairment
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NDA 20-237/S012
Page 10
In long-term treatment were two patients with underlying cardiovascular disease of whom one
experienced a myocardial infarct and another an episode of syncope. The association with drug
is uncertain.
Sjogren's Syndrome Patients: In controlled studies, 376 patients received pilocarpine, of whom
5% were men and 95% were women. Race distribution was 84% Caucasian, 9% Oriental, 3%
Black, and 4% of other origin. Mean age was 55 years. The majority of patients were between
40 and 69 years (70%), 16% were 70 years and older and 14% were younger than 40 years of
age. Of these patients, 161/629 (89/376 receiving pilocarpine) were over the age of 65 years.
The adverse events reported by those over 65 years and those 65 years and younger were
comparable except for notable trends for urinary frequency, diarrhea, and dizziness. The
incidences of urinary frequency and diarrhea in the elderly were about double those in the non-
elderly. The incidence of dizziness was about three times as high in the elderly as in the non-
elderly. These adverse experiences were not considered to be serious. In the 2 placebo-
controlled studies, the most common adverse events related to drug use were sweating, urinary
frequency, chills, and vasodilatation (flushing). The most commonly reported reason for patient
discontinuation of treatment was sweating. Expected pharmacologic effects of pilocarpine
include the following adverse experiences associated with SALAGEN
®
Tablets:
Adverse Event
5 mg q.i.d.
Placebo
(20 mg/day)
(q.i.d.)
n=255
n=253
Sweating
40%
7%
Urinary Frequency
10
4
Nausea
9
9
Flushing
9
2
Rhinitis
7
8
Diarrhea
6
7
Chills
4
2
Increased Salivation
3
0
Asthenia
2
2
In addition, the following adverse events (≥3% incidence) were reported at dosages of 15-30 mg/day in the
controlled clinical trials:
Adverse Event
Pilocarpine HCl
Placebo
5 mg q.i.d.
(20 mg/day)
(q.i.d.)
n=255
n=253
Headache
13%
19%
Flu Syndrome
9
9
Dyspepsia
7
7
Dizziness
6
7
Pain
4
2
Sinusitis
4
5
Abdominal Pain
3
4
Vomiting
3
1
Pharyngitis
2
5
Rash
2
3
Infection
2
6
The following events were reported with treated head and neck cancer patients at incidences of
1% to 2% at dosages of 7.5 to 30 mg/day: abnormal vision, conjunctivitis, dysphagia, epistaxis,
myalgias, pruritus, rash, sinusitis, tachycardia, taste perversion, tremor, voice alteration.
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NDA 20-237/S012
Page 11
The following events were reported rarely in treated Sjogren's patients (<1%) at dosing of 10-30
mg/day: Causal relation is unknown.
Body as a whole: chest pain, cyst, death, moniliasis, neck pain, neck rigidity, photosensitivity
reaction
Cardiovascular: angina pectoris, arrhythmia, ECG abnormality, hypotension, hypertension,
intracranial hemorrhage, migraine, myocardial infarction
Digestive: anorexia, bilirubinemia, cholelithiasis, colitis, dry mouth, eructation, gastritis,
gastroenteritis, gastrointestinal disorder, gingivitis, hepatitis, abnormal liver function tests,
melena, nausea & vomiting, pancreatitis, parotid gland enlargement, salivary gland
enlargement, sputum increased, taste loss, tongue disorder, tooth disorder
Hematologic: hematuria, lymphadenopathy, abnormal platelets, thrombocythemia,
thrombocytopenia, thrombosis, abnormal WBC
Metabolic and Nutritional: peripheral edema, hypoglycemia
Musculoskeletal: arthralgia, arthritis, bone disorder, spontaneous bone fracture, pathological
fracture, myasthenia, tendon disorder, tenosynovitis
Nervous: aphasia, confusion, depression, abnormal dreams, emotional lability, hyperkinesia,
hypesthesia, insomnia, leg cramps, nervousness, paresthesias, abnormal thinking,
tremor
Respiratory: bronchitis, dyspnea, hiccup, laryngismus, laryngitis, pneumonia, viral infection, voice
alteration
Skin: alopecia, contact dermatitis, dry skin, eczema, erythema nodosum, exfoliative dermatitis,
herpes simplex, skin ulcer, vesiculobullous rash
Special senses: cataract, conjunctivitis, dry eyes, ear disorder, ear pain, eye disorder, eye
hemorrhage, glaucoma, lacrimation disorder, retinal disorder, taste perversion, abnormal
vision
Urogenital: breast pain, dysuria, mastitis, menorrhagia, metrorrhagia, ovarian disorder, pyuria,
salpingitis, urethral pain, urinary urgency, vaginal hemorrhage, vaginal moniliasis
The following adverse experiences have been reported rarely with ocular pilocarpine: A-V block,
agitation, ciliary congestion, confusion, delusion, depression, dermatitis, middle ear disturbance,
eyelid twitching, malignant glaucoma, iris cysts, macular hole, shock, and visual hallucination.
MANAGEMENT OF OVERDOSE: Fatal overdosage with pilocarpine has been reported in the
scientific literature at doses presumed to be greater than 100 mg in two hospitalized patients.
100 mg of pilocarpine is considered potentially fatal. Overdosage should be treated with atropine
titration (0.5 mg to 1.0 mg given subcutaneously or intravenously) and supportive measures to
maintain respiration and circulation. Epinephrine (0.3 mg to 1.0 mg, subcutaneously or
intramuscularly) may also be of value in the presence of severe cardiovascular depression or
bronchoconstriction. It is not known if pilocarpine is dialyzable.
DOSAGE AND ADMINISTRATION:
Regardless of the indication, the starting dose in patients with moderate hepatic impairment
should be 5 mg twice daily, followed by adjustment based on therapeutic response and
tolerability. Patients with mild hepatic insufficiency do not require dosage reductions. The use of
pilocarpine in patients with severe hepatic insufficiency is not recommended. If needed, refer to
the Hepatic Insufficiency subsection of the Precautions section of this label for definitions of mild,
moderate and severe hepatic impairment.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-237/S012
Page 12
Head & Neck Cancer Patients:
The recommended initial dose of SALAGEN
®
Tablets is 5 mg taken three times a day. Dosage
should be titrated according to therapeutic response and tolerability. The usual dosage range is
15-30 mg per day. (Not to exceed 10 mg per dose.) Although early improvement may be
realized, at least 12 weeks of uninterrupted therapy with SALAGEN
®
Tablets may be necessary
to assess whether a beneficial response will be achieved. The incidence of the most common
adverse events increases with dose. The lowest dose that is tolerated and effective should be
used for maintenance.
Sjogren's Syndrome Patients:
The recommended dose of SALAGEN
®
Tablets is one tablet (5 mg) taken four times a day.
Efficacy was established by 6 weeks of use.
HOW SUPPLIED:
SALAGEN
®
Tablets, 5 mg, are white, film coated, debossed round tablets, coded SAL 5. Each
tablet contains 5 mg pilocarpine hydrochloride. They are supplied as follows:
NDC 58063-705-10 bottles of 100
Store at Controlled Room Temperature 15°-30°C (59°-86°F).
SALAGEN
®
Tablets, 7.5 mg, are blue, film coated, debossed round tablets, coded SAL 7.5. Each
tablet contains 7.5 mg pilocarpine hydrochloride. They are supplied as follows:
NDC 58063-775-10 bottles of 100
Store at Controlled Room Temperature 15°-30°C (59°-86°F).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
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|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/020237s012lbl.pdf', 'application_number': 20237, 'submission_type': 'SUPPL ', 'submission_number': 12}
|
12,352
|
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:47:10.199738
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/020238s013lbl.pdf', 'application_number': 20238, 'submission_type': 'SUPPL ', 'submission_number': 13}
|
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19apr2004
KYTRIL
(granisetron hydrochloride)
Injection
Rx only
DESCRIPTION
KYTRIL (granisetron hydrochloride) Injection is an antinauseant and antiemetic agent.
Chemically it is endo-N-(9-methyl-9-azabicyclo [3.3.1] non-3-yl)-1-methyl-1H-indazole-
3-carboxamide hydrochloride with a molecular weight of 348.9 (312.4 free base). Its
empirical formula is C18H24N4O•HCl, while its chemical structure is:
granisetron hydrochloride
Granisetron hydrochloride is a white to off-white solid that is readily soluble in water and
normal saline at 20°C. KYTRIL Injection is a clear, colorless, sterile, nonpyrogenic,
aqueous solution for intravenous administration.
KYTRIL is available in 1 mL single-dose and 4 mL multi-dose vials.
Each 1 mL contains 1.12 mg granisetron hydrochloride equivalent to granisetron, 1 mg;
sodium chloride, 9 mg; citric acid, 2 mg; and benzyl alcohol, 10 mg, as a preservative.
The solution’s pH ranges from 4.0 to 6.0.
CLINICAL PHARMACOLOGY
Granisetron is a selective 5-hydroxytryptamine3 (5-HT3) receptor antagonist with little or
no affinity for other serotonin receptors, including 5-HT1; 5-HT1A; 5-HT1B/C; 5-HT2; for
alpha1-, alpha2- or beta-adrenoreceptors; for dopamine-D2; or for histamine-H1;
benzodiazepine; picrotoxin or opioid receptors.
Serotonin receptors of the 5-HT3 type are located peripherally on vagal nerve terminals
and centrally in the chemoreceptor trigger zone of the area postrema. During
chemotherapy-induced vomiting, mucosal enterochromaffin cells release serotonin,
which stimulates 5-HT3 receptors. This evokes vagal afferent discharge and may induce
vomiting. Animal studies demonstrate that, in binding to 5-HT3 receptors, granisetron
1
1
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19apr2004
KYTRIL (granisetron hydrochloride)
blocks serotonin stimulation and subsequent vomiting after emetogenic stimuli such as
cisplatin. In the ferret animal model, a single granisetron injection prevented vomiting
due to high-dose cisplatin or arrested vomiting within 5 to 30 seconds.
In most human studies, granisetron has had little effect on blood pressure, heart rate or
ECG. No evidence of an effect on plasma prolactin or aldosterone concentrations has
been found in other studies.
KYTRIL Injection exhibited no effect on oro-cecal transit time in normal volunteers
given a single intravenous infusion of 50 mcg/kg or 200 mcg/kg. Single and multiple oral
doses slowed colonic transit in normal volunteers.
Pharmacokinetics
Chemotherapy-Induced Nausea and Vomiting
In adult cancer patients undergoing chemotherapy and in volunteers, mean
pharmacokinetic data obtained from an infusion of a single 40 mcg/kg dose of KYTRIL
Injection are shown in Table 1.
Table 1. Pharmacokinetic Parameters in Adult Cancer Patients
Undergoing Chemotherapy and in Volunteers, Following a Single
Intravenous 40 mcg/kg Dose of KYTRIL Injection
Peak Plasma
Concentration
(ng/mL)
Terminal Phase
Plasma Half-Life
(h)
Total
Clearance
(L/h/kg)
Volume of
Distribution
(L/kg)
Cancer Patients
Mean
63.8*
8.95*
0.38*
3.07*
Range
18.0 to 176
0.90 to 31.1
0.14 to 1.54
0.85 to 10.4
Volunteers
21 to 42 years
Mean
64.3†
4.91†
0.79†
3.04†
Range
11.2 to 182
0.88 to 15.2
0.20 to 2.56
1.68 to 6.13
65 to 81 years
Mean
57.0†
7.69†
0.44†
3.97†
Range
14.6 to 153
2.65 to 17.7
0.17 to 1.06
1.75 to 7.01
*5-minute infusion.
†3-minute infusion.
Distribution
Plasma protein binding is approximately 65% and granisetron distributes freely between
plasma and red blood cells.
Metabolism
Granisetron metabolism involves N-demethylation and aromatic ring oxidation followed
by conjugation. In vitro liver microsomal studies show that granisetron’s major route of
metabolism is inhibited by ketoconazole, suggestive of metabolism mediated by the
2
2
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For current labeling information, please visit https://www.fda.gov/drugsatfda
19apr2004
KYTRIL (granisetron hydrochloride)
cytochrome P-450 3A subfamily. Animal studies suggest that some of the metabolites
may also have 5-HT3 receptor antagonist activity.
Elimination
Clearance is predominantly by hepatic metabolism. In normal volunteers, approximately
12% of the administered dose is eliminated unchanged in the urine in 48 hours. The
remainder of the dose is excreted as metabolites, 49% in the urine, and 34% in the feces.
Subpopulations
Gender
There was high inter- and intra-subject variability noted in these studies. No difference in
mean AUC was found between males and females, although males had a higher Cmax
generally.
Geriatrics
The ranges of the pharmacokinetic parameters in geriatric volunteers (mean age 71
years), given a single 40 mcg/kg intravenous dose of KYTRIL Injection, were generally
similar to those in younger healthy volunteers; mean values were lower for clearance and
longer for half-life in the geriatric patients (see Table 1).
Pediatric Patients
A pharmacokinetic study in pediatric cancer patients (2 to 16 years of age), given a single
40 mcg/kg intravenous dose of KYTRIL Injection, showed that volume of distribution
and total clearance increased with age. No relationship with age was observed for peak
plasma concentration or terminal phase plasma half-life. When volume of distribution
and total clearance are adjusted for body weight, the pharmacokinetics of granisetron are
similar in pediatric and adult cancer patients.
Renal Failure Patients
Total clearance of granisetron was not affected in patients with severe renal failure who
received a single 40 mcg/kg intravenous dose of KYTRIL Injection.
Hepatically Impaired Patients
A pharmacokinetic study in patients with hepatic impairment due to neoplastic liver
involvement showed that total clearance was approximately halved compared to patients
without hepatic impairment. Given the wide variability in pharmacokinetic parameters
noted in patients and the good tolerance of doses well above the recommended 10 mcg/kg
dose, dosage adjustment in patients with possible hepatic functional impairment is not
necessary.
Postoperative Nausea and Vomiting
In adult patients (age range, 18 to 64 years) recovering from elective surgery and
receiving general balanced anesthesia, mean pharmacokinetic data obtained from a single
3
3
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19apr2004
KYTRIL (granisetron hydrochloride)
1 mg dose of KYTRIL Injection administered intravenously over 30 seconds are shown
in Table 2.
Table 2. Pharmacokinetic Parameters in 16 Adult Surgical Patients
Following a Single Intravenous 1 mg Dose of KYTRIL Injection
Terminal Phase
Plasma Half-Life
(h)
Total
Clearance
(L/h/kg)
Volume of
Distribution
(L/kg)
Mean
8.63
0.28
2.42
Range
1.77 to 17.73
0.07 to 0.71
0.71 to 4.13
The pharmacokinetics of granisetron in patients undergoing surgery were similar to those
seen in cancer patients undergoing chemotherapy.
CLINICAL TRIALS
Chemotherapy-Induced Nausea and Vomiting
Single-Day Chemotherapy
Cisplatin-Based Chemotherapy
In a double-blind, placebo-controlled study in 28 cancer patients, KYTRIL Injection,
administered as a single intravenous infusion of 40 mcg/kg, was significantly more
effective than placebo in preventing nausea and vomiting induced by cisplatin
chemotherapy (see Table 3).
Table 3. Prevention of Chemotherapy-Induced Nausea and Vomiting —
Single-Day Cisplatin Therapy1
KYTRIL
Injection
Placebo
P-Value
Number of Patients
14
14
Response Over 24 Hours
Complete Response2
93%
7%
<0.001
No Vomiting
93%
14%
<0.001
No More Than Mild Nausea
93%
7%
<0.001
1 Cisplatin administration began within 10 minutes of KYTRIL Injection infusion and
continued for 1.5 to 3.0 hours. Mean cisplatin dose was 86 mg/m2 in the KYTRIL
Injection group and 80 mg/m2 in the placebo group.
2 No vomiting and no moderate or severe nausea.
KYTRIL Injection was also evaluated in a randomized dose response study of cancer
patients receiving cisplatin ≥75 mg/m2. Additional chemotherapeutic agents included:
anthracyclines, carboplatin, cytostatic antibiotics, folic acid derivatives, methylhydrazine,
nitrogen mustard analogs, podophyllotoxin derivatives, pyrimidine analogs, and vinca
alkaloids. KYTRIL Injection doses of 10 and 40 mcg/kg were superior to 2 mcg/kg in
preventing cisplatin-induced nausea and vomiting, but 40 mcg/kg was not significantly
superior to 10 mcg/kg (see Table 4).
4
4
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19apr2004
KYTRIL (granisetron hydrochloride)
Table 4. Prevention of Chemotherapy-Induced Nausea and Vomiting —
Single-Day High-Dose Cisplatin Therapy1
KYTRIL Injection
(mcg/kg)
P-Value
(vs. 2 mcg/kg)
2
10
40
10
40
Number of Patients
52
52
53
Response Over 24 Hours
Complete Response2
31%
62%
68%
<0.002
<0.001
No Vomiting
38%
65%
74%
<0.001
<0.001
No More Than Mild Nausea
58%
75%
79%
NS
0.007
1 Cisplatin administration began within 10 minutes of KYTRIL Injection infusion and
continued for 2.6 hours (mean). Mean cisplatin doses were 96 to 99 mg/m2.
2 No vomiting and no moderate or severe nausea.
KYTRIL Injection was also evaluated in a double-blind, randomized dose response study
of 353 patients stratified for high (≥80 to 120 mg/m2) or low (50 to 79 mg/m2) cisplatin
dose. Response rates of patients for both cisplatin strata are given in Table 5.
Table 5. Prevention of Chemotherapy-Induced Nausea and Vomiting —
Single-Day High-Dose and Low-Dose Cisplatin Therapy1
KYTRIL Injection
(mcg/kg)
P-Value
(vs. 5 mcg/kg)
5
10
20
40
10
20
40
High-Dose Cisplatin
Number of Patients
40
49
48
47
Response Over 24 Hours
Complete Response2
18%
41%
40%
47%
0.018
0.025
0.004
No Vomiting
28%
47%
44%
53%
NS
NS
0.016
No Nausea
15%
35%
38%
43%
0.036
0.019
0.005
Low-Dose Cisplatin
Number of Patients
42
41
40
46
Response Over 24 Hours
Complete Response2
29%
56%
58%
41%
0.012
0.009
NS
No Vomiting
36%
63%
65%
43%
0.012
0.008
NS
No Nausea
29%
56%
38%
33%
0.012
NS
NS
1 Cisplatin administration began within 10 minutes of KYTRIL Injection infusion and
continued for 2 hours (mean). Mean cisplatin doses were 64 and 98 mg/m2 for low and
high strata.
2 No vomiting and no use of rescue antiemetic.
For both the low and high cisplatin strata, the 10, 20, and 40 mcg/kg doses were more
effective than the 5 mcg/kg dose in preventing nausea and vomiting within 24 hours of
chemotherapy administration. The 10 mcg/kg dose was at least as effective as the higher
doses.
5
5
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19apr2004
KYTRIL (granisetron hydrochloride)
Moderately Emetogenic Chemotherapy
KYTRIL Injection, 40 mcg/kg, was compared with the combination of chlorpromazine
(50 to 200 mg/24 hours) and dexamethasone (12 mg) in patients treated with moderately
emetogenic chemotherapy, including primarily carboplatin >300 mg/m2, cisplatin 20 to
50 mg/m2 and cyclophosphamide >600 mg/m2. KYTRIL Injection was superior to the
chlorpromazine regimen in preventing nausea and vomiting (see Table 6).
Table 6. Prevention of Chemotherapy-Induced Nausea and Vomiting—
Single-Day Moderately Emetogenic Chemotherapy
KYTRIL
Injection
Chlorpromazine1
P-Value
Number of Patients
133
133
Response Over 24 Hours
Complete Response2
68%
47%
<0.001
No Vomiting
73%
53%
<0.001
No More Than Mild Nausea
77%
59%
<0.001
1
Patients also received dexamethasone, 12 mg.
2
No vomiting and no moderate or severe nausea.
In other studies of moderately emetogenic chemotherapy, no significant difference in
efficacy was found between KYTRIL doses of 40 mcg/kg and 160 mcg/kg.
Repeat-Cycle Chemotherapy
In an uncontrolled trial, 512 cancer patients received KYTRIL Injection, 40 mcg/kg,
prophylactically, for two cycles of chemotherapy, 224 patients received it for at least four
cycles, and 108 patients received it for at least six cycles. KYTRIL Injection efficacy
remained relatively constant over the first six repeat cycles, with complete response rates
(no vomiting and no moderate or severe nausea in 24 hours) of 60% to 69%. No patients
were studied for more than 15 cycles.
Pediatric Studies
A randomized double-blind study evaluated the 24-hour response of 80 pediatric cancer
patients (age 2 to 16 years) to KYTRIL Injection 10, 20 or 40 mcg/kg. Patients were
treated with cisplatin ≥60 mg/m2, cytarabine ≥3 g/m2, cyclophosphamide ≥1 g/m2 or
nitrogen mustard ≥6 mg/m2 (see Table 7).
Table 7. Prevention of Chemotherapy-Induced Nausea and Vomiting in
Pediatric Patients
KYTRIL Injection Dose (mcg/kg)
10
20
40
Number of Patients
29
26
25
Median Number of Vomiting Episodes
2
3
1
Complete Response Over 24 Hours1
21%
31%
32%
1
No vomiting and no moderate or severe nausea.
6
6
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19apr2004
KYTRIL (granisetron hydrochloride)
A second pediatric study compared KYTRIL Injection 20 mcg/kg to chlorpromazine plus
dexamethasone in 88 patients treated with ifosfamide ≥3 g/m2/day for two or three days.
KYTRIL Injection was administered on each day of ifosfamide treatment. At 24 hours,
22% of KYTRIL Injection patients achieved complete response (no vomiting and no
moderate or severe nausea in 24 hours) compared with 10% on the chlorpromazine
regimen. The median number of vomiting episodes with KYTRIL Injection was 1.5; with
chlorpromazine it was 7.0.
Postoperative Nausea and Vomiting
Prevention of Postoperative Nausea and Vomiting
The efficacy of KYTRIL Injection for prevention of postoperative nausea and vomiting
was evaluated in 868 patients, of which 833 were women, 35 men, 484 Caucasians, 348
Asians, 18 Blacks, 18 Other, with 61 patients 65 years or older. KYTRIL was evaluated
in two randomized, double-blind, placebo-controlled studies in patients who underwent
elective gynecological surgery or cholecystectomy and received general anesthesia.
Patients received a single intravenous dose of KYTRIL Injection (0.1 mg, 1 mg or 3 mg)
or placebo either 5 minutes before induction of anesthesia or immediately before reversal
of anesthesia. The primary endpoint was the proportion of patients with no vomiting for
24 hours after surgery. Episodes of nausea and vomiting and use of rescue antiemetic
therapy were recorded for 24 hours after surgery. In both studies, KYTRIL Injection (1
mg) was more effective than placebo in preventing postoperative nausea and vomiting
(see Table 8). No additional benefit was seen in patients who received the 3 mg dose.
7
7
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19apr2004
KYTRIL (granisetron hydrochloride)
Table 8. Prevention of Postoperative Nausea and Vomiting in Adult
Patients
Study and Efficacy Endpoint
Placebo KYTRIL
0.1 mg
KYTRIL
1 mg
KYTRIL
3 mg
Study 1
Number of Patients
133
132
134
128
No Vomiting
0 to 24 hours
34%
45%
63%**
62%**
No Nausea
0 to 24 hours
22%
28%
50%**
42%**
No Nausea or Vomiting
0 to 24 hours
18%
27%
49%**
42%**
No Use of Rescue Antiemetic
Therapy
0 to 24 hours
60%
67%
75%*
77%*
Study 2
Number of Patients
117
–
110
114
No Vomiting
0 to 24 hours
56%
–
77%**
75%*
No Nausea
0 to 24 hours
37%
–
59%**
56%*
*P<0.05
**P<0.001 versus placebo
Note: No Vomiting = no vomiting and no use of rescue antiemetic therapy; No Nausea =
no nausea and no use of rescue antiemetic therapy
Gender/Race
There were too few male and Black patients to adequately assess differences in effect in
either population.
Treatment of Postoperative Nausea and Vomiting
The efficacy of KYTRIL Injection for treatment of postoperative nausea and vomiting
was evaluated in 844 patients, of which 731 were women, 113 men, 777 Caucasians, 6
Asians, 41 Blacks, 20 Other, with 107 patients 65 years or older. KYTRIL Injection was
evaluated in two randomized, double-blind, placebo-controlled studies of adult surgical
patients who received general anesthesia with no prophylactic antiemetic agent, and who
experienced nausea or vomiting within 4 hours postoperatively. Patients received a single
intravenous dose of KYTRIL Injection (0.1 mg, 1 mg or 3 mg) or placebo after
experiencing postoperative nausea or vomiting. Episodes of nausea and vomiting and use
of rescue antiemetic therapy were recorded for 24 hours after administration of study
medication. KYTRIL Injection was more effective than placebo in treating postoperative
nausea and vomiting (see Table 9). No additional benefit was seen in patients who
received the 3 mg dose.
8
8
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19apr2004
KYTRIL (granisetron hydrochloride)
Table 9. Treatment of Postoperative Nausea and Vomiting in Adult
Patients
Study and Efficacy
Endpoint
Placebo
KYTRIL
0.1 mg
KYTRIL
1 mg
KYTRIL
3 mg
Study 3
Number of Patients
133
128
133
125
No Vomiting
0 to 6 hours
26%
53%***
58%***
60%***
0 to 24 hours
20%
38%***
46%***
49%***
No Nausea
0 to 6 hours
17%
40%***
41%***
42%***
0 to 24 hours
13%
27%**
30%**
37%***
No Use of Rescue
Antiemetic Therapy
0 to 6 hours
–
–
–
–
0 to 24 hours
33%
51%**
61%***
61%***
Study 4
Number of Patients (All
Patients)
162
163
–
–
No Vomiting
0 to 6 hours
20%
32%*
–
–
0 to 24 hours
14%
23%*
–
–
No Nausea
0 to 6 hours
13%
18%
–
–
0 to 24 hours
9%
14%
–
–
No Nausea or Vomiting
0 to 6 hours
13%
18%
–
–
0 to 24 hours
9%
14%
–
–
No Use of Rescue
Antiemetic Therapy
0 to 6 hours
–
–
–
–
0 to 24 hours
24%
34%*
–
–
Number of Patients
(Treated for Vomiting)1
86
103
–
–
No Vomiting
0 to 6 hours
21%
27%
–
–
0 to 24 hours
14%
20%
–
–
*P<0.05
**P<0.01
***P<0.001 versus placebo
1 Protocol Specified Analysis: Patients who had vomiting prior to treatment
Note: No vomiting = no vomiting and no use of rescue antiemetic therapy; No nausea =
no nausea and no use of rescue antiemetic therapy
9
9
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19apr2004
KYTRIL (granisetron hydrochloride)
Gender/Race
There were too few male and Black patients to adequately assess differences in effect in
either population.
INDICATIONS AND USAGE
KYTRIL Injection is indicated for:
• The prevention of nausea and/or vomiting associated with initial and repeat courses of
emetogenic cancer therapy, including high-dose cisplatin.
• The prevention and treatment of postoperative nausea and vomiting. As with other
antiemetics, routine prophylaxis is not recommended in patients in whom there is
little expectation that nausea and/or vomiting will occur postoperatively. In patients
where nausea and/or vomiting must be avoided during the postoperative period,
KYTRIL Injection is recommended even where the incidence of postoperative nausea
and/or vomiting is low.
CONTRAINDICATIONS
KYTRIL Injection is contraindicated in patients with known hypersensitivity to the drug
or to any of its components.
WARNINGS
Hypersensitivity reactions may occur in patients who have exhibited hypersensitivity to
other selective 5-HT3 receptor antagonists.
PRECAUTIONS
KYTRIL is not a drug that stimulates gastric or intestinal peristalsis. It should not be used
instead of nasogastric suction. The use of KYTRIL in patients following abdominal
surgery or in patients with chemotherapy-induced nausea and vomiting may mask a
progressive ileus and/or gastric distention.
Drug Interactions
Granisetron does not induce or inhibit the cytochrome P-450 drug-metabolizing enzyme
system. There have been no definitive drug-drug interaction studies to examine
pharmacokinetic or pharmacodynamic interaction with other drugs, but in humans,
KYTRIL
Injection
has
been
safely
administered
with
drugs
representing
benzodiazepines, neuroleptics and anti-ulcer medications commonly prescribed with
antiemetic treatments. KYTRIL Injection also does not appear to interact with
emetogenic cancer chemotherapies. Because granisetron is metabolized by hepatic
cytochrome P-450 drug-metabolizing enzymes, inducers or inhibitors of these enzymes
may change the clearance and, hence, the half-life of granisetron.
Carcinogenesis, Mutagenesis, Impairment of Fertility
In a 24-month carcinogenicity study, rats were treated orally with granisetron 1, 5 or 50
mg/kg/day (6, 30 or 300 mg/m2/day). The 50 mg/kg/day dose was reduced to 25
10
10
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19apr2004
KYTRIL (granisetron hydrochloride)
mg/kg/day (150 mg/m2/day) during week 59 due to toxicity. For a 50 kg person of
average height (1.46 m2 body surface area), these doses represent 16, 81 and 405 times
the recommended clinical dose (0.37 mg/m2, iv) on a body surface area basis. There was
a statistically significant increase in the incidence of hepatocellular carcinomas and
adenomas in males treated with 5 mg/kg/day (30 mg/m2/day, 81 times the recommended
human dose based on body surface area) and above, and in females treated with 25
mg/kg/day (150 mg/m2/day, 405 times the recommended human dose based on body
surface area). No increase in liver tumors was observed at a dose of 1 mg/kg/day (6
mg/m2/day, 16 times the recommended human dose based on body surface area) in males
and 5 mg/kg/day (30 mg/m2/day, 81 times the recommended human dose based on body
surface area) in females. In a 12-month oral toxicity study, treatment with granisetron
100 mg/kg/day (600 mg/m2/day, 1622 times the recommended human dose based on
body surface area) produced hepatocellular adenomas in male and female rats while no
such tumors were found in the control rats. A 24-month mouse carcinogenicity study of
granisetron did not show a statistically significant increase in tumor incidence, but the
study was not conclusive.
Because of the tumor findings in rat studies, KYTRIL Injection should be prescribed only
at the dose and for the indication recommended (see INDICATIONS AND USAGE and
DOSAGE AND ADMINISTRATION).
Granisetron was not mutagenic in an in vitro Ames test and mouse lymphoma cell
forward mutation assay, and in vivo mouse micronucleus test and in vitro and ex vivo rat
hepatocyte UDS assays. It, however, produced a significant increase in UDS in HeLa
cells in vitro and a significant increased incidence of cells with polyploidy in an in vitro
human lymphocyte chromosomal aberration test.
Granisetron at subcutaneous doses up to 6 mg/kg/day (36 mg/m2/day, 97 times the
recommended human dose based on body surface area) was found to have no effect on
fertility and reproductive performance of male and female rats.
Pregnancy
Teratogenic Effects. Pregnancy Category B.
Reproduction studies have been performed in pregnant rats at intravenous doses up to 9
mg/kg/day (54 mg/m2/day, 146 times the recommended human dose based on body
surface area) and pregnant rabbits at intravenous doses up to 3 mg/kg/day (35.4
mg/m2/day, 96 times the recommended human dose based on body surface area) and have
revealed no evidence of impaired fertility or harm to the fetus due to granisetron. There
are, however, no adequate and well-controlled studies in pregnant women. Because
animal reproduction studies are not always predictive of human response, this drug
should be used during pregnancy only if clearly needed.
Benzyl alcohol may cross the placenta. Granisetron injection preserved with benzyl
alcohol should be used in pregnancy only if the benefit outweighs the potential risk.
11
11
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
19apr2004
KYTRIL (granisetron hydrochloride)
Nursing Mothers
It is not known whether granisetron is excreted in human milk. Because many drugs are
excreted in human milk, caution should be exercised when KYTRIL Injection is
administered to a nursing woman.
Pediatric Use
See DOSAGE AND ADMINISTRATION for use in chemotherapy-induced nausea and
vomiting in pediatric patients 2 to 16 years of age. Safety and effectiveness in pediatric
patients under 2 years of age have not been established. Safety and effectiveness of
KYTRIL Injection have not been established in pediatric patients for the prevention or
treatment of postoperative nausea or vomiting.
Benzyl alcohol, a component of this drug product, has been associated with serious
adverse events and death, particularly in neonates. The “gasping syndrome,”
characterized by central nervous system depression, metabolic acidosis, gasping
respirations, and high levels of benzyl alcohol and metabolites in blood and urine, has
been associated with benzyl alcohol dosages >99 mg/kg/day in neonates and low birth-
weight neonates. Additional symptoms may include gradual neurological deterioration,
seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic
and renal failure, hypotension, bradycardia, and cardiovascular collapse. Although
normal therapeutic doses of this product deliver amounts of benzyl alcohol that are
substantially lower than those reported in association with the “gasping syndrome,” the
minimum amount of benzyl alcohol at which toxicity may occur is not known. Premature
and low birth-weight infants, as well as patients receiving high dosages, may be more
likely to develop toxicity. Practitioners administering this and other medications
containing benzyl alcohol should consider the combined daily metabolic load of benzyl
alcohol from all sources.
Geriatric Use
During chemotherapy clinical trials, 713 patients 65 years of age or older received
KYTRIL Injection. Effectiveness and safety were similar in patients of various ages.
During postoperative nausea and vomiting clinical trials, 168 patients 65 years of age or
older, of which 47 were 75 years of age or older, received KYTRIL Injection. Clinical
studies of KYTRIL Injection did not include sufficient numbers of subjects aged 65 years
and over to determine whether they respond differently from younger subjects. Other
reported clinical experience has not identified differences in responses between the
elderly and younger patients.
ADVERSE REACTIONS
Chemotherapy-Induced Nausea and Vomiting
The following have been reported during controlled clinical trials or in the routine
management of patients. The percentage figures are based on clinical trial experience
only. Table 10 gives the comparative frequencies of the five most commonly reported
adverse events (≥3%) in patients receiving KYTRIL Injection, in single-day
12
12
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
19apr2004
KYTRIL (granisetron hydrochloride)
chemotherapy trials. These patients received chemotherapy, primarily cisplatin, and
intravenous fluids during the 24-hour period following KYTRIL Injection administration.
Events were generally recorded over seven days post-KYTRIL Injection administration.
In the absence of a placebo group, there is uncertainty as to how many of these events
should be attributed to KYTRIL, except for headache, which was clearly more frequent
than in comparison groups.
Table 10. Principal Adverse Events in Clinical Trials — Single-Day
Chemotherapy
Percent of Patients With Event
KYTRIL Injection
40 mcg/kg
(n=1268)
Comparator1
(n=422)
Headache
14%
6%
Asthenia
5%
6%
Somnolence
4%
15%
Diarrhea
4%
6%
Constipation
3%
3%
1
Metoclopramide/dexamethasone and phenothiazines/dexamethasone.
In over 3,000 patients receiving KYTRIL Injection (2 to 160 mcg/kg) in single-day and
multiple-day clinical trials with emetogenic cancer therapies, adverse events, other than
those in Table 10, were observed; attribution of many of these events to KYTRIL is
uncertain.
Hepatic: In comparative trials, mainly with cisplatin regimens, elevations of AST and
ALT (>2 times the upper limit of normal) following administration of KYTRIL Injection
occurred in 2.8% and 3.3% of patients, respectively. These frequencies were not
significantly different from those seen with comparators (AST: 2.1%; ALT: 2.4%).
Cardiovascular: Hypertension (2%); hypotension, arrhythmias such as sinus
bradycardia, atrial fibrillation, varying degrees of A-V block, ventricular ectopy
including non-sustained tachycardia, and ECG abnormalities have been observed rarely.
Central Nervous System: Agitation, anxiety, CNS stimulation and insomnia were seen
in less than 2% of patients. Extrapyramidal syndrome occurred rarely and only in the
presence of other drugs associated with this syndrome.
Hypersensitivity: Rare cases of hypersensitivity reactions, sometimes severe (eg,
anaphylaxis, shortness of breath, hypotension, urticaria) have been reported.
Other: Fever (3%), taste disorder (2%), skin rashes (1%). In multiple-day comparative
studies, fever occurred more frequently with KYTRIL Injection (8.6%) than with
comparative drugs (3.4%, P<0.014), which usually included dexamethasone.
13
13
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
19apr2004
KYTRIL (granisetron hydrochloride)
Postoperative Nausea and Vomiting
The adverse events listed in Table 11 were reported in ≥2% of adults receiving KYTRIL
Injection 1 mg during controlled clinical trials.
Table 11. Adverse Events ≥2%
Percent of Patients With Event
KYTRIL Injection
1 mg
(n=267)
Placebo
(n=266)
Pain
10.1
8.3
Constipation
9.4
12.0
Anemia
9.4
10.2
Headache
8.6
7.1
Fever
7.9
4.5
Abdominal Pain
6.0
6.0
Hepatic Enzymes Increased
5.6
4.1
Insomnia
4.9
6.0
Bradycardia
4.5
5.3
Dizziness
4.1
3.4
Leukocytosis
3.7
4.1
Anxiety
3.4
3.8
Hypotension
3.4
3.8
Diarrhea
3.4
1.1
Flatulence
3.0
3.0
Infection
3.0
2.3
Dyspepsia
3.0
1.9
Hypertension
2.6
4.1
Urinary Tract Infection
2.6
3.4
Oliguria
2.2
1.5
Coughing
2.2
1.1
In a clinical study conducted in Japan, the types of adverse events differed notably from
those reported above in Table 11. The adverse events in the Japanese study that occurred
in ≥2% of patients and were more frequent with KYTRIL 1 mg than with placebo were:
fever (56% to 50%), sputum increased (2.7% to 1.7%), and dermatitis (2.7% to 0%).
OVERDOSAGE
There is no specific antidote for KYTRIL Injection overdosage. In case of overdosage,
symptomatic treatment should be given. Overdosage of up to 38.5 mg of granisetron
hydrochloride injection has been reported without symptoms or only the occurrence of a
slight headache.
DOSAGE AND ADMINISTRATION
NOTE: CONTAINS BENZYL ALCOHOL (see PRECAUTIONS).
14
14
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
19apr2004
KYTRIL (granisetron hydrochloride)
Prevention of Chemotherapy-Induced Nausea and Vomiting
The recommended dosage for KYTRIL Injection is 10 mcg/kg administered
intravenously within 30 minutes before initiation of chemotherapy, and only on the
day(s) chemotherapy is given.
Infusion Preparation
KYTRIL Injection may be administered intravenously either undiluted over 30 seconds,
or diluted with 0.9% Sodium Chloride or 5% Dextrose and infused over 5 minutes.
Stability
Intravenous infusion of KYTRIL Injection should be prepared at the time of
administration. However, KYTRIL Injection has been shown to be stable for at least 24
hours when diluted in 0.9% Sodium Chloride or 5% Dextrose and stored at room
temperature under normal lighting conditions.
As a general precaution, KYTRIL Injection should not be mixed in solution with other
drugs. Parenteral drug products should be inspected visually for particulate matter and
discoloration before administration whenever solution and container permit.
Pediatric Patients
The recommended dose in pediatric patients 2 to 16 years of age is 10 mcg/kg (see
CLINICAL TRIALS). Pediatric patients under 2 years of age have not been studied.
Geriatric Patients, Renal Failure Patients or Hepatically Impaired Patients
No dosage adjustment is recommended (see CLINICAL PHARMACOLOGY:
Pharmacokinetics).
Prevention and Treatment of Postoperative Nausea and Vomiting
The recommended dosage for prevention of postoperative nausea and vomiting is 1 mg of
KYTRIL, undiluted, administered intravenously over 30 seconds, before induction of
anesthesia or immediately before reversal of anesthesia.
The recommended dosage for the treatment of nausea and/or vomiting after surgery is 1
mg of KYTRIL, undiluted, administered intravenously over 30 seconds.
Pediatric Patients
Safety and effectiveness of KYTRIL Injection have not been established in pediatric
patients for the prevention or treatment of postoperative nausea or vomiting.
Geriatric Patients, Renal Failure Patients or Hepatically Impaired Patients
No dosage adjustment is recommended (see CLINICAL PHARMACOLOGY:
Pharmacokinetics).
15
15
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
19apr2004
KYTRIL (granisetron hydrochloride)
16
HOW SUPPLIED
KYTRIL Injection, 1 mg/mL (free base), is supplied in 1 mL Single-Use Vials and 4 mL
Multi-Dose Vials. CONTAINS BENZYL ALCOHOL.
NDC 0004-0239-09 (package of 1 Single-Dose Vial)
NDC 0004-0240-09 (package of 1 Multi-Dose Vial)
Storage
Store single-dose vials and multi-dose vials at 25°C (77°F); excursions permitted to 15°
to 30°C (59° to 86°F). [See USP Controlled Room Temperature]
Once the multi-dose vial is penetrated, its contents should be used within 30 days.
Do not freeze. Protect from light.
Distributed by:
XXXXXXXX
Revised: Month Year
Copyright 1998-2004 by Roche Laboratories Inc. All rights reserved.
16
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
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2025-02-12T13:47:10.250453
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/20239s015lbl.pdf', 'application_number': 20239, 'submission_type': 'SUPPL ', 'submission_number': 15}
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1
1
KYTRIL®
2
(granisetron hydrochloride)
3
INJECTION
4
Rx only
5
DESCRIPTION
6
KYTRIL (granisetron hydrochloride) Injection is an antinauseant and antiemetic agent.
7
Chemically it is endo-N-(9-methyl-9-azabicyclo [3.3.1] non-3-yl)-1-methyl-1H-indazole-
8
3-carboxamide hydrochloride with a molecular weight of 348.9 (312.4 free base). Its
9
empirical formula is C18H24N4O•HCl, while its chemical structure is:
10
11
granisetron hydrochloride
12
Granisetron hydrochloride is a white to off-white solid that is readily soluble in water and
13
normal saline at 20°C. KYTRIL Injection is a clear, colorless, sterile, nonpyrogenic,
14
aqueous solution for intravenous administration.
15
KYTRIL 1 mg/1 mL is available in 1 mL single-use and 4 mL multi-use vials. KYTRIL
16
0.1 mg/1 mL is available in a 1 mL single-use vial.
17
1 mg/1 mL: Each 1 mL contains 1.12 mg granisetron hydrochloride equivalent to
18
granisetron, 1 mg; sodium chloride, 9 mg; citric acid, 2 mg; and benzyl alcohol, 10 mg,
19
as a preservative. The solution’s pH ranges from 4.0 to 6.0.
20
0.1 mg/1 mL: Each 1 mL contains 0.112 mg granisetron hydrochloride equivalent to
21
granisetron, 0.1 mg; sodium chloride, 9 mg; citric acid, 2 mg. Contains no preservative.
22
The solution’s pH ranges from 4.0 to 6.0.
23
CLINICAL PHARMACOLOGY
24
Granisetron is a selective 5-hydroxytryptamine3 (5-HT3) receptor antagonist with little or
25
no affinity for other serotonin receptors, including 5-HT1; 5-HT1A; 5-HT1B/C; 5-HT2; for
26
alpha1-, alpha2- or beta-adrenoreceptors; for dopamine-D2; or for histamine-H1;
27
benzodiazepine; picrotoxin or opioid receptors.
28
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2
Serotonin receptors of the 5-HT3 type are located peripherally on vagal nerve terminals
29
and centrally in the chemoreceptor trigger zone of the area postrema. During
30
chemotherapy-induced vomiting, mucosal enterochromaffin cells release serotonin,
31
which stimulates 5-HT3 receptors. This evokes vagal afferent discharge and may induce
32
vomiting. Animal studies demonstrate that, in binding to 5-HT3 receptors, granisetron
33
blocks serotonin stimulation and subsequent vomiting after emetogenic stimuli such as
34
cisplatin. In the ferret animal model, a single granisetron injection prevented vomiting
35
due to high-dose cisplatin or arrested vomiting within 5 to 30 seconds.
36
In most human studies, granisetron has had little effect on blood pressure, heart rate or
37
ECG. No evidence of an effect on plasma prolactin or aldosterone concentrations has
38
been found in other studies.
39
KYTRIL Injection exhibited no effect on oro-cecal transit time in normal volunteers
40
given a single intravenous infusion of 50 mcg/kg or 200 mcg/kg. Single and multiple oral
41
doses slowed colonic transit in normal volunteers.
42
Pharmacokinetics
43
Chemotherapy-Induced Nausea and Vomiting
44
In adult cancer patients undergoing chemotherapy and in volunteers, mean
45
pharmacokinetic data obtained from an infusion of a single 40 mcg/kg dose of KYTRIL
46
Injection are shown in Table 1.
47
Table 1
Pharmacokinetic Parameters in Adult Cancer Patients
48
Undergoing Chemotherapy and in Volunteers, Following a
49
Single Intravenous 40 mcg/kg Dose of KYTRIL Injection
50
Peak Plasma
Concentration
(ng/mL)
Terminal Phase
Plasma Half-Life
(h)
Total
Clearance
(L/h/kg)
Volume of
Distribution
(L/kg)
Cancer Patients
Mean
63.8*
8.95*
0.38*
3.07*
Range
18.0 to 176
0.90 to 31.1
0.14 to 1.54
0.85 to 10.4
Volunteers
21 to 42 years
Mean
64.3†
4.91†
0.79†
3.04†
Range
11.2 to 182
0.88 to 15.2
0.20 to 2.56
1.68 to 6.13
65 to 81 years
Mean
57.0†
7.69†
0.44†
3.97†
Range
14.6 to 153
2.65 to 17.7
0.17 to 1.06
1.75 to 7.01
*5-minute infusion.
51
†3-minute infusion.
52
Distribution
53
Plasma protein binding is approximately 65% and granisetron distributes freely between
54
plasma and red blood cells.
55
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
3
Metabolism
56
Granisetron metabolism involves N-demethylation and aromatic ring oxidation followed
57
by conjugation. In vitro liver microsomal studies show that granisetron’s major route of
58
metabolism is inhibited by ketoconazole, suggestive of metabolism mediated by the
59
cytochrome P-450 3A subfamily. Animal studies suggest that some of the metabolites
60
may also have 5-HT3 receptor antagonist activity.
61
Elimination
62
Clearance is predominantly by hepatic metabolism. In normal volunteers, approximately
63
12% of the administered dose is eliminated unchanged in the urine in 48 hours. The
64
remainder of the dose is excreted as metabolites, 49% in the urine, and 34% in the feces.
65
Subpopulations
66
Gender
67
There was high inter- and intra-subject variability noted in these studies. No difference in
68
mean AUC was found between males and females, although males had a higher Cmax
69
generally.
70
Elderly
71
The ranges of the pharmacokinetic parameters in elderly volunteers (mean age 71 years),
72
given a single 40 mcg/kg intravenous dose of KYTRIL Injection, were generally similar
73
to those in younger healthy volunteers; mean values were lower for clearance and longer
74
for half-life in the elderly patients (see Table 1).
75
Pediatric Patients
76
A pharmacokinetic study in pediatric cancer patients (2 to 16 years of age), given a single
77
40 mcg/kg intravenous dose of KYTRIL Injection, showed that volume of distribution
78
and total clearance increased with age. No relationship with age was observed for peak
79
plasma concentration or terminal phase plasma half-life. When volume of distribution
80
and total clearance are adjusted for body weight, the pharmacokinetics of granisetron are
81
similar in pediatric and adult cancer patients.
82
Renal Failure Patients
83
Total clearance of granisetron was not affected in patients with severe renal failure who
84
received a single 40 mcg/kg intravenous dose of KYTRIL Injection.
85
Hepatically Impaired Patients
86
A pharmacokinetic study in patients with hepatic impairment due to neoplastic liver
87
involvement showed that total clearance was approximately halved compared to patients
88
without hepatic impairment. Given the wide variability in pharmacokinetic parameters
89
noted in patients and the good tolerance of doses well above the recommended 10 mcg/kg
90
dose, dosage adjustment in patients with possible hepatic functional impairment is not
91
necessary.
92
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
4
Postoperative Nausea and Vomiting
93
In adult patients (age range, 18 to 64 years) recovering from elective surgery and
94
receiving general balanced anesthesia, mean pharmacokinetic data obtained from a single
95
1 mg dose of KYTRIL Injection administered intravenously over 30 seconds are shown
96
in Table 2.
97
Table 2
Pharmacokinetic Parameters in 16 Adult Surgical Patients
98
Following a Single Intravenous 1 mg Dose of KYTRIL
99
Injection
100
Terminal Phase
Plasma Half-Life
(h)
Total
Clearance
(L/h/kg)
Volume of
Distribution
(L/kg)
Mean
8.63
0.28
2.42
Range
1.77 to 17.73
0.07 to 0.71
0.71 to 4.13
101
The pharmacokinetics of granisetron in patients undergoing surgery were similar to those
102
seen in cancer patients undergoing chemotherapy.
103
CLINICAL TRIALS
104
Chemotherapy-Induced Nausea and Vomiting
105
Single-Day Chemotherapy
106
Cisplatin-Based Chemotherapy
107
In a double-blind, placebo-controlled study in 28 cancer patients, KYTRIL Injection,
108
administered as a single intravenous infusion of 40 mcg/kg, was significantly more
109
effective than placebo in preventing nausea and vomiting induced by cisplatin
110
chemotherapy (see Table 3).
111
Table 3
Prevention of Chemotherapy-Induced Nausea and Vomiting
112
— Single-Day Cisplatin Therapy1
113
KYTRIL
Injection
Placebo
P-Value
Number of Patients
14
14
Response Over 24 Hours
Complete Response2
93%
7%
<0.001
No Vomiting
93%
14%
<0.001
No More Than Mild Nausea
93%
7%
<0.001
1 Cisplatin administration began within 10 minutes of KYTRIL Injection infusion and
114
continued for 1.5 to 3.0 hours. Mean cisplatin dose was 86 mg/m2 in the KYTRIL
115
Injection group and 80 mg/m2 in the placebo group.
116
2 No vomiting and no moderate or severe nausea.
117
KYTRIL Injection was also evaluated in a randomized dose response study of cancer
118
patients receiving cisplatin ≥75 mg/m2. Additional chemotherapeutic agents included:
119
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5
anthracyclines, carboplatin, cytostatic antibiotics, folic acid derivatives, methylhydrazine,
120
nitrogen mustard analogs, podophyllotoxin derivatives, pyrimidine analogs, and vinca
121
alkaloids. KYTRIL Injection doses of 10 and 40 mcg/kg were superior to 2 mcg/kg in
122
preventing cisplatin-induced nausea and vomiting, but 40 mcg/kg was not significantly
123
superior to 10 mcg/kg (see Table 4).
124
Table 4
Prevention of Chemotherapy-Induced Nausea and Vomiting
125
— Single-Day High-Dose Cisplatin Therapy1
126
KYTRIL Injection
(mcg/kg)
P-Value
(vs. 2 mcg/kg)
2
10
40
10
40
Number of Patients
52
52
53
Response Over 24 Hours
Complete Response2
31%
62%
68%
<0.002
<0.001
No Vomiting
38%
65%
74%
<0.001
<0.001
No More Than Mild Nausea
58%
75%
79%
NS
0.007
1 Cisplatin administration began within 10 minutes of KYTRIL Injection infusion and
127
continued for 2.6 hours (mean). Mean cisplatin doses were 96 to 99 mg/m2.
128
2 No vomiting and no moderate or severe nausea.
129
KYTRIL Injection was also evaluated in a double-blind, randomized dose response study
130
of 353 patients stratified for high (≥80 to 120 mg/m2) or low (50 to 79 mg/m2) cisplatin
131
dose. Response rates of patients for both cisplatin strata are given in Table 5.
132
Table 5
Prevention of Chemotherapy-Induced Nausea and Vomiting
133
— Single-Day High-Dose and Low-Dose Cisplatin Therapy1
134
KYTRIL Injection
(mcg/kg)
P-Value
(vs. 5 mcg/kg)
5
10
20
40
10
20
40
High-Dose Cisplatin
Number of Patients
40
49
48
47
Response Over 24 Hours
Complete Response2
18%
41%
40%
47%
0.018
0.025
0.004
No Vomiting
28%
47%
44%
53%
NS
NS
0.016
No Nausea
15%
35%
38%
43%
0.036
0.019
0.005
Low-Dose Cisplatin
Number of Patients
42
41
40
46
Response Over 24 Hours
Complete Response2
29%
56%
58%
41%
0.012
0.009
NS
No Vomiting
36%
63%
65%
43%
0.012
0.008
NS
No Nausea
29%
56%
38%
33%
0.012
NS
NS
1 Cisplatin administration began within 10 minutes of KYTRIL Injection infusion and
135
continued for 2 hours (mean). Mean cisplatin doses were 64 and 98 mg/m2 for low and
136
high strata.
137
2 No vomiting and no use of rescue antiemetic.
138
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
6
For both the low and high cisplatin strata, the 10, 20, and 40 mcg/kg doses were more
139
effective than the 5 mcg/kg dose in preventing nausea and vomiting within 24 hours of
140
chemotherapy administration. The 10 mcg/kg dose was at least as effective as the higher
141
doses.
142
Moderately Emetogenic Chemotherapy
143
KYTRIL Injection, 40 mcg/kg, was compared with the combination of chlorpromazine
144
(50 to 200 mg/24 hours) and dexamethasone (12 mg) in patients treated with moderately
145
emetogenic chemotherapy, including primarily carboplatin >300 mg/m2, cisplatin 20 to
146
50 mg/m2 and cyclophosphamide >600 mg/m2. KYTRIL Injection was superior to the
147
chlorpromazine regimen in preventing nausea and vomiting (see Table 6).
148
Table 6
Prevention of Chemotherapy-Induced Nausea and
149
Vomiting—Single-Day Moderately Emetogenic
150
Chemotherapy
151
KYTRIL
Injection
Chlorpromazine1
P-Value
Number of Patients
133
133
Response Over 24 Hours
Complete Response2
68%
47%
<0.001
No Vomiting
73%
53%
<0.001
No More Than Mild Nausea
77%
59%
<0.001
1
Patients also received dexamethasone, 12 mg.
152
2
No vomiting and no moderate or severe nausea.
153
In other studies of moderately emetogenic chemotherapy, no significant difference in
154
efficacy was found between KYTRIL doses of 40 mcg/kg and 160 mcg/kg.
155
Repeat-Cycle Chemotherapy
156
In an uncontrolled trial, 512 cancer patients received KYTRIL Injection, 40 mcg/kg,
157
prophylactically, for two cycles of chemotherapy, 224 patients received it for at least four
158
cycles, and 108 patients received it for at least six cycles. KYTRIL Injection efficacy
159
remained relatively constant over the first six repeat cycles, with complete response rates
160
(no vomiting and no moderate or severe nausea in 24 hours) of 60% to 69%. No patients
161
were studied for more than 15 cycles.
162
Pediatric Studies
163
A randomized double-blind study evaluated the 24-hour response of 80 pediatric cancer
164
patients (age 2 to 16 years) to KYTRIL Injection 10, 20 or 40 mcg/kg. Patients were
165
treated with cisplatin ≥60 mg/m2, cytarabine ≥3 g/m2, cyclophosphamide ≥1 g/m2 or
166
nitrogen mustard ≥6 mg/m2 (see Table 7).
167
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
7
Table 7
Prevention of Chemotherapy-Induced Nausea and Vomiting
168
in Pediatric Patients
169
KYTRIL Injection Dose (mcg/kg)
10
20
40
Number of Patients
29
26
25
Median Number of Vomiting Episodes
2
3
1
Complete Response Over 24 Hours1
21%
31%
32%
1
No vomiting and no moderate or severe nausea.
170
A second pediatric study compared KYTRIL Injection 20 mcg/kg to chlorpromazine plus
171
dexamethasone in 88 patients treated with ifosfamide ≥3 g/m2/day for two or three days.
172
KYTRIL Injection was administered on each day of ifosfamide treatment. At 24 hours,
173
22% of KYTRIL Injection patients achieved complete response (no vomiting and no
174
moderate or severe nausea in 24 hours) compared with 10% on the chlorpromazine
175
regimen. The median number of vomiting episodes with KYTRIL Injection was 1.5; with
176
chlorpromazine it was 7.0.
177
Postoperative Nausea and Vomiting
178
Prevention of Postoperative Nausea and Vomiting
179
The efficacy of KYTRIL Injection for prevention of postoperative nausea and vomiting
180
was evaluated in 868 patients, of which 833 were women, 35 men, 484 Caucasians, 348
181
Asians, 18 Blacks, 18 Other, with 61 patients 65 years or older. KYTRIL was evaluated
182
in two randomized, double-blind, placebo-controlled studies in patients who underwent
183
elective gynecological surgery or cholecystectomy and received general anesthesia.
184
Patients received a single intravenous dose of KYTRIL Injection (0.1 mg, 1 mg or 3 mg)
185
or placebo either 5 minutes before induction of anesthesia or immediately before reversal
186
of anesthesia. The primary endpoint was the proportion of patients with no vomiting for
187
24 hours after surgery. Episodes of nausea and vomiting and use of rescue antiemetic
188
therapy were recorded for 24 hours after surgery. In both studies, KYTRIL Injection (1
189
mg) was more effective than placebo in preventing postoperative nausea and vomiting
190
(see Table 8). No additional benefit was seen in patients who received the 3 mg dose.
191
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
8
Table 8
Prevention of Postoperative Nausea and Vomiting in Adult
192
Patients
193
Study and Efficacy Endpoint
Placebo
KYTRIL
0.1 mg
KYTRIL
1 mg
KYTRIL
3 mg
Study 1
Number of Patients
133
132
134
128
No Vomiting
0 to 24 hours
34%
45%
63%**
62%**
No Nausea
0 to 24 hours
22%
28%
50%**
42%**
No Nausea or Vomiting
0 to 24 hours
18%
27%
49%**
42%**
No Use of Rescue Antiemetic
Therapy
0 to 24 hours
60%
67%
75%*
77%*
Study 2
Number of Patients
117
–
110
114
No Vomiting
0 to 24 hours
56%
–
77%**
75%*
No Nausea
0 to 24 hours
37%
–
59%**
56%*
*P<0.05
194
**P<0.001 versus placebo
195
Note: No Vomiting = no vomiting and no use of rescue antiemetic therapy; No Nausea =
196
no nausea and no use of rescue antiemetic therapy
197
Gender/Race
198
There were too few male and Black patients to adequately assess differences in effect in
199
either population.
200
Treatment of Postoperative Nausea and Vomiting
201
The efficacy of KYTRIL Injection for treatment of postoperative nausea and vomiting
202
was evaluated in 844 patients, of which 731 were women, 113 men, 777 Caucasians, 6
203
Asians, 41 Blacks, 20 Other, with 107 patients 65 years or older. KYTRIL Injection was
204
evaluated in two randomized, double-blind, placebo-controlled studies of adult surgical
205
patients who received general anesthesia with no prophylactic antiemetic agent, and who
206
experienced nausea or vomiting within 4 hours postoperatively. Patients received a single
207
intravenous dose of KYTRIL Injection (0.1 mg, 1 mg or 3 mg) or placebo after
208
experiencing postoperative nausea or vomiting. Episodes of nausea and vomiting and use
209
of rescue antiemetic therapy were recorded for 24 hours after administration of study
210
medication. KYTRIL Injection was more effective than placebo in treating postoperative
211
nausea and vomiting (see Table 9). No additional benefit was seen in patients who
212
received the 3 mg dose.
213
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
9
Table 9
Treatment of Postoperative Nausea and Vomiting in Adult
214
Patients
215
Study and Efficacy Endpoint
Placebo
KYTRIL
0.1 mg
KYTRIL
1 mg
KYTRIL
3 mg
Study 3
Number of Patients
133
128
133
125
No Vomiting
0 to 6 hours
26%
53%***
58%***
60%***
0 to 24 hours
20%
38%***
46%***
49%***
No Nausea
0 to 6 hours
17%
40%***
41%***
42%***
0 to 24 hours
13%
27%**
30%**
37%***
No Use of Rescue Antiemetic
Therapy
0 to 6 hours
–
–
–
–
0 to 24 hours
33%
51%**
61%***
61%***
Study 4
Number of Patients (All
Patients)
162
163
–
–
No Vomiting
0 to 6 hours
20%
32%*
–
–
0 to 24 hours
14%
23%*
–
–
No Nausea
0 to 6 hours
13%
18%
–
–
0 to 24 hours
9%
14%
–
–
No Nausea or Vomiting
0 to 6 hours
13%
18%
–
–
0 to 24 hours
9%
14%
–
–
No Use of Rescue Antiemetic
Therapy
0 to 6 hours
–
–
–
–
0 to 24 hours
24%
34%*
–
–
Number of Patients (Treated
for Vomiting)1
86
103
–
–
No Vomiting
0 to 6 hours
21%
27%
–
–
0 to 24 hours
14%
20%
–
–
*P<0.05
216
**P<0.01
217
***P<0.001 versus placebo
218
1 Protocol Specified Analysis: Patients who had vomiting prior to treatment
219
Note: No vomiting = no vomiting and no use of rescue antiemetic therapy; No nausea =
220
no nausea and no use of rescue antiemetic therapy
221
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
10
Gender/Race
222
There were too few male and Black patients to adequately assess differences in effect in
223
either population.
224
INDICATIONS AND USAGE
225
KYTRIL Injection is indicated for:
226
• The prevention of nausea and/or vomiting associated with initial and repeat courses of
227
emetogenic cancer therapy, including high-dose cisplatin.
228
• The prevention and treatment of postoperative nausea and vomiting. As with other
229
antiemetics, routine prophylaxis is not recommended in patients in whom there is
230
little expectation that nausea and/or vomiting will occur postoperatively. In patients
231
where nausea and/or vomiting must be avoided during the postoperative period,
232
KYTRIL Injection is recommended even where the incidence of postoperative nausea
233
and/or vomiting is low.
234
CONTRAINDICATIONS
235
KYTRIL Injection is contraindicated in patients with known hypersensitivity to the drug
236
or to any of its components.
237
WARNINGS
238
Hypersensitivity reactions may occur in patients who have exhibited hypersensitivity to
239
other selective 5-HT3 receptor antagonists.
240
PRECAUTIONS
241
KYTRIL is not a drug that stimulates gastric or intestinal peristalsis. It should not be used
242
instead of nasogastric suction. The use of KYTRIL in patients following abdominal
243
surgery or in patients with chemotherapy-induced nausea and vomiting may mask a
244
progressive ileus and/or gastric distention.
245
Drug Interactions
246
Granisetron does not induce or inhibit the cytochrome P-450 drug-metabolizing enzyme
247
system in vitro. There have been no definitive drug-drug interaction studies to examine
248
pharmacokinetic or pharmacodynamic interaction with other drugs; however, in humans,
249
KYTRIL
Injection
has
been
safely
administered
with
drugs
representing
250
benzodiazepines, neuroleptics and anti-ulcer medications commonly prescribed with
251
antiemetic treatments. KYTRIL Injection also does not appear to interact with
252
emetogenic cancer chemotherapies. Because granisetron is metabolized by hepatic
253
cytochrome P-450 drug-metabolizing enzymes, inducers or inhibitors of these enzymes
254
may change the clearance and, hence, the half-life of granisetron. No specific interaction
255
studies have been conducted in anesthetized patients. In addition, the activity of the
256
cytochrome P-450 subfamily 3A4 (involved in the metabolism of some of the main
257
narcotic analgesic agents) is not modified by KYTRIL in vitro.
258
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
11
In in vitro human microsomal studies, ketoconazole inhibited ring oxidation of KYTRIL.
259
However, the clinical significance of in vivo pharmacokinetic interactions with
260
ketoconazole is not known. In a human pharmacokinetic study, hepatic enzyme induction
261
with phenobarbital resulted in a 25% increase in total plasma clearance of intravenous
262
KYTRIL. The clinical significance of this change is not known.
263
Carcinogenesis, Mutagenesis, Impairment of Fertility
264
In a 24-month carcinogenicity study, rats were treated orally with granisetron 1, 5 or
265
50 mg/kg/day (6, 30 or 300 mg/m2/day). The 50 mg/kg/day dose was reduced to
266
25 mg/kg/day (150 mg/m2/day) during week 59 due to toxicity. For a 50 kg person of
267
average height (1.46 m2 body surface area), these doses represent 16, 81 and 405 times
268
the recommended clinical dose (0.37 mg/m2, iv) on a body surface area basis. There was
269
a statistically significant increase in the incidence of hepatocellular carcinomas and
270
adenomas in males treated with 5 mg/kg/day (30 mg/m2/day, 81 times the recommended
271
human dose based on body surface area) and above, and in females treated with
272
25 mg/kg/day (150 mg/m2/day, 405 times the recommended human dose based on body
273
surface area). No increase in liver tumors was observed at a dose of 1 mg/kg/day
274
(6 mg/m2/day, 16 times the recommended human dose based on body surface area) in
275
males and 5 mg/kg/day (30 mg/m2/day, 81 times the recommended human dose based on
276
body surface area) in females. In a 12-month oral toxicity study, treatment with
277
granisetron 100 mg/kg/day (600 mg/m2/day, 1622 times the recommended human dose
278
based on body surface area) produced hepatocellular adenomas in male and female rats
279
while no such tumors were found in the control rats. A 24-month mouse carcinogenicity
280
study of granisetron did not show a statistically significant increase in tumor incidence,
281
but the study was not conclusive.
282
Because of the tumor findings in rat studies, KYTRIL Injection should be prescribed only
283
at the dose and for the indication recommended (see INDICATIONS AND USAGE and
284
DOSAGE AND ADMINISTRATION).
285
Granisetron was not mutagenic in an in vitro Ames test and mouse lymphoma cell
286
forward mutation assay, and in vivo mouse micronucleus test and in vitro and ex vivo rat
287
hepatocyte UDS assays. It, however, produced a significant increase in UDS in HeLa
288
cells in vitro and a significant increased incidence of cells with polyploidy in an in vitro
289
human lymphocyte chromosomal aberration test.
290
Granisetron at subcutaneous doses up to 6 mg/kg/day (36 mg/m2/day, 97 times the
291
recommended human dose based on body surface area) was found to have no effect on
292
fertility and reproductive performance of male and female rats.
293
Pregnancy
294
Teratogenic Effects
295
Pregnancy Category B.
296
Reproduction studies have been performed in pregnant rats at intravenous doses up to
297
9 mg/kg/day (54 mg/m2/day, 146 times the recommended human dose based on body
298
surface area) and pregnant rabbits at intravenous doses up to 3 mg/kg/day
299
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
12
(35.4 mg/m2/day, 96 times the recommended human dose based on body surface area)
300
and have revealed no evidence of impaired fertility or harm to the fetus due to
301
granisetron. There are, however, no adequate and well-controlled studies in pregnant
302
women. Because animal reproduction studies are not always predictive of human
303
response, this drug should be used during pregnancy only if clearly needed.
304
Benzyl alcohol may cross the placenta. KYTRIL Injection 1 mg/1 mL is preserved with
305
benzyl alcohol and should be used in pregnancy only if the benefit outweighs the
306
potential risk.
307
Nursing Mothers
308
It is not known whether granisetron is excreted in human milk. Because many drugs are
309
excreted in human milk, caution should be exercised when KYTRIL Injection is
310
administered to a nursing woman.
311
Pediatric Use
312
See DOSAGE AND ADMINISTRATION for use in chemotherapy-induced nausea and
313
vomiting in pediatric patients 2 to 16 years of age. Safety and effectiveness in pediatric
314
patients under 2 years of age have not been established. Safety and effectiveness of
315
KYTRIL Injection have not been established in pediatric patients for the prevention or
316
treatment of postoperative nausea or vomiting.
317
Benzyl alcohol, a component of KYTRIL 1 mg/1 mL, has been associated with serious
318
adverse events and death, particularly in neonates. The “gasping syndrome,”
319
characterized by central nervous system depression, metabolic acidosis, gasping
320
respirations, and high levels of benzyl alcohol and metabolites in blood and urine, has
321
been associated with benzyl alcohol dosages >99 mg/kg/day in neonates and low birth-
322
weight neonates. Additional symptoms may include gradual neurological deterioration,
323
seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic
324
and renal failure, hypotension, bradycardia, and cardiovascular collapse. Although
325
normal therapeutic doses of this product deliver amounts of benzyl alcohol that are
326
substantially lower than those reported in association with the “gasping syndrome,” the
327
minimum amount of benzyl alcohol at which toxicity may occur is not known. Premature
328
and low birth-weight infants, as well as patients receiving high dosages, may be more
329
likely to develop toxicity. Practitioners administering this and other medications
330
containing benzyl alcohol should consider the combined daily metabolic load of benzyl
331
alcohol from all sources.
332
Geriatric Use
333
During chemotherapy clinical trials, 713 patients 65 years of age or older received
334
KYTRIL Injection. Effectiveness and safety were similar in patients of various ages.
335
During postoperative nausea and vomiting clinical trials, 168 patients 65 years of age or
336
older, of which 47 were 75 years of age or older, received KYTRIL Injection. Clinical
337
studies of KYTRIL Injection did not include sufficient numbers of subjects aged 65 years
338
and over to determine whether they respond differently from younger subjects. Other
339
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
13
reported clinical experience has not identified differences in responses between the
340
elderly and younger patients.
341
ADVERSE REACTIONS
342
Chemotherapy-Induced Nausea and Vomiting
343
The following have been reported during controlled clinical trials or in the routine
344
management of patients. The percentage figures are based on clinical trial experience
345
only. Table 10 gives the comparative frequencies of the five most commonly reported
346
adverse events (≥3%) in patients receiving KYTRIL Injection, in single-day
347
chemotherapy trials. These patients received chemotherapy, primarily cisplatin, and
348
intravenous fluids during the 24-hour period following KYTRIL Injection administration.
349
Events were generally recorded over seven days post-KYTRIL Injection administration.
350
In the absence of a placebo group, there is uncertainty as to how many of these events
351
should be attributed to KYTRIL, except for headache, which was clearly more frequent
352
than in comparison groups.
353
Table 10
Principal Adverse Events in Clinical Trials — Single-Day
354
Chemotherapy
355
Percent of Patients With Event
KYTRIL Injection
40 mcg/kg
(n=1268)
Comparator1
(n=422)
Headache
14%
6%
Asthenia
5%
6%
Somnolence
4%
15%
Diarrhea
4%
6%
Constipation
3%
3%
1
Metoclopramide/dexamethasone and phenothiazines/dexamethasone.
356
In over 3,000 patients receiving KYTRIL Injection (2 to 160 mcg/kg) in single-day and
357
multiple-day clinical trials with emetogenic cancer therapies, adverse events, other than
358
those in Table 10, were observed; attribution of many of these events to KYTRIL is
359
uncertain.
360
Hepatic: In comparative trials, mainly with cisplatin regimens, elevations of AST and
361
ALT (>2 times the upper limit of normal) following administration of KYTRIL Injection
362
occurred in 2.8% and 3.3% of patients, respectively. These frequencies were not
363
significantly different from those seen with comparators (AST: 2.1%; ALT: 2.4%).
364
Cardiovascular: Hypertension (2%); hypotension, arrhythmias such as sinus bradycardia,
365
atrial fibrillation, varying degrees of A-V block, ventricular ectopy including non-
366
sustained tachycardia, and ECG abnormalities have been observed rarely.
367
Central Nervous System: Agitation, anxiety, CNS stimulation and insomnia were seen in
368
less than 2% of patients. Extrapyramidal syndrome occurred rarely and only in the
369
presence of other drugs associated with this syndrome.
370
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
14
Hypersensitivity: Rare cases of hypersensitivity reactions, sometimes severe (eg,
371
anaphylaxis, shortness of breath, hypotension, urticaria) have been reported.
372
Other: Fever (3%), taste disorder (2%), skin rashes (1%). In multiple-day comparative
373
studies, fever occurred more frequently with KYTRIL Injection (8.6%) than with
374
comparative drugs (3.4%, P<0.014), which usually included dexamethasone.
375
Postoperative Nausea and Vomiting
376
The adverse events listed in Table 11 were reported in ≥2% of adults receiving KYTRIL
377
Injection 1 mg during controlled clinical trials.
378
Table 11
Adverse Events ≥2%
379
Percent of Patients With Event
KYTRIL Injection
1 mg
(n=267)
Placebo
(n=266)
Pain
10.1
8.3
Constipation
9.4
12.0
Anemia
9.4
10.2
Headache
8.6
7.1
Fever
7.9
4.5
Abdominal Pain
6.0
6.0
Hepatic Enzymes Increased
5.6
4.1
Insomnia
4.9
6.0
Bradycardia
4.5
5.3
Dizziness
4.1
3.4
Leukocytosis
3.7
4.1
Anxiety
3.4
3.8
Hypotension
3.4
3.8
Diarrhea
3.4
1.1
Flatulence
3.0
3.0
Infection
3.0
2.3
Dyspepsia
3.0
1.9
Hypertension
2.6
4.1
Urinary Tract Infection
2.6
3.4
Oliguria
2.2
1.5
Coughing
2.2
1.1
In a clinical study conducted in Japan, the types of adverse events differed notably from
380
those reported above in Table 11. The adverse events in the Japanese study that occurred
381
in ≥2% of patients and were more frequent with KYTRIL 1 mg than with placebo were:
382
fever (56% to 50%), sputum increased (2.7% to 1.7%), and dermatitis (2.7% to 0%).
383
OVERDOSAGE
384
There is no specific antidote for KYTRIL Injection overdosage. In case of overdosage,
385
symptomatic treatment should be given. Overdosage of up to 38.5 mg of granisetron
386
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
15
hydrochloride injection has been reported without symptoms or only the occurrence of a
387
slight headache.
388
DOSAGE AND ADMINISTRATION
389
NOTE:
KYTRIL
1
MG/1
ML
CONTAINS
BENZYL
ALCOHOL
(see
390
PRECAUTIONS).
391
Prevention of Chemotherapy-Induced Nausea and Vomiting
392
The recommended dosage for KYTRIL Injection is 10 mcg/kg administered
393
intravenously within 30 minutes before initiation of chemotherapy, and only on the
394
day(s) chemotherapy is given.
395
Infusion Preparation
396
KYTRIL Injection may be administered intravenously either undiluted over 30 seconds,
397
or diluted with 0.9% Sodium Chloride or 5% Dextrose and infused over 5 minutes.
398
Stability
399
Intravenous infusion of KYTRIL Injection should be prepared at the time of
400
administration. However, KYTRIL Injection has been shown to be stable for at least 24
401
hours when diluted in 0.9% Sodium Chloride or 5% Dextrose and stored at room
402
temperature under normal lighting conditions.
403
As a general precaution, KYTRIL Injection should not be mixed in solution with other
404
drugs. Parenteral drug products should be inspected visually for particulate matter and
405
discoloration before administration whenever solution and container permit.
406
Pediatric Patients
407
The recommended dose in pediatric patients 2 to 16 years of age is 10 mcg/kg (see
408
CLINICAL TRIALS). Pediatric patients under 2 years of age have not been studied.
409
Geriatric Patients, Renal Failure Patients or Hepatically Impaired Patients
410
No dosage adjustment is recommended (see CLINICAL PHARMACOLOGY:
411
Pharmacokinetics).
412
Prevention and Treatment of Postoperative Nausea and Vomiting
413
The recommended dosage for prevention of postoperative nausea and vomiting is 1 mg of
414
KYTRIL, undiluted, administered intravenously over 30 seconds, before induction of
415
anesthesia or immediately before reversal of anesthesia.
416
The recommended dosage for the treatment of nausea and/or vomiting after surgery is 1
417
mg of KYTRIL, undiluted, administered intravenously over 30 seconds.
418
Pediatric Patients
419
Safety and effectiveness of KYTRIL Injection have not been established in pediatric
420
patients for the prevention or treatment of postoperative nausea or vomiting.
421
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
16
Geriatric Patients, Renal Failure Patients or Hepatically Impaired Patients
422
No dosage adjustment is recommended (see CLINICAL PHARMACOLOGY:
423
Pharmacokinetics).
424
HOW SUPPLIED
425
KYTRIL Injection, 1 mg/1 mL (free base), is supplied in 1 mL Single-Use Vials and 4
426
mL Multi-Use Vials. CONTAINS BENZYL ALCOHOL.
427
NDC 0004-0239-09 (package of 1 Single-Use Vial)
428
NDC 0004-0240-09 (package of 1 Multi-Use Vial)
429
KYTRIL Injection, 0.1 mg/1 mL (free base), is supplied in 1 mL Single-Use Vials.
430
CONTAINS NO PRESERVATIVE.
431
NDC 0004-0242-08 (package of 5 Single-Use Vials)
432
Storage
433
Store single-use vials and multi-use vials at 25°C (77°F); excursions permitted to 15° to
434
30°C (59° to 86°F). [See USP Controlled Room Temperature]
435
Once the multi-use vial is penetrated, its contents should be used within 30 days.
436
Do not freeze. Protect from light.
437
438
Distributed by:
439
440
xxxxxxxx
441
xxxxxxxxUSA
442
443
Revised: Month Year
444
Copyright © 1998-2005 by Roche Laboratories Inc. All rights reserved.
445
446
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:47:10.344258
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/020239s018lbl.pdf', 'application_number': 20239, 'submission_type': 'SUPPL ', 'submission_number': 18}
|
12,356
|
______________________________________________________________________________________________________________________________________
______________________________________________________________________________________________________________________________________
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
KYTRIL safely and effectively. See full prescribing information for
KYTRIL.
KYTRIL® (granisetron hydrochloride) injection, for intravenous use
Initial U.S. Approval: 1993
--------------------------- INDICATIONS AND USAGE---------------------------
KYTRIL Injection is a serotonin-3 (5-HT3) receptor antagonist indicated for:
•
Prevention of nausea and/or vomiting associated with initial and repeat
courses of emetogenic cancer therapy, including high-dose cisplatin. (1)
•
Prevention and treatment of postoperative nausea and vomiting in adults.
(1)
-----------------------DOSAGE AND ADMINISTRATION ----------------------
Prevention of chemotherapy-induced nausea and vomiting (2.1):
•
Recommended dosage is 10 mcg/kg intravenously within 30 minutes
before initiation of chemotherapy
•
Pediatric patients (2 to 16 years): Recommended dosage is 10 mcg/kg
Prevention of postoperative nausea and vomiting (2.2):
•
Recommended dosage is 1 mg, undiluted, administered intravenously
over 30 seconds, before anesthetic induction or immediately before
reversal of anesthesia.
Treatment of postoperative nausea and vomiting (2.2):
•
Recommended dosage is 1 mg, undiluted, administered intravenously
over 30 seconds
--------------------- DOSAGE FORMS AND STRENGTHS---------------------
•
Injection 1 mg/mL (free base). (3)
•
Injection 0.1 mg/mL (free base). (3)
------------------------------CONTRAINDICATIONS-------------------------------
•
Hypersensitivity to granisetron or to any of its components. (4)
----------------------- WARNINGS AND PRECAUTIONS-----------------------
•
KYTRIL does not stimulate gastric or intestinal peristalsis and should
not be used instead of nasogastric suction. (5.1)
•
QT prolongation has been reported with KYTRIL. Use with caution in
patients with pre-existing arrhythmias or cardiac conduction disorders.
(5.2)
•
Hypersensitivity reactions, such as anaphylaxis, shortness of breath,
hypotension, and urticaria, may occur in patients with known
hypersensitivity to other selective 5-HT3 receptor antagonists. (5.3)
•
Contains benzyl alcohol. (5.4)
------------------------------ ADVERSE REACTIONS -----------------------------
Most common adverse reactions:
•
Chemotherapy-induced nausea and vomiting (≥3%): Headache, and
constipation (6.1)
•
Postoperative nausea and vomiting (≥2%): Pain, headache, fever,
abdominal pain and hepatic enzymes increased (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Genentech at
1-800-835-2555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
------------------------------ DRUG INTERACTIONS------------------------------
•
KYTRIL Injection has been administered safely with benzodiazepines,
neuroleptics, and anti-ulcer medications. (7)
•
Does not appear to interact with emetogenic cancer chemotherapies. (7)
•
Inducers or inhibitors of CYP450 enzymes may change the clearance
and therefore the half-life of granisetron. (7)
•
Coadministration of KYTRIL with drugs known to prolong the QT
interval and/or are arrhythmogenic may result in clinical consequences.
(7)
----------------------- USE IN SPECIFIC POPULATIONS ----------------------
•
Pregnancy: Use only if clearly needed. (8.1)
•
Nursing mothers: Caution should be exercised when administered to a
nursing woman. (8.3)
•
Pediatric use: Safety and efficacy in pediatric patients have not been
established for use in postoperative nausea and vomiting. (8.4)
•
Geriatric use: No differences in responses between the elderly and
younger patients were observed in reported clinical experience. (8.5)
See 17 for PATIENT COUNSELING INFORMATION.
Revised: April 2011
FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
2
DOSAGE AND ADMINISTRATION
2.1 Prevention of Chemotherapy-Induced Nausea and Vomiting
2.2 Prevention and Treatment of Postoperative Nausea and Vomiting
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1 Gastric or Intestinal Peristalsis
5.2 Cardiovascular Events
5.3 Hypersensitivity Reactions
5.4 Benzyl Alcohol
6
ADVERSE REACTIONS
6.1 Clinical Trials Experience
6.2 Postmarketing Experience
7
DRUG INTERACTIONS
8
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
14.1 Chemotherapy-Induced Nausea and Vomiting
14.2 Postoperative Nausea and Vomiting
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information are not
listed.
Reference ID: 2940404
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
FULL PRESCRIBING INFORMATION
1
INDICATIONS AND USAGE
KYTRIL Injection is a serotonin-3 (5-HT3) receptor antagonist indicated for:
• The prevention of nausea and/or vomiting associated with initial and repeat courses of emetogenic cancer
therapy, including high-dose cisplatin.
• The prevention and treatment of postoperative nausea and vomiting in adults. As with other antiemetics,
routine prophylaxis is not recommended in patients in whom there is little expectation that nausea and/or
vomiting will occur postoperatively. In patients where nausea and/or vomiting must be avoided during the
postoperative period, KYTRIL Injection is recommended even where the incidence of postoperative nausea
and/or vomiting is low.
2
DOSAGE AND ADMINISTRATION
2.1
Prevention of Chemotherapy-Induced Nausea and Vomiting
Adult Patients
The recommended dosage for KYTRIL Injection is 10 mcg/kg administered intravenously within 30 minutes
before initiation of chemotherapy, and only on the day(s) chemotherapy is given.
Infusion Preparation
KYTRIL Injection may be administered intravenously either undiluted over 30 seconds, or diluted with 0.9%
Sodium Chloride or 5% Dextrose and infused over 5 minutes.
Stability
Intravenous infusion of KYTRIL Injection should be prepared at the time of administration. However, KYTRIL
Injection has been shown to be stable for at least 24 hours when diluted in 0.9% Sodium Chloride or 5%
Dextrose and stored at room temperature under normal lighting conditions.
As a general precaution, KYTRIL Injection should not be mixed in solution with other drugs. Parenteral drug
products should be inspected visually for particulate matter and discoloration before administration whenever
solution and container permit.
Pediatric Patients
The recommended dose in pediatric patients 2 to 16 years of age is 10 mcg/kg [see Clinical Studies (14)].
Pediatric patients under 2 years of age have not been studied.
2.2
Prevention and Treatment of Postoperative Nausea and Vomiting
Adult Patients
The recommended dosage for prevention of postoperative nausea and vomiting is 1 mg of KYTRIL, undiluted,
administered intravenously over 30 seconds, before induction of anesthesia or immediately before reversal of
anesthesia.
The recommended dosage for the treatment of nausea and/or vomiting after surgery is 1 mg of KYTRIL,
undiluted, administered intravenously over 30 seconds.
3
DOSAGE FORMS AND STRENGTHS
Single-Use Vials for Injection: 1 mg/mL, 0.1 mg/mL
Multi-Use Vials for Injection: 4 mg/4 mL
Reference ID: 2940404
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For current labeling information, please visit https://www.fda.gov/drugsatfda
4
CONTRAINDICATIONS
KYTRIL Injection is contraindicated in patients with known hypersensitivity (eg. anaphylaxis, shortness of
breath, hypotension, urticaria) to the drug or to any of its components.
5
WARNINGS AND PRECAUTIONS
5.1
Gastric or Intestinal Peristalsis
KYTRIL is not a drug that stimulates gastric or intestinal peristalsis. It should not be used instead of nasogastric
suction. The use of KYTRIL in patients following abdominal surgery or in patients with chemotherapy-induced
nausea and vomiting may mask a progressive ileus and/or gastric distention.
5.2
Cardiovascular Events
An adequate QT assessment has not been conducted, but QT prolongation has been reported with KYTRIL.
Therefore, KYTRIL should be used with caution in patients with pre-existing arrhythmias or cardiac conduction
disorders, as this might lead to clinical consequences. Patients with cardiac disease, on cardio-toxic
chemotherapy, with concomitant electrolyte abnormalities and/or on concomitant medications that prolong the
QT interval are particularly at risk.
5.3
Hypersensitivity Reactions
Hypersensitivity reactions (eg. anaphylaxis, shortness of breath, hypotension, urticaria) may occur in patients
who have exhibited hypersensitivity to other selective 5-HT3 receptor antagonists
5.4
Benzyl Alcohol
KYTRIL 1 mg/mL contains benzyl alcohol. Benzyl alcohol, a component of KYTRIL 1 mg/mL, has been
associated with serious adverse reactions and death, particularly in neonates. The “gasping syndrome,”
characterized by central nervous system depression, metabolic acidosis, gasping respirations, and high levels of
benzyl alcohol and metabolites in blood and urine, has been associated with benzyl alcohol dosages
>99 mg/kg/day in neonates and low birth-weight neonates. Additional symptoms may include gradual
neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown,
hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Although normal therapeutic
doses of this product deliver amounts of benzyl alcohol that are substantially lower than those reported in
association with the “gasping syndrome,” the minimum amount of benzyl alcohol at which toxicity may occur
is not known. Premature and low birth-weight infants, as well as patients receiving high dosages, may be more
likely to develop toxicity. Practitioners administering this and other medications containing benzyl alcohol
should consider the combined daily metabolic load of benzyl alcohol from all sources.
6
ADVERSE REACTIONS
QT prolongation has been reported with KYTRIL [see Warnings and Precautions (5.2) and Drug Interactions
(7)].
6.1
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the
clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not
reflect the rates observed in patients.
Chemotherapy-Induced Nausea and Vomiting
The following have been reported during controlled clinical trials or in the routine management of patients. The
percentage figures are based on clinical trial experience only. Table 1 gives the comparative frequencies of the
two most commonly reported adverse reactions (≥3%) in patients receiving KYTRIL Injection, in single-day
chemotherapy trials. These patients received chemotherapy, primarily cisplatin, and intravenous fluids during
the 24-hour period following KYTRIL Injection administration. Reactions were generally recorded over seven
days post-KYTRIL Injection administration.
Reference ID: 2940404
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 1
Principal Adverse Reactions in Clinical Trials — Single-Day Chemotherapy
Percent of Patients With Reaction
KYTRIL Injection
Comparator1
40 mcg/kg
(n=1268)
(n=422)
Headache
14%
6%
Constipation
3%
3%
1
Metoclopramide/dexamethasone and phenothiazines/dexamethasone.
Additional adverse events reported in clinical trials were asthenia, somnolence and diarrhea.
In over 3,000 patients receiving KYTRIL Injection (2 to 160 mcg/kg) in single-day and multiple-day clinical
trials with emetogenic cancer therapies, adverse events, other than those adverse reactions listed in Table 1,
were observed; attribution of many of these events to KYTRIL is uncertain.
Hepatic: In comparative trials, mainly with cisplatin regimens, elevations of AST and ALT (>2 times the upper
limit of normal) following administration of KYTRIL Injection occurred in 2.8% and 3.3% of patients,
respectively. These frequencies were not significantly different from those seen with comparators (AST: 2.1%;
ALT: 2.4%).
Cardiovascular: Hypertension (2%); hypotension, arrhythmias such as sinus bradycardia, atrial fibrillation,
varying degrees of A-V block, ventricular ectopy including non-sustained tachycardia, and ECG abnormalities
have been observed rarely.
Central Nervous System: Agitation, anxiety, CNS stimulation and insomnia were seen in less than 2% of
patients. Extrapyramidal syndrome occurred rarely and only in the presence of other drugs associated with this
syndrome.
Hypersensitivity: Rare cases of hypersensitivity reactions, sometimes severe (eg, anaphylaxis, shortness of
breath, hypotension, urticaria) have been reported.
Other: Fever (3%), taste disorder (2%), skin rashes (1%). In multiple-day comparative studies, fever occurred
more frequently with KYTRIL Injection (8.6%) than with comparative drugs (3.4%, P<0.014), which usually
included dexamethasone.
Postoperative Nausea and Vomiting
The adverse reactions listed in Table 2 were reported in ≥2% of adults receiving KYTRIL Injection 1 mg during
controlled clinical trials.
Reference ID: 2940404
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 2
Adverse Reactions in Controlled Clinical Trials in Postoperative Nausea and Vomiting
(Reported in ≥ 2% of Adults Receiving KYTRIL Injection 1 mg)
Percent of Patients With Reaction
KYTRIL Injection
Placebo
1 mg
(n=267)
(n=266)
Pain
10.1
8.3
Headache
8.6
7.1
Fever
7.9
4.5
Abdominal Pain
6.0
6.0
Hepatic Enzymes Increased
5.6
4.1
Dizziness
4.1
3.4
Diarrhea
3.4
1.1
Flatulence
3.0
3.0
Dyspepsia
3.0
1.9
Oliguria
2.2
1.5
Coughing
2.2
1.1
Additional adverse events reported in clinical trials were constipation, anemia, insomnia, bradycardia,
leukocytosis, anxiety, hypotension, infection, hypertension, and urinary tract infection.
In a clinical study conducted in Japan, the types of adverse events differed notably from those reported above in
Table 2. The adverse events in the Japanese study that occurred in ≥2% of patients and were more frequent with
KYTRIL 1 mg than with placebo were: fever (56% to 50%), sputum increased (2.7% to 1.7%), and dermatitis
(2.7% to 0%).
6.2
Postmarketing Experience
The following adverse reactions have been identified during post approval use of KYTRIL. Because these
reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably
estimate their frequency or establish a causal relationship to KYTRIL exposure.
QT prolongation has been reported with KYTRIL [see Warnings and Precautions (5.2) and Drug Interactions
(7)].
7
DRUG INTERACTIONS
Granisetron does not induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system in vitro. There
have been no definitive drug-drug interaction studies to examine pharmacokinetic or pharmacodynamic
interaction with other drugs; however, in humans, KYTRIL Injection has been safely administered with drugs
representing benzodiazepines, neuroleptics and anti-ulcer medications commonly prescribed with antiemetic
treatments. KYTRIL Injection also does not appear to interact with emetogenic cancer chemotherapies. Because
granisetron is metabolized by hepatic cytochrome P-450 drug-metabolizing enzymes, inducers or inhibitors of
these enzymes may change the clearance and, hence, the half-life of granisetron. No specific interaction studies
have been conducted in anesthetized patients. In addition, the activity of the cytochrome P-450 subfamily 3A4
(involved in the metabolism of some of the main narcotic analgesic agents) is not modified by KYTRIL in vitro.
In in vitro human microsomal studies, ketoconazole inhibited ring oxidation of KYTRIL. However, the clinical
significance of in vivo pharmacokinetic interactions with ketoconazole is not known. In a human
pharmacokinetic study, hepatic enzyme induction with phenobarbital resulted in a 25% increase in total plasma
clearance of intravenous KYTRIL. The clinical significance of this change is not known.
QT prolongation has been reported with KYTRIL. Use of KYTRIL in patients concurrently treated with drugs
known to prolong the QT interval and/or are arrhythmogenic may result in clinical consequences.
Reference ID: 2940404
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Pregnancy Category B
Reproduction studies have been performed in pregnant rats at intravenous doses up to 9 mg/kg/day
(54 mg/m2/day, 146 times the recommended human dose based on body surface area) and pregnant rabbits at
intravenous doses up to 3 mg/kg/day (35.4 mg/m2/day, 96 times the recommended human dose based on body
surface area) and have revealed no evidence of impaired fertility or harm to the fetus due to granisetron. There
are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies
are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Benzyl alcohol may cross the placenta. KYTRIL Injection 1 mg/mL is preserved with benzyl alcohol and
should be used in pregnancy only if the benefit outweighs the potential risk.
8.3
Nursing Mothers
It is not known whether granisetron is excreted in human milk. Because many drugs are excreted in human
milk, caution should be exercised when KYTRIL Injection is administered to a nursing woman.
8.4
Pediatric Use
Benzyl alcohol, a component of KYTRIL 1 mg/mL, has been associated with serious adverse reactions and
death, particularly in neonates [see Warnings and Precautions (5.4)].
Chemotherapy-Induced Nausea and Vomiting
[See Dosage and Administration (2)] for use in chemotherapy-induced nausea and vomiting in pediatric patients
2 to 16 years of age. Safety and effectiveness in pediatric patients under 2 years of age have not been
established.
Postoperative Nausea and Vomiting
Safety and efficacy have not been established in pediatric patients for the prevention of postoperative nausea
and vomiting (PONV). Granisetron has been evaluated in a pediatric patient clinical trial for use in the
prevention of PONV. Due to the lack of efficacy and the QT prolongation observed in this trial, use of
granisetron for the prevention of PONV in children is not recommended. The trial was a prospective,
multicenter, randomized, double-blind, parallel-group trial that evaluated 157 children aged 2 to 16 years who
were undergoing elective surgery for tonsillectomy or adenotonsillectomy. The purpose of the trial was to
assess two dose levels (20 mcg/kg and 40 mcg/kg) of intravenous granisetron in the prevention of PONV. There
was no active comparator or placebo. The primary endpoint was total control of nausea and vomiting (defined
as no nausea, vomiting/retching, or use of rescue medication) in the 24 hours following surgery. Efficacy was
not established due to lack of a dose response.
The trial also included standard 12 lead ECGs performed pre-dose and after the induction of anesthesia. ECGs
were repeated at the end of surgery after the administration of granisetron and just prior to reversal of
anesthesia. QT prolongation was seen at both dose levels. Five patients in this trial experienced an increase of ≥
60 msec in QTcF. In addition, there were two patients whose QTcF was ≥ 500 msec. Interpretation of the QTcF
prolongation was confounded by multiple factors, including the use of concomitant medication and the lack of
either a placebo or active control. A thorough QT trial in adults has not been performed.
Other adverse events that occurred in the study included: vomiting (5-8%), post-procedural hemorrhage (3-5%),
and dehydration (0-5%).
Pediatric patients under 2 years of age have not been studied.
Reference ID: 2940404
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
8.5
Geriatric Use
During chemotherapy clinical trials, 713 patients 65 years of age or older received KYTRIL Injection. The
safety and effectiveness were similar in patients of various ages.
During postoperative nausea and vomiting clinical trials, 168 patients 65 years of age or older, of which 47 were
75 years of age or older, received KYTRIL Injection. Clinical studies of KYTRIL Injection did not include
sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from
younger subjects. Other reported clinical experience has not identified differences in responses between the
elderly and younger patients.
10
OVERDOSAGE
There is no specific antidote for KYTRIL Injection overdosage. In case of overdosage, symptomatic treatment
should be given. Overdosage of up to 38.5 mg of granisetron hydrochloride injection has been reported without
symptoms or only the occurrence of a slight headache.
11
DESCRIPTION
KYTRIL (granisetron hydrochloride) Injection is a serotonin-3 (5-HT3) receptor antagonist. Chemically it is
endo-N-(9-methyl-9-azabicyclo [3.3.1] non-3-yl)-1-methyl-1H-indazole-3-carboxamide hydrochloride with a
molecular weight of 348.9 (312.4 free base). Its empirical formula is C18H24N4O•HCl, while its chemical
structure is: structural formula
granisetron hydrochloride
Granisetron hydrochloride is a white to off-white solid that is readily soluble in water and normal saline at
20°C. KYTRIL Injection is a clear, colorless, sterile, nonpyrogenic, aqueous solution for intravenous
administration.
KYTRIL 1 mg/mL is available in 1 mL single-use and 4 mL multi-use vials. KYTRIL 0.1 mg/mL is available
in a 1 mL single-use vial.
1 mg/mL: Each 1 mL contains 1.12 mg granisetron hydrochloride equivalent to granisetron, 1 mg; sodium
chloride, 9 mg; citric acid, 2 mg; and benzyl alcohol, 10 mg, as a preservative. The solution’s pH ranges from
4.0 to 6.0.
0.1 mg/mL: Each 1 mL contains 0.112 mg granisetron hydrochloride equivalent to granisetron, 0.1 mg; sodium
chloride, 9 mg; citric acid, 2 mg. Contains no preservative. The solution’s pH ranges from 4.0 to 6.0.
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
Granisetron is a selective 5-hydroxytryptamine3 (5-HT3) receptor antagonist with little or no affinity for other
serotonin receptors, including 5-HT1; 5-HT1A; 5-HT1B/C; 5-HT2; for alpha1-, alpha2- or beta-adrenoreceptors; for
dopamine-D2; or for histamine-H1; benzodiazepine; picrotoxin or opioid receptors.
Reference ID: 2940404
12
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Serotonin receptors of the 5-HT3 type are located peripherally on vagal nerve terminals and centrally in the
chemoreceptor trigger zone of the area postrema. During chemotherapy-induced vomiting, mucosal
enterochromaffin cells release serotonin, which stimulates 5-HT3 receptors. This evokes vagal afferent
discharge and may induce vomiting. Animal studies demonstrate that, in binding to 5-HT3 receptors, granisetron
blocks serotonin stimulation and subsequent vomiting after emetogenic stimuli such as cisplatin. In the ferret
animal model, a single granisetron injection prevented vomiting due to high-dose cisplatin or arrested vomiting
within 5 to 30 seconds.
In most human studies, granisetron has had little effect on blood pressure, heart rate or ECG. No evidence of an
effect on plasma prolactin or aldosterone concentrations has been found in other studies.
KYTRIL Injection exhibited no effect on oro-cecal transit time in normal volunteers given a single intravenous
infusion of 50 mcg/kg or 200 mcg/kg. Single and multiple oral doses slowed colonic transit in normal
volunteers.
12.3
Pharmacokinetics
Chemotherapy-Induced Nausea and Vomiting
In adult cancer patients undergoing chemotherapy and in volunteers, mean pharmacokinetic data obtained from
an infusion of a single 40 mcg/kg dose of KYTRIL Injection are shown in Table 3.
Table 3
Pharmacokinetic Parameters in Adult Cancer Patients Undergoing Chemotherapy and
in Volunteers, Following a Single Intravenous 40 mcg/kg Dose of KYTRIL Injection
Peak Plasma
Terminal Phase
Total
Volume of
Concentration Plasma Half-Life
Clearance
Distribution
(ng/mL)
(h)
(L/h/kg)
(L/kg)
Cancer Patients
Mean
63.8*
8.95*
0.38*
3.07*
Range
18.0 to 176
0.90 to 31.1
0.14 to 1.54
0.85 to 10.4
Volunteers
21 to 42 years
Mean
64.3†
4.91†
0.79†
3.04†
Range
11.2 to 182
0.88 to 15.2
0.20 to 2.56
1.68 to 6.13
65 to 81 years
Mean
57.0†
7.69†
0.44†
3.97†
Range
14.6 to 153
2.65 to 17.7
0.17 to 1.06
1.75 to 7.01
*5-minute infusion.
†3-minute infusion.
Distribution
Plasma protein binding is approximately 65% and granisetron distributes freely between plasma and red blood
cells.
Metabolism
Granisetron metabolism involves N-demethylation and aromatic ring oxidation followed by conjugation. In
vitro liver microsomal studies show that granisetron’s major route of metabolism is inhibited by ketoconazole,
suggestive of metabolism mediated by the cytochrome P-450 3A subfamily. Animal studies suggest that some
of the metabolites may also have 5-HT3 receptor antagonist activity.
Reference ID: 2940404
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Elimination
Clearance is predominantly by hepatic metabolism. In normal volunteers, approximately 12% of the
administered dose is eliminated unchanged in the urine in 48 hours. The remainder of the dose is excreted as
metabolites, 49% in the urine, and 34% in the feces.
Subpopulations
Gender
There was high inter- and intra-subject variability noted in these studies. No difference in mean AUC was found
between males and females, although males had a higher Cmax generally.
Elderly
The ranges of the pharmacokinetic parameters in elderly volunteers (mean age 71 years), given a single 40
mcg/kg intravenous dose of KYTRIL Injection, were generally similar to those in younger healthy volunteers;
mean values were lower for clearance and longer for half-life in the elderly patients (see Table 3).
Pediatric Patients
A pharmacokinetic study in pediatric cancer patients (2 to 16 years of age), given a single 40 mcg/kg
intravenous dose of KYTRIL Injection, showed that volume of distribution and total clearance increased with
age. No relationship with age was observed for peak plasma concentration or terminal phase plasma half-life.
When volume of distribution and total clearance are adjusted for body weight, the pharmacokinetics of
granisetron are similar in pediatric and adult cancer patients.
Renal Failure Patients
Total clearance of granisetron was not affected in patients with severe renal failure who received a single 40
mcg/kg intravenous dose of KYTRIL Injection.
Hepatically Impaired Patients
A pharmacokinetic study in patients with hepatic impairment due to neoplastic liver involvement showed that
total clearance was approximately halved compared to patients without hepatic impairment. Given the wide
variability in pharmacokinetic parameters noted in patients, dosage adjustment in patients with hepatic
functional impairment is not necessary.
Postoperative Nausea and Vomiting
In adult patients (age range, 18 to 64 years) recovering from elective surgery and receiving general balanced
anesthesia, mean pharmacokinetic data obtained from a single 1 mg dose of KYTRIL Injection administered
intravenously over 30 seconds are shown in Table 4.
Table 4
Pharmacokinetic Parameters in 16 Adult Surgical Patients Following a Single
Intravenous 1 mg Dose of KYTRIL Injection
Terminal Phase
Total
Volume of
Plasma Half-Life
Clearance
Distribution
(h)
(L/h/kg)
(L/kg)
Mean
8.63
0.28
2.42
Range
1.77 to 17.73
0.07 to 0.71
0.71 to 4.13
The pharmacokinetics of granisetron in patients undergoing surgery were similar to those seen in cancer
patients undergoing chemotherapy.
Reference ID: 2940404
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
In a 24-month carcinogenicity study, rats were treated orally with granisetron 1, 5 or 50 mg/kg/day (6, 30 or
300 mg/m2/day). The 50 mg/kg/day dose was reduced to 25 mg/kg/day (150 mg/m2/day) during week 59 due to
toxicity. For a 50 kg person of average height (1.46 m2 body surface area), these doses represent 16, 81 and 405
times the recommended clinical dose (0.37 mg/m2, iv) on a body surface area basis. There was a statistically
significant increase in the incidence of hepatocellular carcinomas and adenomas in males treated with
5 mg/kg/day (30 mg/m2/day, 81 times the recommended human dose based on body surface area) and above,
and in females treated with 25 mg/kg/day (150 mg/m2/day, 405 times the recommended human dose based on
body surface area). No increase in liver tumors was observed at a dose of 1 mg/kg/day (6 mg/m2/day, 16 times
the recommended human dose based on body surface area) in males and 5 mg/kg/day (30 mg/m2/day, 81 times
the recommended human dose based on body surface area) in females. In a 12-month oral toxicity study,
treatment with granisetron 100 mg/kg/day (600 mg/m2/day, 1622 times the recommended human dose based on
body surface area) produced hepatocellular adenomas in male and female rats while no such tumors were found
in the control rats. A 24-month mouse carcinogenicity study of granisetron did not show a statistically
significant increase in tumor incidence, but the study was not conclusive.
Because of the tumor findings in rat studies, KYTRIL Injection should be prescribed only at the dose and for
the indication recommended [see Indications and Usage (1) and Dosage and Administration (2)].
Granisetron was not mutagenic in an in vitro Ames test and mouse lymphoma cell forward mutation assay, and
in vivo mouse micronucleus test and in vitro and ex vivo rat hepatocyte UDS assays. It, however, produced a
significant increase in UDS in HeLa cells in vitro and a significant increased incidence of cells with polyploidy
in an in vitro human lymphocyte chromosomal aberration test.
Granisetron at subcutaneous doses up to 6 mg/kg/day (36 mg/m2/day, 97 times the recommended human dose
based on body surface area) was found to have no effect on fertility and reproductive performance of male and
female rats.
14
CLINICAL STUDIES
14.1
Chemotherapy-Induced Nausea and Vomiting
Single-Day Chemotherapy
Cisplatin-Based Chemotherapy
In a double-blind, placebo-controlled study in 28 cancer patients, KYTRIL Injection, administered as a single
intravenous infusion of 40 mcg/kg, was significantly more effective than placebo in preventing nausea and
vomiting induced by cisplatin chemotherapy (see Table 5).
Table 5
Prevention of Chemotherapy-Induced Nausea and Vomiting — Single-Day Cisplatin
Therapy1
Number of Patients
Response Over 24 Hours
Complete Response2
No Vomiting
No More Than Mild Nausea
KYTRIL
Injection
14
93%
93%
93%
Placebo
14
7%
14%
7%
P-Value
<0.001
<0.001
<0.001
1 Cisplatin administration began within 10 minutes of KYTRIL Injection infusion and continued for 1.5 to 3.0
hours. Mean cisplatin dose was 86 mg/m2 in the KYTRIL Injection group and 80 mg/m2 in the placebo group.
2 No vomiting and no moderate or severe nausea.
Reference ID: 2940404
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For current labeling information, please visit https://www.fda.gov/drugsatfda
KYTRIL Injection was also evaluated in a randomized dose response study of cancer patients receiving
cisplatin ≥75 mg/m2. Additional chemotherapeutic agents included: anthracyclines, carboplatin, cytostatic
antibiotics, folic acid derivatives, methylhydrazine, nitrogen mustard analogs, podophyllotoxin derivatives,
pyrimidine analogs, and vinca alkaloids. KYTRIL Injection doses of 10 and 40 mcg/kg were superior to
2 mcg/kg in preventing cisplatin-induced nausea and vomiting, but 40 mcg/kg was not significantly superior to
10 mcg/kg (see Table 6).
Table 6
Prevention of Chemotherapy-Induced Nausea and Vomiting — Single-Day High-Dose
Cisplatin Therapy1
KYTRIL Injection
P-Value
(mcg/kg)
(vs. 2 mcg/kg)
2
10
40
10
40
Number of Patients
52
52
53
Response Over 24 Hours
Complete Response2
31%
62%
68%
<0.002
<0.001
No Vomiting
38%
65%
74%
<0.001
<0.001
No More Than Mild Nausea
58%
75%
79%
NS
0.007
1 Cisplatin administration began within 10 minutes of KYTRIL Injection infusion and continued for 2.6 hours
(mean). Mean cisplatin doses were 96 to 99 mg/m2.
2 No vomiting and no moderate or severe nausea.
KYTRIL Injection was also evaluated in a double-blind, randomized dose response study of 353 patients
stratified for high (≥80 to 120 mg/m2) or low (50 to 79 mg/m2) cisplatin dose. Response rates of patients for
both cisplatin strata are given in Table 7.
Table 7
Prevention of Chemotherapy-Induced Nausea and Vomiting — Single-Day High-Dose
and Low-Dose Cisplatin Therapy1
KYTRIL Injection
P-Value
(mcg/kg)
(vs. 5 mcg/kg)
5
10
20
40
10
20
40
High-Dose Cisplatin
Number of Patients
40
49
48
47
Response Over 24 Hours
Complete Response2
18%
41%
40%
47%
0.018
0.025
0.004
No Vomiting
28%
47%
44%
53%
NS
NS
0.016
No Nausea
15%
35%
38%
43%
0.036
0.019
0.005
Low-Dose Cisplatin
Number of Patients
42
41
40
46
Response Over 24 Hours
Complete Response2
29%
56%
58%
41%
0.012
0.009
NS
No Vomiting
36%
63%
65%
43%
0.012
0.008
NS
No Nausea
29%
56%
38%
33%
0.012
NS
NS
1 Cisplatin administration began within 10 minutes of KYTRIL Injection infusion and continued for 2 hours
(mean). Mean cisplatin doses were 64 and 98 mg/m2 for low and high strata.
2 No vomiting and no use of rescue antiemetic.
For both the low and high cisplatin strata, the 10, 20, and 40 mcg/kg doses were more effective than the
5 mcg/kg dose in preventing nausea and vomiting within 24 hours of chemotherapy administration. The
10 mcg/kg dose was at least as effective as the higher doses.
Reference ID: 2940404
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Moderately Emetogenic Chemotherapy
KYTRIL Injection, 40 mcg/kg, was compared with the combination of chlorpromazine (50 to 200 mg/24 hours)
and dexamethasone (12 mg) in patients treated with moderately emetogenic chemotherapy, including primarily
carboplatin >300 mg/m2, cisplatin 20 to 50 mg/m2 and cyclophosphamide >600 mg/m2. KYTRIL Injection was
superior to the chlorpromazine regimen in preventing nausea and vomiting (see Table 8).
Table 8
Prevention of Chemotherapy-Induced Nausea and Vomiting—Single-Day Moderately
Emetogenic Chemotherapy
KYTRIL
Chlorpromazine1
P-Value
Injection
Number of Patients
133
133
Response Over 24 Hours
Complete Response2
68%
47%
<0.001
No Vomiting
73%
53%
<0.001
No More Than Mild Nausea
77%
59%
<0.001
1
Patients also received dexamethasone, 12 mg.
2
No vomiting and no moderate or severe nausea.
In other studies of moderately emetogenic chemotherapy, no significant difference in efficacy was found
between KYTRIL doses of 40 mcg/kg and 160 mcg/kg.
Repeat-Cycle Chemotherapy
In an uncontrolled trial, 512 cancer patients received KYTRIL Injection, 40 mcg/kg, prophylactically, for two
cycles of chemotherapy, 224 patients received it for at least four cycles, and 108 patients received it for at least
six cycles. KYTRIL Injection efficacy remained relatively constant over the first six repeat cycles, with
complete response rates (no vomiting and no moderate or severe nausea in 24 hours) of 60% to 69%. No
patients were studied for more than 15 cycles.
Pediatric Studies
A randomized double-blind study evaluated the 24-hour response of 80 pediatric cancer patients (age 2 to 16
years) to KYTRIL Injection 10, 20 or 40 mcg/kg. Patients were treated with cisplatin ≥60 mg/m2, cytarabine ≥3
g/m2, cyclophosphamide ≥1 g/m2 or nitrogen mustard ≥6 mg/m2 (see Table 9).
Table 9
Prevention of Chemotherapy-Induced Nausea and Vomiting in Pediatric Patients
KYTRIL Injection Dose (mcg/kg)
10
20
40
Number of Patients
29
26
25
Median Number of Vomiting Episodes
2
3
1
Complete Response Over 24 Hours1
21%
31%
32%
1
No vomiting and no moderate or severe nausea.
A second pediatric study compared KYTRIL Injection 20 mcg/kg to chlorpromazine plus dexamethasone in 88
patients treated with ifosfamide ≥3 g/m2/day for two or three days. KYTRIL Injection was administered on each
day of ifosfamide treatment. At 24 hours, 22% of KYTRIL Injection patients achieved complete response (no
vomiting and no moderate or severe nausea in 24 hours) compared with 10% on the chlorpromazine regimen.
The median number of vomiting episodes with KYTRIL Injection was 1.5; with chlorpromazine it was 7.0.
Reference ID: 2940404
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
14.2
Postoperative Nausea and Vomiting
Prevention of Postoperative Nausea and Vomiting
The efficacy of KYTRIL Injection for prevention of postoperative nausea and vomiting was evaluated in 868
patients, of which 833 were women, 35 men, 484 Caucasians, 348 Asians, 18 Blacks, 18 Other, with 61 patients
65 years or older. KYTRIL was evaluated in two randomized, double-blind, placebo-controlled studies in
patients who underwent elective gynecological surgery or cholecystectomy and received general anesthesia.
Patients received a single intravenous dose of KYTRIL Injection (0.1 mg, 1 mg or 3 mg) or placebo either 5
minutes before induction of anesthesia or immediately before reversal of anesthesia. The primary endpoint was
the proportion of patients with no vomiting for 24 hours after surgery. Episodes of nausea and vomiting and use
of rescue antiemetic therapy were recorded for 24 hours after surgery. In both studies, KYTRIL Injection
(1 mg) was more effective than placebo in preventing postoperative nausea and vomiting (see Table 10). No
additional benefit was seen in patients who received the 3 mg dose.
Table 10
Prevention of Postoperative Nausea and Vomiting in Adult Patients
Study and Efficacy Endpoint
Placebo
KYTRIL
KYTRIL
KYTRIL
0.1 mg
1 mg
3 mg
Study 1
Number of Patients
133
132
134
128
No Vomiting
0 to 24 hours
34%
45%
63%**
62%**
No Nausea
0 to 24 hours
22%
28%
50%**
42%**
No Nausea or Vomiting
0 to 24 hours
18%
27%
49%**
42%**
No Use of Rescue Antiemetic
Therapy
0 to 24 hours
60%
67%
75%*
77%*
Study 2
Number of Patients
117
–
110
114
No Vomiting
0 to 24 hours
56%
–
77%**
75%*
No Nausea
0 to 24 hours
37%
–
59%**
56%*
*P<0.05
**P<0.001 versus placebo
Note: No Vomiting = no vomiting and no use of rescue antiemetic therapy; No Nausea = no nausea and no use
of rescue antiemetic therapy
Gender/Race
There were too few male and Black patients to adequately assess differences in effect in either population.
Treatment of Postoperative Nausea and Vomiting
The efficacy of KYTRIL Injection for treatment of postoperative nausea and vomiting was evaluated in 844
patients, of which 731 were women, 113 men, 777 Caucasians, 6 Asians, 41 Blacks, 20 Other, with 107 patients
65 years or older. KYTRIL Injection was evaluated in two randomized, double-blind, placebo-controlled studies
of adult surgical patients who received general anesthesia with no prophylactic antiemetic agent, and who
experienced nausea or vomiting within 4 hours postoperatively. Patients received a single intravenous dose of
KYTRIL Injection (0.1 mg, 1 mg or 3 mg) or placebo after experiencing postoperative nausea or vomiting.
Episodes of nausea and vomiting and use of rescue antiemetic therapy were recorded for 24 hours after
Reference ID: 2940404
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
administration of study medication. KYTRIL Injection was more effective than placebo in treating
postoperative nausea and vomiting (see Table 11). No additional benefit was seen in patients who received the
3 mg dose.
Table 11
Treatment of Postoperative Nausea and Vomiting in Adult Patients
Study and Efficacy Endpoint
Placebo
KYTRIL
KYTRIL
KYTRIL
0.1 mg
1 mg
3 mg
Study 3
Number of Patients
133
128
133
125
No Vomiting
0 to 6 hours
26%
53%***
58%***
60%***
0 to 24 hours
20%
38%***
46%***
49%***
No Nausea
0 to 6 hours
17%
40%***
41%***
42%***
0 to 24 hours
13%
27%**
30%**
37%***
No Use of Rescue Antiemetic
Therapy
0 to 6 hours
–
–
–
–
0 to 24 hours
33%
51%**
61%***
61%***
Study 4
Number of Patients (All
162
163
–
–
Patients)
No Vomiting
0 to 6 hours
20%
32%*
–
–
0 to 24 hours
14%
23%*
–
–
No Nausea
0 to 6 hours
13%
18%
–
–
0 to 24 hours
9%
14%
–
–
No Nausea or Vomiting
0 to 6 hours
13%
18%
–
–
0 to 24 hours
9%
14%
–
–
No Use of Rescue Antiemetic
Therapy
0 to 6 hours
–
–
–
–
0 to 24 hours
24%
34%*
–
–
Number of Patients (Treated
86
103
–
–
for Vomiting)1
No Vomiting
0 to 6 hours
21%
27%
–
–
0 to 24 hours
14%
20%
–
–
*P<0.05
**P<0.01
***P<0.001 versus placebo
1 Protocol Specified Analysis: Patients who had vomiting prior to treatment
Note: No vomiting = no vomiting and no use of rescue antiemetic therapy; No nausea = no nausea and no use of
rescue antiemetic therapy
Gender/Race
There were too few male and Black patients to adequately assess differences in effect in either population.
Reference ID: 2940404
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
16
HOW SUPPLIED/STORAGE AND HANDLING
KYTRIL Injection, 1 mg/mL (free base), is supplied in 1 mL Single-Use Vials and 4 mg/4 mL Multi-Use Vials.
Contains benzyl alcohol.
NDC 0004-0239-09 (package of 1 Single-Use Vial)
NDC 0004-0240-09 (package of 1 Multi-Use Vial)
KYTRIL Injection, 0.1 mg/mL (free base), is supplied in 1 mL Single-Use Vials. Contains no preservative.
NDC 0004-0242-08 (package of 5 Single-Use Vials)
Store single-use vials and multi-use vials at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F).
[See USP Controlled Room Temperature]
Once the multi-use vial is penetrated, its contents should be used within 30 days.
Do not freeze. Protect from light.
17
PATIENT COUNSELING INFORMATION
Patients should be informed that the most common adverse reactions for the indication of chemotherapy
induced nausea and vomiting are headache and constipation (see Table 1).
Patients should be informed that the most common adverse reactions for the indication of postoperative nausea
and vomiting are pain, headache, fever, abdominal pain and hepatic enzyme increased (see Table 2).
Patients should be advised of the risk of allergic reactions if they have a prior allergic reaction to a class of
antiemetics known as 5-HT3 receptor antagonists.
Electrocardiogram changes (QT prolongation) have been reported with the use of KYTRIL. Patients should be
cautioned about the use of this drug if they have heart problems or take medications for heart problems.
Patients should be informed that KYTRIL Injection (1 mg/mL) contains benzyl alcohol and may cause serious
side effects in newborns. KYTRIL Injection 0.1 mg/mL contains no benzyl alcohol. company logo
KLI_243421_PI_2011_04_K
KYTRIL is a registered trademark of Hoffmann-La Roche Inc.
© xxxx Genentech, Inc. All rights reserved.
Reference ID: 2940404
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:47:10.538210
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020239s023lbl.pdf', 'application_number': 20239, 'submission_type': 'SUPPL ', 'submission_number': 23}
|
12,355
|
Roche logo
KYTRIL®
(granisetron hydrochloride)
INJECTION
Rx only
DESCRIPTION
KYTRIL (granisetron hydrochloride) Injection is an antinauseant and antiemetic agent.
Chemically it is endo-N-(9-methyl-9-azabicyclo [3.3.1] non-3-yl)-1-methyl-1H-indazole
3-carboxamide hydrochloride with a molecular weight of 348.9 (312.4 free base). Its
empirical formula is C18H24N4O•HCl, while its chemical structure is: Structural Formula
granisetron hydrochloride
Granisetron hydrochloride is a white to off-white solid that is readily soluble in water and
normal saline at 20°C. KYTRIL Injection is a clear, colorless, sterile, nonpyrogenic,
aqueous solution for intravenous administration.
KYTRIL 1 mg/1 mL is available in 1 mL single-use and 4 mL multi-use vials. KYTRIL
0.1 mg/1 mL is available in a 1 mL single-use vial.
1 mg/1 mL: Each 1 mL contains 1.12 mg granisetron hydrochloride equivalent to
granisetron, 1 mg; sodium chloride, 9 mg; citric acid, 2 mg; and benzyl alcohol, 10 mg,
as a preservative. The solution’s pH ranges from 4.0 to 6.0.
0.1 mg/1 mL: Each 1 mL contains 0.112 mg granisetron hydrochloride equivalent to
granisetron, 0.1 mg; sodium chloride, 9 mg; citric acid, 2 mg. Contains no preservative.
The solution’s pH ranges from 4.0 to 6.0.
CLINICAL PHARMACOLOGY
Granisetron is a selective 5-hydroxytryptamine3 (5-HT3) receptor antagonist with little or
no affinity for other serotonin receptors, including 5-HT1; 5-HT1A; 5-HT1B/C; 5-HT2; for
alpha1-, alpha2- or beta-adrenoreceptors; for dopamine-D2; or for histamine-H1;
benzodiazepine; picrotoxin or opioid receptors.
1
Serotonin receptors of the 5-HT3 type are located peripherally on vagal nerve terminals
and centrally in the chemoreceptor trigger zone of the area postrema. During
chemotherapy-induced vomiting, mucosal enterochromaffin cells release serotonin,
which stimulates 5-HT3 receptors. This evokes vagal afferent discharge and may induce
vomiting. Animal studies demonstrate that, in binding to 5-HT3 receptors, granisetron
blocks serotonin stimulation and subsequent vomiting after emetogenic stimuli such as
cisplatin. In the ferret animal model, a single granisetron injection prevented vomiting
due to high-dose cisplatin or arrested vomiting within 5 to 30 seconds.
In most human studies, granisetron has had little effect on blood pressure, heart rate or
ECG. No evidence of an effect on plasma prolactin or aldosterone concentrations has
been found in other studies.
KYTRIL Injection exhibited no effect on oro-cecal transit time in normal volunteers
given a single intravenous infusion of 50 mcg/kg or 200 mcg/kg. Single and multiple oral
doses slowed colonic transit in normal volunteers.
Pharmacokinetics
Chemotherapy-Induced Nausea and Vomiting
In adult cancer patients undergoing chemotherapy and in volunteers, mean
pharmacokinetic data obtained from an infusion of a single 40 mcg/kg dose of KYTRIL
Injection are shown in Table 1.
Table 1
Pharmacokinetic Parameters in Adult Cancer Patients
Undergoing Chemotherapy and in Volunteers, Following a
Single Intravenous 40 mcg/kg Dose of KYTRIL Injection
Peak Plasma
Concentration
(ng/mL)
Terminal Phase
Plasma Half-Life
(h)
Total
Clearance
(L/h/kg)
Volume of
Distribution
(L/kg)
Cancer Patients
Mean
Range
63.8*
18.0 to 176
8.95*
0.90 to 31.1
0.38*
0.14 to 1.54
3.07*
0.85 to 10.4
Volunteers
21 to 42 years
Mean
Range
65 to 81 years
Mean
Range
64.3†
11.2 to 182
57.0†
14.6 to 153
4.91†
0.88 to 15.2
7.69†
2.65 to 17.7
0.79†
0.20 to 2.56
0.44†
0.17 to 1.06
3.04†
1.68 to 6.13
3.97†
1.75 to 7.01
*5-minute infusion.
†3-minute infusion.
Distribution
Plasma protein binding is approximately 65% and granisetron distributes freely between
plasma and red blood cells.
2
Metabolism
Granisetron metabolism involves N-demethylation and aromatic ring oxidation followed
by conjugation. In vitro liver microsomal studies show that granisetron’s major route of
metabolism is inhibited by ketoconazole, suggestive of metabolism mediated by the
cytochrome P-450 3A subfamily. Animal studies suggest that some of the metabolites
may also have 5-HT3 receptor antagonist activity.
Elimination
Clearance is predominantly by hepatic metabolism. In normal volunteers, approximately
12% of the administered dose is eliminated unchanged in the urine in 48 hours. The
remainder of the dose is excreted as metabolites, 49% in the urine, and 34% in the feces.
Subpopulations
Gender
There was high inter- and intra-subject variability noted in these studies. No difference in
mean AUC was found between males and females, although males had a higher Cmax
generally.
Elderly
The ranges of the pharmacokinetic parameters in elderly volunteers (mean age 71 years),
given a single 40 mcg/kg intravenous dose of KYTRIL Injection, were generally similar
to those in younger healthy volunteers; mean values were lower for clearance and longer
for half-life in the elderly patients (see Table 1).
Pediatric Patients
A pharmacokinetic study in pediatric cancer patients (2 to 16 years of age), given a single
40 mcg/kg intravenous dose of KYTRIL Injection, showed that volume of distribution
and total clearance increased with age. No relationship with age was observed for peak
plasma concentration or terminal phase plasma half-life. When volume of distribution
and total clearance are adjusted for body weight, the pharmacokinetics of granisetron are
similar in pediatric and adult cancer patients.
Renal Failure Patients
Total clearance of granisetron was not affected in patients with severe renal failure who
received a single 40 mcg/kg intravenous dose of KYTRIL Injection.
Hepatically Impaired Patients
A pharmacokinetic study in patients with hepatic impairment due to neoplastic liver
involvement showed that total clearance was approximately halved compared to patients
without hepatic impairment. Given the wide variability in pharmacokinetic parameters
noted in patients, dosage adjustment in patients with hepatic functional impairment is not
necessary.
Postoperative Nausea and Vomiting
In adult patients (age range, 18 to 64 years) recovering from elective surgery and
receiving general balanced anesthesia, mean pharmacokinetic data obtained from a single
3
1 mg dose of KYTRIL Injection administered intravenously over 30 seconds are shown
in Table 2.
Table 2
Pharmacokinetic Parameters in 16 Adult Surgical Patients
Following a Single Intravenous 1 mg Dose of KYTRIL
Injection
Terminal Phase
Total
Volume of
Plasma Half-Life
Clearance
Distribution
(h)
(L/h/kg)
(L/kg)
Mean
8.63
0.28
2.42
Range
1.77 to 17.73
0.07 to 0.71
0.71 to 4.13
The pharmacokinetics of granisetron in patients undergoing surgery were similar to those
seen in cancer patients undergoing chemotherapy.
CLINICAL TRIALS
Chemotherapy-Induced Nausea and Vomiting
Single-Day Chemotherapy
Cisplatin-Based Chemotherapy
In a double-blind, placebo-controlled study in 28 cancer patients, KYTRIL Injection,
administered as a single intravenous infusion of 40 mcg/kg, was significantly more
effective than placebo in preventing nausea and vomiting induced by cisplatin
chemotherapy (see Table 3).
Table 3
Prevention of Chemotherapy-Induced Nausea and Vomiting
— Single-Day Cisplatin Therapy1
Number of Patients
Response Over 24 Hours
Complete Response2
No Vomiting
No More Than Mild Nausea
KYTRIL
Injection
14
93%
93%
93%
Placebo
14
7%
14%
7%
P-Value
<0.001
<0.001
<0.001
1 Cisplatin administration began within 10 minutes of KYTRIL Injection infusion and
continued for 1.5 to 3.0 hours. Mean cisplatin dose was 86 mg/m2 in the KYTRIL
Injection group and 80 mg/m2 in the placebo group.
2 No vomiting and no moderate or severe nausea.
KYTRIL Injection was also evaluated in a randomized dose response study of cancer
patients receiving cisplatin ≥75 mg/m2. Additional chemotherapeutic agents included:
anthracyclines, carboplatin, cytostatic antibiotics, folic acid derivatives, methylhydrazine,
nitrogen mustard analogs, podophyllotoxin derivatives, pyrimidine analogs, and vinca
alkaloids. KYTRIL Injection doses of 10 and 40 mcg/kg were superior to 2 mcg/kg in
preventing cisplatin-induced nausea and vomiting, but 40 mcg/kg was not significantly
superior to 10 mcg/kg (see Table 4).
4
Table 4
Prevention of Chemotherapy-Induced Nausea and Vomiting
— Single-Day High-Dose Cisplatin Therapy1
KYTRIL Injection
(mcg/kg)
P-Value
(vs. 2 mcg/kg)
2
10
40
10
40
Number of Patients
Response Over 24 Hours
Complete Response2
No Vomiting
No More Than Mild Nausea
52
31%
38%
58%
52
62%
65%
75%
53
68%
74%
79%
<0.002
<0.001
NS
<0.001
<0.001
0.007
1 Cisplatin administration began within 10 minutes of KYTRIL Injection infusion and
continued for 2.6 hours (mean). Mean cisplatin doses were 96 to 99 mg/m2.
2 No vomiting and no moderate or severe nausea.
KYTRIL Injection was also evaluated in a double-blind, randomized dose response study
of 353 patients stratified for high (≥80 to 120 mg/m2) or low (50 to 79 mg/m2) cisplatin
dose. Response rates of patients for both cisplatin strata are given in Table 5.
Table 5
Prevention of Chemotherapy-Induced Nausea and Vomiting
— Single-Day High-Dose and Low-Dose Cisplatin Therapy1
KYTRIL Injection
(mcg/kg)
P-Value
(vs. 5 mcg/kg)
5
10
20
40
10
20
40
High-Dose Cisplatin
Number of Patients
Response Over 24 Hours
Complete Response2
No Vomiting
No Nausea
40
18%
28%
15%
49
41%
47%
35%
48
40%
44%
38%
47
47%
53%
43%
0.018
NS
0.036
0.025
NS
0.019
0.004
0.016
0.005
Low-Dose Cisplatin
Number of Patients
Response Over 24 Hours
Complete Response2
No Vomiting
No Nausea
42
29%
36%
29%
41
56%
63%
56%
40
58%
65%
38%
46
41%
43%
33%
0.012
0.012
0.012
0.009
0.008
NS
NS
NS
NS
1 Cisplatin administration began within 10 minutes of KYTRIL Injection infusion and
continued for 2 hours (mean). Mean cisplatin doses were 64 and 98 mg/m2 for low and
high strata.
2 No vomiting and no use of rescue antiemetic.
For both the low and high cisplatin strata, the 10, 20, and 40 mcg/kg doses were more
effective than the 5 mcg/kg dose in preventing nausea and vomiting within 24 hours of
chemotherapy administration. The 10 mcg/kg dose was at least as effective as the higher
doses.
5
Moderately Emetogenic Chemotherapy
KYTRIL Injection, 40 mcg/kg, was compared with the combination of chlorpromazine
(50 to 200 mg/24 hours) and dexamethasone (12 mg) in patients treated with moderately
emetogenic chemotherapy, including primarily carboplatin >300 mg/m2, cisplatin 20 to
50 mg/m2 and cyclophosphamide >600 mg/m2. KYTRIL Injection was superior to the
chlorpromazine regimen in preventing nausea and vomiting (see Table 6).
Table 6
Prevention of Chemotherapy-Induced Nausea and
Vomiting—Single-Day Moderately Emetogenic
Chemotherapy
Number of Patients
Response Over 24 Hours
Complete Response2
No Vomiting
No More Than Mild Nausea
KYTRIL
Injection
133
68%
73%
77%
Chlorpromazine1
133
47%
53%
59%
P-Value
<0.001
<0.001
<0.001
1
Patients also received dexamethasone, 12 mg.
2
No vomiting and no moderate or severe nausea.
In other studies of moderately emetogenic chemotherapy, no significant difference in
efficacy was found between KYTRIL doses of 40 mcg/kg and 160 mcg/kg.
Repeat-Cycle Chemotherapy
In an uncontrolled trial, 512 cancer patients received KYTRIL Injection, 40 mcg/kg,
prophylactically, for two cycles of chemotherapy, 224 patients received it for at least four
cycles, and 108 patients received it for at least six cycles. KYTRIL Injection efficacy
remained relatively constant over the first six repeat cycles, with complete response rates
(no vomiting and no moderate or severe nausea in 24 hours) of 60% to 69%. No patients
were studied for more than 15 cycles.
Pediatric Studies
A randomized double-blind study evaluated the 24-hour response of 80 pediatric cancer
patients (age 2 to 16 years) to KYTRIL Injection 10, 20 or 40 mcg/kg. Patients were
treated with cisplatin ≥60 mg/m2, cytarabine ≥3 g/m2, cyclophosphamide ≥1 g/m2 or
nitrogen mustard ≥6 mg/m2 (see Table 7).
Table 7
Prevention of Chemotherapy-Induced Nausea and Vomiting
in Pediatric Patients
1
KYTRIL Injection Dose (mcg/kg)
10
20
40
Number of Patients
Median Number of Vomiting Episodes
Complete Response Over 24 Hours1
29
2
21%
26
3
31%
25
1
32%
No vomiting and no moderate or severe nausea.
6
A second pediatric study compared KYTRIL Injection 20 mcg/kg to chlorpromazine plus
dexamethasone in 88 patients treated with ifosfamide ≥3 g/m2/day for two or three days.
KYTRIL Injection was administered on each day of ifosfamide treatment. At 24 hours,
22% of KYTRIL Injection patients achieved complete response (no vomiting and no
moderate or severe nausea in 24 hours) compared with 10% on the chlorpromazine
regimen. The median number of vomiting episodes with KYTRIL Injection was 1.5; with
chlorpromazine it was 7.0.
Postoperative Nausea and Vomiting
Prevention of Postoperative Nausea and Vomiting
The efficacy of KYTRIL Injection for prevention of postoperative nausea and vomiting
was evaluated in 868 patients, of which 833 were women, 35 men, 484 Caucasians, 348
Asians, 18 Blacks, 18 Other, with 61 patients 65 years or older. KYTRIL was evaluated
in two randomized, double-blind, placebo-controlled studies in patients who underwent
elective gynecological surgery or cholecystectomy and received general anesthesia.
Patients received a single intravenous dose of KYTRIL Injection (0.1 mg, 1 mg or 3 mg)
or placebo either 5 minutes before induction of anesthesia or immediately before reversal
of anesthesia. The primary endpoint was the proportion of patients with no vomiting for
24 hours after surgery. Episodes of nausea and vomiting and use of rescue antiemetic
therapy were recorded for 24 hours after surgery. In both studies, KYTRIL Injection (1
mg) was more effective than placebo in preventing postoperative nausea and vomiting
(see Table 8). No additional benefit was seen in patients who received the 3 mg dose.
7
Table 8
Prevention of Postoperative Nausea and Vomiting in Adult
Patients
Study and Efficacy Endpoint
Placebo
KYTRIL
0.1 mg
KYTRIL
1 mg
KYTRIL
3 mg
Study 1
Number of Patients
No Vomiting
133
132
134
128
0 to 24 hours
No Nausea
34%
45%
63%**
62%**
0 to 24 hours
No Nausea or Vomiting
22%
28%
50%**
42%**
0 to 24 hours
No Use of Rescue Antiemetic
Therapy
18%
27%
49%**
42%**
0 to 24 hours
60%
67%
75%*
77%*
Study 2
Number of Patients
No Vomiting
117
–
110
114
0 to 24 hours
No Nausea
56%
–
77%**
75%*
0 to 24 hours
37%
–
59%**
56%*
*P<0.05
**P<0.001 versus placebo
Note: No Vomiting = no vomiting and no use of rescue antiemetic therapy; No Nausea =
no nausea and no use of rescue antiemetic therapy
Gender/Race
There were too few male and Black patients to adequately assess differences in effect in
either population.
Treatment of Postoperative Nausea and Vomiting
The efficacy of KYTRIL Injection for treatment of postoperative nausea and vomiting
was evaluated in 844 patients, of which 731 were women, 113 men, 777 Caucasians, 6
Asians, 41 Blacks, 20 Other, with 107 patients 65 years or older. KYTRIL Injection was
evaluated in two randomized, double-blind, placebo-controlled studies of adult surgical
patients who received general anesthesia with no prophylactic antiemetic agent, and who
experienced nausea or vomiting within 4 hours postoperatively. Patients received a single
intravenous dose of KYTRIL Injection (0.1 mg, 1 mg or 3 mg) or placebo after
experiencing postoperative nausea or vomiting. Episodes of nausea and vomiting and use
of rescue antiemetic therapy were recorded for 24 hours after administration of study
medication. KYTRIL Injection was more effective than placebo in treating postoperative
nausea and vomiting (see Table 9). No additional benefit was seen in patients who
received the 3 mg dose.
8
Table 9
Treatment of Postoperative Nausea and Vomiting in Adult
Patients
Study and Efficacy Endpoint
Placebo
KYTRIL
0.1 mg
KYTRIL
1 mg
KYTRIL
3 mg
Study 3
Number of Patients
No Vomiting
0 to 6 hours
0 to 24 hours
No Nausea
0 to 6 hours
0 to 24 hours
No Use of Rescue Antiemetic
Therapy
0 to 6 hours
0 to 24 hours
133
26%
20%
17%
13%
–
33%
128
53%***
38%***
40%***
27%**
–
51%**
133
58%***
46%***
41%***
30%**
–
61%***
125
60%***
49%***
42%***
37%***
–
61%***
Study 4
Number of Patients (All
Patients)
No Vomiting
0 to 6 hours
0 to 24 hours
No Nausea
0 to 6 hours
0 to 24 hours
No Nausea or Vomiting
0 to 6 hours
0 to 24 hours
No Use of Rescue Antiemetic
Therapy
0 to 6 hours
0 to 24 hours
162
20%
14%
13%
9%
13%
9%
–
24%
163
32%*
23%*
18%
14%
18%
14%
–
34%*
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
Number of Patients (Treated
for Vomiting)1
No Vomiting
86
103
–
–
0 to 6 hours
21%
27%
–
–
0 to 24 hours
14%
20%
–
–
*P<0.05
**P<0.01
***P<0.001 versus placebo
1 Protocol Specified Analysis: Patients who had vomiting prior to treatment
Note: No vomiting = no vomiting and no use of rescue antiemetic therapy; No nausea =
no nausea and no use of rescue antiemetic therapy
9
Gender/Race
There were too few male and Black patients to adequately assess differences in effect in
either population.
INDICATIONS AND USAGE
KYTRIL Injection is indicated for:
• The prevention of nausea and/or vomiting associated with initial and repeat courses of
emetogenic cancer therapy, including high-dose cisplatin.
• The prevention and treatment of postoperative nausea and vomiting in adults. As with
other antiemetics, routine prophylaxis is not recommended in patients in whom there
is little expectation that nausea and/or vomiting will occur postoperatively. In patients
where nausea and/or vomiting must be avoided during the postoperative period,
KYTRIL Injection is recommended even where the incidence of postoperative nausea
and/or vomiting is low.
CONTRAINDICATIONS
KYTRIL Injection is contraindicated in patients with known hypersensitivity to the drug
or to any of its components.
WARNINGS
Hypersensitivity reactions may occur in patients who have exhibited hypersensitivity to
other selective 5-HT3 receptor antagonists.
PRECAUTIONS
KYTRIL is not a drug that stimulates gastric or intestinal peristalsis. It should not be used
instead of nasogastric suction. The use of KYTRIL in patients following abdominal
surgery or in patients with chemotherapy-induced nausea and vomiting may mask a
progressive ileus and/or gastric distention.
An adequate QT assessment has not been conducted, but QT prolongation has been
reported with KYTRIL. Therefore, Kytril should be used with caution in patients with
pre-existing arrhythmias or cardiac conduction disorders, as this might lead to clinical
consequences.
Patients with cardiac disease, on cardio-toxic chemotherapy, with
concomitant electrolyte abnormalities and/or on concomitant medications that prolong
the QT interval are particularly at risk.
Drug Interactions
Granisetron does not induce or inhibit the cytochrome P-450 drug-metabolizing enzyme
system in vitro. There have been no definitive drug-drug interaction studies to examine
pharmacokinetic or pharmacodynamic interaction with other drugs; however, in humans,
KYTRIL
Injection
has
been
safely
administered
with
drugs
representing
benzodiazepines, neuroleptics and anti-ulcer medications commonly prescribed with
antiemetic treatments. KYTRIL Injection also does not appear to interact with
emetogenic cancer chemotherapies. Because granisetron is metabolized by hepatic
cytochrome P-450 drug-metabolizing enzymes, inducers or inhibitors of these enzymes
may change the clearance and, hence, the half-life of granisetron. No specific interaction
10
studies have been conducted in anesthetized patients. In addition, the activity of the
cytochrome P-450 subfamily 3A4 (involved in the metabolism of some of the main
narcotic analgesic agents) is not modified by KYTRIL in vitro.
In in vitro human microsomal studies, ketoconazole inhibited ring oxidation of KYTRIL.
However, the clinical significance of in vivo pharmacokinetic interactions with
ketoconazole is not known. In a human pharmacokinetic study, hepatic enzyme induction
with phenobarbital resulted in a 25% increase in total plasma clearance of intravenous
KYTRIL. The clinical significance of this change is not known.
QT prolongation has been reported with KYTRIL. Use of Kytril in patients concurrently
treated with drugs known to prolong the QT interval and/or are arrhythmogenic, this may
result in to clinical consequences.
Carcinogenesis, Mutagenesis, Impairment of Fertility
In a 24-month carcinogenicity study, rats were treated orally with granisetron 1, 5 or
50 mg/kg/day (6, 30 or 300 mg/m2/day). The 50 mg/kg/day dose was reduced to
25 mg/kg/day (150 mg/m2/day) during week 59 due to toxicity. For a 50 kg person of
average height (1.46 m2 body surface area), these doses represent 16, 81 and 405 times
the recommended clinical dose (0.37 mg/m2, iv) on a body surface area basis. There was
a statistically significant increase in the incidence of hepatocellular carcinomas and
adenomas in males treated with 5 mg/kg/day (30 mg/m2/day, 81 times the recommended
human dose based on body surface area) and above, and in females treated with
25 mg/kg/day (150 mg/m2/day, 405 times the recommended human dose based on body
surface area). No increase in liver tumors was observed at a dose of 1 mg/kg/day
(6 mg/m2/day, 16 times the recommended human dose based on body surface area) in
males and 5 mg/kg/day (30 mg/m2/day, 81 times the recommended human dose based on
body surface area) in females. In a 12-month oral toxicity study, treatment with
granisetron 100 mg/kg/day (600 mg/m2/day, 1622 times the recommended human dose
based on body surface area) produced hepatocellular adenomas in male and female rats
while no such tumors were found in the control rats. A 24-month mouse carcinogenicity
study of granisetron did not show a statistically significant increase in tumor incidence,
but the study was not conclusive.
Because of the tumor findings in rat studies, KYTRIL Injection should be prescribed only
at the dose and for the indication recommended (see INDICATIONS AND USAGE and
DOSAGE AND ADMINISTRATION).
Granisetron was not mutagenic in an in vitro Ames test and mouse lymphoma cell
forward mutation assay, and in vivo mouse micronucleus test and in vitro and ex vivo rat
hepatocyte UDS assays. It, however, produced a significant increase in UDS in HeLa
cells in vitro and a significant increased incidence of cells with polyploidy in an in vitro
human lymphocyte chromosomal aberration test.
Granisetron at subcutaneous doses up to 6 mg/kg/day (36 mg/m2/day, 97 times the
recommended human dose based on body surface area) was found to have no effect on
fertility and reproductive performance of male and female rats.
11
Pregnancy
Teratogenic Effects
Pregnancy Category B.
Reproduction studies have been performed in pregnant rats at intravenous doses up to
9 mg/kg/day (54 mg/m2/day, 146 times the recommended human dose based on body
surface area) and pregnant rabbits at intravenous doses up to 3 mg/kg/day
(35.4 mg/m2/day, 96 times the recommended human dose based on body surface area)
and have revealed no evidence of impaired fertility or harm to the fetus due to
granisetron. There are, however, no adequate and well-controlled studies in pregnant
women. Because animal reproduction studies are not always predictive of human
response, this drug should be used during pregnancy only if clearly needed.
Benzyl alcohol may cross the placenta. KYTRIL Injection 1 mg/1 mL is preserved with
benzyl alcohol and should be used in pregnancy only if the benefit outweighs the
potential risk.
Nursing Mothers
It is not known whether granisetron is excreted in human milk. Because many drugs are
excreted in human milk, caution should be exercised when KYTRIL Injection is
administered to a nursing woman.
Pediatric Use
See DOSAGE AND ADMINISTRATION for use in chemotherapy-induced nausea and
vomiting in pediatric patients 2 to 16 years of age. Safety and effectiveness in pediatric
patients under 2 years of age have not been established. Safety and effectiveness of
KYTRIL Injection have not been established in pediatric patients for the prevention or
treatment of postoperative nausea or vomiting.
Benzyl alcohol, a component of KYTRIL 1 mg/1 mL, has been associated with serious
adverse events and death, particularly in neonates. The “gasping syndrome,”
characterized by central nervous system depression, metabolic acidosis, gasping
respirations, and high levels of benzyl alcohol and metabolites in blood and urine, has
been associated with benzyl alcohol dosages >99 mg/kg/day in neonates and low birth-
weight neonates. Additional symptoms may include gradual neurological deterioration,
seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic
and renal failure, hypotension, bradycardia, and cardiovascular collapse. Although
normal therapeutic doses of this product deliver amounts of benzyl alcohol that are
substantially lower than those reported in association with the “gasping syndrome,” the
minimum amount of benzyl alcohol at which toxicity may occur is not known. Premature
and low birth-weight infants, as well as patients receiving high dosages, may be more
likely to develop toxicity. Practitioners administering this and other medications
containing benzyl alcohol should consider the combined daily metabolic load of benzyl
alcohol from all sources.
12
Geriatric Use
During chemotherapy clinical trials, 713 patients 65 years of age or older received
KYTRIL Injection. Effectiveness and safety were similar in patients of various ages.
During postoperative nausea and vomiting clinical trials, 168 patients 65 years of age or
older, of which 47 were 75 years of age or older, received KYTRIL Injection. Clinical
studies of KYTRIL Injection did not include sufficient numbers of subjects aged 65 years
and over to determine whether they respond differently from younger subjects. Other
reported clinical experience has not identified differences in responses between the
elderly and younger patients.
ADVERSE REACTIONS
QT prolongation has been reported with KYTRIL (see PRECAUTIONS and Drug
Interactions).
Chemotherapy-Induced Nausea and Vomiting
The following have been reported during controlled clinical trials or in the routine
management of patients. The percentage figures are based on clinical trial experience
only. Table 10 gives the comparative frequencies of the five most commonly reported
adverse events (≥3%) in patients receiving KYTRIL Injection, in single-day
chemotherapy trials. These patients received chemotherapy, primarily cisplatin, and
intravenous fluids during the 24-hour period following KYTRIL Injection administration.
Events were generally recorded over seven days post-KYTRIL Injection administration.
In the absence of a placebo group, there is uncertainty as to how many of these events
should be attributed to KYTRIL, except for headache, which was clearly more frequent
than in comparison groups.
Table 10
Principal Adverse Events in Clinical Trials — Single-Day
Chemotherapy
Percent of Patients With Event
KYTRIL Injection
40 mcg/kg
(n=1268)
Comparator1
(n=422)
Headache
Asthenia
Somnolence
Diarrhea
Constipation
14%
5%
4%
4%
3%
6%
6%
15%
6%
3%
Metoclopramide/dexamethasone and phenothiazines/dexamethasone.
In over 3,000 patients receiving KYTRIL Injection (2 to 160 mcg/kg) in single-day and
multiple-day clinical trials with emetogenic cancer therapies, adverse events, other than
those in Table 10, were observed; attribution of many of these events to KYTRIL is
uncertain.
Hepatic: In comparative trials, mainly with cisplatin regimens, elevations of AST and
ALT (>2 times the upper limit of normal) following administration of KYTRIL Injection
13
1
occurred in 2.8% and 3.3% of patients, respectively. These frequencies were not
significantly different from those seen with comparators (AST: 2.1%; ALT: 2.4%).
Cardiovascular: Hypertension (2%); hypotension, arrhythmias such as sinus bradycardia,
atrial fibrillation, varying degrees of A-V block, ventricular ectopy including non-
sustained tachycardia, and ECG abnormalities have been observed rarely.
Central Nervous System: Agitation, anxiety, CNS stimulation and insomnia were seen in
less than 2% of patients. Extrapyramidal syndrome occurred rarely and only in the
presence of other drugs associated with this syndrome.
Hypersensitivity: Rare cases of hypersensitivity reactions, sometimes severe (eg,
anaphylaxis, shortness of breath, hypotension, urticaria) have been reported.
Other: Fever (3%), taste disorder (2%), skin rashes (1%). In multiple-day comparative
studies, fever occurred more frequently with KYTRIL Injection (8.6%) than with
comparative drugs (3.4%, P<0.014), which usually included dexamethasone.
Postoperative Nausea and Vomiting
The adverse events listed in Table 11 were reported in ≥2% of adults receiving KYTRIL
Injection 1 mg during controlled clinical trials.
Table 11
Adverse Events ≥2%
Percent of Patients With Event
KYTRIL Injection
1 mg
(n=267)
Placebo
(n=266)
Pain
10.1
8.3
Constipation
9.4
12.0
Anemia
9.4
10.2
Headache
8.6
7.1
Fever
7.9
4.5
Abdominal Pain
6.0
6.0
Hepatic Enzymes Increased
5.6
4.1
Insomnia
4.9
6.0
Bradycardia
4.5
5.3
Dizziness
4.1
3.4
Leukocytosis
3.7
4.1
Anxiety
3.4
3.8
Hypotension
3.4
3.8
Diarrhea
3.4
1.1
Flatulence
3.0
3.0
Infection
3.0
2.3
Dyspepsia
3.0
1.9
Hypertension
2.6
4.1
Urinary Tract Infection
2.6
3.4
Oliguria
2.2
1.5
Coughing
2.2
1.1
14
In a clinical study conducted in Japan, the types of adverse events differed notably from
those reported above in Table 11. The adverse events in the Japanese study that occurred
in ≥2% of patients and were more frequent with KYTRIL 1 mg than with placebo were:
fever (56% to 50%), sputum increased (2.7% to 1.7%), and dermatitis (2.7% to 0%).
Postmarketing Experience
QT prolongation has been reported with KYTRIL (see PRECAUTIONS and Drug
Interactions).
OVERDOSAGE
There is no specific antidote for KYTRIL Injection overdosage. In case of overdosage,
symptomatic treatment should be given. Overdosage of up to 38.5 mg of granisetron
hydrochloride injection has been reported without symptoms or only the occurrence of a
slight headache.
DOSAGE AND ADMINISTRATION
NOTE:
KYTRIL
1
MG/1
ML
CONTAINS
BENZYL
ALCOHOL
(see
PRECAUTIONS).
Prevention of Chemotherapy-Induced Nausea and Vomiting
The recommended dosage for KYTRIL Injection is 10 mcg/kg administered
intravenously within 30 minutes before initiation of chemotherapy, and only on the
day(s) chemotherapy is given.
Infusion Preparation
KYTRIL Injection may be administered intravenously either undiluted over 30 seconds,
or diluted with 0.9% Sodium Chloride or 5% Dextrose and infused over 5 minutes.
Stability
Intravenous infusion of KYTRIL Injection should be prepared at the time of
administration. However, KYTRIL Injection has been shown to be stable for at least 24
hours when diluted in 0.9% Sodium Chloride or 5% Dextrose and stored at room
temperature under normal lighting conditions.
As a general precaution, KYTRIL Injection should not be mixed in solution with other
drugs. Parenteral drug products should be inspected visually for particulate matter and
discoloration before administration whenever solution and container permit.
Pediatric Patients
The recommended dose in pediatric patients 2 to 16 years of age is 10 mcg/kg (see
CLINICAL TRIALS). Pediatric patients under 2 years of age have not been studied.
Geriatric Patients, Renal Failure Patients or Hepatically Impaired Patients
No dosage adjustment is recommended (see CLINICAL PHARMACOLOGY:
Pharmacokinetics).
15
Prevention and Treatment of Postoperative Nausea and Vomiting
The recommended dosage for prevention of postoperative nausea and vomiting is 1 mg of
KYTRIL, undiluted, administered intravenously over 30 seconds, before induction of
anesthesia or immediately before reversal of anesthesia.
The recommended dosage for the treatment of nausea and/or vomiting after surgery is 1
mg of KYTRIL, undiluted, administered intravenously over 30 seconds.
Pediatric Patients
Safety and effectiveness of KYTRIL Injection have not been established in pediatric
patients for the prevention or treatment of postoperative nausea or vomiting.
Geriatric Patients, Renal Failure Patients or Hepatically Impaired Patients
No dosage adjustment is recommended (see CLINICAL PHARMACOLOGY:
Pharmacokinetics).
HOW SUPPLIED
KYTRIL Injection, 1 mg/1 mL (free base), is supplied in 1 mL Single-Use Vials and 4
mL Multi-Use Vials. CONTAINS BENZYL ALCOHOL.
NDC 0004-0239-09 (package of 1 Single-Use Vial)
NDC 0004-0240-09 (package of 1 Multi-Use Vial)
KYTRIL Injection, 0.1 mg/1 mL (free base), is supplied in 1 mL Single-Use Vials.
CONTAINS NO PRESERVATIVE.
NDC 0004-0242-08 (package of 5 Single-Use Vials)
Storage
Store single-use vials and multi-use vials at 25°C (77°F); excursions permitted to 15° to
30°C (59° to 86°F). [See USP Controlled Room Temperature]
Once the multi-use vial is penetrated, its contents should be used within 30 days.
Do not freeze. Protect from light.
Distributed by: logo
XXXXXXXX
Revised: September 2009
Copyright © 1998-2009 by Roche Laboratories Inc. All rights reserved.
16
Roche logo
KYTRIL®
(granisetron hydrochloride)
TABLETS
ORAL SOLUTION
Rx only
DESCRIPTION
KYTRIL Tablets and KYTRIL Oral Solution contain granisetron hydrochloride, an
antinauseant and antiemetic agent. Chemically it is endo-N-(9-methyl-9-azabicyclo
[3.3.1] non-3-yl)-1-methyl-1H-indazole-3-carboxamide hydrochloride with a molecular
weight of 348.9 (312.4 free base). Its empirical formula is C18H24N4O•HCl, while its
chemical structure is: Structural Formula
granisetron hydrochloride
Granisetron hydrochloride is a white to off-white solid that is readily soluble in water and
normal saline at 20ºC.
Tablets for Oral Administration
Each white, triangular, biconvex, film-coated KYTRIL Tablet contains 1.12 mg
granisetron hydrochloride equivalent to granisetron, 1 mg. Inactive ingredients are:
hydroxypropyl methylcellulose, lactose, magnesium stearate, microcrystalline cellulose,
polyethylene glycol, polysorbate 80, sodium starch glycolate, and titanium dioxide.
Oral Solution
Each 10 mL of clear, orange-colored, orange-flavored KYTRIL Oral Solution contains
2.24 mg of granisetron hydrochloride equivalent to 2 mg granisetron. Inactive
ingredients: citric acid anhydrous, FD&C Yellow No. 6, orange flavor, purified water,
sodium benzoate, and sorbitol.
CLINICAL PHARMACOLOGY
Granisetron is a selective 5-hydroxytryptamine3 (5-HT3) receptor antagonist with little or
no affinity for other serotonin receptors, including 5-HT1; 5-HT1A; 5-HT1B/C; 5-HT2; for
1
KYTRIL® (granisetron hydrochloride)
alpha1-, alpha2-, or beta-adrenoreceptors; for dopamine-D2; or for histamine-H1;
benzodiazepine; picrotoxin or opioid receptors.
Serotonin receptors of the 5-HT3 type are located peripherally on vagal nerve terminals
and centrally in the chemoreceptor trigger zone of the area postrema. During
chemotherapy that induces vomiting, mucosal enterochromaffin cells release serotonin,
which stimulates 5-HT3 receptors. This evokes vagal afferent discharge, inducing
vomiting. Animal studies demonstrate that, in binding to 5-HT3 receptors, granisetron
blocks serotonin stimulation and subsequent vomiting after emetogenic stimuli such as
cisplatin. In the ferret animal model, a single granisetron injection prevented vomiting
due to high-dose cisplatin or arrested vomiting within 5 to 30 seconds.
In most human studies, granisetron has had little effect on blood pressure, heart rate or
ECG. No evidence of an effect on plasma prolactin or aldosterone concentrations has
been found in other studies.
Following single and multiple oral doses, KYTRIL Tablets slowed colonic transit in
normal volunteers. However, KYTRIL had no effect on oro-cecal transit time in normal
volunteers when given as a single intravenous (IV) infusion of 50 mcg/kg or 200 mcg/kg.
Pharmacokinetics
In healthy volunteers and adult cancer patients undergoing chemotherapy, administration
of KYTRIL Tablets produced mean pharmacokinetic data shown in Table 1.
Table 1
Pharmacokinetic Parameters (Median [range]) Following
KYTRIL Tablets (granisetron hydrochloride)
Peak Plasma
Concentration
(ng/mL)
Terminal Phase
Plasma Half-Life
(h)
Volume of
Distribution
(L/kg)
Total
Clearance
(L/h/kg)
Cancer Patients
1 mg bid, 7 days
(n=27)
5.99
[0.63 to 30.9]
N.D.1
N.D.
0.52
[0.09 to 7.37]
Volunteers
single 1 mg dose
(n=39)
3.63
[0.27 to 9.14]
6.23
[0.96 to 19.9]
3.94
[1.89 to 39.4]
0.41
[0.11 to 24.6]
Not determined after oral administration; following a single intravenous dose of 40
mcg/kg, terminal phase half-life was determined to be 8.95 hours.
N.D. Not determined.
A 2 mg dose of KYTRIL Oral Solution is bioequivalent to the corresponding dose of
KYTRIL Tablets (1 mg x 2) and may be used interchangeably.
1
2
KYTRIL® (granisetron hydrochloride)
Absorption
When KYTRIL Tablets were administered with food, AUC was decreased by 5% and
Cmax increased by 30% in non-fasted healthy volunteers who received a single dose of 10
mg.
Distribution
Plasma protein binding is approximately 65% and granisetron distributes freely between
plasma and red blood cells.
Metabolism
Granisetron metabolism involves N-demethylation and aromatic ring oxidation followed
by conjugation. In vitro liver microsomal studies show that granisetron’s major route of
metabolism is inhibited by ketoconazole, suggestive of metabolism mediated by the
cytochrome P-450 3A subfamily. Animal studies suggest that some of the metabolites
may also have 5-HT3 receptor antagonist activity.
Elimination
Clearance is predominantly by hepatic metabolism. In normal volunteers, approximately
11% of the orally administered dose is eliminated unchanged in the urine in 48 hours.
The remainder of the dose is excreted as metabolites, 48% in the urine and 38% in the
feces.
Subpopulations
Gender
The effects of gender on the pharmacokinetics of KYTRIL Tablets have not been studied.
However, after intravenous infusion of KYTRIL, no difference in mean AUC was found
between males and females, although males had a higher Cmax generally.
In elderly and pediatric patients and in patients with renal failure or hepatic impairment,
the pharmacokinetics of granisetron was determined following administration of
intravenous KYTRIL.
Elderly
The ranges of the pharmacokinetic parameters in elderly volunteers (mean age 71 years),
given a single 40 mcg/kg intravenous dose of KYTRIL Injection, were generally similar
to those in younger healthy volunteers; mean values were lower for clearance and longer
for half-life in the elderly.
Renal Failure Patients
Total clearance of granisetron was not affected in patients with severe renal failure who
received a single 40 mcg/kg intravenous dose of KYTRIL Injection.
Hepatically Impaired Patients
A pharmacokinetic study with intravenous KYTRIL in patients with hepatic impairment
due to neoplastic liver involvement showed that total clearance was approximately halved
compared to patients without hepatic impairment. Given the wide variability in
3
KYTRIL® (granisetron hydrochloride)
pharmacokinetic parameters noted in patients, dosage adjustment in patients with hepatic
functional impairment is not necessary.
Pediatric Patients
A pharmacokinetic study in pediatric cancer patients (2 to 16 years of age), given a single
40 mcg/kg intravenous dose of KYTRIL Injection, showed that volume of distribution
and total clearance increased with age. No relationship with age was observed for peak
plasma concentration or terminal phase plasma half-life. When volume of distribution
and total clearance are adjusted for body weight, the pharmacokinetics of granisetron are
similar in pediatric and adult cancer patients.
CLINICAL TRIALS
Chemotherapy-Induced Nausea and Vomiting
KYTRIL Tablets prevent nausea and vomiting associated with initial and repeat courses
of emetogenic cancer therapy, as shown by 24-hour efficacy data from studies using both
moderately- and highly-emetogenic chemotherapy.
Moderately Emetogenic Chemotherapy
The first trial compared KYTRIL Tablets doses of 0.25 mg to 2 mg twice a day, in 930
cancer patients receiving, principally, cyclophosphamide, carboplatin, and cisplatin (20
mg/m2 to 50 mg/m2). Efficacy was based on complete response (ie, no vomiting, no
moderate or severe nausea, no rescue medication), no vomiting, and no nausea. Table 2
summarizes the results of this study.
Table 2
Prevention of Nausea and Vomiting 24 Hours Post
Chemotherapy1
Percentages of Patients
KYTRIL Tablet Dose
Efficacy Measures
0.25 mg
twice a day
(n=229)
%
0.5 mg twice
a day
(n=235)
%
1 mg twice a
day
(n=233)
%
2 mg twice a
day
(n=233)
%
Complete Response2
No Vomiting
No Nausea
61
66
48
70*
77*
57
81*†
88*
63*
72*
79*
54
1
Chemotherapy included oral and injectable cyclophosphamide, carboplatin, cisplatin
(20 mg/m2 to 50 mg/m2), dacarbazine, doxorubicin, epirubicin.
2
No vomiting, no moderate or severe nausea, no rescue medication.
*Statistically significant (P<0.01) vs. 0.25 mg bid.
†Statistically significant (P<0.01) vs. 0.5 mg bid.
4
KYTRIL® (granisetron hydrochloride)
Results from a second double-blind, randomized trial evaluating KYTRIL Tablets 2 mg
once a day and KYTRIL Tablets 1 mg twice a day were compared to prochlorperazine 10
mg twice a day derived from a historical control. At 24 hours, there was no statistically
significant difference in efficacy between the two KYTRIL Tablet regimens. Both
regimens were statistically superior to the prochlorperazine control regimen (see
Table 3).
Table 3
Prevention of Nausea and Vomiting 24 Hours Post
Chemotherapy1
Efficacy Measures
Percentages of Patients
KYTRIL
Tablets
1 mg twice a
day (n = 354)
%
KYTRIL
Tablets
2 mg once a
day
(n = 343)
%
Prochlorperazine2
10 mg twice daily
(n=111)
%
Complete Response3
No Vomiting
No Nausea
Total Control4
69*
82*
51*
51*
64*
77*
53*
50*
41
48
35
33
1
Moderately emetogenic chemotherapeutic agents included cisplatin (20 mg/m2 to 50
mg/m2), oral and intravenous cyclophosphamide, carboplatin, dacarbazine,
doxorubicin.
2
Historical control from a previous double-blind KYTRIL trial.
3
No vomiting, no moderate or severe nausea, no rescue medication.
4
No vomiting, no nausea, no rescue medication.
*Statistically significant (P<0.05) vs. prochlorperazine historical control.
Results from a KYTRIL Tablets 2 mg daily alone treatment arm in a third double-blind,
randomized trial, were compared to prochlorperazine (PCPZ), 10 mg bid, derived from a
historical control. The 24-hour results for KYTRIL Tablets 2 mg daily were statistically
superior to PCPZ for all efficacy parameters: complete response (58%), no vomiting
(79%), no nausea (51%), total control (49%). The PCPZ rates are shown in Table 3.
Cisplatin-Based Chemotherapy
The first double-blind trial compared KYTRIL Tablets 1 mg bid, relative to placebo
(historical control), in 119 cancer patients receiving high-dose cisplatin (mean dose 80
mg/m2). At 24 hours, KYTRIL Tablets 1 mg bid was significantly (P<0.001) superior to
placebo (historical control) in all efficacy parameters: complete response (52%), no
5
KYTRIL® (granisetron hydrochloride)
vomiting (56%) and no nausea (45%). The placebo rates were 7%, 14%, and 7%,
respectively, for the three efficacy parameters.
Results from a KYTRIL Tablets 2 mg once a day alone treatment arm in a second
double-blind, randomized trial, were compared to both KYTRIL Tablets 1 mg twice a
day and placebo historical controls. The 24-hour results for KYTRIL Tablets 2 mg once a
day were: complete response (44%), no vomiting (58%), no nausea (46%), total control
(40%). The efficacy of KYTRIL Tablets 2 mg once a day was comparable to KYTRIL
Tablets 1 mg twice a day and statistically superior to placebo. The placebo rates were
7%, 14%, 7%, and 7%, respectively, for the four parameters.
No controlled study comparing granisetron injection with the oral formulation to prevent
chemotherapy-induced nausea and vomiting has been performed.
Radiation-Induced Nausea and Vomiting
Total Body Irradiation
In a double-blind randomized study, 18 patients receiving KYTRIL Tablets, 2 mg daily,
experienced significantly greater antiemetic protection compared to patients in a
historical negative control group who received conventional (non-5-HT3 antagonist)
antiemetics. Total body irradiation consisted of 11 fractions of 120 cGy administered
over 4 days, with three fractions on each of the first 3 days, and two fractions on the
fourth day. KYTRIL Tablets were given one hour before the first radiation fraction of
each day.
Twenty-two percent (22%) of patients treated with KYTRIL Tablets did not experience
vomiting or receive rescue antiemetics over the entire 4-day dosing period, compared to
0% of patients in the historical negative control group (P<0.01).
In addition, patients who received KYTRIL Tablets also experienced significantly fewer
emetic episodes during the first day of radiation and over the 4-day treatment period,
compared to patients in the historical negative control group. The median time to the first
emetic episode was 36 hours for patients who received KYTRIL Tablets.
Fractionated Abdominal Radiation
The efficacy of KYTRIL Tablets, 2 mg daily, was evaluated in a double-blind, placebo-
controlled randomized trial of 260 patients. KYTRIL Tablets were given 1 hour before
radiation, composed of up to 20 daily fractions of 180 to 300 cGy each. The exceptions
were patients with seminoma or those receiving whole abdomen irradiation who initially
received 150 cGy per fraction. Radiation was administered to the upper abdomen with a
field size of at least 100 cm2.
The proportion of patients without emesis and those without nausea for KYTRIL Tablets,
compared to placebo, was statistically significant (P<0.0001) at 24 hours after radiation,
irrespective of the radiation dose. KYTRIL was superior to placebo in patients receiving
up to 10 daily fractions of radiation, but was not superior to placebo in patients receiving
20 fractions.
6
KYTRIL® (granisetron hydrochloride)
Patients treated with KYTRIL Tablets (n=134) had a significantly longer time to the first
episode of vomiting (35 days vs. 9 days, P<0.001) relative to those patients who received
placebo (n=126), and a significantly longer time to the first episode of nausea (11 days
vs. 1 day, P<0.001). KYTRIL provided significantly greater protection from nausea and
vomiting than placebo.
INDICATIONS AND USAGE
KYTRIL (granisetron hydrochloride) is indicated for the prevention of:
• Nausea and vomiting associated with initial and repeat courses of emetogenic cancer
therapy, including high-dose cisplatin.
• Nausea and vomiting associated with radiation, including total body irradiation and
fractionated abdominal radiation.
CONTRAINDICATIONS
KYTRIL is contraindicated in patients with known hypersensitivity to the drug or any of
its components.
PRECAUTIONS
KYTRIL is not a drug that stimulates gastric or intestinal peristalsis. It should not be used
instead of nasogastric suction. The use of KYTRIL in patients following abdominal
surgery or in patients with chemotherapy-induced nausea and vomiting may mask a
progressive ileus and/or gastric distention.
An adequate QT assessment has not been conducted, but QT prolongation has been
reported with KYTRIL. Therefore, Kytril should be used with caution in patients with
pre-existing arrhythmias or cardiac conduction disorders, as this might lead to clinical
consequences. Patients with cardiac disease, on cardio-toxic chemotherapy, with
concomitant electrolyte abnormalities and/or on concomitant medications that prolong
the QT interval are particularly at risk.
Drug Interactions
Granisetron does not induce or inhibit the cytochrome P-450 drug-metabolizing enzyme
system in vitro. There have been no definitive drug-drug interaction studies to examine
pharmacokinetic or pharmacodynamic interaction with other drugs; however, in humans,
KYTRIL
Injection
has
been
safely
administered
with
drugs
representing
benzodiazepines, neuroleptics, and anti-ulcer medications commonly prescribed with
antiemetic treatments. KYTRIL Injection also does not appear to interact with
emetogenic cancer chemotherapies. Because granisetron is metabolized by hepatic
cytochrome P-450 drug-metabolizing enzymes, inducers or inhibitors of these enzymes
may change the clearance and, hence, the half-life of granisetron. No specific interaction
studies have been conducted in anesthetized patients. In addition, the activity of the
cytochrome P-450 subfamily 3A4 (involved in the metabolism of some of the main
narcotic analgesic agents) is not modified by KYTRIL in vitro.
In in vitro human microsomal studies, ketoconazole inhibited ring oxidation of KYTRIL.
However, the clinical significance of in vivo pharmacokinetic interactions with
ketoconazole is not known. In a human pharmacokinetic study, hepatic enzyme induction
7
KYTRIL® (granisetron hydrochloride)
with phenobarbital resulted in a 25% increase in total plasma clearance of intravenous
KYTRIL. The clinical significance of this change is not known.
QT prolongation has been reported with KYTRIL. Use of Kytril in patients concurrently
treated with drugs known to prolong the QT interval and/or are arrhythmogenic, this may
result in clinical consequences.
Carcinogenesis, Mutagenesis, Impairment of Fertility
In a 24-month carcinogenicity study, rats were treated orally with granisetron 1, 5 or 50
mg/kg/day (6, 30 or 300 mg/m2/day). The 50 mg/kg/day dose was reduced to 25
mg/kg/day (150 mg/m2/day) during week 59 due to toxicity. For a 50 kg person of
average height (1.46 m2 body surface area), these doses represent 4, 20, and 101 times the
recommended clinical dose (1.48 mg/m2, oral) on a body surface area basis. There was a
statistically significant increase in the incidence of hepatocellular carcinomas and
adenomas in males treated with 5 mg/kg/day (30 mg/m2/day, 20 times the recommended
human dose based on body surface area) and above, and in females treated with 25
mg/kg/day (150 mg/m2/day, 101 times the recommended human dose based on body
surface area). No increase in liver tumors was observed at a dose of 1 mg/kg/day (6
mg/m2/day, 4 times the recommended human dose based on body surface area) in males
and 5 mg/kg/day (30 mg/m2/day, 20 times the recommended human dose based on body
surface area) in females. In a 12-month oral toxicity study, treatment with granisetron
100 mg/kg/day (600 mg/m2/day, 405 times the recommended human dose based on body
surface area) produced hepatocellular adenomas in male and female rats while no such
tumors were found in the control rats. A 24-month mouse carcinogenicity study of
granisetron did not show a statistically significant increase in tumor incidence, but the
study was not conclusive.
Because of the tumor findings in rat studies, KYTRIL (granisetron hydrochloride) should
be prescribed only at the dose and for the indication recommended (see INDICATIONS
AND USAGE, and DOSAGE AND ADMINISTRATION).
Granisetron was not mutagenic in in vitro Ames test and mouse lymphoma cell forward
mutation assay, and in vivo mouse micronucleus test and in vitro and ex vivo rat
hepatocyte UDS assays. It, however, produced a significant increase in UDS in HeLa
cells in vitro and a significant increased incidence of cells with polyploidy in an in vitro
human lymphocyte chromosomal aberration test.
Granisetron at oral doses up to 100 mg/kg/day (600 mg/m2/day, 405 times the
recommended human dose based on body surface area) was found to have no effect on
fertility and reproductive performance of male and female rats.
Pregnancy
Teratogenic Effects
Pregnancy Category B.
Reproduction studies have been performed in pregnant rats at oral doses up to 125
mg/kg/day (750 mg/m2/day, 507 times the recommended human dose based on body
surface area) and pregnant rabbits at oral doses up to 32 mg/kg/day (378 mg/m2/day, 255
8
KYTRIL® (granisetron hydrochloride)
times the recommended human dose based on body surface area) and have revealed no
evidence of impaired fertility or harm to the fetus due to granisetron. There are, however,
no adequate and well-controlled studies in pregnant women. Because animal
reproduction studies are not always predictive of human response, this drug should be
used during pregnancy only if clearly needed.
Nursing Mothers
It is not known whether granisetron is excreted in human milk. Because many drugs are
excreted in human milk, caution should be exercised when KYTRIL is administered to a
nursing woman.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Geriatric Use
During clinical trials, 325 patients 65 years of age or older received KYTRIL Tablets;
298 were 65 to 74 years of age, and 27 were 75 years of age or older. Efficacy and safety
were maintained with increasing age.
ADVERSE REACTIONS
QT prolongation has been reported with KYTRIL (see PRECAUTIONS and Drug
Interactions).
Chemotherapy-Induced Nausea and Vomiting
Over 3700 patients have received KYTRIL Tablets in clinical trials with emetogenic
cancer therapies consisting primarily of cyclophosphamide or cisplatin regimens.
In patients receiving KYTRIL Tablets 1 mg bid for 1, 7 or 14 days, or 2 mg daily for 1
day, adverse experiences reported in more than 5% of the patients with comparator and
placebo incidences are listed in Table 4.
9
KYTRIL® (granisetron hydrochloride)
Table 4
Principal Adverse Events in Clinical Trials
Percent of Patients With Event
KYTRIL1
Tablets
1 mg twice a
day
(n=978)
KYTRIL1
Tablets
2 mg once a
day
(n=1450)
Comparator2
(n=599)
Placebo
(n=185)
Headache3
Constipation
Asthenia
Diarrhea
Abdominal pain
Dyspepsia
21%
18%
14%
8%
6%
4%
20%
14%
18%
9%
4%
6%
13%
16%
10%
10%
6%
5%
12%
8%
4%
4%
3%
4%
1
Adverse events were recorded for 7 days when KYTRIL Tablets were given on a
single day and for up to 28 days when KYTRIL Tablets were administered for 7 or 14
days.
2
Metoclopramide/dexamethasone; phenothiazines/dexamethasone; dexamethasone
alone; prochlorperazine.
Other adverse events reported in clinical trials were:
Gastrointestinal: In single-day dosing studies in which adverse events were collected for
7 days, nausea (20%) and vomiting (12%) were recorded as adverse events after the 24
hour efficacy assessment period.
Hepatic: In comparative trials, elevation of AST and ALT (>2 times the upper limit of
normal) following the administration of KYTRIL Tablets occurred in 5% and 6% of
patients, respectively. These frequencies were not significantly different from those seen
with comparators (AST: 2%; ALT: 9%).
Cardiovascular: Hypertension (1%); hypotension, angina pectoris, atrial fibrillation, and
syncope have been observed rarely.
Central Nervous System: Dizziness (5%), insomnia (5%), anxiety (2%), somnolence
(1%). One case compatible with, but not diagnostic of, extrapyramidal symptoms has
been reported in a patient treated with KYTRIL Tablets.
Hypersensitivity: Rare cases of hypersensitivity reactions, sometimes severe (eg,
anaphylaxis, shortness of breath, hypotension, urticaria) have been reported.
Other: Fever (5%). Events often associated with chemotherapy also have been reported:
leukopenia
(9%),
decreased
appetite
(6%),
anemia
(4%),
alopecia
(3%),
thrombocytopenia (2%).
10
KYTRIL® (granisetron hydrochloride)
Over 5000 patients have received injectable KYTRIL in clinical trials.
Table 5 gives the comparative frequencies of the five commonly reported adverse events
(≥3%) in patients receiving KYTRIL Injection, 40 mcg/kg, in single-day chemotherapy
trials. These patients received chemotherapy, primarily cisplatin, and intravenous fluids
during the 24-hour period following KYTRIL Injection administration.
Table 5
Principal Adverse Events in Clinical Trials — Single-Day
Chemotherapy
Percent of Patients with Event
KYTRIL Injection1
40 mcg/kg
(n=1268)
Comparator2
(n=422)
Headache
Asthenia
Somnolence
Diarrhea
Constipation
14%
5%
4%
4%
3%
6%
6%
15%
6%
3%
1
Adverse events were generally recorded over 7 days post-KYTRIL Injection
administration.
2
Metoclopramide/dexamethasone and phenothiazines/dexamethasone.
In the absence of a placebo group, there is uncertainty as to how many of these events
should be attributed to KYTRIL, except for headache, which was clearly more frequent
than in comparison groups.
Radiation-Induced Nausea and Vomiting
In controlled clinical trials, the adverse events reported by patients receiving KYTRIL
Tablets and concurrent radiation were similar to those reported by patients receiving
KYTRIL Tablets prior to chemotherapy. The most frequently reported adverse events
were diarrhea, asthenia, and constipation. Headache, however, was less prevalent in this
patient population.
Postmarketing Experience
QT prolongation has been reported with KYTRIL (see PRECAUTIONS and Drug
Interactions).
OVERDOSAGE
There is no specific treatment for granisetron hydrochloride overdosage. In case of
overdosage, symptomatic treatment should be given. Overdosage of up to 38.5 mg of
granisetron hydrochloride injection has been reported without symptoms or only the
occurrence of a slight headache.
11
KYTRIL® (granisetron hydrochloride)
DOSAGE AND ADMINISTRATION
Emetogenic Chemotherapy
The recommended adult dosage of oral KYTRIL (granisetron hydrochloride) is 2 mg
once daily or 1 mg twice daily. In the 2 mg once-daily regimen, two 1 mg tablets or 10
mL of KYTRIL Oral Solution (2 teaspoonfuls, equivalent to 2 mg of granisetron) are
given up to 1 hour before chemotherapy. In the 1 mg twice-daily regimen, the first 1 mg
tablet or one teaspoonful (5 mL) of KYTRIL Oral Solution is given up to 1 hour before
chemotherapy, and the second tablet or second teaspoonful (5 mL) of KYTRIL Oral
Solution, 12 hours after the first. Either regimen is administered only on the day(s)
chemotherapy is given. Continued treatment, while not on chemotherapy, has not been
found to be useful.
Use in the Elderly, Renal Failure Patients or Hepatically Impaired Patients
No dosage adjustment is recommended (see CLINICAL PHARMACOLOGY:
Pharmacokinetics).
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Radiation (Either Total Body Irradiation or Fractionated Abdominal
Radiation)
The recommended adult dosage of oral KYTRIL is 2 mg once daily. Two 1 mg tablets or
10 mL of KYTRIL Oral Solution (2 teaspoonfuls, equivalent to 2 mg of granisetron) are
taken within 1 hour of radiation.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Use in the Elderly
No dosage adjustment is recommended.
HOW SUPPLIED
Tablets
White, triangular, biconvex, film-coated tablets; tablets are debossed K1 on one face.
1 mg Unit of Use 2’s: NDC 0004-0241-33
1 mg Single Unit Package 20’s: NDC 0004-0241-26 (intended for institutional use only)
Storage
Store between 15º and 30ºC (59º and 86ºF). Keep container closed tightly. Protect from
light.
12
KYTRIL® (granisetron hydrochloride)
Oral Solution
Clear, orange-colored, orange-flavored, 2 mg/10 mL, in 30 mL amber glass bottles with
child-resistant closures: NDC 0004-0237-09
Storage
Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP
Controlled Room Temperature]. Keep bottle closed tightly and stored in an upright
position. Protect from light.
Distributed by: logo
XXXXXXXX
Revised: September 2009
Copyright © 1999-2009 by Roche Laboratories Inc. All rights reserved.
13
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020239s021,020305s014,021238s007lbl.pdf', 'application_number': 20239, 'submission_type': 'SUPPL ', 'submission_number': 21}
|
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This label may not be the latest approved by FDA.
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This label may not be the latest approved by FDA.
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1
PRESCRIBING INFORMATION
1
LAMICTAL®
2
(lamotrigine)
3
Tablets
4
5
LAMICTAL®
6
(lamotrigine)
7
Chewable Dispersible Tablets
8
9
SERIOUS RASHES REQUIRING HOSPITALIZATION AND DISCONTINUATION
10
OF TREATMENT HAVE BEEN REPORTED IN ASSOCIATION WITH THE USE OF
11
LAMICTAL. THE INCIDENCE OF THESE RASHES, WHICH HAVE INCLUDED
12
STEVENS-JOHNSON SYNDROME, IS APPROXIMATELY 0.8% (8 PER 1,000) IN
13
PEDIATRIC PATIENTS (AGE <16 YEARS) RECEIVING LAMICTAL AS
14
ADJUNCTIVE THERAPY FOR EPILEPSY AND 0.3% (3 PER 1,000) IN ADULTS ON
15
ADJUNCTIVE THERAPY FOR EPILEPSY. IN CLINICAL TRIALS OF BIPOLAR AND
16
OTHER MOOD DISORDERS, THE RATE OF SERIOUS RASH WAS 0.08% (0.8 PER
17
1,000) IN ADULT PATIENTS RECEIVING LAMICTAL AS INITIAL MONOTHERAPY
18
AND 0.13% (1.3 PER 1,000) IN ADULT PATIENTS RECEIVING LAMICTAL AS
19
ADJUNCTIVE THERAPY. IN A PROSPECTIVELY FOLLOWED COHORT OF
20
1,983 PEDIATRIC PATIENTS WITH EPILEPSY TAKING ADJUNCTIVE LAMICTAL,
21
THERE WAS 1 RASH-RELATED DEATH. IN WORLDWIDE POSTMARKETING
22
EXPERIENCE, RARE CASES OF TOXIC EPIDERMAL NECROLYSIS AND/OR
23
RASH-RELATED DEATH HAVE BEEN REPORTED IN ADULT AND PEDIATRIC
24
PATIENTS, BUT THEIR NUMBERS ARE TOO FEW TO PERMIT A PRECISE
25
ESTIMATE OF THE RATE.
26
OTHER THAN AGE, THERE ARE AS YET NO FACTORS IDENTIFIED THAT ARE
27
KNOWN TO PREDICT THE RISK OF OCCURRENCE OR THE SEVERITY OF RASH
28
ASSOCIATED WITH LAMICTAL. THERE ARE SUGGESTIONS, YET TO BE
29
PROVEN, THAT THE RISK OF RASH MAY ALSO BE INCREASED BY (1)
30
COADMINISTRATION OF LAMICTAL WITH VALPROATE (INCLUDES VALPROIC
31
ACID AND DIVALPROEX SODIUM), (2) EXCEEDING THE RECOMMENDED
32
INITIAL DOSE OF LAMICTAL, OR (3) EXCEEDING THE RECOMMENDED DOSE
33
ESCALATION FOR LAMICTAL. HOWEVER, CASES HAVE BEEN REPORTED IN
34
THE ABSENCE OF THESE FACTORS.
35
NEARLY ALL CASES OF LIFE-THREATENING RASHES ASSOCIATED WITH
36
LAMICTAL HAVE OCCURRED WITHIN 2 TO 8 WEEKS OF TREATMENT
37
INITIATION. HOWEVER, ISOLATED CASES HAVE BEEN REPORTED AFTER
38
PROLONGED TREATMENT (E.G., 6 MONTHS). ACCORDINGLY, DURATION OF
39
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2
THERAPY CANNOT BE RELIED UPON AS A MEANS TO PREDICT THE
40
POTENTIAL RISK HERALDED BY THE FIRST APPEARANCE OF A RASH.
41
ALTHOUGH BENIGN RASHES ALSO OCCUR WITH LAMICTAL, IT IS NOT
42
POSSIBLE TO PREDICT RELIABLY WHICH RASHES WILL PROVE TO BE
43
SERIOUS OR LIFE THREATENING. ACCORDINGLY, LAMICTAL SHOULD
44
ORDINARILY BE DISCONTINUED AT THE FIRST SIGN OF RASH, UNLESS THE
45
RASH IS CLEARLY NOT DRUG RELATED. DISCONTINUATION OF TREATMENT
46
MAY NOT PREVENT A RASH FROM BECOMING LIFE THREATENING OR
47
PERMANENTLY DISABLING OR DISFIGURING.
48
49
DESCRIPTION
50
LAMICTAL (lamotrigine), an antiepileptic drug (AED) of the phenyltriazine class, is
51
chemically unrelated to existing antiepileptic drugs. Its chemical name is 3,5-diamino-6-(2,3-
52
dichlorophenyl)-as-triazine, its molecular formula is C9H7N5Cl2, and its molecular weight is
53
256.09. Lamotrigine is a white to pale cream-colored powder and has a pKa of 5.7. Lamotrigine
54
is very slightly soluble in water (0.17 mg/mL at 25°C) and slightly soluble in 0.1 M HCl
55
(4.1 mg/mL at 25°C). The structural formula is:
56
57
58
59
LAMICTAL Tablets are supplied for oral administration as 25-mg (white), 100-mg (peach),
60
150-mg (cream), and 200-mg (blue) tablets. Each tablet contains the labeled amount of
61
lamotrigine and the following inactive ingredients: lactose; magnesium stearate; microcrystalline
62
cellulose; povidone; sodium starch glycolate; FD&C Yellow No. 6 Lake (100-mg tablet only);
63
ferric oxide, yellow (150-mg tablet only); and FD&C Blue No. 2 Lake (200-mg tablet only).
64
LAMICTAL Chewable Dispersible Tablets are supplied for oral administration. The tablets
65
contain 2 mg (white), 5 mg (white), or 25 mg (white) of lamotrigine and the following inactive
66
ingredients: blackcurrant flavor, calcium carbonate, low-substituted hydroxypropylcellulose,
67
magnesium aluminum silicate, magnesium stearate, povidone, saccharin sodium, and sodium
68
starch glycolate.
69
CLINICAL PHARMACOLOGY
70
Mechanism of Action: The precise mechanism(s) by which lamotrigine exerts its
71
anticonvulsant action are unknown. In animal models designed to detect anticonvulsant activity,
72
lamotrigine was effective in preventing seizure spread in the maximum electroshock (MES) and
73
pentylenetetrazol (scMet) tests, and prevented seizures in the visually and electrically evoked
74
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
3
after-discharge (EEAD) tests for antiepileptic activity. LAMICTAL also displayed inhibitory
75
properties in the kindling model in rats both during kindling development and in the fully
76
kindled state. The relevance of these models to human epilepsy, however, is not known.
77
One proposed mechanism of action of LAMICTAL, the relevance of which remains to be
78
established in humans, involves an effect on sodium channels. In vitro pharmacological studies
79
suggest that lamotrigine inhibits voltage-sensitive sodium channels, thereby stabilizing neuronal
80
membranes and consequently modulating presynaptic transmitter release of excitatory amino
81
acids (e.g., glutamate and aspartate).
82
The mechanisms by which lamotrigine exerts its therapeutic action in Bipolar Disorder have
83
not been established.
84
Pharmacological Properties: Although the relevance for human use is unknown, the
85
following data characterize the performance of LAMICTAL in receptor binding assays.
86
Lamotrigine had a weak inhibitory effect on the serotonin 5-HT3 receptor (IC50 = 18 µM). It does
87
not exhibit high affinity binding (IC50>100 µM) to the following neurotransmitter receptors:
88
adenosine A1 and A2; adrenergic α1, α2, and β; dopamine D1 and D2; γ-aminobutyric acid
89
(GABA) A and B; histamine H1; kappa opioid; muscarinic acetylcholine; and serotonin 5-HT2.
90
Studies have failed to detect an effect of lamotrigine on dihydropyridine-sensitive calcium
91
channels. It had weak effects at sigma opioid receptors (IC50 = 145 µM). Lamotrigine did not
92
inhibit the uptake of norepinephrine, dopamine, or serotonin, (IC50>200 µM) when tested in rat
93
synaptosomes and/or human platelets in vitro.
94
Effect of Lamotrigine on N-Methyl d-Aspartate-Receptor Mediated Activity:
95
Lamotrigine did not inhibit N-methyl d-aspartate (NMDA)-induced depolarizations in rat cortical
96
slices or NMDA-induced cyclic GMP formation in immature rat cerebellum, nor did lamotrigine
97
displace compounds that are either competitive or noncompetitive ligands at this glutamate
98
receptor complex (CNQX, CGS, TCHP). The IC50 for lamotrigine effects on NMDA-induced
99
currents (in the presence of 3 µM of glycine) in cultured hippocampal neurons exceeded
100
100 µM.
101
Folate Metabolism: In vitro, lamotrigine was shown to be an inhibitor of dihydrofolate
102
reductase, the enzyme that catalyzes the reduction of dihydrofolate to tetrahydrofolate. Inhibition
103
of this enzyme may interfere with the biosynthesis of nucleic acids and proteins. When oral daily
104
doses of lamotrigine were given to pregnant rats during organogenesis, fetal, placental, and
105
maternal folate concentrations were reduced. Significantly reduced concentrations of folate are
106
associated with teratogenesis (see PRECAUTIONS: Pregnancy). Folate concentrations were also
107
reduced in male rats given repeated oral doses of lamotrigine. Reduced concentrations were
108
partially returned to normal when supplemented with folinic acid.
109
Accumulation in Kidneys: Lamotrigine was found to accumulate in the kidney of the
110
male rat, causing chronic progressive nephrosis, necrosis, and mineralization. These findings are
111
attributed to α-2 microglobulin, a species- and sex-specific protein that has not been detected in
112
humans or other animal species.
113
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4
Melanin Binding: Lamotrigine binds to melanin-containing tissues, e.g., in the eye and
114
pigmented skin. It has been found in the uveal tract up to 52 weeks after a single dose in rodents.
115
Cardiovascular: In dogs, lamotrigine is extensively metabolized to a 2-N-methyl
116
metabolite. This metabolite causes dose-dependent prolongations of the PR interval, widening of
117
the QRS complex, and, at higher doses, complete AV conduction block. Similar cardiovascular
118
effects are not anticipated in humans because only trace amounts of the 2-N-methyl metabolite
119
(<0.6% of lamotrigine dose) have been found in human urine (see Drug Disposition). However,
120
it is conceivable that plasma concentrations of this metabolite could be increased in patients with
121
a reduced capacity to glucuronidate lamotrigine (e.g., in patients with liver disease).
122
Pharmacokinetics and Drug Metabolism: The pharmacokinetics of lamotrigine have been
123
studied in patients with epilepsy, healthy young and elderly volunteers, and volunteers with
124
chronic renal failure. Lamotrigine pharmacokinetic parameters for adult and pediatric patients
125
and healthy normal volunteers are summarized in Tables 1 and 2.
126
127
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5
Table 1. Mean* Pharmacokinetic Parameters in Healthy Volunteers and Adult Patients
128
With Epilepsy
129
Adult Study Population
Number of
Subjects
Tmax: Time of
Maximum
Plasma
Concentration
(h)
t½:
Elimination
Half-life
(h)
Cl/F:
Apparent Plasma
Clearance
(mL/min/kg)
Healthy volunteers taking
no other medications:
Single-dose LAMICTAL
Multiple-dose LAMICTAL
179
36
2.2
(0.25-12.0)
1.7
(0.5-4.0)
32.8
(14.0-103.0)
25.4
(11.6-61.6)
0.44
(0.12-1.10)
0.58
(0.24-1.15)
Healthy volunteers taking
valproate:
Single-dose LAMICTAL
Multiple-dose LAMICTAL
6
18
1.8
(1.0-4.0)
1.9
(0.5-3.5)
48.3
(31.5-88.6)
70.3
(41.9-113.5)
0.30
(0.14-0.42)
0.18
(0.12-0.33)
Patients with epilepsy taking
valproate only:
Single-dose LAMICTAL
4
4.8
(1.8-8.4)
58.8
(30.5-88.8)
0.28
(0.16-0.40)
Patients with epilepsy taking
carbamazepine, phenytoin,
phenobarbital, or primidone†
plus valproate:
Single-dose LAMICTAL
25
3.8
(1.0-10.0)
27.2
(11.2-51.6)
0.53
(0.27-1.04)
Patients with epilepsy taking
carbamazepine, phenytoin,
phenobarbital, or primidone†:
Single-dose LAMICTAL
Multiple-dose LAMICTAL
24
17
2.3
(0.5-5.0)
2.0
(0.75-5.93)
14.4
(6.4-30.4)
12.6
(7.5-23.1)
1.10
(0.51-2.22)
1.21
(0.66-1.82)
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6
*The majority of parameter means determined in each study had coefficients of variation
130
between 20% and 40% for half-life and Cl/F and between 30% and 70% for Tmax. The
131
overall mean values were calculated from individual study means that were weighted based
132
on the number of volunteers/patients in each study. The numbers in parentheses below each
133
parameter mean represent the range of individual volunteer/patient values across studies.
134
† Carbamazepine, phenobarbital, phenytoin, and primidone have been shown to increase the
135
apparent clearance of lamotrigine. Estrogen-containing oral contraceptives and rifampin have
136
also been shown to increase the apparent clearance of lamotrigine (see CLINICAL
137
PHARMACOLOGY: Drug Interactions and PRECAUTIONS: Drug Interactions).
138
139
Absorption: Lamotrigine is rapidly and completely absorbed after oral administration with
140
negligible first-pass metabolism (absolute bioavailability is 98%). The bioavailability is not
141
affected by food. Peak plasma concentrations occur anywhere from 1.4 to 4.8 hours following
142
drug administration. The lamotrigine chewable/dispersible tablets were found to be equivalent,
143
whether they were administered as dispersed in water, chewed and swallowed, or swallowed as
144
whole, to the lamotrigine compressed tablets in terms of rate and extent of absorption.
145
Distribution: Estimates of the mean apparent volume of distribution (Vd/F) of lamotrigine
146
following oral administration ranged from 0.9 to 1.3 L/kg. Vd/F is independent of dose and is
147
similar following single and multiple doses in both patients with epilepsy and in healthy
148
volunteers.
149
Protein Binding: Data from in vitro studies indicate that lamotrigine is approximately 55%
150
bound to human plasma proteins at plasma lamotrigine concentrations from 1 to 10 mcg/mL
151
(10 mcg/mL is 4 to 6 times the trough plasma concentration observed in the controlled efficacy
152
trials). Because lamotrigine is not highly bound to plasma proteins, clinically significant
153
interactions with other drugs through competition for protein binding sites are unlikely. The
154
binding of lamotrigine to plasma proteins did not change in the presence of therapeutic
155
concentrations of phenytoin, phenobarbital, or valproate. Lamotrigine did not displace other
156
AEDs (carbamazepine, phenytoin, phenobarbital) from protein binding sites.
157
Drug Disposition: Lamotrigine is metabolized predominantly by glucuronic acid
158
conjugation; the major metabolite is an inactive 2-N-glucuronide conjugate. After oral
159
administration of 240 mg of 14C-lamotrigine (15 μCi) to 6 healthy volunteers, 94% was
160
recovered in the urine and 2% was recovered in the feces. The radioactivity in the urine consisted
161
of unchanged lamotrigine (10%), the 2-N-glucuronide (76%), a 5-N-glucuronide (10%), a
162
2-N-methyl metabolite (0.14%), and other unidentified minor metabolites (4%).
163
Drug Interactions: The apparent clearance of lamotrigine is affected by the
164
coadministration of certain medications. Because lamotrigine is metabolized predominantly
165
by glucuronic acid conjugation, drugs that induce or inhibit glucuronidation may affect the
166
apparent clearance of lamotrigine.
167
Carbamazepine, phenytoin, phenobarbital, and primidone have been shown to increase the
168
apparent clearance of lamotrigine (see DOSAGE AND ADMINISTRATION and
169
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7
PRECAUTIONS: Drug Interactions). Most clinical experience is derived from patients taking
170
these AEDs.
171
Estrogen-containing oral contraceptives and rifampin have also been shown to increase the
172
apparent clearance of lamotrigine (see PRECAUTIONS: Drug Interactions).
173
Valproate decreases the apparent clearance of lamotrigine (i.e., more than doubles the
174
elimination half-life of lamotrigine), whether given with or without carbamazepine,
175
phenytoin, phenobarbital, or primidone. Accordingly, if lamotrigine is to be administered to a
176
patient receiving valproate, lamotrigine must be given at a reduced dosage, of no more than half
177
the dose used in patients not receiving valproate, even in the presence of drugs that increase the
178
apparent clearance of lamotrigine (see DOSAGE AND ADMINISTRATION and
179
PRECAUTIONS: Drug Interactions).
180
The following drugs were shown not to increase the apparent clearance of lamotrigine:
181
felbamate, gabapentin, levetiracetam, oxcarbazepine, pregabalin, and topiramate. Zonisamide
182
does not appear to change the pharmacokinetic profile of lamotrigine (see PRECAUTIONS:
183
Drug Interactions).
184
In vitro inhibition experiments indicated that the formation of the primary metabolite of
185
lamotrigine, the 2-N-glucuronide, was not significantly affected by co-incubation with clozapine,
186
fluoxetine, phenelzine, risperidone, sertraline, or trazodone, and was minimally affected by co-
187
incubation with amitriptyline, bupropion, clonazepam, haloperidol, or lorazepam. In addition,
188
bufuralol metabolism data from human liver microsomes suggested that lamotrigine does not
189
inhibit the metabolism of drugs eliminated predominantly by CYP2D6.
190
LAMICTAL has no effects on the pharmacokinetics of lithium (see PRECAUTIONS: Drug
191
Interactions).
192
The pharmacokinetics of LAMICTAL were not changed by co-administration of bupropion
193
(see PRECAUTIONS: Drug Interactions).
194
Co-administration of olanzapine did not have a clinically relevant effect on LAMICTAL
195
pharmacokinetics (see PRECAUTIONS: Drug Interactions).
196
Enzyme Induction: The effects of lamotrigine on the induction of specific families of
197
mixed-function oxidase isozymes have not been systematically evaluated.
198
Following multiple administrations (150 mg twice daily) to normal volunteers taking no other
199
medications, lamotrigine induced its own metabolism, resulting in a 25% decrease in t½ and a
200
37% increase in Cl/F at steady state compared to values obtained in the same volunteers
201
following a single dose. Evidence gathered from other sources suggests that self-induction by
202
LAMICTAL may not occur when LAMICTAL is given as adjunctive therapy in patients
203
receiving carbamazepine, phenytoin, phenobarbital, primidone, or rifampin.
204
Dose Proportionality: In healthy volunteers not receiving any other medications and given
205
single doses, the plasma concentrations of lamotrigine increased in direct proportion to the dose
206
administered over the range of 50 to 400 mg. In 2 small studies (n = 7 and 8) of patients with
207
epilepsy who were maintained on other AEDs, there also was a linear relationship between dose
208
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8
and lamotrigine plasma concentrations at steady state following doses of 50 to 350 mg twice
209
daily.
210
Elimination: (see Table 1).
211
Special Populations: Patients With Renal Insufficiency: Twelve volunteers with
212
chronic renal failure (mean creatinine clearance = 13 mL/min; range = 6 to 23) and another
213
6 individuals undergoing hemodialysis were each given a single 100-mg dose of LAMICTAL.
214
The mean plasma half-lives determined in the study were 42.9 hours (chronic renal failure),
215
13.0 hours (during hemodialysis), and 57.4 hours (between hemodialysis) compared to
216
26.2 hours in healthy volunteers. On average, approximately 20% (range = 5.6 to 35.1) of the
217
amount of lamotrigine present in the body was eliminated by hemodialysis during a 4-hour
218
session.
219
Hepatic Disease: The pharmacokinetics of lamotrigine following a single 100-mg dose
220
of LAMICTAL were evaluated in 24 subjects with mild, moderate, and severe hepatic
221
dysfunction (Child-Pugh Classification system) and compared with 12 subjects without hepatic
222
impairment. The patients with severe hepatic impairment were without ascites (n = 2) or with
223
ascites (n = 5). The mean apparent clearance of lamotrigine in patients with mild (n = 12),
224
moderate (n = 5), severe without ascites (n = 2), and severe with ascites (n = 5) liver impairment
225
was 0.30 ± 0.09, 0.24 ± 0.1, 0.21 ± 0.04, and 0.15 ± 0.09 mL/min/kg, respectively, as compared
226
to 0.37 ± 0.1 mL/min/kg in the healthy controls. Mean half-life of lamotrigine in patients with
227
mild, moderate, severe without ascites, and severe with ascites liver impairment was 46 ± 20,
228
72 ± 44, 67 ± 11, and 100 ± 48 hours, respectively, as compared to 33 ± 7 hours in healthy
229
controls (for dosing guidelines, see DOSAGE AND ADMINISTRATION: Patient With Hepatic
230
Impairment).
231
Age: Pediatric Patients: The pharmacokinetics of LAMICTAL following a single
232
2-mg/kg dose were evaluated in 2 studies of pediatric patients (n = 29 for patients aged
233
10 months to 5.9 years and n = 26 for patients aged 5 to 11 years). Forty-three patients received
234
concomitant therapy with other AEDs and 12 patients received LAMICTAL as monotherapy.
235
Lamotrigine pharmacokinetic parameters for pediatric patients are summarized in Table 2.
236
Population pharmacokinetic analyses involving patients aged 2 to 18 years demonstrated that
237
lamotrigine clearance was influenced predominantly by total body weight and concurrent AED
238
therapy. The oral clearance of lamotrigine was higher, on a body weight basis, in pediatric
239
patients than in adults. Weight-normalized lamotrigine clearance was higher in those subjects
240
weighing less than 30 kg, compared with those weighing greater than 30 kg. Accordingly,
241
patients weighing less than 30 kg may need an increase of as much as 50% in maintenance doses,
242
based on clinical response, as compared with subjects weighing more than 30 kg being
243
administered the same AEDs (see DOSAGE AND ADMINISTRATION). These analyses also
244
revealed that, after accounting for body weight, lamotrigine clearance was not significantly
245
influenced by age. Thus, the same weight-adjusted doses should be administered to children
246
irrespective of differences in age. Concomitant AEDs which influence lamotrigine clearance in
247
adults were found to have similar effects in children.
248
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9
249
Table 2. Mean Pharmacokinetic Parameters in Pediatric Patients With Epilepsy
250
Pediatric Study Population
Number
of
Subjects
Tmax
(h)
t½
(h)
Cl/F
(mL/min/kg)
Ages 10 months-5.3 years
Patients taking carbamazepine,
phenytoin, phenobarbital, or
primidone*
10
3.0
(1.0-5.9)
7.7
(5.7-11.4)
3.62
(2.44-5.28)
Patients taking antiepileptic drugs
(AEDs) with no known effect on
the apparent clearance of
lamotrigine
7
5.2
(2.9-6.1)
19.0
(12.9-27.1)
1.2
(0.75-2.42)
Patients taking valproate only
8
2.9
(1.0-6.0)
44.9
(29.5-52.5)
0.47
(0.23-0.77)
Ages 5-11 years
Patients taking carbamazepine,
phenytoin, phenobarbital, or
primidone*
7
1.6
(1.0-3.0)
7.0
(3.8-9.8)
2.54
(1.35-5.58)
Patients taking carbamazepine,
phenytoin, phenobarbital, or
primidone* plus valproate
8
3.3
(1.0-6.4)
19.1
(7.0-31.2)
0.89
(0.39-1.93)
Patients taking valproate only
†
3
4.5
(3.0-6.0)
65.8
(50.7-73.7)
0.24
(0.21-0.26)
Ages 13-18 years
Patients taking carbamazepine,
phenytoin, phenobarbital, or
primidone*
11
‡
‡
1.3
Patients taking carbamazepine,
phenytoin, phenobarbital, or
primidone*plus valproate
8
‡
‡
0.5
Patients taking valproate only
4
‡
‡
0.3
*Carbamazepine, phenobarbital, phenytoin, and primidone have been shown to increase the
251
apparent clearance of lamotrigine. Estrogen-containing oral contraceptives and rifampin have
252
also been shown to increase the apparent clearance of lamotrigine (see CLINICAL
253
PHARMACOLOGY: Drug Interactions and PRECAUTIONS: Drug Interactions).
254
†Two subjects were included in the calculation for mean Tmax.
255
‡Parameter not estimated.
256
257
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10
Elderly: The pharmacokinetics of lamotrigine following a single 150-mg dose of
258
LAMICTAL were evaluated in 12 elderly volunteers between the ages of 65 and 76 years (mean
259
creatinine clearance = 61 mL/min, range = 33 to 108 mL/min). The mean half-life of lamotrigine
260
in these subjects was 31.2 hours (range, 24.5 to 43.4 hours), and the mean clearance was
261
0.40 mL/min/kg (range, 0.26 to 0.48 mL/min/kg).
262
Gender: The clearance of lamotrigine is not affected by gender. However, during dose
263
escalation of LAMICTAL in one clinical trial in patients with epilepsy on a stable dose of
264
valproate (n = 77), mean trough lamotrigine concentrations, unadjusted for weight, were 24% to
265
45% higher (0.3 to 1.7 mcg/mL) in females than in males.
266
Race: The apparent oral clearance of lamotrigine was 25% lower in non-Caucasians than
267
Caucasians.
268
CLINICAL STUDIES
269
Epilepsy: The results of controlled clinical trials established the efficacy of LAMICTAL as
270
monotherapy in adults with partial onset seizures already receiving treatment with
271
carbamazepine, phenytoin, phenobarbital, or primidone as the single antiepileptic drug (AED), as
272
adjunctive therapy in adults and pediatric patients age 2 to 16 with partial seizures, and as
273
adjunctive therapy in the generalized seizures of Lennox-Gastaut syndrome in pediatric and adult
274
patients.
275
Monotherapy With LAMICTAL in Adults With Partial Seizures Already Receiving
276
Treatment With Carbamazepine, Phenytoin, Phenobarbital, or Primidone as the
277
Single AED: The effectiveness of monotherapy with LAMICTAL was established in a
278
multicenter, double-blind clinical trial enrolling 156 adult outpatients with partial seizures. The
279
patients experienced at least 4 simple partial, complex partial, and/or secondarily generalized
280
seizures during each of 2 consecutive 4-week periods while receiving carbamazepine or
281
phenytoin monotherapy during baseline. LAMICTAL (target dose of 500 mg/day) or valproate
282
(1,000 mg/day) was added to either carbamazepine or phenytoin monotherapy over a 4-week
283
period. Patients were then converted to monotherapy with LAMICTAL or valproate during the
284
next 4 weeks, then continued on monotherapy for an additional 12-week period.
285
Study endpoints were completion of all weeks of study treatment or meeting an escape
286
criterion. Criteria for escape relative to baseline were: (1) doubling of average monthly seizure
287
count, (2) doubling of highest consecutive 2-day seizure frequency, (3) emergence of a new
288
seizure type (defined as a seizure that did not occur during the 8-week baseline) that is more
289
severe than seizure types that occur during study treatment, or (4) clinically significant
290
prolongation of generalized-tonic-clonic (GTC) seizures. The primary efficacy variable was the
291
proportion of patients in each treatment group who met escape criteria.
292
The percentage of patients who met escape criteria was 42% (32/76) in the LAMICTAL
293
group and 69% (55/80) in the valproate group. The difference in the percentage of patients
294
meeting escape criteria was statistically significant (p = 0.0012) in favor of LAMICTAL. No
295
differences in efficacy based on age, sex, or race were detected.
296
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11
Patients in the control group were intentionally treated with a relatively low dose of valproate;
297
as such, the sole objective of this study was to demonstrate the effectiveness and safety of
298
monotherapy with LAMICTAL, and cannot be interpreted to imply the superiority of
299
LAMICTAL to an adequate dose of valproate.
300
Adjunctive Therapy With LAMICTAL in Adults With Partial Seizures: The
301
effectiveness of LAMICTAL as adjunctive therapy (added to other AEDs) was established in
302
3 multicenter, placebo-controlled, double-blind clinical trials in 355 adults with refractory partial
303
seizures. The patients had a history of at least 4 partial seizures per month in spite of receiving
304
one or more AEDs at therapeutic concentrations and, in 2 of the studies, were observed on their
305
established AED regimen during baselines that varied between 8 to 12 weeks. In the third,
306
patients were not observed in a prospective baseline. In patients continuing to have at least
307
4 seizures per month during the baseline, LAMICTAL or placebo was then added to the existing
308
therapy. In all 3 studies, change from baseline in seizure frequency was the primary measure of
309
effectiveness. The results given below are for all partial seizures in the intent-to-treat population
310
(all patients who received at least one dose of treatment) in each study, unless otherwise
311
indicated. The median seizure frequency at baseline was 3 per week while the mean at baseline
312
was 6.6 per week for all patients enrolled in efficacy studies.
313
One study (n = 216) was a double-blind, placebo-controlled, parallel trial consisting of a
314
24-week treatment period. Patients could not be on more than 2 other anticonvulsants and
315
valproate was not allowed. Patients were randomized to receive placebo, a target dose of
316
300 mg/day of LAMICTAL, or a target dose of 500 mg/day of LAMICTAL. The median
317
reductions in the frequency of all partial seizures relative to baseline were 8% in patients
318
receiving placebo, 20% in patients receiving 300 mg/day of LAMICTAL, and 36% in patients
319
receiving 500 mg/day of LAMICTAL. The seizure frequency reduction was statistically
320
significant in the 500-mg/day group compared to the placebo group, but not in the 300-mg/day
321
group.
322
A second study (n = 98) was a double-blind, placebo-controlled, randomized, crossover trial
323
consisting of two 14-week treatment periods (the last 2 weeks of which consisted of dose
324
tapering) separated by a 4-week washout period. Patients could not be on more than 2 other
325
anticonvulsants and valproate was not allowed. The target dose of LAMICTAL was 400 mg/day.
326
When the first 12 weeks of the treatment periods were analyzed, the median change in seizure
327
frequency was a 25% reduction on LAMICTAL compared to placebo (p<0.001).
328
The third study (n = 41) was a double-blind, placebo-controlled, crossover trial consisting of
329
two 12-week treatment periods separated by a 4-week washout period. Patients could not be on
330
more than 2 other anticonvulsants. Thirteen patients were on concomitant valproate; these
331
patients received 150 mg/day of LAMICTAL. The 28 other patients had a target dose of
332
300 mg/day of LAMICTAL. The median change in seizure frequency was a 26% reduction on
333
LAMICTAL compared to placebo (p<0.01).
334
No differences in efficacy based on age, sex, or race, as measured by change in seizure
335
frequency, were detected.
336
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12
Adjunctive Therapy With LAMICTAL in Pediatric Patients With Partial Seizures:
337
The effectiveness of LAMICTAL as adjunctive therapy in pediatric patients with partial seizures
338
was established in a multicenter, double-blind, placebo-controlled trial in 199 patients aged 2 to
339
16 years (n = 98 on LAMICTAL, n = 101 on placebo). Following an 8-week baseline phase,
340
patients were randomized to 18 weeks of treatment with LAMICTAL or placebo added to their
341
current AED regimen of up to 2 drugs. Patients were dosed based on body weight and valproate
342
use. Target doses were designed to approximate 5 mg/kg per day for patients taking valproate
343
(maximum dose, 250 mg/day) and 15 mg/kg per day for the patients not taking valproate
344
(maximum dose, 750 mg per day). The primary efficacy endpoint was percentage change from
345
baseline in all partial seizures. For the intent-to-treat population, the median reduction of all
346
partial seizures was 36% in patients treated with LAMICTAL and 7% on placebo, a difference
347
that was statistically significant (p<0.01).
348
Adjunctive Therapy With LAMICTAL in Pediatric and Adult Patients With
349
Lennox-Gastaut Syndrome: The effectiveness of LAMICTAL as adjunctive therapy in
350
patients with Lennox-Gastaut syndrome was established in a multicenter, double-blind,
351
placebo-controlled trial in 169 patients aged 3 to 25 years (n = 79 on LAMICTAL, n = 90 on
352
placebo). Following a 4-week single-blind, placebo phase, patients were randomized to 16 weeks
353
of treatment with LAMICTAL or placebo added to their current AED regimen of up to 3 drugs.
354
Patients were dosed on a fixed-dose regimen based on body weight and valproate use. Target
355
doses were designed to approximate 5 mg/kg per day for patients taking valproate (maximum
356
dose, 200 mg/day) and 15 mg/kg per day for patients not taking valproate (maximum dose,
357
400 mg/day). The primary efficacy endpoint was percentage change from baseline in major
358
motor seizures (atonic, tonic, major myoclonic, and tonic-clonic seizures). For the intent-to-treat
359
population, the median reduction of major motor seizures was 32% in patients treated with
360
LAMICTAL and 9% on placebo, a difference that was statistically significant (p<0.05). Drop
361
attacks were significantly reduced by LAMICTAL (34%) compared to placebo (9%), as were
362
tonic-clonic seizures (36% reduction versus 10% increase for LAMICTAL and placebo,
363
respectively).
364
Adjunctive Therapy With LAMICTAL in Pediatric and Adult Patients With
365
Primary Generalized Tonic-Clonic Seizures: The effectiveness of LAMICTAL as
366
adjunctive therapy in patients with primary generalized tonic-clonic seizures was established in a
367
multicenter, double-blind, placebo-controlled trial in 117 pediatric and adult patients ≥ 2 years
368
(n = 58 on LAMICTAL, n = 59 on placebo). Patients with at least 3 primary generalized tonic-
369
clonic seizures during an 8-week baseline phase were randomized to 19 to 24 weeks of treatment
370
with LAMICTAL or placebo added to their current AED regimen of up to 2 drugs. Patients were
371
dosed on a fixed-dose regimen, with target doses ranging from 3 mg/kg/day to 12 mg/kg/day for
372
pediatric patients and from 200 mg/day to 400 mg/day for adult patients based on concomitant
373
AED.
374
The primary efficacy endpoint was percentage change from baseline in primary generalized
375
tonic-clonic seizures. For the intent-to-treat population, the median percent reduction of primary
376
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
13
generalized tonic-clonic seizures was 66% in patients treated with LAMICTAL and 34% on
377
placebo, a difference that was statistically significant (p=0.006).
378
379
Bipolar Disorder: The effectiveness of LAMICTAL in the maintenance treatment of Bipolar I
380
Disorder was established in 2 multicenter, double-blind, placebo-controlled studies in adult
381
patients who met DSM-IV criteria for Bipolar I Disorder. Study 1 enrolled patients with a current
382
or recent (within 60 days) depressive episode as defined by DSM-IV and Study 2 included
383
patients with a current or recent (within 60 days) episode of mania or hypomania as defined by
384
DSM-IV. Both studies included a cohort of patients (30% of 404 patients in Study 1 and 28% of
385
171 patients in Study 2) with rapid cycling Bipolar Disorder (4 to 6 episodes per year).
386
In both studies, patients were titrated to a target dose of 200 mg of LAMICTAL, as add-on
387
therapy or as monotherapy, with gradual withdrawal of any psychotropic medications during an
388
8- to 16-week open-label period. Overall 81% of 1,305 patients participating in the open-label
389
period were receiving 1 or more other psychotropic medications, including benzodiazepines,
390
selective serotonin reuptake inhibitors (SSRIs), atypical antipsychotics (including olanzapine),
391
valproate, or lithium, during titration of LAMICTAL. Patients with a CGI-severity score of 3 or
392
less maintained for at least 4 continuous weeks, including at least the final week on monotherapy
393
with LAMICTAL, were randomized to a placebo-controlled, double-blind treatment period for
394
up to 18 months. The primary endpoint was TIME (time to intervention for a mood episode or
395
one that was emerging, time to discontinuation for either an adverse event that was judged to be
396
related to Bipolar Disorder, or for lack of efficacy). The mood episode could be depression,
397
mania, hypomania, or a mixed episode.
398
In Study 1, patients received double-blind monotherapy with LAMICTAL, 50 mg/day
399
(n = 50), LAMICTAL 200 mg/day (n = 124), LAMICTAL 400 mg/day (n = 47), or placebo
400
(n = 121). LAMICTAL (200- and 400-mg/day treatment groups combined) was superior to
401
placebo in delaying the time to occurrence of a mood episode. Separate analyses of the 200 and
402
400 mg/day dose groups revealed no added benefit from the higher dose.
403
In Study 2, patients received double-blind monotherapy with LAMICTAL (100 to
404
400 mg/day, n = 59), or placebo (n = 70). LAMICTAL was superior to placebo in delaying time
405
to occurrence of a mood episode. The mean LAMICTAL dose was about 211 mg/day.
406
Although these studies were not designed to separately evaluate time to the occurrence of
407
depression or mania, a combined analysis for the 2 studies revealed a statistically significant
408
benefit for LAMICTAL over placebo in delaying the time to occurrence of both depression and
409
mania, although the finding was more robust for depression.
410
INDICATIONS AND USAGE
411
Epilepsy:
412
Adjunctive Use: LAMICTAL is indicated as adjunctive therapy for partial seizures, the
413
generalized seizures of Lennox-Gastaut syndrome, and primary generalized tonic-clonic seizures
414
in adults and pediatric patients (≥2 years of age).
415
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
14
416
Monotherapy Use: LAMICTAL is indicated for conversion to monotherapy in adults with
417
partial seizures.who are receiving treatment with carbamazepine, phenytoin, phenobarbital,
418
primidone, or valproate as the single AED.
419
Safety and effectiveness of LAMICTAL have not been established (1) as initial monotherapy,
420
(2) for conversion to monotherapy from AEDs other than carbamazepine, phenytoin,
421
phenobarbital, primidone, or valproate, or (3) for simultaneous conversion to monotherapy from
422
2 or more concomitant AEDs (see DOSAGE AND ADMINISTRATION).
423
424
Bipolar Disorder: LAMICTAL is indicated for the maintenance treatment of Bipolar I
425
Disorder to delay the time to occurrence of mood episodes (depression, mania, hypomania,
426
mixed episodes) in patients treated for acute mood episodes with standard therapy. The
427
effectiveness of LAMICTAL in the acute treatment of mood episodes has not been established.
428
The effectiveness of LAMICTAL as maintenance treatment was established in
429
2 placebo-controlled trials of 18 months’ duration in patients with Bipolar I Disorder as defined
430
by DSM-IV (see CLINICAL STUDIES, Bipolar Disorder). The physician who elects to use
431
LAMICTAL for periods extending beyond 18 months should periodically re-evaluate the
432
long-term usefulness of the drug for the individual patient.
433
CONTRAINDICATIONS
434
LAMICTAL is contraindicated in patients who have demonstrated hypersensitivity to the drug
435
or its ingredients.
436
WARNINGS
437
SEE BOX WARNING REGARDING THE RISK OF SERIOUS RASHES REQUIRING
438
HOSPITALIZATION AND DISCONTINUATION OF LAMICTAL.
439
ALTHOUGH BENIGN RASHES ALSO OCCUR WITH LAMICTAL, IT IS NOT
440
POSSIBLE TO PREDICT RELIABLY WHICH RASHES WILL PROVE TO BE
441
SERIOUS OR LIFE THREATENING. ACCORDINGLY, LAMICTAL SHOULD
442
ORDINARILY BE DISCONTINUED AT THE FIRST SIGN OF RASH, UNLESS THE
443
RASH IS CLEARLY NOT DRUG RELATED. DISCONTINUATION OF TREATMENT
444
MAY NOT PREVENT A RASH FROM BECOMING LIFE THREATENING OR
445
PERMANENTLY DISABLING OR DISFIGURING.
446
Serious Rash: Pediatric Population: The incidence of serious rash associated with
447
hospitalization and discontinuation of LAMICTAL in a prospectively followed cohort of
448
pediatric patients with epilepsy receiving adjunctive therapy was approximately 0.8% (16 of
449
1,983). When 14 of these cases were reviewed by 3 expert dermatologists, there was
450
considerable disagreement as to their proper classification. To illustrate, one dermatologist
451
considered none of the cases to be Stevens-Johnson syndrome; another assigned 7 of the 14 to
452
this diagnosis. There was 1 rash-related death in this 1,983 patient cohort. Additionally, there
453
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
15
have been rare cases of toxic epidermal necrolysis with and without permanent sequelae and/or
454
death in US and foreign postmarketing experience.
455
There is evidence that the inclusion of valproate in a multidrug regimen increases the risk of
456
serious, potentially life-threatening rash in pediatric patients. In pediatric patients who used
457
valproate concomitantly, 1.2% (6 of 482) experienced a serious rash compared to 0.6% (6 of
458
952) patients not taking valproate.
459
Adult Population: Serious rash associated with hospitalization and discontinuation of
460
LAMICTAL occurred in 0.3% (11 of 3,348) of adult patients who received LAMICTAL in
461
premarketing clinical trials of epilepsy. In the bipolar and other mood disorders clinical trials, the
462
rate of serious rash was 0.08% (1 of 1,233) of adult patients who received LAMICTAL as initial
463
monotherapy and 0.13% (2 of 1,538) of adult patients who received LAMICTAL as adjunctive
464
therapy. No fatalities occurred among these individuals. However, in worldwide postmarketing
465
experience, rare cases of rash-related death have been reported, but their numbers are too few to
466
permit a precise estimate of the rate.
467
Among the rashes leading to hospitalization were Stevens-Johnson syndrome, toxic epidermal
468
necrolysis, angioedema, and a rash associated with a variable number of the following systemic
469
manifestations: fever, lymphadenopathy, facial swelling, hematologic, and hepatologic
470
abnormalities.
471
There is evidence that the inclusion of valproate in a multidrug regimen increases the risk of
472
serious, potentially life-threatening rash in adults. Specifically, of 584 patients administered
473
LAMICTAL with valproate in epilepsy clinical trials, 6 (1%) were hospitalized in association
474
with rash; in contrast, 4 (0.16%) of 2,398 clinical trial patients and volunteers administered
475
LAMICTAL in the absence of valproate were hospitalized.
476
Other examples of serious and potentially life-threatening rash that did not lead to
477
hospitalization also occurred in premarketing development. Among these, 1 case was reported to
478
be Stevens-Johnson–like.
479
Hypersensitivity Reactions: Hypersensitivity reactions, some fatal or life threatening, have
480
also occurred. Some of these reactions have included clinical features of multiorgan
481
failure/dysfunction, including hepatic abnormalities and evidence of disseminated intravascular
482
coagulation. It is important to note that early manifestations of hypersensitivity (e.g., fever,
483
lymphadenopathy) may be present even though a rash is not evident. If such signs or symptoms
484
are present, the patient should be evaluated immediately. LAMICTAL should be discontinued if
485
an alternative etiology for the signs or symptoms cannot be established.
486
Prior to initiation of treatment with LAMICTAL, the patient should be instructed that a
487
rash or other signs or symptoms of hypersensitivity (e.g., fever, lymphadenopathy) may
488
herald a serious medical event and that the patient should report any such occurrence to a
489
physician immediately.
490
Acute Multiorgan Failure: Multiorgan failure, which in some cases has been fatal or
491
irreversible, has been observed in patients receiving LAMICTAL. Fatalities associated with
492
multiorgan failure and various degrees of hepatic failure have been reported in 2 of 3,796 adult
493
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
16
patients and 4 of 2,435 pediatric patients who received LAMICTAL in clinical trials. No such
494
fatalities have been reported in bipolar patients in clinical trials. Rare fatalities from multiorgan
495
failure have also been reported in compassionate plea and postmarketing use. The majority of
496
these deaths occurred in association with other serious medical events, including status
497
epilepticus and overwhelming sepsis, and hantavirus making it difficult to identify the initial
498
cause.
499
Additionally, 3 patients (a 45-year-old woman, a 3.5-year-old boy, and an 11-year-old girl)
500
developed multiorgan dysfunction and disseminated intravascular coagulation 9 to 14 days after
501
LAMICTAL was added to their AED regimens. Rash and elevated transaminases were also
502
present in all patients and rhabdomyolysis was noted in 2 patients. Both pediatric patients were
503
receiving concomitant therapy with valproate, while the adult patient was being treated with
504
carbamazepine and clonazepam. All patients subsequently recovered with supportive care after
505
treatment with LAMICTAL was discontinued.
506
Blood Dyscrasias: There have been reports of blood dyscrasias that may or may not be
507
associated with the hypersensitivity syndrome. These have included neutropenia, leukopenia,
508
anemia, thrombocytopenia, pancytopenia, and, rarely, aplastic anemia and pure red cell aplasia.
509
Withdrawal Seizures: As with other AEDs, LAMICTAL should not be abruptly discontinued.
510
In patients with epilepsy there is a possibility of increasing seizure frequency. In clinical trials in
511
patients with Bipolar Disorder, 2 patients experienced seizures shortly after abrupt withdrawal of
512
LAMICTAL. However, there were confounding factors that may have contributed to the
513
occurrence of seizures in these bipolar patients. Unless safety concerns require a more rapid
514
withdrawal, the dose of LAMICTAL should be tapered over a period of at least 2 weeks (see
515
DOSAGE AND ADMINISTRATION).
516
PRECAUTIONS
517
518
Concomitant Use With Oral Contraceptives: Some estrogen-containing oral
519
contraceptives have been shown to decrease serum concentrations of lamotrigine (see
520
PRECAUTIONS: Drug Interactions). Dosage adjustments will be necessary in most patients
521
who start or stop estrogen-containing oral contraceptives while taking LAMICTAL (see
522
DOSAGE AND ADMINISTRATION: Special Populations: Women and Oral
523
Contraceptives: Adjustments to the Maintenance Dose of LAMICTAL). During the week of
524
inactive hormone preparation (“pill-free” week) of oral contraceptive therapy, plasma levels are
525
expected to rise, as much as doubling by the end of the week. Adverse events consistent with
526
elevated levels of lamotrigine, such as dizziness, ataxia, and diplopia, could occur.
527
Dermatological Events (see BOX WARNING, WARNINGS): Serious rashes associated
528
with hospitalization and discontinuation of LAMICTAL have been reported. Rare deaths have
529
been reported, but their numbers are too few to permit a precise estimate of the rate. There are
530
suggestions, yet to be proven, that the risk of rash may also be increased by (1) coadministration
531
of LAMICTAL with valproate, (2) exceeding the recommended initial dose of LAMICTAL, or
532
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
17
(3) exceeding the recommended dose escalation for LAMICTAL. However, cases have been
533
reported in the absence of these factors.
534
In epilepsy clinical trials, approximately 10% of all patients exposed to LAMICTAL
535
developed a rash. In the Bipolar Disorder clinical trials, 14% of patients exposed to LAMICTAL
536
developed a rash. Rashes associated with LAMICTAL do not appear to have unique identifying
537
features. Typically, rash occurs in the first 2 to 8 weeks following treatment initiation. However,
538
isolated cases have been reported after prolonged treatment (e.g., 6 months). Accordingly,
539
duration of therapy cannot be relied upon as a means to predict the potential risk heralded by the
540
first appearance of a rash.
541
Although most rashes resolved even with continuation of treatment with LAMICTAL, it is not
542
possible to predict reliably which rashes will prove to be serious or life threatening.
543
ACCORDINGLY, LAMICTAL SHOULD ORDINARILY BE DISCONTINUED AT THE
544
FIRST SIGN OF RASH, UNLESS THE RASH IS CLEARLY NOT DRUG RELATED.
545
DISCONTINUATION OF TREATMENT MAY NOT PREVENT A RASH FROM
546
BECOMING LIFE THREATENING OR PERMANENTLY DISABLING OR
547
DISFIGURING.
548
It is recommended that LAMICTAL not be restarted in patients who discontinued due to rash
549
associated with prior treatment with LAMICTAL unless the potential benefits clearly outweigh
550
the risks. If the decision is made to restart a patient who has discontinued LAMICTAL, the need
551
to restart with the initial dosing recommendations should be assessed. The greater the interval of
552
time since the previous dose, the greater consideration should be given to restarting with the
553
initial dosing recommendations. If a patient has discontinued LAMICTAL for a period of more
554
than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be
555
followed. The half-life of LAMICTAL is affected by other concomitant medications (see
556
CLINICAL PHARMACOLOGY: Pharmacokinetics and Drug Metabolism, and DOSAGE AND
557
ADMINISTRATION).
558
Use in Patients With Epilepsy:
559
Sudden Unexplained Death in Epilepsy (SUDEP): During the premarketing
560
development of LAMICTAL, 20 sudden and unexplained deaths were recorded among a cohort
561
of 4,700 patients with epilepsy (5,747 patient-years of exposure).
562
Some of these could represent seizure-related deaths in which the seizure was not observed,
563
e.g., at night. This represents an incidence of 0.0035 deaths per patient-year. Although this rate
564
exceeds that expected in a healthy population matched for age and sex, it is within the range of
565
estimates for the incidence of sudden unexplained deaths in patients with epilepsy not receiving
566
LAMICTAL (ranging from 0.0005 for the general population of patients with epilepsy, to 0.004
567
for a recently studied clinical trial population similar to that in the clinical development program
568
for LAMICTAL, to 0.005 for patients with refractory epilepsy). Consequently, whether these
569
figures are reassuring or suggest concern depends on the comparability of the populations
570
reported upon to the cohort receiving LAMICTAL and the accuracy of the estimates provided.
571
Probably most reassuring is the similarity of estimated SUDEP rates in patients receiving
572
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
18
LAMICTAL and those receiving another antiepileptic drug that underwent clinical testing in a
573
similar population at about the same time. Importantly, that drug is chemically unrelated to
574
LAMICTAL. This evidence suggests, although it certainly does not prove, that the high SUDEP
575
rates reflect population rates, not a drug effect.
576
Status Epilepticus: Valid estimates of the incidence of treatment emergent status
577
epilepticus among patients treated with LAMICTAL are difficult to obtain because reporters
578
participating in clinical trials did not all employ identical rules for identifying cases. At a
579
minimum, 7 of 2,343 adult patients had episodes that could unequivocally be described as status.
580
In addition, a number of reports of variably defined episodes of seizure exacerbation (e.g.,
581
seizure clusters, seizure flurries, etc.) were made.
582
Use in Patients With Bipolar Disorder:
583
Acute Treatment of Mood Episodes: Safety and effectiveness of LAMICTAL in the
584
acute treatment of mood episodes has not been established.
585
Children and Adolescents (less than 18 years of age): Treatment with
586
antidepressants is associated with an increased risk of suicidal thinking and behavior in children
587
and adolescents with major depressive disorder and other psychiatric disorders. It is not known
588
whether LAMICTAL is associated with a similar risk in this population (see PRECAUTIONS:
589
Clinical Worsening and Suicide Risk Associated With Bipolar Disorder).
590
Safety and effectiveness of LAMICTAL in patients below the age of 18 years with mood
591
disorders have not been established.
592
Clinical Worsening and Suicide Risk Associated with Bipolar Disorder:
593
Patients with bipolar disorder may experience worsening of their depressive symptoms and/or
594
the emergence of suicidal ideation and behaviors (suicidality) whether or not they are taking
595
medications for bipolar disorder. Patients should be closely monitored for clinical worsening
596
(including development of new symptoms) and suicidality, especially at the beginning of a
597
course of treatment, or at the time of dose changes.
598
In addition, patients with a history of suicidal behavior or thoughts, those patients exhibiting a
599
significant degree of suicidal ideation prior to commencement of treatment, and young adults,
600
are at an increased risk of suicidal thoughts or suicide attempts, and should receive careful
601
monitoring during treatment.
602
Patients (and caregivers of patients) should be alerted about the need to monitor for any
603
worsening of their condition (including development of new symptoms) and /or the emergence
604
of suicidal ideation/behavior or thoughts of harming themselves and to seek medical advice
605
immediately if these symptoms present.
606
Consideration should be given to changing the therapeutic regimen, including possibly
607
discontinuing the medication, in patients who experience clinical worsening (including
608
development of new symptoms) and/or the emergence of suicidal ideation/behavior especially if
609
these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting
610
symptoms.
611
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
19
Prescriptions for LAMICTAL should be written for the smallest quantity of tablets consistent
612
with good patient management, in order to reduce the risk of overdose. Overdoses have been
613
reported for LAMICTAL, some of which have been fatal (see OVERDOSAGE).
614
Addition of LAMICTAL to a Multidrug Regimen That Includes Valproate (Dosage
615
Reduction): Because valproate reduces the clearance of lamotrigine, the dosage of lamotrigine
616
in the presence of valproate is less than half of that required in its absence (see DOSAGE AND
617
ADMINISTRATION).
618
Use in Patients With Concomitant Illness: Clinical experience with LAMICTAL in
619
patients with concomitant illness is limited. Caution is advised when using LAMICTAL in
620
patients with diseases or conditions that could affect metabolism or elimination of the drug, such
621
as renal, hepatic, or cardiac functional impairment.
622
Hepatic metabolism to the glucuronide followed by renal excretion is the principal route of
623
elimination of lamotrigine (see CLINICAL PHARMACOLOGY).
624
A study in individuals with severe chronic renal failure (mean creatinine
625
clearance = 13 mL/min) not receiving other AEDs indicated that the elimination half-life of
626
unchanged lamotrigine is prolonged relative to individuals with normal renal function. Until
627
adequate numbers of patients with severe renal impairment have been evaluated during chronic
628
treatment with LAMICTAL, it should be used with caution in these patients, generally using a
629
reduced maintenance dose for patients with significant impairment.
630
Because there is limited experience with the use of LAMICTAL in patients with impaired
631
liver function, the use in such patients may be associated with as yet unrecognized risks (see
632
CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).
633
Binding in the Eye and Other Melanin-Containing Tissues: Because lamotrigine binds
634
to melanin, it could accumulate in melanin-rich tissues over time. This raises the possibility that
635
lamotrigine may cause toxicity in these tissues after extended use. Although ophthalmological
636
testing was performed in one controlled clinical trial, the testing was inadequate to exclude
637
subtle effects or injury occurring after long-term exposure. Moreover, the capacity of available
638
tests to detect potentially adverse consequences, if any, of lamotrigine's binding to melanin is
639
unknown.
640
Accordingly, although there are no specific recommendations for periodic ophthalmological
641
monitoring, prescribers should be aware of the possibility of long-term ophthalmologic effects.
642
Information for Patients: Prior to initiation of treatment with LAMICTAL, the patient should
643
be instructed that a rash or other signs or symptoms of hypersensitivity (e.g., fever,
644
lymphadenopathy) may herald a serious medical event and that the patient should report any
645
such occurrence to a physician immediately. In addition, the patient should notify his or her
646
physician if worsening of seizure control occurs.
647
Patients should be advised that LAMICTAL may cause dizziness, somnolence, and other
648
symptoms and signs of central nervous system (CNS) depression. Accordingly, they should be
649
advised neither to drive a car nor to operate other complex machinery until they have gained
650
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
20
sufficient experience on LAMICTAL to gauge whether or not it adversely affects their mental
651
and/or motor performance.
652
Patients should be advised to notify their physicians if they become pregnant or intend to
653
become pregnant during therapy. Patients should be advised to notify their physicians if they
654
intend to breast-feed or are breast-feeding an infant.
655
Women should be advised to notify their physician if they plan to start or stop use of oral
656
contraceptives or other female hormonal preparations. Starting estrogen-containing oral
657
contraceptives may significantly decrease lamotrigine plasma levels and stopping estrogen-
658
containing oral contraceptives (including the “pill-free” week) may significantly increase
659
lamotrigine plasma levels (see PRECAUTIONS: Drug Interactions). Women should also be
660
advised to promptly notify their physician if they experience adverse events or changes in
661
menstrual pattern (e.g., break-through bleeding) while receiving LAMICTAL in combination
662
with these medications.
663
Patients should be advised to notify their physician if they stop taking LAMICTAL for any
664
reason and not to resume LAMICTAL without consulting their physician.
665
Patients should be informed of the availability of a patient information leaflet, and they should
666
be instructed to read the leaflet prior to taking LAMICTAL. See PATIENT INFORMATION at
667
the end of this labeling for the text of the leaflet provided for patients.
668
Laboratory Tests: The value of monitoring plasma concentrations of LAMICTAL has not
669
been established. Because of the possible pharmacokinetic interactions between LAMICTAL
670
and other drugs including AEDs (see Table 3), monitoring of the plasma levels of LAMICTAL
671
and concomitant drugs may be indicated, particularly during dosage adjustments. In general,
672
clinical judgment should be exercised regarding monitoring of plasma levels of LAMICTAL and
673
other drugs and whether or not dosage adjustments are necessary.
674
675
Drug Interactions:
676
677
The net effects of drug interactions with LAMICTAL are summarized in Table 3 (see also
678
DOSAGE AND ADMINISTRATION).
679
680
Oral Contraceptives: In 16 female volunteers, an oral contraceptive preparation containing
681
30 mcg ethinylestradiol and 150 mcg levonorgestrel increased the apparent clearance of
682
lamotrigine (300 mg/day) by approximately 2-fold with a mean decrease in AUC of 52% and in
683
Cmax of 39%. In this study, trough serum lamotrigine concentrations gradually increased and
684
were approximately 2-fold higher on average at the end of the week of the inactive preparation
685
compared to trough lamotrigine concentrations at the end of the active hormone cycle.
686
Gradual transient increases in lamotrigine plasma levels (approximate 2-fold increase)
687
occurred during the week of inactive hormone preparation (“pill-free” week) for women not also
688
taking a drug that increased the clearance of lamotrigine (carbamazepine, phenytoin,
689
phenobarbital, primidone, or rifampin). The increase in lamotrigine plasma levels will be greater
690
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
21
if the dose of LAMICTAL is increased in the few days before or during the “pill-free” week.
691
Increases in lamotrigine plasma levels could result in dose-dependent adverse effects (see
692
PRECAUTIONS: Concomitant Use With Oral Contraceptives).
693
In the same study, co-administration of LAMICTAL (300 mg/day) in 16 female volunteers
694
did not affect the pharmacokinetics of the ethinylestradiol component of the oral contraceptive
695
preparation. There was a mean decrease in the AUC and Cmax of the levonorgestrel component of
696
19% and 12%, respectively. Measurement of serum progesterone indicated that there was no
697
hormonal evidence of ovulation in any of the 16 volunteers, although measurement of serum
698
FSH, LH, and estradiol indicated that there was some loss of suppression of the hypothalamic-
699
pituitary-ovarian axis.
700
The effects of doses of LAMICTAL other than 300 mg/day have not been studied in clinical
701
trials.
702
The clinical significance of the observed hormonal changes on ovulatory activity is unknown.
703
However, the possibility of decreased contraceptive efficacy in some patients cannot be
704
excluded. Therefore, patients should be instructed to promptly report changes in their menstrual
705
pattern (e.g., break-through bleeding).
706
Dosage adjustments will be necessary for most women receiving estrogen-containing oral
707
contraceptive preparations (see DOSAGE AND ADMINISTRATION: Special Populations:
708
Women and Oral Contraceptives).
709
Other Hormonal Contraceptives or Hormone Replacement Therapy: The effect of
710
other hormonal contraceptive preparations or hormone replacement therapy on the
711
pharmacokinetics of lamotrigine has not been systematically evaluated, It has been reported that
712
ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the
713
progestin only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the
714
dosage of LAMICTAL in the presence of progestogens alone will likely not be needed.
715
716
Bupropion: The pharmacokinetics of a 100-mg single dose of LAMICTAL in healthy
717
volunteers (n = 12) were not changed by co-administration of bupropion sustained-release
718
formulation (150 mg twice a day) starting 11 days before LAMICTAL.
719
Carbamazepine: LAMICTAL has no appreciable effect on steady-state carbamazepine
720
plasma concentration. Limited clinical data suggest there is a higher incidence of dizziness,
721
diplopia, ataxia, and blurred vision in patients receiving carbamazepine with LAMICTAL than in
722
patients receiving other AEDs with LAMICTAL (see ADVERSE REACTIONS). The
723
mechanism of this interaction is unclear. The effect of LAMICTAL on plasma concentrations of
724
carbamazepine-epoxide is unclear. In a small subset of patients (n = 7) studied in a
725
placebo-controlled trial, LAMICTAL had no effect on carbamazepine-epoxide plasma
726
concentrations, but in a small, uncontrolled study (n = 9), carbamazepine-epoxide levels
727
increased.
728
The addition of carbamazepine decreases lamotrigine steady-state concentrations by
729
approximately 40%.
730
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
22
Felbamate: In a study of 21 healthy volunteers, coadministration of felbamate (1,200 mg
731
twice daily) with LAMICTAL (100 mg twice daily for 10 days) appeared to have no clinically
732
relevant effects on the pharmacokinetics of lamotrigine.
733
Folate Inhibitors: Lamotrigine is a weak inhibitor of dihydrofolate reductase. Prescribers
734
should be aware of this action when prescribing other medications that inhibit folate metabolism.
735
Gabapentin: Based on a retrospective analysis of plasma levels in 34 patients who received
736
LAMICTAL both with and without gabapentin, gabapentin does not appear to change the
737
apparent clearance of lamotrigine.
738
Levetiracetam: Potential drug interactions between levetiracetam and LAMICTAL were
739
assessed by evaluating serum concentrations of both agents during placebo-controlled clinical
740
trials. These data indicate that LAMICTAL does not influence the pharmacokinetics of
741
levetiracetam and that levetiracetam does not influence the pharmacokinetics of LAMICTAL.
742
Lithium: The pharmacokinetics of lithium were not altered in healthy subjects (n = 20) by
743
co-administration of LAMICTAL (100 mg/day) for 6 days.
744
Olanzapine: The AUC and Cmax of olanzapine were similar following the addition of
745
olanzapine (15 mg once daily) to LAMICTAL (200 mg once daily) in healthy male volunteers
746
(n = 16) compared to the AUC and Cmax in healthy male volunteers receiving olanzapine alone
747
(n = 16).
748
In the same study, the AUC and Cmax of lamotrigine was reduced on average by 24% and
749
20%, respectively, following the addition of olanzapine to LAMICTAL in healthy male
750
volunteers compared to those receiving LAMICTAL alone. This reduction in lamotrigine plasma
751
concentrations is not expected to be clinically relevant.
752
Oxcarbazepine: The AUC and Cmax of oxcarbazepine and its active 10-monohydroxy
753
oxcarbazepine metabolite were not significantly different following the addition of
754
oxcarbazepine (600 mg twice daily) to LAMICTAL (200 mg once daily) in healthy male
755
volunteers (n = 13) compared to healthy male volunteers receiving oxcarbazepine alone (n = 13).
756
In the same study, the AUC and Cmax of lamotrigine were similar following the addition of
757
oxcarbazepine (600 mg twice daily) to LAMICTAL in healthy male volunteers compared to
758
those receiving LAMICTAL alone. Limited clinical data suggest a higher incidence of headache,
759
dizziness, nausea, and somnolence with coadministration of LAMICTAL and oxcarbazepine
760
compared to LAMICTAL alone or oxcarbazepine alone.
761
Phenobarbital, Primidone: The addition of phenobarbital or primidone decreases
762
lamotrigine steady-state concentrations by approximately 40%.
763
Phenytoin: LAMICTAL has no appreciable effect on steady-state phenytoin plasma
764
concentrations in patients with epilepsy. The addition of phenytoin decreases lamotrigine steady-
765
state concentrations by approximately 40%.
766
Pregabalin: Steady-state trough plasma concentrations of lamotrigine were not affected by
767
concomitant pregabalin (200 mg 3 times daily) administration. There are no pharmacokinetic
768
interactions between LAMICTAL and pregabalin.
769
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
23
Rifampin: In 10 male volunteers, rifampin (600 mg/day for 5 days) significantly increased
770
the apparent clearance of a single 25 mg dose of LAMICTAL by approximately 2-fold (AUC
771
decreased by approximately 40%).
772
Topiramate: Topiramate resulted in no change in plasma concentrations of lamotrigine.
773
Administration of LAMICTAL resulted in a 15% increase in topiramate concentrations.
774
Valproate: When LAMICTAL was administered to healthy volunteers (n = 18) receiving
775
valproate, the trough steady-state valproate plasma concentrations decreased by an average of
776
25% over a 3-week period, and then stabilized. However, adding LAMICTAL to the existing
777
therapy did not cause a change in valproate plasma concentrations in either adult or pediatric
778
patients in controlled clinical trials.
779
The addition of valproate increased lamotrigine steady-state concentrations in normal
780
volunteers by slightly more than 2-fold. In one study, maximal inhibition of lamotrigine
781
clearance was reached at valproate doses between 250 mg/day and 500 mg/day and did not
782
increase as the valproate dose was further increased.
783
Zonisamide: In a study of 18 patients with epilepsy, coadministration of zonisamide (200 to
784
400 mg/day) with LAMICTAL (150 to 500 mg/day) for 35 days had no significant effect on the
785
pharmacokinetics of lamotrigine.
786
Known Inducers or Inhibitors of Glucuronidation: Drugs other than those listed above
787
have not been systematically evaluated in combination with LAMICTAL. Since lamotrigine is
788
metabolized predominately by glucuronic acid conjugation, drugs that are known to induce or
789
inhibit glucuronidation may affect the apparent clearance of lamotrigine, and doses of
790
LAMICTAL may require adjustment based on clinical response.
791
Other: Results of in vitro experiments suggest that clearance of lamotrigine is unlikely to be
792
reduced by concomitant administration of amitriptyline, clonazepam, clozapine, fluoxetine,
793
haloperidol, lorazepam, phenelzine, risperidone, sertraline, or trazodone (see CLINICAL
794
PHARMACOLOGY: Pharmacokinetics and Drug Metabolism).
Results of in vitro
795
experiments suggest that lamotrigine does not reduce the clearance of drugs eliminated
796
predominantly by CYP2D6 (see CLINICAL PHARMACOLOGY).
797
.
798
Table 3. Summary of Drug Interactions With LAMICTAL
799
Drug
Drug Plasma
Concentration With
Adjunctive
LAMICTAL*
Lamotrigine Plasma
Concentration With Adjunctive
Drugs†
Oral contraceptives (e.g.,
ethinylestradiol/levonorgestrel)‡
↔§
↓
Bupropion
Not assessed
↔
Carbamazepine (CBZ)
↔
↓
CBZ epoxide║
?
Felbamate
Not assessed
↔
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
24
Gabapentin
Not assessed
↔
Levetiracetam
↔
↔
Lithium
↔
Not assessed
Olanzapine
↔
↔¶
Oxcarbazepine
↔
↔
10-monohydroxy oxcarbazepine
metabolite#
↔
Phenobarbital/primidone
↔
↓
Phenytoin (PHT)
↔
↓
Pregabalin
↔
↔
Rifampin
Not assessed
↓
Topiramate
↔**
↔
Valproate
↓
↑
Valproate + PHT and/or CBZ
Not assessed
↔
Zonisamide
Not assessed
↔
* From adjunctive clinical trials and volunteer studies.
800
† Net effects were estimated by comparing the mean clearance values obtained in adjunctive
801
clinical trials and volunteers studies.
802
‡ The effect of other hormonal contraceptive preparations or hormone replacement therapy on the
803
pharmacokinetics of lamotrigine has not been systematically evaluated in clinical trials and
804
the effect may not be similar to that seen with the ethinylestradiol/levonorgestrel
805
combinations.
806
§Modest decrease in levonorgestrel (see PRECAUTIONS: Drug Interactions: Effect of
807
LAMICTAL on Oral Contraceptives).
808
║Not administered, but an active metabolite of carbamazepine.
809
¶Slight decrease, not expected to be clinically relevant.
810
#Not administered, but an active metabolite of oxcarbazepine.
811
** Slight increase not expected to be clinically relevant.
812
↔ = No significant effect.
813
814
Drug/Laboratory Test Interactions: None known.
815
Carcinogenesis, Mutagenesis, Impairment of Fertility: No evidence of carcinogenicity
816
was seen in 1 mouse study or 2 rat studies following oral administration of lamotrigine for up to
817
2 years at maximum tolerated doses (30 mg/kg per day for mice and 10 to 15 mg/kg per day for
818
rats, doses that are equivalent to 90 mg/m2 and 60 to 90 mg/m2, respectively). Steady-state
819
plasma concentrations ranged from 1 to 4 mcg/mL in the mouse study and 1 to 10 mcg/mL in the
820
rat study. Plasma concentrations associated with the recommended human doses of 300 to
821
500 mg/day are generally in the range of 2 to 5 mcg/mL, but concentrations as high as
822
19 mcg/mL have been recorded.
823
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
25
Lamotrigine was not mutagenic in the presence or absence of metabolic activation when
824
tested in 2 gene mutation assays (the Ames test and the in vitro mammalian mouse lymphoma
825
assay). In 2 cytogenetic assays (the in vitro human lymphocyte assay and the in vivo rat bone
826
marrow assay), lamotrigine did not increase the incidence of structural or numerical
827
chromosomal abnormalities.
828
No evidence of impairment of fertility was detected in rats given oral doses of lamotrigine up
829
to 2.4 times the highest usual human maintenance dose of 8.33 mg/kg per day or 0.4 times the
830
human dose on a mg/m2 basis. The effect of lamotrigine on human fertility is unknown.
831
Pregnancy: Teratogenic Effects: Pregnancy Category C. No evidence of teratogenicity was
832
found in mice, rats, or rabbits when lamotrigine was orally administered to pregnant animals
833
during the period of organogenesis at doses up to 1.2, 0.5, and 1.1 times, respectively, on a
834
mg/m2 basis, the highest usual human maintenance dose (i.e., 500 mg/day). However, maternal
835
toxicity and secondary fetal toxicity producing reduced fetal weight and/or delayed ossification
836
were seen in mice and rats, but not in rabbits at these doses. Teratology studies were also
837
conducted using bolus intravenous administration of the isethionate salt of lamotrigine in rats
838
and rabbits. In rat dams administered an intravenous dose at 0.6 times the highest usual human
839
maintenance dose, the incidence of intrauterine death without signs of teratogenicity was
840
increased.
841
A behavioral teratology study was conducted in rats dosed during the period of organogenesis.
842
At day 21 postpartum, offspring of dams receiving 5 mg/kg per day or higher displayed a
843
significantly longer latent period for open field exploration and a lower frequency of rearing. In a
844
swimming maze test performed on days 39 to 44 postpartum, time to completion was increased
845
in offspring of dams receiving 25 mg/kg per day. These doses represent 0.1 and 0.5 times the
846
clinical dose on a mg/m2 basis, respectively.
847
Lamotrigine did not affect fertility, teratogenesis, or postnatal development when rats were
848
dosed prior to and during mating, and throughout gestation and lactation at doses equivalent to
849
0.4 times the highest usual human maintenance dose on a mg/m2 basis.
850
When pregnant rats were orally dosed at 0.1, 0.14, or 0.3 times the highest human
851
maintenance dose (on a mg/m2 basis) during the latter part of gestation (days 15 to 20), maternal
852
toxicity and fetal death were seen. In dams, food consumption and weight gain were reduced,
853
and the gestation period was slightly prolonged (22.6 vs. 22.0 days in the control group).
854
Stillborn pups were found in all 3 drug-treated groups with the highest number in the high-dose
855
group. Postnatal death was also seen, but only in the 2 highest doses, and occurred between day 1
856
and 20. Some of these deaths appear to be drug-related and not secondary to the maternal
857
toxicity. A no-observed-effect level (NOEL) could not be determined for this study.
858
Although LAMICTAL was not found to be teratogenic in the above studies, lamotrigine
859
decreases fetal folate concentrations in rats, an effect known to be associated with teratogenesis
860
in animals and humans. There are no adequate and well-controlled studies in pregnant women.
861
Because animal reproduction studies are not always predictive of human response, this drug
862
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
26
should be used during pregnancy only if the potential benefit justifies the potential risk to the
863
fetus.
864
Non-Teratogenic Effects: As with other antiepileptic drugs, physiological changes during
865
pregnancy may affect lamotrigine concentrations and/or therapeutic effect. There have been
866
reports of decreased lamotrigine concentrations during pregnancy and restoration of pre-partum
867
concentrations after delivery. Dosage adjustments may be necessary to maintain clinical
868
response.
869
Pregnancy Exposure Registry: To facilitate monitoring fetal outcomes of pregnant women
870
exposed to lamotrigine, physicians are encouraged to register patients, before fetal outcome
871
(e.g., ultrasound, results of amniocentesis, birth, etc.) is known, and can obtain information
872
by calling the Lamotrigine Pregnancy Registry at (800) 336-2176 (toll-free). Patients can enroll
873
themselves in the North American Antiepileptic Drug Pregnancy Registry by calling (888) 233-
874
2334 (toll-free).
875
Labor and Delivery: The effect of LAMICTAL on labor and delivery in humans is unknown.
876
Use in Nursing Mothers: Preliminary data indicate that lamotrigine passes into human milk.
877
Because the effects on the infant exposed to LAMICTAL by this route are unknown,
878
breast-feeding while taking LAMICTAL is not recommended.
879
Pediatric Use: LAMICTAL is indicated as adjunctive therapy for partial seizures, for the
880
generalized seizures of Lennox-Gastaut syndrome, and primary generalized tonic-clonic seizures
881
in patients above 2 years of age. .
882
Safety and effectiveness in patients below the age of 18 years with Bipolar Disorder has not
883
been established.
884
Geriatric Use: Clinical studies of LAMICTAL for epilepsy and in Bipolar Disorder did not
885
include sufficient numbers of subjects aged 65 and over to determine whether they respond
886
differently from younger subjects. In general, dose selection for an elderly patient should be
887
cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of
888
decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
889
ADVERSE REACTIONS
890
SERIOUS RASH REQUIRING HOSPITALIZATION AND DISCONTINUATION OF
891
LAMICTAL, INCLUDING STEVENS-JOHNSON SYNDROME AND TOXIC
892
EPIDERMAL NECROLYSIS, HAVE OCCURRED IN ASSOCIATION WITH
893
THERAPY WITH LAMICTAL. RARE DEATHS HAVE BEEN REPORTED, BUT
894
THEIR NUMBERS ARE TOO FEW TO PERMIT A PRECISE ESTIMATE OF THE
895
RATE (see BOX WARNING).
896
Epilepsy:
897
Most Common Adverse Events in All Clinical Studies: Adjunctive Therapy in
898
Adults With Epilepsy: The most commonly observed (≥5%) adverse experiences seen in
899
association with LAMICTAL during adjunctive therapy in adults and not seen at an equivalent
900
frequency among placebo-treated patients were: dizziness, ataxia, somnolence, headache,
901
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
27
diplopia, blurred vision, nausea, vomiting, and rash. Dizziness, diplopia, ataxia, blurred vision,
902
nausea, and vomiting were dose related. Dizziness, diplopia, ataxia, and blurred vision occurred
903
more commonly in patients receiving carbamazepine with LAMICTAL than in patients receiving
904
other AEDs with LAMICTAL. Clinical data suggest a higher incidence of rash, including serious
905
rash, in patients receiving concomitant valproate than in patients not receiving valproate (see
906
WARNINGS).
907
Approximately 11% of the 3,378 adult patients who received LAMICTAL as adjunctive
908
therapy in premarketing clinical trials discontinued treatment because of an adverse experience.
909
The adverse events most commonly associated with discontinuation were rash (3.0%), dizziness
910
(2.8%), and headache (2.5%).
911
In a dose response study in adults, the rate of discontinuation of LAMICTAL for dizziness,
912
ataxia, diplopia, blurred vision, nausea, and vomiting was dose related.
913
Monotherapy in Adults With Epilepsy: The most commonly observed (≥5%) adverse
914
experiences seen in association with the use of LAMICTAL during the monotherapy phase of the
915
controlled trial in adults not seen at an equivalent rate in the control group were vomiting,
916
coordination abnormality, dyspepsia, nausea, dizziness, rhinitis, anxiety, insomnia, infection,
917
pain, weight decrease, chest pain, and dysmenorrhea. The most commonly observed (≥5%)
918
adverse experiences associated with the use of LAMICTAL during the conversion to
919
monotherapy (add-on) period, not seen at an equivalent frequency among low-dose
920
valproate-treated patients, were dizziness, headache, nausea, asthenia, coordination abnormality,
921
vomiting, rash, somnolence, diplopia, ataxia, accidental injury, tremor, blurred vision, insomnia,
922
nystagmus, diarrhea, lymphadenopathy, pruritus, and sinusitis.
923
Approximately 10% of the 420 adult patients who received LAMICTAL as monotherapy in
924
premarketing clinical trials discontinued treatment because of an adverse experience. The
925
adverse events most commonly associated with discontinuation were rash (4.5%), headache
926
(3.1%), and asthenia (2.4%).
927
Adjunctive Therapy in Pediatric Patients With Epilepsy: The most commonly
928
observed (≥5%) adverse experiences seen in association with the use of LAMICTAL as
929
adjunctive treatment in pediatric patients and not seen at an equivalent rate in the control group
930
were infection, vomiting, rash, fever, somnolence, accidental injury, dizziness, diarrhea,
931
abdominal pain, nausea, ataxia, tremor, asthenia, bronchitis, flu syndrome, and diplopia.
932
In 339 patients age 2 to 16 years with partial seizures or generalized seizures of Lennox-
933
Gastaut syndrome, 4.2% of patients on LAMICTAL and 2.9% of patients on placebo
934
discontinued due to adverse experiences. The most commonly reported adverse experiences that
935
led to discontinuation were rash for patients treated with LAMICTAL and deterioration of
936
seizure control for patients treated with placebo.
937
Approximately 11.5% of the 1,081 pediatric patients who received LAMICTAL as adjunctive
938
therapy in premarketing clinical trials discontinued treatment because of an adverse experience.
939
The adverse events most commonly associated with discontinuation were rash (4.4%), reaction
940
aggravated (1.7%), and ataxia (0.6%).
941
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
28
Incidence in Controlled Clinical Studies of Epilepsy: The prescriber should be aware
942
that the figures in Tables 4, 5, 6, and 7 cannot be used to predict the frequency of adverse
943
experiences in the course of usual medical practice where patient characteristics and other factors
944
may differ from those prevailing during clinical studies. Similarly, the cited frequencies cannot
945
be directly compared with figures obtained from other clinical investigations involving different
946
treatments, uses, or investigators. An inspection of these frequencies, however, does provide the
947
prescriber with one basis to estimate the relative contribution of drug and nondrug factors to the
948
adverse event incidences in the population studied.
949
Incidence in Controlled Adjunctive Clinical Studies in Adults With Epilepsy:
950
Table 4 lists treatment-emergent signs and symptoms that occurred in at least 2% of adult
951
patients with epilepsy treated with LAMICTAL in placebo-controlled trials and were
952
numerically more common in the patients treated with LAMICTAL. In these studies, either
953
LAMICTAL or placebo was added to the patient's current AED therapy. Adverse events were
954
usually mild to moderate in intensity.
955
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
29
Table 4. Treatment-Emergent Adverse Event Incidence in Placebo-Controlled
956
Adjunctive Trials in Adult Patients With Epilepsy* (Events in at least 2% of patients
957
treated with LAMICTAL and numerically more frequent than in the placebo group.)
958
Body System/
Adverse Experience†
Percent of Patients
Receiving Adjunctive
LAMICTAL
(n = 711)
Percent of Patients
Receiving Adjunctive Placebo
(n = 419)
Body as a whole
Headache
29
19
Flu syndrome
7
6
Fever
6
4
Abdominal pain
5
4
Neck pain
2
1
Reaction aggravated
(seizure exacerbation)
2
1
Digestive
Nausea
19
10
Vomiting
9
4
Diarrhea
6
4
Dyspepsia
5
2
Constipation
4
3
Tooth disorder
3
2
Anorexia
2
1
Musculoskeletal
Arthralgia
2
0
Nervous
Dizziness
38
13
Ataxia
22
6
Somnolence
14
7
Incoordination
6
2
Insomnia
6
2
Tremor
4
1
Depression
4
3
Anxiety
4
3
Convulsion
3
1
Irritability
3
2
Speech disorder
3
0
Concentration
disturbance
2
1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
30
Respiratory
Rhinitis
14
9
Pharyngitis
10
9
Cough increased
8
6
Skin and appendages
Rash
10
5
Pruritus
3
2
Special senses
Diplopia
28
7
Blurred vision
16
5
Vision abnormality
3
1
Urogenital
Female patients only
(n = 365)
(n = 207)
Dysmenorrhea
7
6
Vaginitis
4
1
Amenorrhea
2
1
* Patients in these adjunctive studies were receiving 1 to 3 of the following concomitant
959
AEDs (carbamazepine, phenytoin, phenobarbital, or primidone) in addition to LAMICTAL
960
or placebo. Patients may have reported multiple adverse experiences during the study or at
961
discontinuation; thus, patients may be included in more than one category.
962
† Adverse experiences reported by at least 2% of patients treated with LAMICTAL are
963
included.
964
965
In a randomized, parallel study comparing placebo and 300 and 500 mg/day of LAMICTAL,
966
some of the more common drug-related adverse events were dose related (see Table 5).
967
968
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
31
Table 5. Dose-Related Adverse Events From a Randomized, Placebo-Controlled Trial
969
in Adults With Epilepsy
970
Percent of Patients Experiencing Adverse Experiences
Adverse Experience
Placebo
(n = 73)
LAMICTAL
300 mg
(n = 71)
LAMICTAL
500 mg
(n = 72)
Ataxia
10
10
28*†
Blurred vision
10
11
25*†
Diplopia
8
24*
49*†
Dizziness
27
31
54*†
Nausea
11
18
25*
Vomiting
4
11
18*
*Significantly greater than placebo group (p<0.05).
971
†Significantly greater than group receiving LAMICTAL 300 mg (p<0.05).
972
973
Other events that occurred in more than 1% of patients but equally or more frequently in the
974
placebo group included: asthenia, back pain, chest pain, flatulence, menstrual disorder, myalgia,
975
paresthesia, respiratory disorder, and urinary tract infection.
976
The overall adverse experience profile for LAMICTAL was similar between females and
977
males, and was independent of age. Because the largest non-Caucasian racial subgroup was only
978
6% of patients exposed to LAMICTAL in placebo-controlled trials, there are insufficient data to
979
support a statement regarding the distribution of adverse experience reports by race. Generally,
980
females receiving either adjunctive LAMICTAL or placebo were more likely to report adverse
981
experiences than males. The only adverse experience for which the reports on LAMICTAL were
982
greater than 10% more frequent in females than males (without a corresponding difference by
983
gender on placebo) was dizziness (difference = 16.5%). There was little difference between
984
females and males in the rates of discontinuation of LAMICTAL for individual adverse
985
experiences.
986
Incidence in a Controlled Monotherapy Trial in Adults With Partial Seizures:
987
Table 6 lists treatment-emergent signs and symptoms that occurred in at least 5% of patients with
988
epilepsy treated with monotherapy with LAMICTAL in a double-blind trial following
989
discontinuation of either concomitant carbamazepine or phenytoin not seen at an equivalent
990
frequency in the control group.
991
992
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
32
Table 6. Treatment-Emergent Adverse Event Incidence in Adults With Partial Seizures in
993
a Controlled Monotherapy Trial* (Events in at least 5% of patients treated with
994
LAMICTAL and numerically more frequent than in the valproate group.)
995
Body System/
Adverse Experience†
Percent of Patients Receiving
LAMICTAL Monotherapy‡
(n = 43)
Percent of Patients Receiving
Low-Dose Valproate§
Monotherapy
(n = 44)
Body as a whole
Pain
5
0
Infection
5
2
Chest pain
5
2
Digestive
Vomiting
9
0
Dyspepsia
7
2
Nausea
7
2
Metabolic and nutritional
Weight decrease
5
2
Nervous
Coordination
abnormality
7
0
Dizziness
7
0
Anxiety
5
0
Insomnia
5
2
Respiratory
Rhinitis
7
2
Urogenital (female
patients only)
(n = 21)
(n = 28)
Dysmenorrhea
5
0
* Patients in these studies were converted to LAMICTAL or valproate monotherapy from
996
adjunctive therapy with carbamazepine or phenytoin. Patients may have reported multiple
997
adverse experiences during the study; thus, patients may be included in more than one
998
category.
999
† Adverse experiences reported by at least 5% of patients are included.
1000
‡ Up to 500 mg/day.
1001
§ 1,000 mg/day.
1002
1003
Adverse events that occurred with a frequency of less than 5% and greater than 2% of patients
1004
receiving LAMICTAL and numerically more frequent than placebo were:
1005
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
33
Body as a Whole: Asthenia, fever.
1006
Digestive: Anorexia, dry mouth, rectal hemorrhage, peptic ulcer.
1007
Metabolic and Nutritional: Peripheral edema.
1008
Nervous System: Amnesia, ataxia, depression, hypesthesia, libido increase, decreased
1009
reflexes, increased reflexes, nystagmus, irritability, suicidal ideation.
1010
Respiratory: Epistaxis, bronchitis, dyspnea.
1011
Skin and Appendages: Contact dermatitis, dry skin, sweating.
1012
Special Senses: Vision abnormality.
1013
Incidence in Controlled Adjunctive Trials in Pediatric Patients With Epilepsy:
1014
Table 7 lists adverse events that occurred in at least 2% of 339 pediatric patients with partial
1015
seizures or generalized seizures of Lennox-Gastaut syndrome, who received LAMICTAL up to
1016
15 mg/kg per day or a maximum of 750 mg per day. Reported adverse events were classified
1017
using COSTART terminology.
1018
1019
Table 7. Treatment-Emergent Adverse Event Incidence in Placebo-Controlled Adjunctive
1020
Trials in Pediatric Patients With Epilepsy (Events in at least 2% of patients treated with
1021
LAMICTAL and numerically more frequent than in the placebo group.)
1022
Body System/
Adverse Experience
Percent of Patients
Receiving LAMICTAL
(n = 168)
Percent of Patients
Receiving Placebo
(n = 171)
Body as a whole
Infection
20
17
Fever
15
14
Accidental injury
14
12
Abdominal pain
10
5
Asthenia
8
4
Flu syndrome
7
6
Pain
5
4
Facial edema
2
1
Photosensitivity
2
0
Cardiovascular
Hemorrhage
2
1
Digestive
Vomiting
20
16
Diarrhea
11
9
Nausea
10
2
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
34
Constipation
4
2
Dyspepsia
2
1
Tooth disorder
2
1
Hemic and lymphatic
Lymphadenopathy
2
1
Metabolic and nutritional
Edema
2
0
Nervous system
Somnolence
17
15
Dizziness
14
4
Ataxia
11
3
Tremor
10
1
Emotional lability
4
2
Gait abnormality
4
2
Thinking abnormality
3
2
Convulsions
2
1
Nervousness
2
1
Vertigo
2
1
Respiratory
Pharyngitis
14
11
Bronchitis
7
5
Increased cough
7
6
Sinusitis
2
1
Bronchospasm
2
1
Skin
Rash
14
12
Eczema
2
1
Pruritus
2
1
Special senses
Diplopia
5
1
Blurred vision
4
1
Ear disorder
2
1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
35
Visual abnormality
2
0
Urogenital
Male and female patients
Urinary tract infection
3
0
Male patients only
n = 93
n = 92
Penis disorder
2
0
1023
Bipolar Disorder: The most commonly observed (≥5%) adverse experiences seen in
1024
association with the use of LAMICTAL as monotherapy (100 to 400 mg/day) in Bipolar
1025
Disorder in the 2 double-blind, placebo-controlled trials of 18 months’ duration, and numerically
1026
more frequent than in placebo-treated patients are included in Table 8. Adverse events that
1027
occurred in at least 5% of patients and were numerically more common during the dose
1028
escalation phase of LAMICTAL in these trials (when patients may have been receiving
1029
concomitant medications) compared to the monotherapy phase were: headache (25%), rash
1030
(11%), dizziness (10%), diarrhea (8%), dream abnormality (6%), and pruritus (6%).
1031
During the monotherapy phase of the double-blind, placebo-controlled trials of 18 months’
1032
duration, 13% of 227 patients who received LAMICTAL (100 to 400 mg/day), 16% of
1033
190 patients who received placebo, and 23% of 166 patients who received lithium discontinued
1034
therapy because of an adverse experience. The adverse events which most commonly led to
1035
discontinuation of LAMICTAL were rash (3%) and mania/hypomania/mixed mood adverse
1036
events (2%). Approximately 16% of 2,401 patients who received LAMICTAL (50 to
1037
500 mg/day) for Bipolar Disorder in premarketing trials discontinued therapy because of an
1038
adverse experience; most commonly due to rash (5%) and mania/hypomania/mixed mood
1039
adverse events (2%).
1040
Incidence in Controlled Clinical Studies of LAMICTAL for the Maintenance
1041
Treatment of Bipolar I Disorder: Table 8 lists treatment-emergent signs and symptoms that
1042
occurred in at least 5% of patients with Bipolar Disorder treated with LAMICTAL monotherapy
1043
(100 to 400 mg/day), following the discontinuation of other psychotropic drugs, in
1044
2 double-blind, placebo-controlled trials of 18 months’ duration and were numerically more
1045
frequent than in the placebo group.
1046
1047
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
36
Table 8. Treatment-Emergent Adverse Event Incidence in 2 Placebo-Controlled Trials
1048
in Adults With Bipolar I Disorder* (Events in at least 5% of patients treated with
1049
LAMICTAL monotherapy and numerically more frequent than in the placebo group.)
1050
Body System/
Adverse Experience†
Percent of Patients
Receiving LAMICTAL
n = 227
Percent of Patients
Receiving Placebo
n = 190
General
Back pain
8
6
Fatigue
8
5
Abdominal pain
6
3
Digestive
Nausea
14
11
Constipation
5
2
Vomiting
5
2
Nervous System
Insomnia
10
6
Somnolence
9
7
Xerostomia (dry mouth)
6
4
Respiratory
Rhinitis
7
4
Exacerbation of cough
5
3
Pharyngitis
5
4
Skin
Rash (nonserious)‡
7
5
* Patients in these studies were converted to LAMICTAL (100 to 400 mg/day) or placebo
1051
monotherapy from add-on therapy with other psychotropic medications. Patients may
1052
have reported multiple adverse experiences during the study; thus, patients may be
1053
included in more than one category.
1054
† Adverse experiences reported by at least 5% of patients are included.
1055
‡ In the overall bipolar and other mood disorders clinical trials, the rate of serious rash
1056
was 0.08% (1 of 1,233) of adult patients who received LAMICTAL as initial
1057
monotherapy and 0.13% (2 of 1,538) of adult patients who received LAMICTAL as
1058
adjunctive therapy (see WARNINGS).
1059
1060
These adverse events were usually mild to moderate in intensity.
1061
Other events that occurred in 5% or more patients but equally or more frequently in the
1062
placebo group included: dizziness, mania, headache, infection, influenza, pain, accidental injury,
1063
diarrhea, and dyspepsia.
1064
Adverse events that occurred with a frequency of less than 5% and greater than 1% of patients
1065
receiving LAMICTAL and numerically more frequent than placebo were:
1066
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
37
General: Fever, neck pain.
1067
Cardiovascular: Migraine.
1068
Digestive: Flatulence.
1069
Metabolic and Nutritional: Weight gain, edema.
1070
Musculoskeletal: Arthralgia, myalgia.
1071
Nervous System: Amnesia, depression, agitation, emotional lability, dyspraxia, abnormal
1072
thoughts, dream abnormality, hypoesthesia.
1073
Respiratory: Sinusitis.
1074
Urogenital: Urinary frequency.
1075
Adverse Events Following Abrupt Discontinuation: In the 2 maintenance trials, there
1076
was no increase in the incidence, severity or type of adverse events in Bipolar Disorder patients
1077
after abruptly terminating LAMICTAL therapy. In clinical trials in patients with Bipolar
1078
Disorder, 2 patients experienced seizures shortly after abrupt withdrawal of LAMICTAL.
1079
However, there were confounding factors that may have contributed to the occurrence of seizures
1080
in these bipolar patients (see DOSAGE AND ADMINISTRATION).
1081
Mania/Hypomania/Mixed Episodes: During the double-blind, placebo-controlled clinical
1082
trials in Bipolar I Disorder in which patients were converted to LAMICTAL monotherapy (100
1083
to 400 mg/day) from other psychotropic medications and followed for durations up to 18 months,
1084
the rate of manic or hypomanic or mixed mood episodes reported as adverse experiences was 5%
1085
for patients treated with LAMICTAL (n = 227), 4% for patients treated with lithium (n = 166),
1086
and 7% for patients treated with placebo (n = 190). In all bipolar controlled trials combined,
1087
adverse events of mania (including hypomania and mixed mood episodes) were reported in 5%
1088
of patients treated with LAMICTAL (n = 956), 3% of patients treated with lithium (n = 280), and
1089
4% of patients treated with placebo (n = 803).
1090
The overall adverse event profile for LAMICTAL was similar between females and males,
1091
between elderly and nonelderly patients, and among racial groups.
1092
Other Adverse Events Observed During All Clinical Trials For Pediatric and Adult
1093
Patients With Epilepsy or Bipolar Disorder and Other Mood Disorders: LAMICTAL
1094
has been administered to 6,694 individuals for whom complete adverse event data was captured
1095
during all clinical trials, only some of which were placebo controlled. During these trials, all
1096
adverse events were recorded by the clinical investigators using terminology of their own
1097
choosing. To provide a meaningful estimate of the proportion of individuals having adverse
1098
events, similar types of events were grouped into a smaller number of standardized categories
1099
using modified COSTART dictionary terminology. The frequencies presented represent the
1100
proportion of the 6,694 individuals exposed to LAMICTAL who experienced an event of the
1101
type cited on at least one occasion while receiving LAMICTAL. All reported events are included
1102
except those already listed in the previous tables or elsewhere in the labeling, those too general
1103
to be informative, and those not reasonably associated with the use of the drug.
1104
Events are further classified within body system categories and enumerated in order of
1105
decreasing frequency using the following definitions: frequent adverse events are defined as
1106
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
38
those occurring in at least 1/100 patients; infrequent adverse events are those occurring in 1/100
1107
to 1/1,000 patients; rare adverse events are those occurring in fewer than 1/1,000 patients.
1108
Body as a Whole: Infrequent: Allergic reaction, chills, halitosis, and malaise. Rare:
1109
Abdomen enlarged, abscess, and suicide/suicide attempt.
1110
Cardiovascular System: Infrequent: Flushing, hot flashes, hypertension, palpitations,
1111
postural hypotension, syncope, tachycardia, and vasodilation. Rare: Angina pectoris, atrial
1112
fibrillation, deep thrombophlebitis, ECG abnormality, and myocardial infarction.
1113
Dermatological: Infrequent: Acne, alopecia, hirsutism, maculopapular rash, skin
1114
discoloration, and urticaria. Rare: Angioedema, erythema, exfoliative dermatitis, fungal
1115
dermatitis, herpes zoster, leukoderma, multiforme erythema, petechial rash, pustular rash,
1116
seborrhea, Stevens-Johnson syndrome, and vesiculobullous rash.
1117
Digestive System: Infrequent: Dysphagia, eructation, gastritis, gingivitis, increased
1118
appetite, increased salivation, liver function tests abnormal, and mouth ulceration. Rare:
1119
Gastrointestinal hemorrhage, glossitis, gum hemorrhage, gum hyperplasia, hematemesis,
1120
hemorrhagic colitis, hepatitis, melena, stomach ulcer, stomatitis, thirst, and tongue edema.
1121
Endocrine System: Rare: Goiter and hypothyroidism.
1122
Hematologic and Lymphatic System: Infrequent: Ecchymosis and leukopenia. Rare:
1123
Anemia, eosinophilia, fibrin decrease, fibrinogen decrease, iron deficiency anemia, leukocytosis,
1124
lymphocytosis, macrocytic anemia, petechia, and thrombocytopenia.
1125
Metabolic and Nutritional Disorders: Infrequent: Aspartate transaminase increased.
1126
Rare: Alcohol intolerance, alkaline phosphatase increase, alanine transaminase increase,
1127
bilirubinemia, general edema, gamma glutamyl transpeptidase increase, and hyperglycemia.
1128
Musculoskeletal System: Infrequent: Arthritis, leg cramps, myasthenia, and twitching.
1129
Rare: Bursitis, joint disorder, muscle atrophy, pathological fracture, and tendinous contracture.
1130
Nervous System: Frequent: Confusion and paresthesia. Infrequent: Akathisia, apathy,
1131
aphasia, CNS depression, depersonalization, dysarthria, dyskinesia, euphoria, hallucinations,
1132
hostility, hyperkinesia, hypertonia, libido decreased, memory decrease, mind racing, movement
1133
disorder, myoclonus, panic attack, paranoid reaction, personality disorder, psychosis, sleep
1134
disorder, stupor, and suicidal ideation. Rare: Cerebellar syndrome, cerebrovascular accident,
1135
cerebral sinus thrombosis, choreoathetosis, CNS stimulation, delirium, delusions, dysphoria,
1136
dystonia, extrapyramidal syndrome, faintness, grand mal convulsions, hemiplegia, hyperalgesia,
1137
hyperesthesia, hypokinesia, hypotonia, manic depression reaction, muscle spasm, neuralgia,
1138
neurosis, paralysis, and peripheral neuritis.
1139
Respiratory System: Infrequent: Yawn. Rare: Hiccup and hyperventilation.
1140
Special Senses: Frequent: Amblyopia. Infrequent: Abnormality of accommodation,
1141
conjunctivitis, dry eyes, ear pain, photophobia, taste perversion, and tinnitus. Rare: Deafness,
1142
lacrimation disorder, oscillopsia, parosmia, ptosis, strabismus, taste loss, uveitis, and visual field
1143
defect.
1144
Urogenital System: Infrequent: Abnormal ejaculation, breast pain, hematuria, impotence,
1145
menorrhagia, polyuria, urinary incontinence, and urine abnormality. Rare: Acute kidney failure,
1146
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
39
anorgasmia, breast abscess, breast neoplasm, creatinine increase, cystitis, dysuria, epididymitis,
1147
female lactation, kidney failure, kidney pain, nocturia, urinary retention, urinary urgency, and
1148
vaginal moniliasis.
1149
Postmarketing and Other Experience: In addition to the adverse experiences reported
1150
during clinical testing of LAMICTAL, the following adverse experiences have been reported in
1151
patients receiving marketed LAMICTAL and from worldwide noncontrolled investigational use.
1152
These adverse experiences have not been listed above, and data are insufficient to support an
1153
estimate of their incidence or to establish causation.
1154
Blood and Lymphatic: Agranulocytosis, aplastic anemia, disseminated intravascular
1155
coagulation, hemolytic anemia, neutropenia, pancytopenia, red cell aplasia.
1156
Gastrointestinal: Esophagitis.
1157
Hepatobiliary Tract and Pancreas: Pancreatitis.
1158
Immunologic: Lupus-like reaction, vasculitis.
1159
Lower Respiratory: Apnea.
1160
Musculoskeletal: Rhabdomyolysis has been observed in patients experiencing
1161
hypersensitivity reactions.
1162
Neurology: Exacerbation of parkinsonian symptoms in patients with pre-existing
1163
Parkinson’s disease, tics.
1164
Non-site Specific: Hypersensitivity reaction, multiorgan failure, progressive
1165
immunosuppression.
1166
DRUG ABUSE AND DEPENDENCE
1167
The abuse and dependence potential of LAMICTAL have not been evaluated in human
1168
studies.
1169
OVERDOSAGE
1170
Human Overdose Experience: Overdoses involving quantities up to 15 g have been
1171
reported for LAMICTAL, some of which have been fatal. Overdose has resulted in ataxia,
1172
nystagmus, increased seizures, decreased level of consciousness, coma, and intraventricular
1173
conduction delay.
1174
Management of Overdose: There are no specific antidotes for LAMICTAL. Following a
1175
suspected overdose, hospitalization of the patient is advised. General supportive care is
1176
indicated, including frequent monitoring of vital signs and close observation of the patient. If
1177
indicated, emesis should be induced or gastric lavage should be performed; usual precautions
1178
should be taken to protect the airway. It should be kept in mind that lamotrigine is rapidly
1179
absorbed (see CLINICAL PHARMACOLOGY). It is uncertain whether hemodialysis is an
1180
effective means of removing lamotrigine from the blood. In 6 renal failure patients, about 20% of
1181
the amount of lamotrigine in the body was removed by hemodialysis during a 4-hour session. A
1182
Poison Control Center should be contacted for information on the management of overdosage of
1183
LAMICTAL.
1184
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
40
DOSAGE AND ADMINISTRATION
1185
Epilepsy:
1186
Adjunctive Use: LAMICTAL is indicated as adjunctive therapy for partial seizures, the
1187
generalized seizures of Lennox-Gastaut syndrome, and primary generalized tonic-clonic seizures
1188
in adult and pediatric patients (≥2 years of age).
1189
Monotherapy Use: LAMICTAL is indicated for conversion to monotherapy in adults with
1190
partial seizures who are receiving treatment with carbamazepine, phenytoin, phenobarbital,
1191
primidone, or valproate as the single AED.
1192
Safety and effectiveness of LAMICTAL have not been established. (1) as initial
1193
monotherapy, (2) for conversion to monotherapy from AEDs other than carbamazepine,
1194
phenytoin, phenobarbital, primidone, or valproate, or (3) for simultaneous conversion to
1195
monotherapy from 2 or more concomitant AEDs.
1196
1197
Bipolar Disorder: LAMICTAL is indicated for the maintenance treatment of Bipolar I
1198
Disorder to delay the time to occurrence of mood episodes (depression, mania, hypomania,
1199
mixed episodes) in patients treated for acute mood episodes with standard therapy. The
1200
effectiveness of LAMICTAL in the acute treatment of mood episodes has not been established.
1201
General Dosing Considerations for Epilepsy and Bipolar Disorder Patients: The
1202
risk of nonserious rash is increased when the recommended initial dose and/or the rate of dose
1203
escalation of LAMICTAL is exceeded. There are suggestions, yet to be proven, that the risk of
1204
severe, potentially life-threatening rash may be increased by (1) coadministration of LAMICTAL
1205
with valproate, (2) exceeding the recommended initial dose of LAMICTAL, or (3) exceeding the
1206
recommended dose escalation for LAMICTAL. However, cases have been reported in the
1207
absence of these factors (see BOX WARNING). Therefore, it is important that the dosing
1208
recommendations be followed closely.
1209
It is recommended that LAMICTAL not be restarted in patients who discontinued due to rash
1210
associated with prior treatment with LAMICTAL, unless the potential benefits clearly outweigh
1211
the risks. If the decision is made to restart a patient who has discontinued LAMICTAL, the need
1212
to restart with the initial dosing recommendations should be assessed. The greater the interval of
1213
time since the previous dose, the greater consideration should be given to restarting with the
1214
initial dosing recommendations. If a patient has discontinued LAMICTAL for a period of more
1215
than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be
1216
followed.
1217
1218
LAMICTAL Added to Drugs Known to Induce or Inhibit Glucuronidation: Drugs
1219
other than those listed in PRECAUTIONS: Drug Interactions have not been systematically
1220
evaluated in combination with LAMICTAL. Since lamotrigine is metabolized predominantly by
1221
glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may
1222
affect the apparent clearance of lamotrigine, and doses of LAMICTAL may require adjustment
1223
based on clinical response.
1224
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
41
Target Plasma Levels for Patients With Epilepsy or Bipolar Disorder: A
1225
therapeutic plasma concentration range has not been established for lamotrigine. Dosing of
1226
LAMICTAL should be based on therapeutic response.
1227
The half-life of LAMICTAL is affected by other concomitant medications (see CLINICAL
1228
PHARMACOLOGY: Pharmacokinetics and Drug Metabolism).
1229
See also DOSAGE AND ADMINISTRATION: Special Populations.
1230
Special Populations: Women and Oral Contraceptives: Starting LAMICTAL in
1231
Women Taking Oral Contraceptives: Although estrogen-containing oral contraceptives
1232
have been shown to increase the clearance of lamotrigine (see PRECAUTIONS: Drug
1233
Interactions), no adjustments to the recommended dose escalation guidelines for LAMICTAL
1234
should be necessary solely based on the use of estrogen-containing oral contraceptives.
1235
Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive
1236
therapy with LAMICTAL based on the concomitant AED (see Table 11). See below for
1237
adjustments to maintenance doses of LAMICTAL in women taking estrogen-containing oral
1238
contraceptives.
1239
Adjustments to the Maintenance Dose of LAMICTAL: (1) Taking Estrogen-
1240
Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin,
1241
phenobarbital, primidone, or rifampin, the maintenance dose of LAMICTAL will in most cases
1242
need to be increased, by as much as 2-fold over the recommended target maintenance dose, in
1243
order to maintain a consistent lamotrigine plasma level (see PRECAUTIONS: Drug
1244
Interactions). (2) Starting Estrogen-Containing Oral Contraceptives: In women taking a stable
1245
dose of LAMICTAL and not taking carbamazepine, phenytoin, phenobarbital, primidone, or
1246
rifampin, the maintenance dose will in most cases need to be increased by as much as 2-fold, in
1247
order to maintain a consistent lamotrigine plasma level. The dose increases should begin at the
1248
same time that the oral contraceptive is introduced and continue, based on clinical response, no
1249
more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the
1250
recommended rate unless lamotrigine plasma levels or clinical response support larger increases
1251
(see Table 11, column 2). Gradual transient increases in lamotrigine plasma levels may occur
1252
during the week of inactive hormonal preparation (“pill-free” week), and these increases will be
1253
greater if dose increases are made in the days before or during the week of inactive hormonal
1254
preparation. Increased lamotrigine plasma levels could result in additional adverse events, such
1255
as dizziness, ataxia, and diplopia (see PRECAUTIONS: Drug Interactions). If adverse events
1256
attributable to LAMICTAL consistently occur during the “pill-free” week, dose adjustments to
1257
the overall maintenance dose may be necessary. Dose adjustments limited to the “pill-free” week
1258
are not recommended. For women taking LAMICTAL in addition to carbamazepine, phenytoin,
1259
phenobarbital, primidone, or rifampin, no adjustment should be necessary to the dose of
1260
LAMICTAL. (3) Stopping Estrogen-Containing Oral Contraceptives: For women not taking
1261
carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, the maintenance dose of
1262
LAMICTAL will in most cases need to be decreased by as much as 50%, in order to maintain a
1263
consistent lamotrigine plasma level. The decrease in dose of LAMICTAL should not exceed
1264
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
42
25% of the total daily dose per week over a 2-week period, unless clinical response or
1265
lamotrigine plasma levels indicate otherwise (see PRECAUTIONS: Drug Interactions). For
1266
women taking LAMICTAL in addition to carbamazepine, phenytoin, phenobarbital, primidone,
1267
or rifampin, no adjustment to the dose of LAMICTAL should be necessary.
1268
Women and Other Hormonal Contraceptive Preparations or Hormone
1269
Replacement Therapy: The effect of other hormonal contraceptive preparations or hormone
1270
replacement therapy on the pharmacokinetics of lamotrigine has not been systematically
1271
evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of
1272
lamotrigine up to 2-fold, and the progestin only pills had no effect on lamotrigine plasma levels.
1273
Therefore, adjustments to the dosage of LAMICTAL in the presence of progestogens alone will
1274
likely not be needed.
1275
Patients With Hepatic Impairment: Experience in patients with hepatic impairment is
1276
limited. Based on a clinical pharmacology study in 24 patients with mild, moderate, and severe
1277
liver dysfunction (see CLINICAL PHARMACOLOGY), the following general
1278
recommendations can be made. No dosage adjustment is needed in patients with mild liver
1279
impairment. Initial, escalation, and maintenance doses should generally be reduced by
1280
approximately 25% in patients with moderate and severe liver impairment without ascites and
1281
50% in patients with severe liver impairment with ascites. Escalation and maintenance doses
1282
may be adjusted according to clinical response.
1283
Patients With Renal Functional Impairment: Initial doses of LAMICTAL should be
1284
based on patients' AED regimen (see above); reduced maintenance doses may be effective for
1285
patients with significant renal functional impairment (see CLINICAL PHARMACOLOGY).
1286
Few patients with severe renal impairment have been evaluated during chronic treatment with
1287
LAMICTAL. Because there is inadequate experience in this population, LAMICTAL should be
1288
used with caution in these patients.
1289
Epilepsy:
1290
Adjunctive Therapy With LAMICTAL for Epilepsy: This section provides specific
1291
dosing recommendations for patients 2 to 12 years of age and patients greater than 12 years of
1292
age. Within each of these age-groups, specific dosing recommendations are provided depending
1293
upon concomitant AED (Table 9 for patients 2 to 12 years of age and Table 11 for patients
1294
greater than 12 years of age). A weight based dosing guide for pediatric patients on concomitant
1295
valproate is provided in Table 10.
1296
Patients 2 to 12 Years of Age: Recommended dosing guidelines are summarized in Table 9.
1297
Note that some of the starting doses and dose escalations listed in Table 9 are different than
1298
those used in clinical trials; however, the maintenance doses are the same as in clinical trials.
1299
Smaller starting doses and slower dose escalations than those used in clinical trials are
1300
recommended because of the suggestions that the risk of rash may be decreased by smaller
1301
starting doses and slower dose escalations. Therefore, maintenance doses will take longer to
1302
reach in clinical practice than in clinical trials. It may take several weeks to months to achieve an
1303
individualized maintenance dose. Maintenance doses in patients weighing less than 30 kg,
1304
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
43
regardless of age or concomitant AED, may need to be increased as much as 50%, based on
1305
clinical response.
1306
The smallest available strength of LAMICTAL Chewable Dispersible Tablets is 2 mg,
1307
and only whole tablets should be administered. If the calculated dose cannot be achieved
1308
using whole tablets, the dose should be rounded down to the nearest whole tablet (see
1309
HOW SUPPLIED and PATIENT INFORMATION for a description of the available sizes
1310
of LAMICTAL Chewable Dispersible Tablets).
1311
1312
Table 9. Escalation Regimen for LAMICTAL in Patients 2 to 12 Years of Age With
1313
Epilepsy
1314
For Patients Taking
Valproate (see Table 10 for
weight-based dosing guide)
For Patients Taking AEDs
Other Than
Carbamazepine,
Phenytoin, Phenobarbital,
Primidone, or Valproate*
For Patients Taking
Carbamazepine,
Phenytoin,
Phenobarbital,
Primidone* and Not
Taking Valproate
Weeks 1 and 2
0.15 mg/kg/day
in 1 or 2 divided doses,
rounded down to the
nearest whole tablet (see
Table 10 for weight-based
dosing guide).
0.3 mg/kg/day
in 1 or 2 divided doses,
rounded down to the
nearest whole tablet.
0.6 mg/kg/day
in 2 divided doses,
rounded down to the
nearest whole tablet.
Weeks 3 and 4
0.3 mg/kg/day
in 1 or 2 divided doses,
rounded down to the
nearest whole tablet (see
Table 10 for weight-based
dosing guide).
0.6 mg/kg/day
in 2 divided doses,
rounded down to the
nearest whole tablet.
1.2 mg/kg/day
in 2 divided doses,
rounded down to the
nearest whole tablet.
Weeks 5
onwards to
maintenance
The dose should be
increased every 1 to 2
weeks as follows: calculate
0.3 mg/kg/day, round this
amount down to the nearest
whole tablet, and add this
amount to the previously
administered daily dose.
The dose should be
increased every 1 to 2
weeks as follows:
calculate 0.6 mg/kg/day,
round this amount down
to the nearest whole
tablet, and add this
amount to the previously
administered daily dose
The dose should be
increased every 1 to
2 weeks as follows:
calculate
1.2 mg/kg/day,
round this amount
down to the nearest
whole tablet, and
add this amount to
the previously
administered daily
dose
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
44
Usual
Maintenance
Dose
1 to 5 mg/kg/day
(maximum 200 mg/day in
1 or 2 divided doses).
1 to 3 mg/kg/day with
valproate alone
4.5 to 7.5 mg/kg/day
(maximum 300 mg/day in
2 divided doses)
5 to 15 mg/kg/day
(maximum
400 mg/day in 2
divided doses)
Maintenance
dose in
patients less
than 30 kg
May need to be increased
by as much as 50%, based
on clinical response
May need to be increased
by as much as 50%, based
on clinical response
May need to be
increased by as
much as 50%, based
on clinical response
Note: Only whole tablets should be used for dosing
1315
* Rifampin and estrogen-containing oral contraceptives have also been shown to increase the
1316
apparent clearance of lamotrigine (see PRECAUTIONS: Drug Interactions).
1317
1318
1319
Table 10. The Initial Weight-Based Dosing Guide for Patients 2 to 12 Years Taking
1320
Valproate (Weeks 1 to 4) With Epilepsy
1321
:
If the patient’s weight is
Give this daily dose, using the most appropriate
combination of LAMICTAL 2-mg and 5-mg tablets
Greater than
And less than
Weeks 1 and 2
Weeks 3 and 4
6.7 kg
14 kg
2 mg every other day
2 mg every day
14.1 kg
27 kg
2 mg every day
4 mg every day
27.1 kg
34 kg
4 mg every day
8 mg every day
34.1 kg
40 kg
5 mg every day
10 mg every day
1322
Patients Over 12 Years of Age: Recommended dosing guidelines are summarized in
1323
Table 11.
1324
1325
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
45
Table 11. Escalation Regimen for LAMICTAL in Patients Over 12 Years of Age With
1326
Epilepsy
1327
For Patients Taking
Valproate
For Patients Taking
AEDs Other Than
Carbamazepine,
Phenytoin,
Phenobarbital,
Primidone, or
Valproate*
For Patients Taking
Carbamazepine,
Phenytoin,
Phenobarbital,
Primidone* and Not
Taking Valproate
Weeks 1 and 2
25 mg every other day
25 mg every day
50 mg/day
Weeks 3 and 4
25 mg every day
50 mg/day
100 mg/day
(in 2 divided doses)
Weeks 5 onwards
to maintenance
Increase by 25 to
50 mg/day every 1 to
2 weeks
Increase by 50 mg/day
every 1 to 2 weeks
Increase by
100 mg/day every 1 to
2 weeks.
Usual Maintenance
Dose
100 to 400 mg/day
(1 or 2 divided doses)
100 to 200 mg/day with
valproate alone
225 to 375 mg/day
(in 2 divided doses).
300 to 500 mg/day
(in 2 divided doses).
* Rifampin and estrogen-containing oral contraceptives have also been shown to increase the
1328
apparent clearance of lamotrigine (see PRECAUTIONS: Drug Interactions).
1329
1330
1331
Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin,
1332
Phenobarbital, Primidone, or Valproate as the Single AED to Monotherapy With
1333
LAMICTAL in Patients ≥16 Years of Age With Epilepsy: The goal of the transition
1334
regimen is to effect the conversion to monotherapy with LAMICTAL under conditions that
1335
ensure adequate seizure control while mitigating the risk of serious rash associated with the rapid
1336
titration of LAMICTAL.
1337
The recommended maintenance dose of LAMICTAL as monotherapy is 500 mg/day given in
1338
2 divided doses.
1339
To avoid an increased risk of rash, the recommended initial dose and subsequent dose
1340
escalations of LAMICTAL should not be exceeded (see BOX WARNING).
1341
Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin,
1342
Phenobarbital, or Primidone to Monotherapy With LAMICTAL: After achieving a dose
1343
of 500 mg/day of LAMICTAL according to Table 11, the concomitant AED should be
1344
withdrawn by 20% decrements each week over a 4-week period. The regimen for the withdrawal
1345
of the concomitant AED is based on experience gained in the controlled monotherapy clinical
1346
trial.
1347
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
46
Conversion from Adjunctive Therapy With Valproate to Monotherapy With
1348
LAMICTAL: The conversion regimen involves 4 steps (see Table 12).
1349
1350
Table 12. Conversion From Adjunctive Therapy With Valproate to Monotherapy With
1351
LAMICTAL in Patients ≥16 Years of Age With Epilepsy
1352
LAMICTAL
Valproate
Step 1
Achieve a dose of 200 mg/day
according to guidelines in Table 11
(if not already on 200 mg/day).
Maintain previous stable dose.
Step 2
Maintain at 200 mg/day.
Decrease to 500 mg/day by decrements no
greater than 500 mg/day per week and then
maintain the dose of 500 mg/day for 1 week.
Step 3
Increase to 300 mg/day and maintain
for 1 week.
Simultaneously decrease to 250 mg/day and
maintain for 1 week.
Step 4
Increase by 100 mg/day every week
to achieve maintenance dose of
500 mg/day.
Discontinue.
1353
Conversion from Adjunctive Therapy With Antiepileptic Drugs Other Than
1354
Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to
1355
Monotherapy With LAMICTAL: No specific dosing guidelines can be provided for
1356
conversion to monotherapy with LAMICTAL with AEDs other than carbamazepine,
1357
phenobarbital, phenytoin, primidone, or valproate.
1358
Usual Maintenance Dose for Epilepsy: The usual maintenance doses identified in
1359
Tables 9-11 are derived from dosing regimens employed in the placebo-controlled adjunctive
1360
studies in which the efficacy of LAMICTAL was established. In patients receiving multidrug
1361
regimens employing carbamazepine, phenytoin, phenobarbital, or primidone without valproate,
1362
maintenance doses of adjunctive LAMICTAL as high as 700 mg/day have been used. In patients
1363
receiving valproate alone, maintenance doses of adjunctive LAMICTAL as high as 200 mg/day
1364
have been used. The advantage of using doses above those recommended in Tables 9-12 has not
1365
been established in controlled trials.
1366
Discontinuation Strategy for Patients With Epilepsy: For patients receiving
1367
LAMICTAL in combination with other AEDs, a reevaluation of all AEDs in the regimen should
1368
be considered if a change in seizure control or an appearance or worsening of adverse
1369
experiences is observed.
1370
If a decision is made to discontinue therapy with LAMICTAL, a step-wise reduction of dose
1371
over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns
1372
require a more rapid withdrawal (see PRECAUTIONS).
1373
Discontinuing carbamazepine, phenytoin, phenobarbital, or primidone should prolong the
1374
half-life of lamotrigine; discontinuing valproate should shorten the half-life of lamotrigine.
1375
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
47
.
1376
Bipolar Disorder: The goal of maintenance treatment with LAMICTAL is to delay the time to
1377
occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated
1378
for acute mood episodes with standard therapy. The target dose of LAMICTAL is 200 mg/day
1379
(100 mg/day in patients taking valproate,which decreases the apparent clearance of lamotrigine,
1380
and 400 mg/day in patients not taking valproate and taking either Carbamazepine, phenytoin,
1381
phenobarbital, primidone, or rifampin, which increase the apparent clearance of lamotrigine). In
1382
the clinical trials, doses up to 400 mg/day as monotherapy were evaluated, however, no
1383
additional benefit was seen at 400 mg/day compared to 200 mg/day (see CLINICAL STUDIES:
1384
Bipolar Disorder). Accordingly, doses above 200 mg/day are not recommended. Treatment with
1385
LAMICTAL is introduced, based on concurrent medications, according to the regimen outlined
1386
in Table 13. If other psychotropic medications are withdrawn following stabilization, the dose of
1387
LAMICTAL should be adjusted. For patients discontinuing valproate, the dose of LAMICTAL
1388
should be doubled over a 2-week period in equal weekly increments (see Table 14). For patients
1389
discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, the dose of
1390
LAMICTAL should remain constant for the first week and then should be decreased by half over
1391
a 2-week period in equal weekly decrements (see Table 14). The dose of LAMICTAL may then
1392
be further adjusted to the target dose (200 mg) as clinically indicated.
1393
Dosage adjustments will be necessary in most patients who start or stop estrogen-containing
1394
oral contraceptives while taking LAMICTAL (see DOSAGE AND ADMINISTRATION:
1395
Special Populations: Women and Oral Contraceptives: Adjustments to the Maintenance Dose of
1396
LAMICTAL).
1397
If other drugs are subsequently introduced, the dose of LAMICTAL may need to be adjusted.
1398
In particular, the introduction of valproate requires reduction in the dose of LAMICTAL (see
1399
CLINICAL PHARMACOLOGY: Drug Interactions).
1400
To avoid an increased risk of rash, the recommended initial dose and subsequent dose
1401
escalations of LAMICTAL should not be exceeded (see BOX WARNING).
1402
1403
Table 13. Escalation Regimen for LAMICTAL for Patients With Bipolar Disorder*
1404
For Patients Not Taking
Carbamazepine (or
Other Enzyme-Inducing
Drugs†) or Valproate‡
For Patients
Taking
Valproate‡
For Patients Taking
Carbamazepine (or Other
Enzyme-Inducing Drugs)
and Not Taking Valproate‡
Weeks 1 and 2
25 mg daily
25 mg every
other day
50 mg daily
Weeks 3 and 4
50 mg daily
25 mg daily
100 mg daily, in divided
doses
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
48
Week 5
100 mg daily
50 mg daily
200 mg daily, in divided
doses
Week 6
200 mg daily
100 mg daily
300 mg daily, in divided
doses
Week 7
200 mg daily
100 mg daily
up to 400 mg daily, in
divided doses
*See CLINICAL PHARMACOLOGY: Drug Interactions and PRECAUTIONS: Drug
1405
Interactions for a description of known drug interactions.
1406
†Carbamazepine, phenytoin, phenobarbital, primidone, rifampin, have been shown to increase
1407
the apparent clearance of lamotrigine.
1408
‡Valproate has been shown to decrease the apparent clearance of lamotrigine.
1409
1410
Table 14. Adjustments to LAMICTAL Dosing for Patients With Bipolar Disorder
1411
Following Discontinuation of Psychotropic Medications*
1412
After Discontinuation
of Valproate‡
After Discontinuation of
Carbamazepine or Other
Enzyme-Inducing Drugs†
Discontinuation of
Psychotropic Drugs
(excluding Valproate‡,
Carbamazepine, or Other
Enzyme-Inducing
Drugs†)
Current LAMICTAL
dose (mg/day)
100
Current LAMICTAL dose
(mg/day)
400
Week 1 Maintain current
LAMICTAL dose
150
400
Week 2
Maintain current
LAMICTAL dose
200
300
Week 3
onward
Maintain current
LAMICTAL dose
200
200
*See CLINICAL PHARMACOLOGY: Drug Interactions and PRECAUTIONS: Drug
1413
Interactions for a description of known drug interactions.
1414
†Carbamazepine, phenytoin, phenobarbital, primidone, rifampin, have been shown to increase
1415
the apparent clearance of lamotrigine.
1416
‡Valproate has been shown to decrease the apparent clearance of lamotrigine.
1417
1418
There is no body of evidence available to answer the question of how long the patient should
1419
remain on LAMICTAL therapy. Systematic evaluation of the efficacy of LAMICTAL in patients
1420
with either depression or mania who responded to standard therapy during an acute 8 to 16 week
1421
treatment phase and were then randomized to LAMICTAL or placebo for up to 76 weeks of
1422
observation for affective relapse demonstrated a benefit of such maintenance treatment (see
1423
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
49
CLINICAL STUDIES: Bipolar Disorder). Nevertheless, patients should be periodically
1424
reassessed to determine the need for maintenance treatment.
1425
Discontinuation Strategy in Bipolar Disorder: As with other AEDs, LAMICTAL
1426
should not be abruptly discontinued. In the controlled clinical trials, there was no increase in the
1427
incidence, type, or severity of adverse experiences following abrupt termination of LAMICTAL.
1428
In clinical trials in patients with bipolar disorder, 2 patients experienced seizures shortly after
1429
abrupt withdrawal of LAMICTAL. However, there were confounding factors that may have
1430
contributed to the occurrence of seizures in these bipolar patients. Discontinuation of
1431
LAMICTAL should involve a step-wise reduction of dose over at least 2 weeks (approximately
1432
50% per week) unless safety concerns require a more rapid withdrawal.
1433
1434
Administration of LAMICTAL Chewable Dispersible Tablets: LAMICTAL Chewable
1435
Dispersible Tablets may be swallowed whole, chewed, or dispersed in water or diluted fruit
1436
juice. If the tablets are chewed, consume a small amount of water or diluted fruit juice to aid in
1437
swallowing.
1438
To disperse LAMICTAL Chewable Dispersible Tablets, add the tablets to a small amount of
1439
liquid (1 teaspoon, or enough to cover the medication). Approximately 1 minute later, when the
1440
tablets are completely dispersed, swirl the solution and consume the entire quantity immediately.
1441
No attempt should be made to administer partial quantities of the dispersed tablets.
1442
HOW SUPPLIED
1443
LAMICTAL Tablets, 25-mg
1444
White, scored, shield-shaped tablets debossed with "LAMICTAL" and "25", bottles of 100
1445
(NDC 0173-0633-02).
1446
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled
1447
Room Temperature] in a dry place.
1448
LAMICTAL Tablets, 100-mg
1449
Peach, scored, shield-shaped tablets debossed with "LAMICTAL" and "100", bottles of 100
1450
(NDC 0173-0642-55).
1451
LAMICTAL Tablets, 150-mg
1452
Cream, scored, shield-shaped tablets debossed with "LAMICTAL" and "150", bottles of 60
1453
(NDC 0173-0643-60).
1454
LAMICTAL Tablets, 200-mg
1455
Blue, scored, shield-shaped tablets debossed with "LAMICTAL" and "200", bottles of 60
1456
(NDC 0173-0644-60).
1457
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled
1458
Room Temperature] in a dry place and protect from light.
1459
1460
LAMICTAL Chewable Dispersible Tablets, 2-mg
1461
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
50
White to off-white, round tablets debossed with “LTG” over “2”, bottles of 30 (NDC 0173-
1462
0699-00). ORDER DIRECTLY FROM GlaxoSmithKline 1-800-334-4153.
1463
LAMICTAL Chewable Dispersible Tablets, 5-mg
1464
White to off-white, caplet-shaped tablets debossed with “GX CL2”, bottles of 100 (NDC
1465
0173-0526-00).
1466
LAMICTAL Chewable Dispersible Tablets, 25-mg
1467
White, super elliptical-shaped tablets debossed with “GX CL5”, bottles of 100 (NDC 0173-
1468
0527-00).
1469
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled
1470
Room Temperature] in a dry place.
1471
1472
LAMICTAL Starter Kit for Patients Taking Valproate
1473
25-mg, white, scored, shield-shaped tablets debossed with "LAMICTAL" and "25",
1474
blisterpack of 35 tablets (NDC 0173-0633-10).
1475
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled
1476
Room Temperature] in a dry place.
1477
1478
LAMICTAL Starter Kit for Patients Taking Carbamazepine, Phenytoin, Phenobarbital,
1479
Primidone, or Rifampin and Not Taking Valproate
1480
25-mg, white, scored, shield-shaped tablets debossed with "LAMICTAL" and "25" and
1481
100-mg, peach, scored, shield-shaped tablets debossed with "LAMICTAL" and “100”,
1482
blisterpack of 84, 25-mg tablets and 14, 100-mg tablets (NDC 0173-0594-01)
1483
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled
1484
Room Temperature] in a dry place and protect from light.
1485
1486
LAMICTAL Starter Kit for Patients Not Taking Carbamazepine, Phenytoin,
1487
Phenobarbital, Primidone, Rifampin, or Valproate
1488
1489
25-mg, white, scored, shield-shaped tablets debossed with "LAMICTAL" and "25" and
1490
100-mg, peach, scored, shield-shaped tablets debossed with "LAMICTAL" and “100”,
1491
blisterpack of 42, 25-mg tablets and 7, 100-mg tablets (NDC 0173-0594-02).
1492
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled
1493
Room Temperature] in a dry place and protect from light.
1494
PATIENT INFORMATION
1495
The following wording is contained in a separate leaflet provided for patients.
1496
1497
Information for the Patient
1498
1499
LAMICTAL® (lamotrigine) Tablets
1500
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
51
LAMICTAL® (lamotrigine) Chewable Dispersible Tablets
1501
1502
ALWAYS CHECK THAT YOU RECEIVE LAMICTAL
1503
Patients prescribed LAMICTAL (lah-MICK-tall) have sometimes been given the wrong
1504
medicine in error because many medicines have names similar to LAMICTAL. Taking the
1505
wrong medication can cause serious health problems. When your healthcare provider gives you a
1506
prescription for LAMICTAL
1507
• make sure you can read it clearly.
1508
• talk to your pharmacist to check that you are given the correct medicine.
1509
• check the tablets you receive against the pictures of the tablets below. The pictures show
1510
actual tablet shape and size and the wording describes the color and printing that is on each
1511
strength of LAMICTAL Tablets and Chewable Dispersible Tablets.
1512
1513
LAMICTAL (lamotrigine) Tablets
1514
1515
25 mg, white
Imprinted with
LAMICTAL 25
100 mg, peach
Imprinted with
LAMICTAL 100
150 mg, cream
Imprinted with
LAMICTAL 150
200 mg, blue
Imprinted with
LAMICTAL 200
1516
LAMICTAL (lamotrigine) Chewable Dispersible Tablets
1517
1518
2 mg, white
Imprinted with
LTG 2
5 mg, white
Imprinted with
GX CL2
25 mg, white
Imprinted with
GX CL5
1519
Please read this leaflet carefully before you take LAMICTAL and read the leaflet provided
1520
with any refill, in case any information has changed. This leaflet provides a summary of the
1521
information about your medicine. Please do not throw away this leaflet until you have finished
1522
your medicine. This leaflet does not contain all the information about LAMICTAL and is not
1523
meant to take the place of talking with your doctor. If you have any questions about
1524
LAMICTAL, ask your doctor or pharmacist.
1525
1526
Information About Your Medicine:
1527
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
52
The name of your medicine is LAMICTAL (lamotrigine). The decision to use LAMICTAL is
1528
one that you and your doctor should make together. When taking lamotrigine, it is important to
1529
follow your doctor's instructions.
1530
1531
1. The Purpose of Your Medicine:
1532
For Patients With Epilepsy: LAMICTAL is intended to be used either alone or in
1533
combination with other medicines to treat seizures in people aged 2 years or older.
1534
For Patients With Bipolar Disorder: LAMICTAL is used as maintenance treatment of
1535
Bipolar I Disorder to delay the time to occurrence of mood episodes in people aged 18 years or
1536
older treated for acute mood episodes with standard therapy.
1537
If you are taking LAMICTAL to help prevent extreme mood swings, you may not experience
1538
the full effect for several weeks. Occasionally, the symptoms of depression or bipolar disorder
1539
may include thoughts of harming yourself or committing suicide. Tell your doctor immediately
1540
or go to the nearest hospital if you have any distressing thoughts or experiences during this initial
1541
period or at any other time. Also contact your doctor if you experience any worsening of your
1542
condition or develop other new symptoms at any time during your treatment.
1543
Some medicines used to treat depression have been associated with suicidal thoughts and
1544
suicidal behavior in children or teenagers. LAMICTAL is not approved for treating children or
1545
teenagers with mood disorders such as bipolar disorder or depression.
1546
2. Who Should Not Take LAMICTAL:
1547
You should not take LAMICTAL if you had an allergic reaction to it in the past.
1548
3. Side Effects to Watch for:
1549
• Most people who take LAMICTAL tolerate it well. Common side effects with LAMICTAL
1550
include dizziness, headache, blurred or double vision, lack of coordination, sleepiness,
1551
nausea, vomiting, insomnia, and rash. LAMICTAL may cause other side effects not listed in
1552
this leaflet. If you develop any side effects or symptoms you are concerned about or need
1553
more information, call your doctor.
1554
• Although most patients who develop rash while receiving LAMICTAL have mild to
1555
moderate symptoms, some individuals may develop a serious skin reaction that requires
1556
hospitalization. Rarely, deaths have been reported. These serious skin reactions are most
1557
likely to happen within the first 8 weeks of treatment with LAMICTAL. Serious skin
1558
reactions occur more often in children than in adults.
1559
• Rashes may be more likely to occur if you: (1) take LAMICTAL in combination with
1560
valproate [DEPAKENE® (valproic acid) or DEPAKOTE® (divalproex sodium)], (2) take a
1561
higher starting dose of LAMICTAL than your doctor prescribed, or (3) increase your dose of
1562
LAMICTAL faster than prescribed.
1563
• It is not possible to predict whether a mild rash will develop into a more serious reaction.
1564
Therefore, if you experience a skin rash, hives, fever, swollen lymph glands, painful
1565
sores in the mouth or around the eyes, or swelling of lips or tongue, tell a doctor
1566
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
53
immediately, since these symptoms may be the first signs of a serious reaction. A doctor
1567
should evaluate your condition and decide if you should continue taking LAMICTAL.
1568
4. The Use of LAMICTAL During Pregnancy and Breastfeeding:
1569
The effects of LAMICTAL during pregnancy are not known at this time. If you are pregnant
1570
or are planning to become pregnant, talk to your doctor. Some LAMICTAL passes into breast
1571
milk and the effects of this on infants are unknown. Therefore, if you are breast-feeding, you
1572
should discuss this with your doctor to determine if you should continue to take LAMICTAL.
1573
5. Use of Birth Control Pills or Other Female Hormonal Products:
1574
• Do not start or stop using birth control pills or other female hormonal products until you
1575
have consulted your doctor. Stopping or starting these products may cause side effects
1576
(such as dizziness, lack of coordination, or double vision) or decrease the effectiveness
1577
of LAMICTAL.
1578
• Tell your doctor as soon as possible if you experience side effects or changes in your menstrual
1579
pattern (e.g., break-through bleeding) while taking LAMICTAL and birth control pills or
1580
other female hormonal products.
1581
6. How to Use LAMICTAL:
1582
• It is important to take LAMICTAL exactly as instructed by your doctor. The dose of
1583
LAMICTAL must be increased slowly. It may take several weeks or months before your
1584
final dosage can be determined by your doctor, based on your response.
1585
• Do not increase your dose of LAMICTAL or take more frequent doses than those indicated
1586
by your doctor. Contact your doctor, if you stop taking LAMICTAL for any reason. Do not
1587
restart without consulting your doctor.
1588
• If you miss a dose of LAMICTAL, do not double your next dose.
1589
• Always tell your doctor and pharmacist if you are taking any other prescription or
1590
over-the-counter medicines. Tell your doctor before you start any other medicines.
1591
• Do NOT stop taking LAMICTAL or any of your other medicines unless instructed by your
1592
doctor.
1593
• Use caution before driving a car or operating complex, hazardous machinery until you know
1594
if LAMICTAL affects your ability to perform these tasks.
1595
• If you have epilepsy, tell your doctor if your seizures get worse or if you have any new types
1596
of seizures.
1597
7. How to Take LAMICTAL:
1598
LAMICTAL Tablets should be swallowed whole. Chewing the tablets may leave a bitter taste.
1599
LAMICTAL Chewable Dispersible Tablets may be swallowed whole, chewed, or mixed in
1600
water or diluted fruit juice. If the tablets are chewed, consume a small amount of water or diluted
1601
fruit juice to aid in swallowing.
1602
To disperse LAMICTAL Chewable Dispersible Tablets, add the tablets to a small amount of
1603
liquid (1 teaspoon, or enough to cover the medication) in a glass or spoon. Approximately
1604
1 minute later, when the tablets are completely dispersed, mix the solution and take the entire
1605
amount immediately.
1606
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
54
8. Storing Your Medicine:
1607
Store LAMICTAL at room temperature away from heat and light. Always keep your
1608
medicines out of the reach of children.
1609
This medicine was prescribed for your use only to treat seizures or to treat Bipolar Disorder.
1610
Do not give the drug to others.
1611
If your doctor decides to stop your treatment, do not keep any leftover medicine unless your
1612
doctor tells you to. Throw away your medicine as instructed.
1613
1614
1615
Manufactured for
1616
GlaxoSmithKline
1617
Research Triangle Park, NC 27709
1618
by DSM Pharmaceuticals, Inc.
1619
Greenville, NC 27834 or
1620
GlaxoSmithKline
1621
Research Triangle Park, NC 27709
1622
1623
DEPAKENE and DEPAKOTE are registered trademarks of Abbott Laboratories.
1624
1625
©2005, GlaxoSmithKline. All rights reserved.
1626
1627
(Date of Issue)
RL-
1628
1629
PHARMACIST--DETACH HERE AND GIVE INSTRUCTIONS TO PATIENT
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
1630
1631
Information for the Patient
1632
1633
LAMICTAL® (lamotrigine) Tablets
1634
LAMICTAL® (lamotrigine) Chewable Dispersible Tablets
1635
1636
ALWAYS CHECK THAT YOU RECEIVE LAMICTAL
1637
Patients prescribed LAMICTAL (lah-MICK-tall) have sometimes been given the wrong
1638
medicine in error because many medicines have names similar to LAMICTAL. Taking the
1639
wrong medication can cause serious health problems. When your healthcare provider gives you a
1640
prescription for LAMICTAL
1641
• make sure you can read it clearly.
1642
• talk to your pharmacist to check that you are given the correct medicine.
1643
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
55
• check the tablets you receive against the pictures of the tablets below. The pictures show
1644
actual tablet shape and size and the wording describes the color and printing that is on each
1645
strength of LAMICTAL Tablets and Chewable Dispersible Tablets.
1646
1647
LAMICTAL (lamotrigine) Tablets
1648
1649
25 mg, white
Imprinted with
LAMICTAL 25
100 mg, peach
Imprinted with
LAMICTAL 100
150 mg, cream
Imprinted with
LAMICTAL 150
200 mg, blue
Imprinted with
LAMICTAL 200
1650
LAMICTAL (lamotrigine) Chewable Dispersible Tablets
1651
1652
2 mg, white
Imprinted with
LTG 2
5 mg, white
Imprinted with
GX CL2
25 mg, white
Imprinted with
GX CL5
1653
Please read this leaflet carefully before you take LAMICTAL and read the leaflet provided
1654
with any refill, in case any information has changed. This leaflet provides a summary of the
1655
information about your medicine. Please do not throw away this leaflet until you have finished
1656
your medicine. This leaflet does not contain all the information about LAMICTAL and is not
1657
meant to take the place of talking with your doctor. If you have any questions about
1658
LAMICTAL, ask your doctor or pharmacist.
1659
1660
Information About Your Medicine:
1661
The name of your medicine is LAMICTAL (lamotrigine). The decision to use LAMICTAL is
1662
one that you and your doctor should make together. When taking lamotrigine, it is important to
1663
follow your doctor's instructions.
1664
1665
1. The Purpose of Your Medicine:
1666
For Patients With Epilepsy: LAMICTAL is intended to be used either alone or in
1667
combination with other medicines to treat seizures in people aged 2 years or older.
1668
For Patients With Bipolar Disorder: LAMICTAL is used as maintenance treatment of
1669
Bipolar I Disorder to delay the time to occurrence of mood episodes in people aged 18 years or
1670
older treated for acute mood episodes with standard therapy.
1671
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
56
If you are taking LAMICTAL to help prevent extreme mood swings, you may not experience
1672
the full effect for several weeks. Occasionally, the symptoms of depression or bipolar disorder
1673
may include thoughts of harming yourself or committing suicide. Tell your doctor immediately
1674
or go to the nearest hospital if you have any distressing thoughts or experiences during this initial
1675
period or at any other time. Also contact your doctor if you experience any worsening of your
1676
condition or develop other new symptoms at any time during your treatment.
1677
Some medicines used to treat depression have been associated with suicidal thoughts and
1678
suicidal behavior in children or teenagers. LAMICTAL is not approved for treating children or
1679
teenagers with mood disorders such as bipolar disorder or depression.
1680
2. Who Should Not Take LAMICTAL:
1681
You should not take LAMICTAL if you had an allergic reaction to it in the past.
1682
3. Side Effects to Watch for:
1683
• Most people who take LAMICTAL tolerate it well. Common side effects with
1684
LAMICTAL include dizziness, headache, blurred or double vision, lack of coordination,
1685
sleepiness, nausea, vomiting, insomnia, and rash. LAMICTAL may cause other side effects
1686
not listed in this leaflet. If you develop any side effects or symptoms you are concerned about
1687
or need more information, call your doctor.
1688
• Although most patients who develop rash while receiving LAMICTAL have mild to
1689
moderate symptoms, some individuals may develop a serious skin reaction that requires
1690
hospitalization. Rarely, deaths have been reported. These serious skin reactions are most
1691
likely to happen within the first 8 weeks of treatment with LAMICTAL. Serious skin
1692
reactions occur more often in children than in adults.
1693
• Rashes may be more likely to occur if you: (1) take LAMICTAL in combination with
1694
valproate [DEPAKENE® (valproic acid) or DEPAKOTE® (divalproex sodium)], (2) take a
1695
higher starting dose of LAMICTAL than your doctor prescribed, or (3) increase your dose of
1696
LAMICTAL faster than prescribed.
1697
• It is not possible to predict whether a mild rash will develop into a more serious reaction.
1698
Therefore, if you experience a skin rash, hives, fever, swollen lymph glands, painful
1699
sores in the mouth or around the eyes, or swelling of lips or tongue, tell a doctor
1700
immediately, since these symptoms may be the first signs of a serious reaction. A doctor
1701
should evaluate your condition and decide if you should continue taking LAMICTAL.
1702
4. The Use of LAMICTAL During Pregnancy and Breastfeeding:
1703
The effects of LAMICTAL during pregnancy are not known at this time. If you are pregnant
1704
or are planning to become pregnant, talk to your doctor. Some LAMICTAL passes into breast
1705
milk and the effects of this on infants are unknown. Therefore, if you are breastfeeding, you
1706
should discuss this with your doctor to determine if you should continue to take LAMICTAL.
1707
5. Use of Birth Control Pills or Other Female Hormonal Products:
1708
• Do not start or stop using birth control pills or other female hormonal products until you
1709
have consulted your doctor. Stopping or starting these products may cause side effects
1710
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
57
(such as dizziness, lack of coordination, or double vision) or to decrease the
1711
effectiveness of LAMICTAL.
1712
1713
1714
• Tell your doctor as soon as possible if you experience side effects changes in your menstrual
1715
pattern (e.g., break-through bleeding) while taking LAMICTAL and birth control pills or
1716
other female hormonal products.
1717
6. How to Use LAMICTAL:
1718
• It is important to take LAMICTAL exactly as instructed by your doctor. The dose of
1719
LAMICTAL must be increased slowly. It may take several weeks or months before your
1720
final dosage can be determined by your doctor, based on your response.
1721
• Do not increase your dose of LAMICTAL or take more frequent doses than those indicated
1722
by your doctor. Contact your doctor, if you stop taking LAMICTAL for any reason. Do not
1723
restart without consulting your doctor.
1724
• If you miss a dose of LAMICTAL, do not double your next dose.
1725
• Always tell your doctor and pharmacist if you are taking any other prescription or
1726
over-the-counter medicines. Tell your doctor before you start any other medicines.
1727
• Do NOT stop taking LAMICTAL or any of your other medicines unless instructed by your
1728
doctor.
1729
• Use caution before driving a car or operating complex, hazardous machinery until you know
1730
if LAMICTAL affects your ability to perform these tasks.
1731
• If you have epilepsy, tell your doctor if your seizures get worse or if you have any new types
1732
of seizures.
1733
7. How to Take LAMICTAL:
1734
LAMICTAL Tablets should be swallowed whole. Chewing the tablets may leave a bitter taste.
1735
LAMICTAL Chewable Dispersible Tablets may be swallowed whole, chewed, or mixed in
1736
water or diluted fruit juice. If the tablets are chewed, consume a small amount of water or diluted
1737
fruit juice to aid in swallowing.
1738
To disperse LAMICTAL Chewable Dispersible Tablets, add the tablets to a small amount of
1739
liquid (1 teaspoon, or enough to cover the medication) in a glass or spoon. Approximately
1740
1 minute later, when the tablets are completely dispersed, mix the solution and take the entire
1741
amount immediately.
1742
8. Storing Your Medicine:
1743
Store LAMICTAL at room temperature away from heat and light. Always keep your
1744
medicines out of the reach of children.
1745
This medicine was prescribed for your use only to treat seizures or to treat Bipolar Disorder.
1746
Do not give the drug to others.
1747
If your doctor decides to stop your treatment, do not keep any leftover medicine unless your
1748
doctor tells you to. Throw away your medicine as instructed.
1749
1750
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
58
1751
Manufactured for
1752
GlaxoSmithKline
1753
Research Triangle Park, NC 27709
1754
by DSM Pharmaceuticals, Inc.
1755
Greenville, NC 27834 or
1756
GlaxoSmithKline
1757
Research Triangle Park, NC 27709
1758
1759
DEPAKENE and DEPAKOTE are registered trademarks of Abbott Laboratories.
1760
1761
©2005, GlaxoSmithKline. All rights reserved.
1762
1763
(Date of Issue)
RL-
1764
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:47:10.946805
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/020241SLRs10s21s25s26s27,020764SLRs3s14s18s19s20lbl.pdf', 'application_number': 20241, 'submission_type': 'SUPPL ', 'submission_number': 10}
|
12,359
|
1
PRESCRIBING INFORMATION
1
LAMICTAL®
2
(lamotrigine)
3
Tablets
4
5
LAMICTAL®
6
(lamotrigine)
7
Chewable Dispersible Tablets
8
9
SERIOUS RASHES REQUIRING HOSPITALIZATION AND DISCONTINUATION
10
OF TREATMENT HAVE BEEN REPORTED IN ASSOCIATION WITH THE USE OF
11
LAMICTAL. THE INCIDENCE OF THESE RASHES, WHICH HAVE INCLUDED
12
STEVENS-JOHNSON SYNDROME, IS APPROXIMATELY 0.8% (8 PER 1,000) IN
13
PEDIATRIC PATIENTS (AGE <16 YEARS) RECEIVING LAMICTAL AS
14
ADJUNCTIVE THERAPY FOR EPILEPSY AND 0.3% (3 PER 1,000) IN ADULTS ON
15
ADJUNCTIVE THERAPY FOR EPILEPSY. IN CLINICAL TRIALS OF BIPOLAR AND
16
OTHER MOOD DISORDERS, THE RATE OF SERIOUS RASH WAS 0.08% (0.8 PER
17
1,000) IN ADULT PATIENTS RECEIVING LAMICTAL AS INITIAL MONOTHERAPY
18
AND 0.13% (1.3 PER 1,000) IN ADULT PATIENTS RECEIVING LAMICTAL AS
19
ADJUNCTIVE THERAPY. IN A PROSPECTIVELY FOLLOWED COHORT OF
20
1,983 PEDIATRIC PATIENTS WITH EPILEPSY TAKING ADJUNCTIVE LAMICTAL,
21
THERE WAS 1 RASH-RELATED DEATH. IN WORLDWIDE POSTMARKETING
22
EXPERIENCE, RARE CASES OF TOXIC EPIDERMAL NECROLYSIS AND/OR
23
RASH-RELATED DEATH HAVE BEEN REPORTED IN ADULT AND PEDIATRIC
24
PATIENTS, BUT THEIR NUMBERS ARE TOO FEW TO PERMIT A PRECISE
25
ESTIMATE OF THE RATE.
26
OTHER THAN AGE, THERE ARE AS YET NO FACTORS IDENTIFIED THAT ARE
27
KNOWN TO PREDICT THE RISK OF OCCURRENCE OR THE SEVERITY OF RASH
28
ASSOCIATED WITH LAMICTAL. THERE ARE SUGGESTIONS, YET TO BE
29
PROVEN, THAT THE RISK OF RASH MAY ALSO BE INCREASED BY (1)
30
COADMINISTRATION OF LAMICTAL WITH VALPROATE (INCLUDES VALPROIC
31
ACID AND DIVALPROEX SODIUM), (2) EXCEEDING THE RECOMMENDED
32
INITIAL DOSE OF LAMICTAL, OR (3) EXCEEDING THE RECOMMENDED DOSE
33
ESCALATION FOR LAMICTAL. HOWEVER, CASES HAVE BEEN REPORTED IN
34
THE ABSENCE OF THESE FACTORS.
35
NEARLY ALL CASES OF LIFE-THREATENING RASHES ASSOCIATED WITH
36
LAMICTAL HAVE OCCURRED WITHIN 2 TO 8 WEEKS OF TREATMENT
37
INITIATION. HOWEVER, ISOLATED CASES HAVE BEEN REPORTED AFTER
38
PROLONGED TREATMENT (E.G., 6 MONTHS). ACCORDINGLY, DURATION OF
39
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2
THERAPY CANNOT BE RELIED UPON AS A MEANS TO PREDICT THE
40
POTENTIAL RISK HERALDED BY THE FIRST APPEARANCE OF A RASH.
41
ALTHOUGH BENIGN RASHES ALSO OCCUR WITH LAMICTAL, IT IS NOT
42
POSSIBLE TO PREDICT RELIABLY WHICH RASHES WILL PROVE TO BE
43
SERIOUS OR LIFE THREATENING. ACCORDINGLY, LAMICTAL SHOULD
44
ORDINARILY BE DISCONTINUED AT THE FIRST SIGN OF RASH, UNLESS THE
45
RASH IS CLEARLY NOT DRUG RELATED. DISCONTINUATION OF TREATMENT
46
MAY NOT PREVENT A RASH FROM BECOMING LIFE THREATENING OR
47
PERMANENTLY DISABLING OR DISFIGURING.
48
49
DESCRIPTION
50
LAMICTAL (lamotrigine), an antiepileptic drug (AED) of the phenyltriazine class, is
51
chemically unrelated to existing antiepileptic drugs. Its chemical name is 3,5-diamino-6-(2,3-
52
dichlorophenyl)-as-triazine, its molecular formula is C9H7N5Cl2, and its molecular weight is
53
256.09. Lamotrigine is a white to pale cream-colored powder and has a pKa of 5.7. Lamotrigine
54
is very slightly soluble in water (0.17 mg/mL at 25°C) and slightly soluble in 0.1 M HCl
55
(4.1 mg/mL at 25°C). The structural formula is:
56
57
58
59
LAMICTAL Tablets are supplied for oral administration as 25-mg (white), 100-mg (peach),
60
150-mg (cream), and 200-mg (blue) tablets. Each tablet contains the labeled amount of
61
lamotrigine and the following inactive ingredients: lactose; magnesium stearate; microcrystalline
62
cellulose; povidone; sodium starch glycolate; FD&C Yellow No. 6 Lake (100-mg tablet only);
63
ferric oxide, yellow (150-mg tablet only); and FD&C Blue No. 2 Lake (200-mg tablet only).
64
LAMICTAL Chewable Dispersible Tablets are supplied for oral administration. The tablets
65
contain 2 mg (white), 5 mg (white), or 25 mg (white) of lamotrigine and the following inactive
66
ingredients: blackcurrant flavor, calcium carbonate, low-substituted hydroxypropylcellulose,
67
magnesium aluminum silicate, magnesium stearate, povidone, saccharin sodium, and sodium
68
starch glycolate.
69
CLINICAL PHARMACOLOGY
70
Mechanism of Action: The precise mechanism(s) by which lamotrigine exerts its
71
anticonvulsant action are unknown. In animal models designed to detect anticonvulsant activity,
72
lamotrigine was effective in preventing seizure spread in the maximum electroshock (MES) and
73
pentylenetetrazol (scMet) tests, and prevented seizures in the visually and electrically evoked
74
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
3
after-discharge (EEAD) tests for antiepileptic activity. LAMICTAL also displayed inhibitory
75
properties in the kindling model in rats both during kindling development and in the fully
76
kindled state. The relevance of these models to human epilepsy, however, is not known.
77
One proposed mechanism of action of LAMICTAL, the relevance of which remains to be
78
established in humans, involves an effect on sodium channels. In vitro pharmacological studies
79
suggest that lamotrigine inhibits voltage-sensitive sodium channels, thereby stabilizing neuronal
80
membranes and consequently modulating presynaptic transmitter release of excitatory amino
81
acids (e.g., glutamate and aspartate).
82
The mechanisms by which lamotrigine exerts its therapeutic action in Bipolar Disorder have
83
not been established.
84
Pharmacological Properties: Although the relevance for human use is unknown, the
85
following data characterize the performance of LAMICTAL in receptor binding assays.
86
Lamotrigine had a weak inhibitory effect on the serotonin 5-HT3 receptor (IC50 = 18 µM). It does
87
not exhibit high affinity binding (IC50>100 µM) to the following neurotransmitter receptors:
88
adenosine A1 and A2; adrenergic α1, α2, and β; dopamine D1 and D2; γ-aminobutyric acid
89
(GABA) A and B; histamine H1; kappa opioid; muscarinic acetylcholine; and serotonin 5-HT2.
90
Studies have failed to detect an effect of lamotrigine on dihydropyridine-sensitive calcium
91
channels. It had weak effects at sigma opioid receptors (IC50 = 145 µM). Lamotrigine did not
92
inhibit the uptake of norepinephrine, dopamine, or serotonin, (IC50>200 µM) when tested in rat
93
synaptosomes and/or human platelets in vitro.
94
Effect of Lamotrigine on N-Methyl d-Aspartate-Receptor Mediated Activity:
95
Lamotrigine did not inhibit N-methyl d-aspartate (NMDA)-induced depolarizations in rat cortical
96
slices or NMDA-induced cyclic GMP formation in immature rat cerebellum, nor did lamotrigine
97
displace compounds that are either competitive or noncompetitive ligands at this glutamate
98
receptor complex (CNQX, CGS, TCHP). The IC50 for lamotrigine effects on NMDA-induced
99
currents (in the presence of 3 µM of glycine) in cultured hippocampal neurons exceeded
100
100 µM.
101
Folate Metabolism: In vitro, lamotrigine was shown to be an inhibitor of dihydrofolate
102
reductase, the enzyme that catalyzes the reduction of dihydrofolate to tetrahydrofolate. Inhibition
103
of this enzyme may interfere with the biosynthesis of nucleic acids and proteins. When oral daily
104
doses of lamotrigine were given to pregnant rats during organogenesis, fetal, placental, and
105
maternal folate concentrations were reduced. Significantly reduced concentrations of folate are
106
associated with teratogenesis (see PRECAUTIONS: Pregnancy). Folate concentrations were also
107
reduced in male rats given repeated oral doses of lamotrigine. Reduced concentrations were
108
partially returned to normal when supplemented with folinic acid.
109
Accumulation in Kidneys: Lamotrigine was found to accumulate in the kidney of the
110
male rat, causing chronic progressive nephrosis, necrosis, and mineralization. These findings are
111
attributed to α-2 microglobulin, a species- and sex-specific protein that has not been detected in
112
humans or other animal species.
113
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
4
Melanin Binding: Lamotrigine binds to melanin-containing tissues, e.g., in the eye and
114
pigmented skin. It has been found in the uveal tract up to 52 weeks after a single dose in rodents.
115
Cardiovascular: In dogs, lamotrigine is extensively metabolized to a 2-N-methyl
116
metabolite. This metabolite causes dose-dependent prolongations of the PR interval, widening of
117
the QRS complex, and, at higher doses, complete AV conduction block. Similar cardiovascular
118
effects are not anticipated in humans because only trace amounts of the 2-N-methyl metabolite
119
(<0.6% of lamotrigine dose) have been found in human urine (see Drug Disposition). However,
120
it is conceivable that plasma concentrations of this metabolite could be increased in patients with
121
a reduced capacity to glucuronidate lamotrigine (e.g., in patients with liver disease).
122
Pharmacokinetics and Drug Metabolism: The pharmacokinetics of lamotrigine have been
123
studied in patients with epilepsy, healthy young and elderly volunteers, and volunteers with
124
chronic renal failure. Lamotrigine pharmacokinetic parameters for adult and pediatric patients
125
and healthy normal volunteers are summarized in Tables 1 and 2.
126
127
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5
Table 1. Mean* Pharmacokinetic Parameters in Healthy Volunteers and Adult Patients
128
With Epilepsy
129
Adult Study Population
Number of
Subjects
Tmax: Time of
Maximum
Plasma
Concentration
(h)
t½:
Elimination
Half-life
(h)
Cl/F:
Apparent Plasma
Clearance
(mL/min/kg)
Healthy volunteers taking
no other medications:
Single-dose LAMICTAL
Multiple-dose LAMICTAL
179
36
2.2
(0.25-12.0)
1.7
(0.5-4.0)
32.8
(14.0-103.0)
25.4
(11.6-61.6)
0.44
(0.12-1.10)
0.58
(0.24-1.15)
Healthy volunteers taking
valproate:
Single-dose LAMICTAL
Multiple-dose LAMICTAL
6
18
1.8
(1.0-4.0)
1.9
(0.5-3.5)
48.3
(31.5-88.6)
70.3
(41.9-113.5)
0.30
(0.14-0.42)
0.18
(0.12-0.33)
Patients with epilepsy taking
valproate only:
Single-dose LAMICTAL
4
4.8
(1.8-8.4)
58.8
(30.5-88.8)
0.28
(0.16-0.40)
Patients with epilepsy taking
carbamazepine, phenytoin,
phenobarbital, or primidone†
plus valproate:
Single-dose LAMICTAL
25
3.8
(1.0-10.0)
27.2
(11.2-51.6)
0.53
(0.27-1.04)
Patients with epilepsy taking
carbamazepine, phenytoin,
phenobarbital, or primidone†:
Single-dose LAMICTAL
Multiple-dose LAMICTAL
24
17
2.3
(0.5-5.0)
2.0
(0.75-5.93)
14.4
(6.4-30.4)
12.6
(7.5-23.1)
1.10
(0.51-2.22)
1.21
(0.66-1.82)
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
6
*The majority of parameter means determined in each study had coefficients of variation
130
between 20% and 40% for half-life and Cl/F and between 30% and 70% for Tmax. The
131
overall mean values were calculated from individual study means that were weighted based
132
on the number of volunteers/patients in each study. The numbers in parentheses below each
133
parameter mean represent the range of individual volunteer/patient values across studies.
134
† Carbamazepine, phenobarbital, phenytoin, and primidone have been shown to increase the
135
apparent clearance of lamotrigine. Estrogen-containing oral contraceptives and rifampin have
136
also been shown to increase the apparent clearance of lamotrigine (see CLINICAL
137
PHARMACOLOGY: Drug Interactions and PRECAUTIONS: Drug Interactions).
138
139
Absorption: Lamotrigine is rapidly and completely absorbed after oral administration with
140
negligible first-pass metabolism (absolute bioavailability is 98%). The bioavailability is not
141
affected by food. Peak plasma concentrations occur anywhere from 1.4 to 4.8 hours following
142
drug administration. The lamotrigine chewable/dispersible tablets were found to be equivalent,
143
whether they were administered as dispersed in water, chewed and swallowed, or swallowed as
144
whole, to the lamotrigine compressed tablets in terms of rate and extent of absorption.
145
Distribution: Estimates of the mean apparent volume of distribution (Vd/F) of lamotrigine
146
following oral administration ranged from 0.9 to 1.3 L/kg. Vd/F is independent of dose and is
147
similar following single and multiple doses in both patients with epilepsy and in healthy
148
volunteers.
149
Protein Binding: Data from in vitro studies indicate that lamotrigine is approximately 55%
150
bound to human plasma proteins at plasma lamotrigine concentrations from 1 to 10 mcg/mL
151
(10 mcg/mL is 4 to 6 times the trough plasma concentration observed in the controlled efficacy
152
trials). Because lamotrigine is not highly bound to plasma proteins, clinically significant
153
interactions with other drugs through competition for protein binding sites are unlikely. The
154
binding of lamotrigine to plasma proteins did not change in the presence of therapeutic
155
concentrations of phenytoin, phenobarbital, or valproate. Lamotrigine did not displace other
156
AEDs (carbamazepine, phenytoin, phenobarbital) from protein binding sites.
157
Drug Disposition: Lamotrigine is metabolized predominantly by glucuronic acid
158
conjugation; the major metabolite is an inactive 2-N-glucuronide conjugate. After oral
159
administration of 240 mg of 14C-lamotrigine (15 μCi) to 6 healthy volunteers, 94% was
160
recovered in the urine and 2% was recovered in the feces. The radioactivity in the urine consisted
161
of unchanged lamotrigine (10%), the 2-N-glucuronide (76%), a 5-N-glucuronide (10%), a
162
2-N-methyl metabolite (0.14%), and other unidentified minor metabolites (4%).
163
Drug Interactions: The apparent clearance of lamotrigine is affected by the
164
coadministration of certain medications. Because lamotrigine is metabolized predominantly
165
by glucuronic acid conjugation, drugs that induce or inhibit glucuronidation may affect the
166
apparent clearance of lamotrigine.
167
Carbamazepine, phenytoin, phenobarbital, and primidone have been shown to increase the
168
apparent clearance of lamotrigine (see DOSAGE AND ADMINISTRATION and
169
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7
PRECAUTIONS: Drug Interactions). Most clinical experience is derived from patients taking
170
these AEDs.
171
Estrogen-containing oral contraceptives and rifampin have also been shown to increase the
172
apparent clearance of lamotrigine (see PRECAUTIONS: Drug Interactions).
173
Valproate decreases the apparent clearance of lamotrigine (i.e., more than doubles the
174
elimination half-life of lamotrigine), whether given with or without carbamazepine,
175
phenytoin, phenobarbital, or primidone. Accordingly, if lamotrigine is to be administered to a
176
patient receiving valproate, lamotrigine must be given at a reduced dosage, of no more than half
177
the dose used in patients not receiving valproate, even in the presence of drugs that increase the
178
apparent clearance of lamotrigine (see DOSAGE AND ADMINISTRATION and
179
PRECAUTIONS: Drug Interactions).
180
The following drugs were shown not to increase the apparent clearance of lamotrigine:
181
felbamate, gabapentin, levetiracetam, oxcarbazepine, pregabalin, and topiramate. Zonisamide
182
does not appear to change the pharmacokinetic profile of lamotrigine (see PRECAUTIONS:
183
Drug Interactions).
184
In vitro inhibition experiments indicated that the formation of the primary metabolite of
185
lamotrigine, the 2-N-glucuronide, was not significantly affected by co-incubation with clozapine,
186
fluoxetine, phenelzine, risperidone, sertraline, or trazodone, and was minimally affected by co-
187
incubation with amitriptyline, bupropion, clonazepam, haloperidol, or lorazepam. In addition,
188
bufuralol metabolism data from human liver microsomes suggested that lamotrigine does not
189
inhibit the metabolism of drugs eliminated predominantly by CYP2D6.
190
LAMICTAL has no effects on the pharmacokinetics of lithium (see PRECAUTIONS: Drug
191
Interactions).
192
The pharmacokinetics of LAMICTAL were not changed by co-administration of bupropion
193
(see PRECAUTIONS: Drug Interactions).
194
Co-administration of olanzapine did not have a clinically relevant effect on LAMICTAL
195
pharmacokinetics (see PRECAUTIONS: Drug Interactions).
196
Enzyme Induction: The effects of lamotrigine on the induction of specific families of
197
mixed-function oxidase isozymes have not been systematically evaluated.
198
Following multiple administrations (150 mg twice daily) to normal volunteers taking no other
199
medications, lamotrigine induced its own metabolism, resulting in a 25% decrease in t½ and a
200
37% increase in Cl/F at steady state compared to values obtained in the same volunteers
201
following a single dose. Evidence gathered from other sources suggests that self-induction by
202
LAMICTAL may not occur when LAMICTAL is given as adjunctive therapy in patients
203
receiving carbamazepine, phenytoin, phenobarbital, primidone, or rifampin.
204
Dose Proportionality: In healthy volunteers not receiving any other medications and given
205
single doses, the plasma concentrations of lamotrigine increased in direct proportion to the dose
206
administered over the range of 50 to 400 mg. In 2 small studies (n = 7 and 8) of patients with
207
epilepsy who were maintained on other AEDs, there also was a linear relationship between dose
208
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8
and lamotrigine plasma concentrations at steady state following doses of 50 to 350 mg twice
209
daily.
210
Elimination: (see Table 1).
211
Special Populations: Patients With Renal Insufficiency: Twelve volunteers with
212
chronic renal failure (mean creatinine clearance = 13 mL/min; range = 6 to 23) and another
213
6 individuals undergoing hemodialysis were each given a single 100-mg dose of LAMICTAL.
214
The mean plasma half-lives determined in the study were 42.9 hours (chronic renal failure),
215
13.0 hours (during hemodialysis), and 57.4 hours (between hemodialysis) compared to
216
26.2 hours in healthy volunteers. On average, approximately 20% (range = 5.6 to 35.1) of the
217
amount of lamotrigine present in the body was eliminated by hemodialysis during a 4-hour
218
session.
219
Hepatic Disease: The pharmacokinetics of lamotrigine following a single 100-mg dose
220
of LAMICTAL were evaluated in 24 subjects with mild, moderate, and severe hepatic
221
dysfunction (Child-Pugh Classification system) and compared with 12 subjects without hepatic
222
impairment. The patients with severe hepatic impairment were without ascites (n = 2) or with
223
ascites (n = 5). The mean apparent clearance of lamotrigine in patients with mild (n = 12),
224
moderate (n = 5), severe without ascites (n = 2), and severe with ascites (n = 5) liver impairment
225
was 0.30 ± 0.09, 0.24 ± 0.1, 0.21 ± 0.04, and 0.15 ± 0.09 mL/min/kg, respectively, as compared
226
to 0.37 ± 0.1 mL/min/kg in the healthy controls. Mean half-life of lamotrigine in patients with
227
mild, moderate, severe without ascites, and severe with ascites liver impairment was 46 ± 20,
228
72 ± 44, 67 ± 11, and 100 ± 48 hours, respectively, as compared to 33 ± 7 hours in healthy
229
controls (for dosing guidelines, see DOSAGE AND ADMINISTRATION: Patient With Hepatic
230
Impairment).
231
Age: Pediatric Patients: The pharmacokinetics of LAMICTAL following a single
232
2-mg/kg dose were evaluated in 2 studies of pediatric patients (n = 29 for patients aged
233
10 months to 5.9 years and n = 26 for patients aged 5 to 11 years). Forty-three patients received
234
concomitant therapy with other AEDs and 12 patients received LAMICTAL as monotherapy.
235
Lamotrigine pharmacokinetic parameters for pediatric patients are summarized in Table 2.
236
Population pharmacokinetic analyses involving patients aged 2 to 18 years demonstrated that
237
lamotrigine clearance was influenced predominantly by total body weight and concurrent AED
238
therapy. The oral clearance of lamotrigine was higher, on a body weight basis, in pediatric
239
patients than in adults. Weight-normalized lamotrigine clearance was higher in those subjects
240
weighing less than 30 kg, compared with those weighing greater than 30 kg. Accordingly,
241
patients weighing less than 30 kg may need an increase of as much as 50% in maintenance doses,
242
based on clinical response, as compared with subjects weighing more than 30 kg being
243
administered the same AEDs (see DOSAGE AND ADMINISTRATION). These analyses also
244
revealed that, after accounting for body weight, lamotrigine clearance was not significantly
245
influenced by age. Thus, the same weight-adjusted doses should be administered to children
246
irrespective of differences in age. Concomitant AEDs which influence lamotrigine clearance in
247
adults were found to have similar effects in children.
248
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9
249
Table 2. Mean Pharmacokinetic Parameters in Pediatric Patients With Epilepsy
250
Pediatric Study Population
Number
of
Subjects
Tmax
(h)
t½
(h)
Cl/F
(mL/min/kg)
Ages 10 months-5.3 years
Patients taking carbamazepine,
phenytoin, phenobarbital, or
primidone*
10
3.0
(1.0-5.9)
7.7
(5.7-11.4)
3.62
(2.44-5.28)
Patients taking antiepileptic drugs
(AEDs) with no known effect on
the apparent clearance of
lamotrigine
7
5.2
(2.9-6.1)
19.0
(12.9-27.1)
1.2
(0.75-2.42)
Patients taking valproate only
8
2.9
(1.0-6.0)
44.9
(29.5-52.5)
0.47
(0.23-0.77)
Ages 5-11 years
Patients taking carbamazepine,
phenytoin, phenobarbital, or
primidone*
7
1.6
(1.0-3.0)
7.0
(3.8-9.8)
2.54
(1.35-5.58)
Patients taking carbamazepine,
phenytoin, phenobarbital, or
primidone* plus valproate
8
3.3
(1.0-6.4)
19.1
(7.0-31.2)
0.89
(0.39-1.93)
Patients taking valproate only
†
3
4.5
(3.0-6.0)
65.8
(50.7-73.7)
0.24
(0.21-0.26)
Ages 13-18 years
Patients taking carbamazepine,
phenytoin, phenobarbital, or
primidone*
11
‡
‡
1.3
Patients taking carbamazepine,
phenytoin, phenobarbital, or
primidone*plus valproate
8
‡
‡
0.5
Patients taking valproate only
4
‡
‡
0.3
*Carbamazepine, phenobarbital, phenytoin, and primidone have been shown to increase the
251
apparent clearance of lamotrigine. Estrogen-containing oral contraceptives and rifampin have
252
also been shown to increase the apparent clearance of lamotrigine (see CLINICAL
253
PHARMACOLOGY: Drug Interactions and PRECAUTIONS: Drug Interactions).
254
†Two subjects were included in the calculation for mean Tmax.
255
‡Parameter not estimated.
256
257
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10
Elderly: The pharmacokinetics of lamotrigine following a single 150-mg dose of
258
LAMICTAL were evaluated in 12 elderly volunteers between the ages of 65 and 76 years (mean
259
creatinine clearance = 61 mL/min, range = 33 to 108 mL/min). The mean half-life of lamotrigine
260
in these subjects was 31.2 hours (range, 24.5 to 43.4 hours), and the mean clearance was
261
0.40 mL/min/kg (range, 0.26 to 0.48 mL/min/kg).
262
Gender: The clearance of lamotrigine is not affected by gender. However, during dose
263
escalation of LAMICTAL in one clinical trial in patients with epilepsy on a stable dose of
264
valproate (n = 77), mean trough lamotrigine concentrations, unadjusted for weight, were 24% to
265
45% higher (0.3 to 1.7 mcg/mL) in females than in males.
266
Race: The apparent oral clearance of lamotrigine was 25% lower in non-Caucasians than
267
Caucasians.
268
CLINICAL STUDIES
269
Epilepsy: The results of controlled clinical trials established the efficacy of LAMICTAL as
270
monotherapy in adults with partial onset seizures already receiving treatment with
271
carbamazepine, phenytoin, phenobarbital, or primidone as the single antiepileptic drug (AED), as
272
adjunctive therapy in adults and pediatric patients age 2 to 16 with partial seizures, and as
273
adjunctive therapy in the generalized seizures of Lennox-Gastaut syndrome in pediatric and adult
274
patients.
275
Monotherapy With LAMICTAL in Adults With Partial Seizures Already Receiving
276
Treatment With Carbamazepine, Phenytoin, Phenobarbital, or Primidone as the
277
Single AED: The effectiveness of monotherapy with LAMICTAL was established in a
278
multicenter, double-blind clinical trial enrolling 156 adult outpatients with partial seizures. The
279
patients experienced at least 4 simple partial, complex partial, and/or secondarily generalized
280
seizures during each of 2 consecutive 4-week periods while receiving carbamazepine or
281
phenytoin monotherapy during baseline. LAMICTAL (target dose of 500 mg/day) or valproate
282
(1,000 mg/day) was added to either carbamazepine or phenytoin monotherapy over a 4-week
283
period. Patients were then converted to monotherapy with LAMICTAL or valproate during the
284
next 4 weeks, then continued on monotherapy for an additional 12-week period.
285
Study endpoints were completion of all weeks of study treatment or meeting an escape
286
criterion. Criteria for escape relative to baseline were: (1) doubling of average monthly seizure
287
count, (2) doubling of highest consecutive 2-day seizure frequency, (3) emergence of a new
288
seizure type (defined as a seizure that did not occur during the 8-week baseline) that is more
289
severe than seizure types that occur during study treatment, or (4) clinically significant
290
prolongation of generalized-tonic-clonic (GTC) seizures. The primary efficacy variable was the
291
proportion of patients in each treatment group who met escape criteria.
292
The percentage of patients who met escape criteria was 42% (32/76) in the LAMICTAL
293
group and 69% (55/80) in the valproate group. The difference in the percentage of patients
294
meeting escape criteria was statistically significant (p = 0.0012) in favor of LAMICTAL. No
295
differences in efficacy based on age, sex, or race were detected.
296
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11
Patients in the control group were intentionally treated with a relatively low dose of valproate;
297
as such, the sole objective of this study was to demonstrate the effectiveness and safety of
298
monotherapy with LAMICTAL, and cannot be interpreted to imply the superiority of
299
LAMICTAL to an adequate dose of valproate.
300
Adjunctive Therapy With LAMICTAL in Adults With Partial Seizures: The
301
effectiveness of LAMICTAL as adjunctive therapy (added to other AEDs) was established in
302
3 multicenter, placebo-controlled, double-blind clinical trials in 355 adults with refractory partial
303
seizures. The patients had a history of at least 4 partial seizures per month in spite of receiving
304
one or more AEDs at therapeutic concentrations and, in 2 of the studies, were observed on their
305
established AED regimen during baselines that varied between 8 to 12 weeks. In the third,
306
patients were not observed in a prospective baseline. In patients continuing to have at least
307
4 seizures per month during the baseline, LAMICTAL or placebo was then added to the existing
308
therapy. In all 3 studies, change from baseline in seizure frequency was the primary measure of
309
effectiveness. The results given below are for all partial seizures in the intent-to-treat population
310
(all patients who received at least one dose of treatment) in each study, unless otherwise
311
indicated. The median seizure frequency at baseline was 3 per week while the mean at baseline
312
was 6.6 per week for all patients enrolled in efficacy studies.
313
One study (n = 216) was a double-blind, placebo-controlled, parallel trial consisting of a
314
24-week treatment period. Patients could not be on more than 2 other anticonvulsants and
315
valproate was not allowed. Patients were randomized to receive placebo, a target dose of
316
300 mg/day of LAMICTAL, or a target dose of 500 mg/day of LAMICTAL. The median
317
reductions in the frequency of all partial seizures relative to baseline were 8% in patients
318
receiving placebo, 20% in patients receiving 300 mg/day of LAMICTAL, and 36% in patients
319
receiving 500 mg/day of LAMICTAL. The seizure frequency reduction was statistically
320
significant in the 500-mg/day group compared to the placebo group, but not in the 300-mg/day
321
group.
322
A second study (n = 98) was a double-blind, placebo-controlled, randomized, crossover trial
323
consisting of two 14-week treatment periods (the last 2 weeks of which consisted of dose
324
tapering) separated by a 4-week washout period. Patients could not be on more than 2 other
325
anticonvulsants and valproate was not allowed. The target dose of LAMICTAL was 400 mg/day.
326
When the first 12 weeks of the treatment periods were analyzed, the median change in seizure
327
frequency was a 25% reduction on LAMICTAL compared to placebo (p<0.001).
328
The third study (n = 41) was a double-blind, placebo-controlled, crossover trial consisting of
329
two 12-week treatment periods separated by a 4-week washout period. Patients could not be on
330
more than 2 other anticonvulsants. Thirteen patients were on concomitant valproate; these
331
patients received 150 mg/day of LAMICTAL. The 28 other patients had a target dose of
332
300 mg/day of LAMICTAL. The median change in seizure frequency was a 26% reduction on
333
LAMICTAL compared to placebo (p<0.01).
334
No differences in efficacy based on age, sex, or race, as measured by change in seizure
335
frequency, were detected.
336
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12
Adjunctive Therapy With LAMICTAL in Pediatric Patients With Partial Seizures:
337
The effectiveness of LAMICTAL as adjunctive therapy in pediatric patients with partial seizures
338
was established in a multicenter, double-blind, placebo-controlled trial in 199 patients aged 2 to
339
16 years (n = 98 on LAMICTAL, n = 101 on placebo). Following an 8-week baseline phase,
340
patients were randomized to 18 weeks of treatment with LAMICTAL or placebo added to their
341
current AED regimen of up to 2 drugs. Patients were dosed based on body weight and valproate
342
use. Target doses were designed to approximate 5 mg/kg per day for patients taking valproate
343
(maximum dose, 250 mg/day) and 15 mg/kg per day for the patients not taking valproate
344
(maximum dose, 750 mg per day). The primary efficacy endpoint was percentage change from
345
baseline in all partial seizures. For the intent-to-treat population, the median reduction of all
346
partial seizures was 36% in patients treated with LAMICTAL and 7% on placebo, a difference
347
that was statistically significant (p<0.01).
348
Adjunctive Therapy With LAMICTAL in Pediatric and Adult Patients With
349
Lennox-Gastaut Syndrome: The effectiveness of LAMICTAL as adjunctive therapy in
350
patients with Lennox-Gastaut syndrome was established in a multicenter, double-blind,
351
placebo-controlled trial in 169 patients aged 3 to 25 years (n = 79 on LAMICTAL, n = 90 on
352
placebo). Following a 4-week single-blind, placebo phase, patients were randomized to 16 weeks
353
of treatment with LAMICTAL or placebo added to their current AED regimen of up to 3 drugs.
354
Patients were dosed on a fixed-dose regimen based on body weight and valproate use. Target
355
doses were designed to approximate 5 mg/kg per day for patients taking valproate (maximum
356
dose, 200 mg/day) and 15 mg/kg per day for patients not taking valproate (maximum dose,
357
400 mg/day). The primary efficacy endpoint was percentage change from baseline in major
358
motor seizures (atonic, tonic, major myoclonic, and tonic-clonic seizures). For the intent-to-treat
359
population, the median reduction of major motor seizures was 32% in patients treated with
360
LAMICTAL and 9% on placebo, a difference that was statistically significant (p<0.05). Drop
361
attacks were significantly reduced by LAMICTAL (34%) compared to placebo (9%), as were
362
tonic-clonic seizures (36% reduction versus 10% increase for LAMICTAL and placebo,
363
respectively).
364
Adjunctive Therapy With LAMICTAL in Pediatric and Adult Patients With
365
Primary Generalized Tonic-Clonic Seizures: The effectiveness of LAMICTAL as
366
adjunctive therapy in patients with primary generalized tonic-clonic seizures was established in a
367
multicenter, double-blind, placebo-controlled trial in 117 pediatric and adult patients ≥ 2 years
368
(n = 58 on LAMICTAL, n = 59 on placebo). Patients with at least 3 primary generalized tonic-
369
clonic seizures during an 8-week baseline phase were randomized to 19 to 24 weeks of treatment
370
with LAMICTAL or placebo added to their current AED regimen of up to 2 drugs. Patients were
371
dosed on a fixed-dose regimen, with target doses ranging from 3 mg/kg/day to 12 mg/kg/day for
372
pediatric patients and from 200 mg/day to 400 mg/day for adult patients based on concomitant
373
AED.
374
The primary efficacy endpoint was percentage change from baseline in primary generalized
375
tonic-clonic seizures. For the intent-to-treat population, the median percent reduction of primary
376
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13
generalized tonic-clonic seizures was 66% in patients treated with LAMICTAL and 34% on
377
placebo, a difference that was statistically significant (p=0.006).
378
379
Bipolar Disorder: The effectiveness of LAMICTAL in the maintenance treatment of Bipolar I
380
Disorder was established in 2 multicenter, double-blind, placebo-controlled studies in adult
381
patients who met DSM-IV criteria for Bipolar I Disorder. Study 1 enrolled patients with a current
382
or recent (within 60 days) depressive episode as defined by DSM-IV and Study 2 included
383
patients with a current or recent (within 60 days) episode of mania or hypomania as defined by
384
DSM-IV. Both studies included a cohort of patients (30% of 404 patients in Study 1 and 28% of
385
171 patients in Study 2) with rapid cycling Bipolar Disorder (4 to 6 episodes per year).
386
In both studies, patients were titrated to a target dose of 200 mg of LAMICTAL, as add-on
387
therapy or as monotherapy, with gradual withdrawal of any psychotropic medications during an
388
8- to 16-week open-label period. Overall 81% of 1,305 patients participating in the open-label
389
period were receiving 1 or more other psychotropic medications, including benzodiazepines,
390
selective serotonin reuptake inhibitors (SSRIs), atypical antipsychotics (including olanzapine),
391
valproate, or lithium, during titration of LAMICTAL. Patients with a CGI-severity score of 3 or
392
less maintained for at least 4 continuous weeks, including at least the final week on monotherapy
393
with LAMICTAL, were randomized to a placebo-controlled, double-blind treatment period for
394
up to 18 months. The primary endpoint was TIME (time to intervention for a mood episode or
395
one that was emerging, time to discontinuation for either an adverse event that was judged to be
396
related to Bipolar Disorder, or for lack of efficacy). The mood episode could be depression,
397
mania, hypomania, or a mixed episode.
398
In Study 1, patients received double-blind monotherapy with LAMICTAL, 50 mg/day
399
(n = 50), LAMICTAL 200 mg/day (n = 124), LAMICTAL 400 mg/day (n = 47), or placebo
400
(n = 121). LAMICTAL (200- and 400-mg/day treatment groups combined) was superior to
401
placebo in delaying the time to occurrence of a mood episode. Separate analyses of the 200 and
402
400 mg/day dose groups revealed no added benefit from the higher dose.
403
In Study 2, patients received double-blind monotherapy with LAMICTAL (100 to
404
400 mg/day, n = 59), or placebo (n = 70). LAMICTAL was superior to placebo in delaying time
405
to occurrence of a mood episode. The mean LAMICTAL dose was about 211 mg/day.
406
Although these studies were not designed to separately evaluate time to the occurrence of
407
depression or mania, a combined analysis for the 2 studies revealed a statistically significant
408
benefit for LAMICTAL over placebo in delaying the time to occurrence of both depression and
409
mania, although the finding was more robust for depression.
410
INDICATIONS AND USAGE
411
Epilepsy:
412
Adjunctive Use: LAMICTAL is indicated as adjunctive therapy for partial seizures, the
413
generalized seizures of Lennox-Gastaut syndrome, and primary generalized tonic-clonic seizures
414
in adults and pediatric patients (≥2 years of age).
415
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14
416
Monotherapy Use: LAMICTAL is indicated for conversion to monotherapy in adults with
417
partial seizures.who are receiving treatment with carbamazepine, phenytoin, phenobarbital,
418
primidone, or valproate as the single AED.
419
Safety and effectiveness of LAMICTAL have not been established (1) as initial monotherapy,
420
(2) for conversion to monotherapy from AEDs other than carbamazepine, phenytoin,
421
phenobarbital, primidone, or valproate, or (3) for simultaneous conversion to monotherapy from
422
2 or more concomitant AEDs (see DOSAGE AND ADMINISTRATION).
423
424
Bipolar Disorder: LAMICTAL is indicated for the maintenance treatment of Bipolar I
425
Disorder to delay the time to occurrence of mood episodes (depression, mania, hypomania,
426
mixed episodes) in patients treated for acute mood episodes with standard therapy. The
427
effectiveness of LAMICTAL in the acute treatment of mood episodes has not been established.
428
The effectiveness of LAMICTAL as maintenance treatment was established in
429
2 placebo-controlled trials of 18 months’ duration in patients with Bipolar I Disorder as defined
430
by DSM-IV (see CLINICAL STUDIES, Bipolar Disorder). The physician who elects to use
431
LAMICTAL for periods extending beyond 18 months should periodically re-evaluate the
432
long-term usefulness of the drug for the individual patient.
433
CONTRAINDICATIONS
434
LAMICTAL is contraindicated in patients who have demonstrated hypersensitivity to the drug
435
or its ingredients.
436
WARNINGS
437
SEE BOX WARNING REGARDING THE RISK OF SERIOUS RASHES REQUIRING
438
HOSPITALIZATION AND DISCONTINUATION OF LAMICTAL.
439
ALTHOUGH BENIGN RASHES ALSO OCCUR WITH LAMICTAL, IT IS NOT
440
POSSIBLE TO PREDICT RELIABLY WHICH RASHES WILL PROVE TO BE
441
SERIOUS OR LIFE THREATENING. ACCORDINGLY, LAMICTAL SHOULD
442
ORDINARILY BE DISCONTINUED AT THE FIRST SIGN OF RASH, UNLESS THE
443
RASH IS CLEARLY NOT DRUG RELATED. DISCONTINUATION OF TREATMENT
444
MAY NOT PREVENT A RASH FROM BECOMING LIFE THREATENING OR
445
PERMANENTLY DISABLING OR DISFIGURING.
446
Serious Rash: Pediatric Population: The incidence of serious rash associated with
447
hospitalization and discontinuation of LAMICTAL in a prospectively followed cohort of
448
pediatric patients with epilepsy receiving adjunctive therapy was approximately 0.8% (16 of
449
1,983). When 14 of these cases were reviewed by 3 expert dermatologists, there was
450
considerable disagreement as to their proper classification. To illustrate, one dermatologist
451
considered none of the cases to be Stevens-Johnson syndrome; another assigned 7 of the 14 to
452
this diagnosis. There was 1 rash-related death in this 1,983 patient cohort. Additionally, there
453
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For current labeling information, please visit https://www.fda.gov/drugsatfda
15
have been rare cases of toxic epidermal necrolysis with and without permanent sequelae and/or
454
death in US and foreign postmarketing experience.
455
There is evidence that the inclusion of valproate in a multidrug regimen increases the risk of
456
serious, potentially life-threatening rash in pediatric patients. In pediatric patients who used
457
valproate concomitantly, 1.2% (6 of 482) experienced a serious rash compared to 0.6% (6 of
458
952) patients not taking valproate.
459
Adult Population: Serious rash associated with hospitalization and discontinuation of
460
LAMICTAL occurred in 0.3% (11 of 3,348) of adult patients who received LAMICTAL in
461
premarketing clinical trials of epilepsy. In the bipolar and other mood disorders clinical trials, the
462
rate of serious rash was 0.08% (1 of 1,233) of adult patients who received LAMICTAL as initial
463
monotherapy and 0.13% (2 of 1,538) of adult patients who received LAMICTAL as adjunctive
464
therapy. No fatalities occurred among these individuals. However, in worldwide postmarketing
465
experience, rare cases of rash-related death have been reported, but their numbers are too few to
466
permit a precise estimate of the rate.
467
Among the rashes leading to hospitalization were Stevens-Johnson syndrome, toxic epidermal
468
necrolysis, angioedema, and a rash associated with a variable number of the following systemic
469
manifestations: fever, lymphadenopathy, facial swelling, hematologic, and hepatologic
470
abnormalities.
471
There is evidence that the inclusion of valproate in a multidrug regimen increases the risk of
472
serious, potentially life-threatening rash in adults. Specifically, of 584 patients administered
473
LAMICTAL with valproate in epilepsy clinical trials, 6 (1%) were hospitalized in association
474
with rash; in contrast, 4 (0.16%) of 2,398 clinical trial patients and volunteers administered
475
LAMICTAL in the absence of valproate were hospitalized.
476
Other examples of serious and potentially life-threatening rash that did not lead to
477
hospitalization also occurred in premarketing development. Among these, 1 case was reported to
478
be Stevens-Johnson–like.
479
Hypersensitivity Reactions: Hypersensitivity reactions, some fatal or life threatening, have
480
also occurred. Some of these reactions have included clinical features of multiorgan
481
failure/dysfunction, including hepatic abnormalities and evidence of disseminated intravascular
482
coagulation. It is important to note that early manifestations of hypersensitivity (e.g., fever,
483
lymphadenopathy) may be present even though a rash is not evident. If such signs or symptoms
484
are present, the patient should be evaluated immediately. LAMICTAL should be discontinued if
485
an alternative etiology for the signs or symptoms cannot be established.
486
Prior to initiation of treatment with LAMICTAL, the patient should be instructed that a
487
rash or other signs or symptoms of hypersensitivity (e.g., fever, lymphadenopathy) may
488
herald a serious medical event and that the patient should report any such occurrence to a
489
physician immediately.
490
Acute Multiorgan Failure: Multiorgan failure, which in some cases has been fatal or
491
irreversible, has been observed in patients receiving LAMICTAL. Fatalities associated with
492
multiorgan failure and various degrees of hepatic failure have been reported in 2 of 3,796 adult
493
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
16
patients and 4 of 2,435 pediatric patients who received LAMICTAL in clinical trials. No such
494
fatalities have been reported in bipolar patients in clinical trials. Rare fatalities from multiorgan
495
failure have also been reported in compassionate plea and postmarketing use. The majority of
496
these deaths occurred in association with other serious medical events, including status
497
epilepticus and overwhelming sepsis, and hantavirus making it difficult to identify the initial
498
cause.
499
Additionally, 3 patients (a 45-year-old woman, a 3.5-year-old boy, and an 11-year-old girl)
500
developed multiorgan dysfunction and disseminated intravascular coagulation 9 to 14 days after
501
LAMICTAL was added to their AED regimens. Rash and elevated transaminases were also
502
present in all patients and rhabdomyolysis was noted in 2 patients. Both pediatric patients were
503
receiving concomitant therapy with valproate, while the adult patient was being treated with
504
carbamazepine and clonazepam. All patients subsequently recovered with supportive care after
505
treatment with LAMICTAL was discontinued.
506
Blood Dyscrasias: There have been reports of blood dyscrasias that may or may not be
507
associated with the hypersensitivity syndrome. These have included neutropenia, leukopenia,
508
anemia, thrombocytopenia, pancytopenia, and, rarely, aplastic anemia and pure red cell aplasia.
509
Withdrawal Seizures: As with other AEDs, LAMICTAL should not be abruptly discontinued.
510
In patients with epilepsy there is a possibility of increasing seizure frequency. In clinical trials in
511
patients with Bipolar Disorder, 2 patients experienced seizures shortly after abrupt withdrawal of
512
LAMICTAL. However, there were confounding factors that may have contributed to the
513
occurrence of seizures in these bipolar patients. Unless safety concerns require a more rapid
514
withdrawal, the dose of LAMICTAL should be tapered over a period of at least 2 weeks (see
515
DOSAGE AND ADMINISTRATION).
516
PRECAUTIONS
517
518
Concomitant Use With Oral Contraceptives: Some estrogen-containing oral
519
contraceptives have been shown to decrease serum concentrations of lamotrigine (see
520
PRECAUTIONS: Drug Interactions). Dosage adjustments will be necessary in most patients
521
who start or stop estrogen-containing oral contraceptives while taking LAMICTAL (see
522
DOSAGE AND ADMINISTRATION: Special Populations: Women and Oral
523
Contraceptives: Adjustments to the Maintenance Dose of LAMICTAL). During the week of
524
inactive hormone preparation (“pill-free” week) of oral contraceptive therapy, plasma levels are
525
expected to rise, as much as doubling by the end of the week. Adverse events consistent with
526
elevated levels of lamotrigine, such as dizziness, ataxia, and diplopia, could occur.
527
Dermatological Events (see BOX WARNING, WARNINGS): Serious rashes associated
528
with hospitalization and discontinuation of LAMICTAL have been reported. Rare deaths have
529
been reported, but their numbers are too few to permit a precise estimate of the rate. There are
530
suggestions, yet to be proven, that the risk of rash may also be increased by (1) coadministration
531
of LAMICTAL with valproate, (2) exceeding the recommended initial dose of LAMICTAL, or
532
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
17
(3) exceeding the recommended dose escalation for LAMICTAL. However, cases have been
533
reported in the absence of these factors.
534
In epilepsy clinical trials, approximately 10% of all patients exposed to LAMICTAL
535
developed a rash. In the Bipolar Disorder clinical trials, 14% of patients exposed to LAMICTAL
536
developed a rash. Rashes associated with LAMICTAL do not appear to have unique identifying
537
features. Typically, rash occurs in the first 2 to 8 weeks following treatment initiation. However,
538
isolated cases have been reported after prolonged treatment (e.g., 6 months). Accordingly,
539
duration of therapy cannot be relied upon as a means to predict the potential risk heralded by the
540
first appearance of a rash.
541
Although most rashes resolved even with continuation of treatment with LAMICTAL, it is not
542
possible to predict reliably which rashes will prove to be serious or life threatening.
543
ACCORDINGLY, LAMICTAL SHOULD ORDINARILY BE DISCONTINUED AT THE
544
FIRST SIGN OF RASH, UNLESS THE RASH IS CLEARLY NOT DRUG RELATED.
545
DISCONTINUATION OF TREATMENT MAY NOT PREVENT A RASH FROM
546
BECOMING LIFE THREATENING OR PERMANENTLY DISABLING OR
547
DISFIGURING.
548
It is recommended that LAMICTAL not be restarted in patients who discontinued due to rash
549
associated with prior treatment with LAMICTAL unless the potential benefits clearly outweigh
550
the risks. If the decision is made to restart a patient who has discontinued LAMICTAL, the need
551
to restart with the initial dosing recommendations should be assessed. The greater the interval of
552
time since the previous dose, the greater consideration should be given to restarting with the
553
initial dosing recommendations. If a patient has discontinued LAMICTAL for a period of more
554
than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be
555
followed. The half-life of LAMICTAL is affected by other concomitant medications (see
556
CLINICAL PHARMACOLOGY: Pharmacokinetics and Drug Metabolism, and DOSAGE AND
557
ADMINISTRATION).
558
Use in Patients With Epilepsy:
559
Sudden Unexplained Death in Epilepsy (SUDEP): During the premarketing
560
development of LAMICTAL, 20 sudden and unexplained deaths were recorded among a cohort
561
of 4,700 patients with epilepsy (5,747 patient-years of exposure).
562
Some of these could represent seizure-related deaths in which the seizure was not observed,
563
e.g., at night. This represents an incidence of 0.0035 deaths per patient-year. Although this rate
564
exceeds that expected in a healthy population matched for age and sex, it is within the range of
565
estimates for the incidence of sudden unexplained deaths in patients with epilepsy not receiving
566
LAMICTAL (ranging from 0.0005 for the general population of patients with epilepsy, to 0.004
567
for a recently studied clinical trial population similar to that in the clinical development program
568
for LAMICTAL, to 0.005 for patients with refractory epilepsy). Consequently, whether these
569
figures are reassuring or suggest concern depends on the comparability of the populations
570
reported upon to the cohort receiving LAMICTAL and the accuracy of the estimates provided.
571
Probably most reassuring is the similarity of estimated SUDEP rates in patients receiving
572
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
18
LAMICTAL and those receiving another antiepileptic drug that underwent clinical testing in a
573
similar population at about the same time. Importantly, that drug is chemically unrelated to
574
LAMICTAL. This evidence suggests, although it certainly does not prove, that the high SUDEP
575
rates reflect population rates, not a drug effect.
576
Status Epilepticus: Valid estimates of the incidence of treatment emergent status
577
epilepticus among patients treated with LAMICTAL are difficult to obtain because reporters
578
participating in clinical trials did not all employ identical rules for identifying cases. At a
579
minimum, 7 of 2,343 adult patients had episodes that could unequivocally be described as status.
580
In addition, a number of reports of variably defined episodes of seizure exacerbation (e.g.,
581
seizure clusters, seizure flurries, etc.) were made.
582
Use in Patients With Bipolar Disorder:
583
Acute Treatment of Mood Episodes: Safety and effectiveness of LAMICTAL in the
584
acute treatment of mood episodes has not been established.
585
Children and Adolescents (less than 18 years of age): Treatment with
586
antidepressants is associated with an increased risk of suicidal thinking and behavior in children
587
and adolescents with major depressive disorder and other psychiatric disorders. It is not known
588
whether LAMICTAL is associated with a similar risk in this population (see PRECAUTIONS:
589
Clinical Worsening and Suicide Risk Associated With Bipolar Disorder).
590
Safety and effectiveness of LAMICTAL in patients below the age of 18 years with mood
591
disorders have not been established.
592
Clinical Worsening and Suicide Risk Associated with Bipolar Disorder:
593
Patients with bipolar disorder may experience worsening of their depressive symptoms and/or
594
the emergence of suicidal ideation and behaviors (suicidality) whether or not they are taking
595
medications for bipolar disorder. Patients should be closely monitored for clinical worsening
596
(including development of new symptoms) and suicidality, especially at the beginning of a
597
course of treatment, or at the time of dose changes.
598
In addition, patients with a history of suicidal behavior or thoughts, those patients exhibiting a
599
significant degree of suicidal ideation prior to commencement of treatment, and young adults,
600
are at an increased risk of suicidal thoughts or suicide attempts, and should receive careful
601
monitoring during treatment.
602
Patients (and caregivers of patients) should be alerted about the need to monitor for any
603
worsening of their condition (including development of new symptoms) and /or the emergence
604
of suicidal ideation/behavior or thoughts of harming themselves and to seek medical advice
605
immediately if these symptoms present.
606
Consideration should be given to changing the therapeutic regimen, including possibly
607
discontinuing the medication, in patients who experience clinical worsening (including
608
development of new symptoms) and/or the emergence of suicidal ideation/behavior especially if
609
these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting
610
symptoms.
611
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
19
Prescriptions for LAMICTAL should be written for the smallest quantity of tablets consistent
612
with good patient management, in order to reduce the risk of overdose. Overdoses have been
613
reported for LAMICTAL, some of which have been fatal (see OVERDOSAGE).
614
Addition of LAMICTAL to a Multidrug Regimen That Includes Valproate (Dosage
615
Reduction): Because valproate reduces the clearance of lamotrigine, the dosage of lamotrigine
616
in the presence of valproate is less than half of that required in its absence (see DOSAGE AND
617
ADMINISTRATION).
618
Use in Patients With Concomitant Illness: Clinical experience with LAMICTAL in
619
patients with concomitant illness is limited. Caution is advised when using LAMICTAL in
620
patients with diseases or conditions that could affect metabolism or elimination of the drug, such
621
as renal, hepatic, or cardiac functional impairment.
622
Hepatic metabolism to the glucuronide followed by renal excretion is the principal route of
623
elimination of lamotrigine (see CLINICAL PHARMACOLOGY).
624
A study in individuals with severe chronic renal failure (mean creatinine
625
clearance = 13 mL/min) not receiving other AEDs indicated that the elimination half-life of
626
unchanged lamotrigine is prolonged relative to individuals with normal renal function. Until
627
adequate numbers of patients with severe renal impairment have been evaluated during chronic
628
treatment with LAMICTAL, it should be used with caution in these patients, generally using a
629
reduced maintenance dose for patients with significant impairment.
630
Because there is limited experience with the use of LAMICTAL in patients with impaired
631
liver function, the use in such patients may be associated with as yet unrecognized risks (see
632
CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).
633
Binding in the Eye and Other Melanin-Containing Tissues: Because lamotrigine binds
634
to melanin, it could accumulate in melanin-rich tissues over time. This raises the possibility that
635
lamotrigine may cause toxicity in these tissues after extended use. Although ophthalmological
636
testing was performed in one controlled clinical trial, the testing was inadequate to exclude
637
subtle effects or injury occurring after long-term exposure. Moreover, the capacity of available
638
tests to detect potentially adverse consequences, if any, of lamotrigine's binding to melanin is
639
unknown.
640
Accordingly, although there are no specific recommendations for periodic ophthalmological
641
monitoring, prescribers should be aware of the possibility of long-term ophthalmologic effects.
642
Information for Patients: Prior to initiation of treatment with LAMICTAL, the patient should
643
be instructed that a rash or other signs or symptoms of hypersensitivity (e.g., fever,
644
lymphadenopathy) may herald a serious medical event and that the patient should report any
645
such occurrence to a physician immediately. In addition, the patient should notify his or her
646
physician if worsening of seizure control occurs.
647
Patients should be advised that LAMICTAL may cause dizziness, somnolence, and other
648
symptoms and signs of central nervous system (CNS) depression. Accordingly, they should be
649
advised neither to drive a car nor to operate other complex machinery until they have gained
650
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
20
sufficient experience on LAMICTAL to gauge whether or not it adversely affects their mental
651
and/or motor performance.
652
Patients should be advised to notify their physicians if they become pregnant or intend to
653
become pregnant during therapy. Patients should be advised to notify their physicians if they
654
intend to breast-feed or are breast-feeding an infant.
655
Women should be advised to notify their physician if they plan to start or stop use of oral
656
contraceptives or other female hormonal preparations. Starting estrogen-containing oral
657
contraceptives may significantly decrease lamotrigine plasma levels and stopping estrogen-
658
containing oral contraceptives (including the “pill-free” week) may significantly increase
659
lamotrigine plasma levels (see PRECAUTIONS: Drug Interactions). Women should also be
660
advised to promptly notify their physician if they experience adverse events or changes in
661
menstrual pattern (e.g., break-through bleeding) while receiving LAMICTAL in combination
662
with these medications.
663
Patients should be advised to notify their physician if they stop taking LAMICTAL for any
664
reason and not to resume LAMICTAL without consulting their physician.
665
Patients should be informed of the availability of a patient information leaflet, and they should
666
be instructed to read the leaflet prior to taking LAMICTAL. See PATIENT INFORMATION at
667
the end of this labeling for the text of the leaflet provided for patients.
668
Laboratory Tests: The value of monitoring plasma concentrations of LAMICTAL has not
669
been established. Because of the possible pharmacokinetic interactions between LAMICTAL
670
and other drugs including AEDs (see Table 3), monitoring of the plasma levels of LAMICTAL
671
and concomitant drugs may be indicated, particularly during dosage adjustments. In general,
672
clinical judgment should be exercised regarding monitoring of plasma levels of LAMICTAL and
673
other drugs and whether or not dosage adjustments are necessary.
674
675
Drug Interactions:
676
677
The net effects of drug interactions with LAMICTAL are summarized in Table 3 (see also
678
DOSAGE AND ADMINISTRATION).
679
680
Oral Contraceptives: In 16 female volunteers, an oral contraceptive preparation containing
681
30 mcg ethinylestradiol and 150 mcg levonorgestrel increased the apparent clearance of
682
lamotrigine (300 mg/day) by approximately 2-fold with a mean decrease in AUC of 52% and in
683
Cmax of 39%. In this study, trough serum lamotrigine concentrations gradually increased and
684
were approximately 2-fold higher on average at the end of the week of the inactive preparation
685
compared to trough lamotrigine concentrations at the end of the active hormone cycle.
686
Gradual transient increases in lamotrigine plasma levels (approximate 2-fold increase)
687
occurred during the week of inactive hormone preparation (“pill-free” week) for women not also
688
taking a drug that increased the clearance of lamotrigine (carbamazepine, phenytoin,
689
phenobarbital, primidone, or rifampin). The increase in lamotrigine plasma levels will be greater
690
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
21
if the dose of LAMICTAL is increased in the few days before or during the “pill-free” week.
691
Increases in lamotrigine plasma levels could result in dose-dependent adverse effects (see
692
PRECAUTIONS: Concomitant Use With Oral Contraceptives).
693
In the same study, co-administration of LAMICTAL (300 mg/day) in 16 female volunteers
694
did not affect the pharmacokinetics of the ethinylestradiol component of the oral contraceptive
695
preparation. There was a mean decrease in the AUC and Cmax of the levonorgestrel component of
696
19% and 12%, respectively. Measurement of serum progesterone indicated that there was no
697
hormonal evidence of ovulation in any of the 16 volunteers, although measurement of serum
698
FSH, LH, and estradiol indicated that there was some loss of suppression of the hypothalamic-
699
pituitary-ovarian axis.
700
The effects of doses of LAMICTAL other than 300 mg/day have not been studied in clinical
701
trials.
702
The clinical significance of the observed hormonal changes on ovulatory activity is unknown.
703
However, the possibility of decreased contraceptive efficacy in some patients cannot be
704
excluded. Therefore, patients should be instructed to promptly report changes in their menstrual
705
pattern (e.g., break-through bleeding).
706
Dosage adjustments will be necessary for most women receiving estrogen-containing oral
707
contraceptive preparations (see DOSAGE AND ADMINISTRATION: Special Populations:
708
Women and Oral Contraceptives).
709
Other Hormonal Contraceptives or Hormone Replacement Therapy: The effect of
710
other hormonal contraceptive preparations or hormone replacement therapy on the
711
pharmacokinetics of lamotrigine has not been systematically evaluated, It has been reported that
712
ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the
713
progestin only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the
714
dosage of LAMICTAL in the presence of progestogens alone will likely not be needed.
715
716
Bupropion: The pharmacokinetics of a 100-mg single dose of LAMICTAL in healthy
717
volunteers (n = 12) were not changed by co-administration of bupropion sustained-release
718
formulation (150 mg twice a day) starting 11 days before LAMICTAL.
719
Carbamazepine: LAMICTAL has no appreciable effect on steady-state carbamazepine
720
plasma concentration. Limited clinical data suggest there is a higher incidence of dizziness,
721
diplopia, ataxia, and blurred vision in patients receiving carbamazepine with LAMICTAL than in
722
patients receiving other AEDs with LAMICTAL (see ADVERSE REACTIONS). The
723
mechanism of this interaction is unclear. The effect of LAMICTAL on plasma concentrations of
724
carbamazepine-epoxide is unclear. In a small subset of patients (n = 7) studied in a
725
placebo-controlled trial, LAMICTAL had no effect on carbamazepine-epoxide plasma
726
concentrations, but in a small, uncontrolled study (n = 9), carbamazepine-epoxide levels
727
increased.
728
The addition of carbamazepine decreases lamotrigine steady-state concentrations by
729
approximately 40%.
730
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
22
Felbamate: In a study of 21 healthy volunteers, coadministration of felbamate (1,200 mg
731
twice daily) with LAMICTAL (100 mg twice daily for 10 days) appeared to have no clinically
732
relevant effects on the pharmacokinetics of lamotrigine.
733
Folate Inhibitors: Lamotrigine is a weak inhibitor of dihydrofolate reductase. Prescribers
734
should be aware of this action when prescribing other medications that inhibit folate metabolism.
735
Gabapentin: Based on a retrospective analysis of plasma levels in 34 patients who received
736
LAMICTAL both with and without gabapentin, gabapentin does not appear to change the
737
apparent clearance of lamotrigine.
738
Levetiracetam: Potential drug interactions between levetiracetam and LAMICTAL were
739
assessed by evaluating serum concentrations of both agents during placebo-controlled clinical
740
trials. These data indicate that LAMICTAL does not influence the pharmacokinetics of
741
levetiracetam and that levetiracetam does not influence the pharmacokinetics of LAMICTAL.
742
Lithium: The pharmacokinetics of lithium were not altered in healthy subjects (n = 20) by
743
co-administration of LAMICTAL (100 mg/day) for 6 days.
744
Olanzapine: The AUC and Cmax of olanzapine were similar following the addition of
745
olanzapine (15 mg once daily) to LAMICTAL (200 mg once daily) in healthy male volunteers
746
(n = 16) compared to the AUC and Cmax in healthy male volunteers receiving olanzapine alone
747
(n = 16).
748
In the same study, the AUC and Cmax of lamotrigine was reduced on average by 24% and
749
20%, respectively, following the addition of olanzapine to LAMICTAL in healthy male
750
volunteers compared to those receiving LAMICTAL alone. This reduction in lamotrigine plasma
751
concentrations is not expected to be clinically relevant.
752
Oxcarbazepine: The AUC and Cmax of oxcarbazepine and its active 10-monohydroxy
753
oxcarbazepine metabolite were not significantly different following the addition of
754
oxcarbazepine (600 mg twice daily) to LAMICTAL (200 mg once daily) in healthy male
755
volunteers (n = 13) compared to healthy male volunteers receiving oxcarbazepine alone (n = 13).
756
In the same study, the AUC and Cmax of lamotrigine were similar following the addition of
757
oxcarbazepine (600 mg twice daily) to LAMICTAL in healthy male volunteers compared to
758
those receiving LAMICTAL alone. Limited clinical data suggest a higher incidence of headache,
759
dizziness, nausea, and somnolence with coadministration of LAMICTAL and oxcarbazepine
760
compared to LAMICTAL alone or oxcarbazepine alone.
761
Phenobarbital, Primidone: The addition of phenobarbital or primidone decreases
762
lamotrigine steady-state concentrations by approximately 40%.
763
Phenytoin: LAMICTAL has no appreciable effect on steady-state phenytoin plasma
764
concentrations in patients with epilepsy. The addition of phenytoin decreases lamotrigine steady-
765
state concentrations by approximately 40%.
766
Pregabalin: Steady-state trough plasma concentrations of lamotrigine were not affected by
767
concomitant pregabalin (200 mg 3 times daily) administration. There are no pharmacokinetic
768
interactions between LAMICTAL and pregabalin.
769
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
23
Rifampin: In 10 male volunteers, rifampin (600 mg/day for 5 days) significantly increased
770
the apparent clearance of a single 25 mg dose of LAMICTAL by approximately 2-fold (AUC
771
decreased by approximately 40%).
772
Topiramate: Topiramate resulted in no change in plasma concentrations of lamotrigine.
773
Administration of LAMICTAL resulted in a 15% increase in topiramate concentrations.
774
Valproate: When LAMICTAL was administered to healthy volunteers (n = 18) receiving
775
valproate, the trough steady-state valproate plasma concentrations decreased by an average of
776
25% over a 3-week period, and then stabilized. However, adding LAMICTAL to the existing
777
therapy did not cause a change in valproate plasma concentrations in either adult or pediatric
778
patients in controlled clinical trials.
779
The addition of valproate increased lamotrigine steady-state concentrations in normal
780
volunteers by slightly more than 2-fold. In one study, maximal inhibition of lamotrigine
781
clearance was reached at valproate doses between 250 mg/day and 500 mg/day and did not
782
increase as the valproate dose was further increased.
783
Zonisamide: In a study of 18 patients with epilepsy, coadministration of zonisamide (200 to
784
400 mg/day) with LAMICTAL (150 to 500 mg/day) for 35 days had no significant effect on the
785
pharmacokinetics of lamotrigine.
786
Known Inducers or Inhibitors of Glucuronidation: Drugs other than those listed above
787
have not been systematically evaluated in combination with LAMICTAL. Since lamotrigine is
788
metabolized predominately by glucuronic acid conjugation, drugs that are known to induce or
789
inhibit glucuronidation may affect the apparent clearance of lamotrigine, and doses of
790
LAMICTAL may require adjustment based on clinical response.
791
Other: Results of in vitro experiments suggest that clearance of lamotrigine is unlikely to be
792
reduced by concomitant administration of amitriptyline, clonazepam, clozapine, fluoxetine,
793
haloperidol, lorazepam, phenelzine, risperidone, sertraline, or trazodone (see CLINICAL
794
PHARMACOLOGY: Pharmacokinetics and Drug Metabolism).
Results of in vitro
795
experiments suggest that lamotrigine does not reduce the clearance of drugs eliminated
796
predominantly by CYP2D6 (see CLINICAL PHARMACOLOGY).
797
.
798
Table 3. Summary of Drug Interactions With LAMICTAL
799
Drug
Drug Plasma
Concentration With
Adjunctive
LAMICTAL*
Lamotrigine Plasma
Concentration With Adjunctive
Drugs†
Oral contraceptives (e.g.,
ethinylestradiol/levonorgestrel)‡
↔§
↓
Bupropion
Not assessed
↔
Carbamazepine (CBZ)
↔
↓
CBZ epoxide║
?
Felbamate
Not assessed
↔
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
24
Gabapentin
Not assessed
↔
Levetiracetam
↔
↔
Lithium
↔
Not assessed
Olanzapine
↔
↔¶
Oxcarbazepine
↔
↔
10-monohydroxy oxcarbazepine
metabolite#
↔
Phenobarbital/primidone
↔
↓
Phenytoin (PHT)
↔
↓
Pregabalin
↔
↔
Rifampin
Not assessed
↓
Topiramate
↔**
↔
Valproate
↓
↑
Valproate + PHT and/or CBZ
Not assessed
↔
Zonisamide
Not assessed
↔
* From adjunctive clinical trials and volunteer studies.
800
† Net effects were estimated by comparing the mean clearance values obtained in adjunctive
801
clinical trials and volunteers studies.
802
‡ The effect of other hormonal contraceptive preparations or hormone replacement therapy on the
803
pharmacokinetics of lamotrigine has not been systematically evaluated in clinical trials and
804
the effect may not be similar to that seen with the ethinylestradiol/levonorgestrel
805
combinations.
806
§Modest decrease in levonorgestrel (see PRECAUTIONS: Drug Interactions: Effect of
807
LAMICTAL on Oral Contraceptives).
808
║Not administered, but an active metabolite of carbamazepine.
809
¶Slight decrease, not expected to be clinically relevant.
810
#Not administered, but an active metabolite of oxcarbazepine.
811
** Slight increase not expected to be clinically relevant.
812
↔ = No significant effect.
813
814
Drug/Laboratory Test Interactions: None known.
815
Carcinogenesis, Mutagenesis, Impairment of Fertility: No evidence of carcinogenicity
816
was seen in 1 mouse study or 2 rat studies following oral administration of lamotrigine for up to
817
2 years at maximum tolerated doses (30 mg/kg per day for mice and 10 to 15 mg/kg per day for
818
rats, doses that are equivalent to 90 mg/m2 and 60 to 90 mg/m2, respectively). Steady-state
819
plasma concentrations ranged from 1 to 4 mcg/mL in the mouse study and 1 to 10 mcg/mL in the
820
rat study. Plasma concentrations associated with the recommended human doses of 300 to
821
500 mg/day are generally in the range of 2 to 5 mcg/mL, but concentrations as high as
822
19 mcg/mL have been recorded.
823
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
25
Lamotrigine was not mutagenic in the presence or absence of metabolic activation when
824
tested in 2 gene mutation assays (the Ames test and the in vitro mammalian mouse lymphoma
825
assay). In 2 cytogenetic assays (the in vitro human lymphocyte assay and the in vivo rat bone
826
marrow assay), lamotrigine did not increase the incidence of structural or numerical
827
chromosomal abnormalities.
828
No evidence of impairment of fertility was detected in rats given oral doses of lamotrigine up
829
to 2.4 times the highest usual human maintenance dose of 8.33 mg/kg per day or 0.4 times the
830
human dose on a mg/m2 basis. The effect of lamotrigine on human fertility is unknown.
831
Pregnancy: Teratogenic Effects: Pregnancy Category C. No evidence of teratogenicity was
832
found in mice, rats, or rabbits when lamotrigine was orally administered to pregnant animals
833
during the period of organogenesis at doses up to 1.2, 0.5, and 1.1 times, respectively, on a
834
mg/m2 basis, the highest usual human maintenance dose (i.e., 500 mg/day). However, maternal
835
toxicity and secondary fetal toxicity producing reduced fetal weight and/or delayed ossification
836
were seen in mice and rats, but not in rabbits at these doses. Teratology studies were also
837
conducted using bolus intravenous administration of the isethionate salt of lamotrigine in rats
838
and rabbits. In rat dams administered an intravenous dose at 0.6 times the highest usual human
839
maintenance dose, the incidence of intrauterine death without signs of teratogenicity was
840
increased.
841
A behavioral teratology study was conducted in rats dosed during the period of organogenesis.
842
At day 21 postpartum, offspring of dams receiving 5 mg/kg per day or higher displayed a
843
significantly longer latent period for open field exploration and a lower frequency of rearing. In a
844
swimming maze test performed on days 39 to 44 postpartum, time to completion was increased
845
in offspring of dams receiving 25 mg/kg per day. These doses represent 0.1 and 0.5 times the
846
clinical dose on a mg/m2 basis, respectively.
847
Lamotrigine did not affect fertility, teratogenesis, or postnatal development when rats were
848
dosed prior to and during mating, and throughout gestation and lactation at doses equivalent to
849
0.4 times the highest usual human maintenance dose on a mg/m2 basis.
850
When pregnant rats were orally dosed at 0.1, 0.14, or 0.3 times the highest human
851
maintenance dose (on a mg/m2 basis) during the latter part of gestation (days 15 to 20), maternal
852
toxicity and fetal death were seen. In dams, food consumption and weight gain were reduced,
853
and the gestation period was slightly prolonged (22.6 vs. 22.0 days in the control group).
854
Stillborn pups were found in all 3 drug-treated groups with the highest number in the high-dose
855
group. Postnatal death was also seen, but only in the 2 highest doses, and occurred between day 1
856
and 20. Some of these deaths appear to be drug-related and not secondary to the maternal
857
toxicity. A no-observed-effect level (NOEL) could not be determined for this study.
858
Although LAMICTAL was not found to be teratogenic in the above studies, lamotrigine
859
decreases fetal folate concentrations in rats, an effect known to be associated with teratogenesis
860
in animals and humans. There are no adequate and well-controlled studies in pregnant women.
861
Because animal reproduction studies are not always predictive of human response, this drug
862
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
26
should be used during pregnancy only if the potential benefit justifies the potential risk to the
863
fetus.
864
Non-Teratogenic Effects: As with other antiepileptic drugs, physiological changes during
865
pregnancy may affect lamotrigine concentrations and/or therapeutic effect. There have been
866
reports of decreased lamotrigine concentrations during pregnancy and restoration of pre-partum
867
concentrations after delivery. Dosage adjustments may be necessary to maintain clinical
868
response.
869
Pregnancy Exposure Registry: To facilitate monitoring fetal outcomes of pregnant women
870
exposed to lamotrigine, physicians are encouraged to register patients, before fetal outcome
871
(e.g., ultrasound, results of amniocentesis, birth, etc.) is known, and can obtain information
872
by calling the Lamotrigine Pregnancy Registry at (800) 336-2176 (toll-free). Patients can enroll
873
themselves in the North American Antiepileptic Drug Pregnancy Registry by calling (888) 233-
874
2334 (toll-free).
875
Labor and Delivery: The effect of LAMICTAL on labor and delivery in humans is unknown.
876
Use in Nursing Mothers: Preliminary data indicate that lamotrigine passes into human milk.
877
Because the effects on the infant exposed to LAMICTAL by this route are unknown,
878
breast-feeding while taking LAMICTAL is not recommended.
879
Pediatric Use: LAMICTAL is indicated as adjunctive therapy for partial seizures, for the
880
generalized seizures of Lennox-Gastaut syndrome, and primary generalized tonic-clonic seizures
881
in patients above 2 years of age. .
882
Safety and effectiveness in patients below the age of 18 years with Bipolar Disorder has not
883
been established.
884
Geriatric Use: Clinical studies of LAMICTAL for epilepsy and in Bipolar Disorder did not
885
include sufficient numbers of subjects aged 65 and over to determine whether they respond
886
differently from younger subjects. In general, dose selection for an elderly patient should be
887
cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of
888
decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
889
ADVERSE REACTIONS
890
SERIOUS RASH REQUIRING HOSPITALIZATION AND DISCONTINUATION OF
891
LAMICTAL, INCLUDING STEVENS-JOHNSON SYNDROME AND TOXIC
892
EPIDERMAL NECROLYSIS, HAVE OCCURRED IN ASSOCIATION WITH
893
THERAPY WITH LAMICTAL. RARE DEATHS HAVE BEEN REPORTED, BUT
894
THEIR NUMBERS ARE TOO FEW TO PERMIT A PRECISE ESTIMATE OF THE
895
RATE (see BOX WARNING).
896
Epilepsy:
897
Most Common Adverse Events in All Clinical Studies: Adjunctive Therapy in
898
Adults With Epilepsy: The most commonly observed (≥5%) adverse experiences seen in
899
association with LAMICTAL during adjunctive therapy in adults and not seen at an equivalent
900
frequency among placebo-treated patients were: dizziness, ataxia, somnolence, headache,
901
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
27
diplopia, blurred vision, nausea, vomiting, and rash. Dizziness, diplopia, ataxia, blurred vision,
902
nausea, and vomiting were dose related. Dizziness, diplopia, ataxia, and blurred vision occurred
903
more commonly in patients receiving carbamazepine with LAMICTAL than in patients receiving
904
other AEDs with LAMICTAL. Clinical data suggest a higher incidence of rash, including serious
905
rash, in patients receiving concomitant valproate than in patients not receiving valproate (see
906
WARNINGS).
907
Approximately 11% of the 3,378 adult patients who received LAMICTAL as adjunctive
908
therapy in premarketing clinical trials discontinued treatment because of an adverse experience.
909
The adverse events most commonly associated with discontinuation were rash (3.0%), dizziness
910
(2.8%), and headache (2.5%).
911
In a dose response study in adults, the rate of discontinuation of LAMICTAL for dizziness,
912
ataxia, diplopia, blurred vision, nausea, and vomiting was dose related.
913
Monotherapy in Adults With Epilepsy: The most commonly observed (≥5%) adverse
914
experiences seen in association with the use of LAMICTAL during the monotherapy phase of the
915
controlled trial in adults not seen at an equivalent rate in the control group were vomiting,
916
coordination abnormality, dyspepsia, nausea, dizziness, rhinitis, anxiety, insomnia, infection,
917
pain, weight decrease, chest pain, and dysmenorrhea. The most commonly observed (≥5%)
918
adverse experiences associated with the use of LAMICTAL during the conversion to
919
monotherapy (add-on) period, not seen at an equivalent frequency among low-dose
920
valproate-treated patients, were dizziness, headache, nausea, asthenia, coordination abnormality,
921
vomiting, rash, somnolence, diplopia, ataxia, accidental injury, tremor, blurred vision, insomnia,
922
nystagmus, diarrhea, lymphadenopathy, pruritus, and sinusitis.
923
Approximately 10% of the 420 adult patients who received LAMICTAL as monotherapy in
924
premarketing clinical trials discontinued treatment because of an adverse experience. The
925
adverse events most commonly associated with discontinuation were rash (4.5%), headache
926
(3.1%), and asthenia (2.4%).
927
Adjunctive Therapy in Pediatric Patients With Epilepsy: The most commonly
928
observed (≥5%) adverse experiences seen in association with the use of LAMICTAL as
929
adjunctive treatment in pediatric patients and not seen at an equivalent rate in the control group
930
were infection, vomiting, rash, fever, somnolence, accidental injury, dizziness, diarrhea,
931
abdominal pain, nausea, ataxia, tremor, asthenia, bronchitis, flu syndrome, and diplopia.
932
In 339 patients age 2 to 16 years with partial seizures or generalized seizures of Lennox-
933
Gastaut syndrome, 4.2% of patients on LAMICTAL and 2.9% of patients on placebo
934
discontinued due to adverse experiences. The most commonly reported adverse experiences that
935
led to discontinuation were rash for patients treated with LAMICTAL and deterioration of
936
seizure control for patients treated with placebo.
937
Approximately 11.5% of the 1,081 pediatric patients who received LAMICTAL as adjunctive
938
therapy in premarketing clinical trials discontinued treatment because of an adverse experience.
939
The adverse events most commonly associated with discontinuation were rash (4.4%), reaction
940
aggravated (1.7%), and ataxia (0.6%).
941
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
28
Incidence in Controlled Clinical Studies of Epilepsy: The prescriber should be aware
942
that the figures in Tables 4, 5, 6, and 7 cannot be used to predict the frequency of adverse
943
experiences in the course of usual medical practice where patient characteristics and other factors
944
may differ from those prevailing during clinical studies. Similarly, the cited frequencies cannot
945
be directly compared with figures obtained from other clinical investigations involving different
946
treatments, uses, or investigators. An inspection of these frequencies, however, does provide the
947
prescriber with one basis to estimate the relative contribution of drug and nondrug factors to the
948
adverse event incidences in the population studied.
949
Incidence in Controlled Adjunctive Clinical Studies in Adults With Epilepsy:
950
Table 4 lists treatment-emergent signs and symptoms that occurred in at least 2% of adult
951
patients with epilepsy treated with LAMICTAL in placebo-controlled trials and were
952
numerically more common in the patients treated with LAMICTAL. In these studies, either
953
LAMICTAL or placebo was added to the patient's current AED therapy. Adverse events were
954
usually mild to moderate in intensity.
955
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
29
Table 4. Treatment-Emergent Adverse Event Incidence in Placebo-Controlled
956
Adjunctive Trials in Adult Patients With Epilepsy* (Events in at least 2% of patients
957
treated with LAMICTAL and numerically more frequent than in the placebo group.)
958
Body System/
Adverse Experience†
Percent of Patients
Receiving Adjunctive
LAMICTAL
(n = 711)
Percent of Patients
Receiving Adjunctive Placebo
(n = 419)
Body as a whole
Headache
29
19
Flu syndrome
7
6
Fever
6
4
Abdominal pain
5
4
Neck pain
2
1
Reaction aggravated
(seizure exacerbation)
2
1
Digestive
Nausea
19
10
Vomiting
9
4
Diarrhea
6
4
Dyspepsia
5
2
Constipation
4
3
Tooth disorder
3
2
Anorexia
2
1
Musculoskeletal
Arthralgia
2
0
Nervous
Dizziness
38
13
Ataxia
22
6
Somnolence
14
7
Incoordination
6
2
Insomnia
6
2
Tremor
4
1
Depression
4
3
Anxiety
4
3
Convulsion
3
1
Irritability
3
2
Speech disorder
3
0
Concentration
disturbance
2
1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
30
Respiratory
Rhinitis
14
9
Pharyngitis
10
9
Cough increased
8
6
Skin and appendages
Rash
10
5
Pruritus
3
2
Special senses
Diplopia
28
7
Blurred vision
16
5
Vision abnormality
3
1
Urogenital
Female patients only
(n = 365)
(n = 207)
Dysmenorrhea
7
6
Vaginitis
4
1
Amenorrhea
2
1
* Patients in these adjunctive studies were receiving 1 to 3 of the following concomitant
959
AEDs (carbamazepine, phenytoin, phenobarbital, or primidone) in addition to LAMICTAL
960
or placebo. Patients may have reported multiple adverse experiences during the study or at
961
discontinuation; thus, patients may be included in more than one category.
962
† Adverse experiences reported by at least 2% of patients treated with LAMICTAL are
963
included.
964
965
In a randomized, parallel study comparing placebo and 300 and 500 mg/day of LAMICTAL,
966
some of the more common drug-related adverse events were dose related (see Table 5).
967
968
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
31
Table 5. Dose-Related Adverse Events From a Randomized, Placebo-Controlled Trial
969
in Adults With Epilepsy
970
Percent of Patients Experiencing Adverse Experiences
Adverse Experience
Placebo
(n = 73)
LAMICTAL
300 mg
(n = 71)
LAMICTAL
500 mg
(n = 72)
Ataxia
10
10
28*†
Blurred vision
10
11
25*†
Diplopia
8
24*
49*†
Dizziness
27
31
54*†
Nausea
11
18
25*
Vomiting
4
11
18*
*Significantly greater than placebo group (p<0.05).
971
†Significantly greater than group receiving LAMICTAL 300 mg (p<0.05).
972
973
Other events that occurred in more than 1% of patients but equally or more frequently in the
974
placebo group included: asthenia, back pain, chest pain, flatulence, menstrual disorder, myalgia,
975
paresthesia, respiratory disorder, and urinary tract infection.
976
The overall adverse experience profile for LAMICTAL was similar between females and
977
males, and was independent of age. Because the largest non-Caucasian racial subgroup was only
978
6% of patients exposed to LAMICTAL in placebo-controlled trials, there are insufficient data to
979
support a statement regarding the distribution of adverse experience reports by race. Generally,
980
females receiving either adjunctive LAMICTAL or placebo were more likely to report adverse
981
experiences than males. The only adverse experience for which the reports on LAMICTAL were
982
greater than 10% more frequent in females than males (without a corresponding difference by
983
gender on placebo) was dizziness (difference = 16.5%). There was little difference between
984
females and males in the rates of discontinuation of LAMICTAL for individual adverse
985
experiences.
986
Incidence in a Controlled Monotherapy Trial in Adults With Partial Seizures:
987
Table 6 lists treatment-emergent signs and symptoms that occurred in at least 5% of patients with
988
epilepsy treated with monotherapy with LAMICTAL in a double-blind trial following
989
discontinuation of either concomitant carbamazepine or phenytoin not seen at an equivalent
990
frequency in the control group.
991
992
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
32
Table 6. Treatment-Emergent Adverse Event Incidence in Adults With Partial Seizures in
993
a Controlled Monotherapy Trial* (Events in at least 5% of patients treated with
994
LAMICTAL and numerically more frequent than in the valproate group.)
995
Body System/
Adverse Experience†
Percent of Patients Receiving
LAMICTAL Monotherapy‡
(n = 43)
Percent of Patients Receiving
Low-Dose Valproate§
Monotherapy
(n = 44)
Body as a whole
Pain
5
0
Infection
5
2
Chest pain
5
2
Digestive
Vomiting
9
0
Dyspepsia
7
2
Nausea
7
2
Metabolic and nutritional
Weight decrease
5
2
Nervous
Coordination
abnormality
7
0
Dizziness
7
0
Anxiety
5
0
Insomnia
5
2
Respiratory
Rhinitis
7
2
Urogenital (female
patients only)
(n = 21)
(n = 28)
Dysmenorrhea
5
0
* Patients in these studies were converted to LAMICTAL or valproate monotherapy from
996
adjunctive therapy with carbamazepine or phenytoin. Patients may have reported multiple
997
adverse experiences during the study; thus, patients may be included in more than one
998
category.
999
† Adverse experiences reported by at least 5% of patients are included.
1000
‡ Up to 500 mg/day.
1001
§ 1,000 mg/day.
1002
1003
Adverse events that occurred with a frequency of less than 5% and greater than 2% of patients
1004
receiving LAMICTAL and numerically more frequent than placebo were:
1005
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
33
Body as a Whole: Asthenia, fever.
1006
Digestive: Anorexia, dry mouth, rectal hemorrhage, peptic ulcer.
1007
Metabolic and Nutritional: Peripheral edema.
1008
Nervous System: Amnesia, ataxia, depression, hypesthesia, libido increase, decreased
1009
reflexes, increased reflexes, nystagmus, irritability, suicidal ideation.
1010
Respiratory: Epistaxis, bronchitis, dyspnea.
1011
Skin and Appendages: Contact dermatitis, dry skin, sweating.
1012
Special Senses: Vision abnormality.
1013
Incidence in Controlled Adjunctive Trials in Pediatric Patients With Epilepsy:
1014
Table 7 lists adverse events that occurred in at least 2% of 339 pediatric patients with partial
1015
seizures or generalized seizures of Lennox-Gastaut syndrome, who received LAMICTAL up to
1016
15 mg/kg per day or a maximum of 750 mg per day. Reported adverse events were classified
1017
using COSTART terminology.
1018
1019
Table 7. Treatment-Emergent Adverse Event Incidence in Placebo-Controlled Adjunctive
1020
Trials in Pediatric Patients With Epilepsy (Events in at least 2% of patients treated with
1021
LAMICTAL and numerically more frequent than in the placebo group.)
1022
Body System/
Adverse Experience
Percent of Patients
Receiving LAMICTAL
(n = 168)
Percent of Patients
Receiving Placebo
(n = 171)
Body as a whole
Infection
20
17
Fever
15
14
Accidental injury
14
12
Abdominal pain
10
5
Asthenia
8
4
Flu syndrome
7
6
Pain
5
4
Facial edema
2
1
Photosensitivity
2
0
Cardiovascular
Hemorrhage
2
1
Digestive
Vomiting
20
16
Diarrhea
11
9
Nausea
10
2
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
34
Constipation
4
2
Dyspepsia
2
1
Tooth disorder
2
1
Hemic and lymphatic
Lymphadenopathy
2
1
Metabolic and nutritional
Edema
2
0
Nervous system
Somnolence
17
15
Dizziness
14
4
Ataxia
11
3
Tremor
10
1
Emotional lability
4
2
Gait abnormality
4
2
Thinking abnormality
3
2
Convulsions
2
1
Nervousness
2
1
Vertigo
2
1
Respiratory
Pharyngitis
14
11
Bronchitis
7
5
Increased cough
7
6
Sinusitis
2
1
Bronchospasm
2
1
Skin
Rash
14
12
Eczema
2
1
Pruritus
2
1
Special senses
Diplopia
5
1
Blurred vision
4
1
Ear disorder
2
1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
35
Visual abnormality
2
0
Urogenital
Male and female patients
Urinary tract infection
3
0
Male patients only
n = 93
n = 92
Penis disorder
2
0
1023
Bipolar Disorder: The most commonly observed (≥5%) adverse experiences seen in
1024
association with the use of LAMICTAL as monotherapy (100 to 400 mg/day) in Bipolar
1025
Disorder in the 2 double-blind, placebo-controlled trials of 18 months’ duration, and numerically
1026
more frequent than in placebo-treated patients are included in Table 8. Adverse events that
1027
occurred in at least 5% of patients and were numerically more common during the dose
1028
escalation phase of LAMICTAL in these trials (when patients may have been receiving
1029
concomitant medications) compared to the monotherapy phase were: headache (25%), rash
1030
(11%), dizziness (10%), diarrhea (8%), dream abnormality (6%), and pruritus (6%).
1031
During the monotherapy phase of the double-blind, placebo-controlled trials of 18 months’
1032
duration, 13% of 227 patients who received LAMICTAL (100 to 400 mg/day), 16% of
1033
190 patients who received placebo, and 23% of 166 patients who received lithium discontinued
1034
therapy because of an adverse experience. The adverse events which most commonly led to
1035
discontinuation of LAMICTAL were rash (3%) and mania/hypomania/mixed mood adverse
1036
events (2%). Approximately 16% of 2,401 patients who received LAMICTAL (50 to
1037
500 mg/day) for Bipolar Disorder in premarketing trials discontinued therapy because of an
1038
adverse experience; most commonly due to rash (5%) and mania/hypomania/mixed mood
1039
adverse events (2%).
1040
Incidence in Controlled Clinical Studies of LAMICTAL for the Maintenance
1041
Treatment of Bipolar I Disorder: Table 8 lists treatment-emergent signs and symptoms that
1042
occurred in at least 5% of patients with Bipolar Disorder treated with LAMICTAL monotherapy
1043
(100 to 400 mg/day), following the discontinuation of other psychotropic drugs, in
1044
2 double-blind, placebo-controlled trials of 18 months’ duration and were numerically more
1045
frequent than in the placebo group.
1046
1047
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
36
Table 8. Treatment-Emergent Adverse Event Incidence in 2 Placebo-Controlled Trials
1048
in Adults With Bipolar I Disorder* (Events in at least 5% of patients treated with
1049
LAMICTAL monotherapy and numerically more frequent than in the placebo group.)
1050
Body System/
Adverse Experience†
Percent of Patients
Receiving LAMICTAL
n = 227
Percent of Patients
Receiving Placebo
n = 190
General
Back pain
8
6
Fatigue
8
5
Abdominal pain
6
3
Digestive
Nausea
14
11
Constipation
5
2
Vomiting
5
2
Nervous System
Insomnia
10
6
Somnolence
9
7
Xerostomia (dry mouth)
6
4
Respiratory
Rhinitis
7
4
Exacerbation of cough
5
3
Pharyngitis
5
4
Skin
Rash (nonserious)‡
7
5
* Patients in these studies were converted to LAMICTAL (100 to 400 mg/day) or placebo
1051
monotherapy from add-on therapy with other psychotropic medications. Patients may
1052
have reported multiple adverse experiences during the study; thus, patients may be
1053
included in more than one category.
1054
† Adverse experiences reported by at least 5% of patients are included.
1055
‡ In the overall bipolar and other mood disorders clinical trials, the rate of serious rash
1056
was 0.08% (1 of 1,233) of adult patients who received LAMICTAL as initial
1057
monotherapy and 0.13% (2 of 1,538) of adult patients who received LAMICTAL as
1058
adjunctive therapy (see WARNINGS).
1059
1060
These adverse events were usually mild to moderate in intensity.
1061
Other events that occurred in 5% or more patients but equally or more frequently in the
1062
placebo group included: dizziness, mania, headache, infection, influenza, pain, accidental injury,
1063
diarrhea, and dyspepsia.
1064
Adverse events that occurred with a frequency of less than 5% and greater than 1% of patients
1065
receiving LAMICTAL and numerically more frequent than placebo were:
1066
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
37
General: Fever, neck pain.
1067
Cardiovascular: Migraine.
1068
Digestive: Flatulence.
1069
Metabolic and Nutritional: Weight gain, edema.
1070
Musculoskeletal: Arthralgia, myalgia.
1071
Nervous System: Amnesia, depression, agitation, emotional lability, dyspraxia, abnormal
1072
thoughts, dream abnormality, hypoesthesia.
1073
Respiratory: Sinusitis.
1074
Urogenital: Urinary frequency.
1075
Adverse Events Following Abrupt Discontinuation: In the 2 maintenance trials, there
1076
was no increase in the incidence, severity or type of adverse events in Bipolar Disorder patients
1077
after abruptly terminating LAMICTAL therapy. In clinical trials in patients with Bipolar
1078
Disorder, 2 patients experienced seizures shortly after abrupt withdrawal of LAMICTAL.
1079
However, there were confounding factors that may have contributed to the occurrence of seizures
1080
in these bipolar patients (see DOSAGE AND ADMINISTRATION).
1081
Mania/Hypomania/Mixed Episodes: During the double-blind, placebo-controlled clinical
1082
trials in Bipolar I Disorder in which patients were converted to LAMICTAL monotherapy (100
1083
to 400 mg/day) from other psychotropic medications and followed for durations up to 18 months,
1084
the rate of manic or hypomanic or mixed mood episodes reported as adverse experiences was 5%
1085
for patients treated with LAMICTAL (n = 227), 4% for patients treated with lithium (n = 166),
1086
and 7% for patients treated with placebo (n = 190). In all bipolar controlled trials combined,
1087
adverse events of mania (including hypomania and mixed mood episodes) were reported in 5%
1088
of patients treated with LAMICTAL (n = 956), 3% of patients treated with lithium (n = 280), and
1089
4% of patients treated with placebo (n = 803).
1090
The overall adverse event profile for LAMICTAL was similar between females and males,
1091
between elderly and nonelderly patients, and among racial groups.
1092
Other Adverse Events Observed During All Clinical Trials For Pediatric and Adult
1093
Patients With Epilepsy or Bipolar Disorder and Other Mood Disorders: LAMICTAL
1094
has been administered to 6,694 individuals for whom complete adverse event data was captured
1095
during all clinical trials, only some of which were placebo controlled. During these trials, all
1096
adverse events were recorded by the clinical investigators using terminology of their own
1097
choosing. To provide a meaningful estimate of the proportion of individuals having adverse
1098
events, similar types of events were grouped into a smaller number of standardized categories
1099
using modified COSTART dictionary terminology. The frequencies presented represent the
1100
proportion of the 6,694 individuals exposed to LAMICTAL who experienced an event of the
1101
type cited on at least one occasion while receiving LAMICTAL. All reported events are included
1102
except those already listed in the previous tables or elsewhere in the labeling, those too general
1103
to be informative, and those not reasonably associated with the use of the drug.
1104
Events are further classified within body system categories and enumerated in order of
1105
decreasing frequency using the following definitions: frequent adverse events are defined as
1106
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
38
those occurring in at least 1/100 patients; infrequent adverse events are those occurring in 1/100
1107
to 1/1,000 patients; rare adverse events are those occurring in fewer than 1/1,000 patients.
1108
Body as a Whole: Infrequent: Allergic reaction, chills, halitosis, and malaise. Rare:
1109
Abdomen enlarged, abscess, and suicide/suicide attempt.
1110
Cardiovascular System: Infrequent: Flushing, hot flashes, hypertension, palpitations,
1111
postural hypotension, syncope, tachycardia, and vasodilation. Rare: Angina pectoris, atrial
1112
fibrillation, deep thrombophlebitis, ECG abnormality, and myocardial infarction.
1113
Dermatological: Infrequent: Acne, alopecia, hirsutism, maculopapular rash, skin
1114
discoloration, and urticaria. Rare: Angioedema, erythema, exfoliative dermatitis, fungal
1115
dermatitis, herpes zoster, leukoderma, multiforme erythema, petechial rash, pustular rash,
1116
seborrhea, Stevens-Johnson syndrome, and vesiculobullous rash.
1117
Digestive System: Infrequent: Dysphagia, eructation, gastritis, gingivitis, increased
1118
appetite, increased salivation, liver function tests abnormal, and mouth ulceration. Rare:
1119
Gastrointestinal hemorrhage, glossitis, gum hemorrhage, gum hyperplasia, hematemesis,
1120
hemorrhagic colitis, hepatitis, melena, stomach ulcer, stomatitis, thirst, and tongue edema.
1121
Endocrine System: Rare: Goiter and hypothyroidism.
1122
Hematologic and Lymphatic System: Infrequent: Ecchymosis and leukopenia. Rare:
1123
Anemia, eosinophilia, fibrin decrease, fibrinogen decrease, iron deficiency anemia, leukocytosis,
1124
lymphocytosis, macrocytic anemia, petechia, and thrombocytopenia.
1125
Metabolic and Nutritional Disorders: Infrequent: Aspartate transaminase increased.
1126
Rare: Alcohol intolerance, alkaline phosphatase increase, alanine transaminase increase,
1127
bilirubinemia, general edema, gamma glutamyl transpeptidase increase, and hyperglycemia.
1128
Musculoskeletal System: Infrequent: Arthritis, leg cramps, myasthenia, and twitching.
1129
Rare: Bursitis, joint disorder, muscle atrophy, pathological fracture, and tendinous contracture.
1130
Nervous System: Frequent: Confusion and paresthesia. Infrequent: Akathisia, apathy,
1131
aphasia, CNS depression, depersonalization, dysarthria, dyskinesia, euphoria, hallucinations,
1132
hostility, hyperkinesia, hypertonia, libido decreased, memory decrease, mind racing, movement
1133
disorder, myoclonus, panic attack, paranoid reaction, personality disorder, psychosis, sleep
1134
disorder, stupor, and suicidal ideation. Rare: Cerebellar syndrome, cerebrovascular accident,
1135
cerebral sinus thrombosis, choreoathetosis, CNS stimulation, delirium, delusions, dysphoria,
1136
dystonia, extrapyramidal syndrome, faintness, grand mal convulsions, hemiplegia, hyperalgesia,
1137
hyperesthesia, hypokinesia, hypotonia, manic depression reaction, muscle spasm, neuralgia,
1138
neurosis, paralysis, and peripheral neuritis.
1139
Respiratory System: Infrequent: Yawn. Rare: Hiccup and hyperventilation.
1140
Special Senses: Frequent: Amblyopia. Infrequent: Abnormality of accommodation,
1141
conjunctivitis, dry eyes, ear pain, photophobia, taste perversion, and tinnitus. Rare: Deafness,
1142
lacrimation disorder, oscillopsia, parosmia, ptosis, strabismus, taste loss, uveitis, and visual field
1143
defect.
1144
Urogenital System: Infrequent: Abnormal ejaculation, breast pain, hematuria, impotence,
1145
menorrhagia, polyuria, urinary incontinence, and urine abnormality. Rare: Acute kidney failure,
1146
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
39
anorgasmia, breast abscess, breast neoplasm, creatinine increase, cystitis, dysuria, epididymitis,
1147
female lactation, kidney failure, kidney pain, nocturia, urinary retention, urinary urgency, and
1148
vaginal moniliasis.
1149
Postmarketing and Other Experience: In addition to the adverse experiences reported
1150
during clinical testing of LAMICTAL, the following adverse experiences have been reported in
1151
patients receiving marketed LAMICTAL and from worldwide noncontrolled investigational use.
1152
These adverse experiences have not been listed above, and data are insufficient to support an
1153
estimate of their incidence or to establish causation.
1154
Blood and Lymphatic: Agranulocytosis, aplastic anemia, disseminated intravascular
1155
coagulation, hemolytic anemia, neutropenia, pancytopenia, red cell aplasia.
1156
Gastrointestinal: Esophagitis.
1157
Hepatobiliary Tract and Pancreas: Pancreatitis.
1158
Immunologic: Lupus-like reaction, vasculitis.
1159
Lower Respiratory: Apnea.
1160
Musculoskeletal: Rhabdomyolysis has been observed in patients experiencing
1161
hypersensitivity reactions.
1162
Neurology: Exacerbation of parkinsonian symptoms in patients with pre-existing
1163
Parkinson’s disease, tics.
1164
Non-site Specific: Hypersensitivity reaction, multiorgan failure, progressive
1165
immunosuppression.
1166
DRUG ABUSE AND DEPENDENCE
1167
The abuse and dependence potential of LAMICTAL have not been evaluated in human
1168
studies.
1169
OVERDOSAGE
1170
Human Overdose Experience: Overdoses involving quantities up to 15 g have been
1171
reported for LAMICTAL, some of which have been fatal. Overdose has resulted in ataxia,
1172
nystagmus, increased seizures, decreased level of consciousness, coma, and intraventricular
1173
conduction delay.
1174
Management of Overdose: There are no specific antidotes for LAMICTAL. Following a
1175
suspected overdose, hospitalization of the patient is advised. General supportive care is
1176
indicated, including frequent monitoring of vital signs and close observation of the patient. If
1177
indicated, emesis should be induced or gastric lavage should be performed; usual precautions
1178
should be taken to protect the airway. It should be kept in mind that lamotrigine is rapidly
1179
absorbed (see CLINICAL PHARMACOLOGY). It is uncertain whether hemodialysis is an
1180
effective means of removing lamotrigine from the blood. In 6 renal failure patients, about 20% of
1181
the amount of lamotrigine in the body was removed by hemodialysis during a 4-hour session. A
1182
Poison Control Center should be contacted for information on the management of overdosage of
1183
LAMICTAL.
1184
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
40
DOSAGE AND ADMINISTRATION
1185
Epilepsy:
1186
Adjunctive Use: LAMICTAL is indicated as adjunctive therapy for partial seizures, the
1187
generalized seizures of Lennox-Gastaut syndrome, and primary generalized tonic-clonic seizures
1188
in adult and pediatric patients (≥2 years of age).
1189
Monotherapy Use: LAMICTAL is indicated for conversion to monotherapy in adults with
1190
partial seizures who are receiving treatment with carbamazepine, phenytoin, phenobarbital,
1191
primidone, or valproate as the single AED.
1192
Safety and effectiveness of LAMICTAL have not been established. (1) as initial
1193
monotherapy, (2) for conversion to monotherapy from AEDs other than carbamazepine,
1194
phenytoin, phenobarbital, primidone, or valproate, or (3) for simultaneous conversion to
1195
monotherapy from 2 or more concomitant AEDs.
1196
1197
Bipolar Disorder: LAMICTAL is indicated for the maintenance treatment of Bipolar I
1198
Disorder to delay the time to occurrence of mood episodes (depression, mania, hypomania,
1199
mixed episodes) in patients treated for acute mood episodes with standard therapy. The
1200
effectiveness of LAMICTAL in the acute treatment of mood episodes has not been established.
1201
General Dosing Considerations for Epilepsy and Bipolar Disorder Patients: The
1202
risk of nonserious rash is increased when the recommended initial dose and/or the rate of dose
1203
escalation of LAMICTAL is exceeded. There are suggestions, yet to be proven, that the risk of
1204
severe, potentially life-threatening rash may be increased by (1) coadministration of LAMICTAL
1205
with valproate, (2) exceeding the recommended initial dose of LAMICTAL, or (3) exceeding the
1206
recommended dose escalation for LAMICTAL. However, cases have been reported in the
1207
absence of these factors (see BOX WARNING). Therefore, it is important that the dosing
1208
recommendations be followed closely.
1209
It is recommended that LAMICTAL not be restarted in patients who discontinued due to rash
1210
associated with prior treatment with LAMICTAL, unless the potential benefits clearly outweigh
1211
the risks. If the decision is made to restart a patient who has discontinued LAMICTAL, the need
1212
to restart with the initial dosing recommendations should be assessed. The greater the interval of
1213
time since the previous dose, the greater consideration should be given to restarting with the
1214
initial dosing recommendations. If a patient has discontinued LAMICTAL for a period of more
1215
than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be
1216
followed.
1217
1218
LAMICTAL Added to Drugs Known to Induce or Inhibit Glucuronidation: Drugs
1219
other than those listed in PRECAUTIONS: Drug Interactions have not been systematically
1220
evaluated in combination with LAMICTAL. Since lamotrigine is metabolized predominantly by
1221
glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may
1222
affect the apparent clearance of lamotrigine, and doses of LAMICTAL may require adjustment
1223
based on clinical response.
1224
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
41
Target Plasma Levels for Patients With Epilepsy or Bipolar Disorder: A
1225
therapeutic plasma concentration range has not been established for lamotrigine. Dosing of
1226
LAMICTAL should be based on therapeutic response.
1227
The half-life of LAMICTAL is affected by other concomitant medications (see CLINICAL
1228
PHARMACOLOGY: Pharmacokinetics and Drug Metabolism).
1229
See also DOSAGE AND ADMINISTRATION: Special Populations.
1230
Special Populations: Women and Oral Contraceptives: Starting LAMICTAL in
1231
Women Taking Oral Contraceptives: Although estrogen-containing oral contraceptives
1232
have been shown to increase the clearance of lamotrigine (see PRECAUTIONS: Drug
1233
Interactions), no adjustments to the recommended dose escalation guidelines for LAMICTAL
1234
should be necessary solely based on the use of estrogen-containing oral contraceptives.
1235
Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive
1236
therapy with LAMICTAL based on the concomitant AED (see Table 11). See below for
1237
adjustments to maintenance doses of LAMICTAL in women taking estrogen-containing oral
1238
contraceptives.
1239
Adjustments to the Maintenance Dose of LAMICTAL: (1) Taking Estrogen-
1240
Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin,
1241
phenobarbital, primidone, or rifampin, the maintenance dose of LAMICTAL will in most cases
1242
need to be increased, by as much as 2-fold over the recommended target maintenance dose, in
1243
order to maintain a consistent lamotrigine plasma level (see PRECAUTIONS: Drug
1244
Interactions). (2) Starting Estrogen-Containing Oral Contraceptives: In women taking a stable
1245
dose of LAMICTAL and not taking carbamazepine, phenytoin, phenobarbital, primidone, or
1246
rifampin, the maintenance dose will in most cases need to be increased by as much as 2-fold, in
1247
order to maintain a consistent lamotrigine plasma level. The dose increases should begin at the
1248
same time that the oral contraceptive is introduced and continue, based on clinical response, no
1249
more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the
1250
recommended rate unless lamotrigine plasma levels or clinical response support larger increases
1251
(see Table 11, column 2). Gradual transient increases in lamotrigine plasma levels may occur
1252
during the week of inactive hormonal preparation (“pill-free” week), and these increases will be
1253
greater if dose increases are made in the days before or during the week of inactive hormonal
1254
preparation. Increased lamotrigine plasma levels could result in additional adverse events, such
1255
as dizziness, ataxia, and diplopia (see PRECAUTIONS: Drug Interactions). If adverse events
1256
attributable to LAMICTAL consistently occur during the “pill-free” week, dose adjustments to
1257
the overall maintenance dose may be necessary. Dose adjustments limited to the “pill-free” week
1258
are not recommended. For women taking LAMICTAL in addition to carbamazepine, phenytoin,
1259
phenobarbital, primidone, or rifampin, no adjustment should be necessary to the dose of
1260
LAMICTAL. (3) Stopping Estrogen-Containing Oral Contraceptives: For women not taking
1261
carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, the maintenance dose of
1262
LAMICTAL will in most cases need to be decreased by as much as 50%, in order to maintain a
1263
consistent lamotrigine plasma level. The decrease in dose of LAMICTAL should not exceed
1264
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
42
25% of the total daily dose per week over a 2-week period, unless clinical response or
1265
lamotrigine plasma levels indicate otherwise (see PRECAUTIONS: Drug Interactions). For
1266
women taking LAMICTAL in addition to carbamazepine, phenytoin, phenobarbital, primidone,
1267
or rifampin, no adjustment to the dose of LAMICTAL should be necessary.
1268
Women and Other Hormonal Contraceptive Preparations or Hormone
1269
Replacement Therapy: The effect of other hormonal contraceptive preparations or hormone
1270
replacement therapy on the pharmacokinetics of lamotrigine has not been systematically
1271
evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of
1272
lamotrigine up to 2-fold, and the progestin only pills had no effect on lamotrigine plasma levels.
1273
Therefore, adjustments to the dosage of LAMICTAL in the presence of progestogens alone will
1274
likely not be needed.
1275
Patients With Hepatic Impairment: Experience in patients with hepatic impairment is
1276
limited. Based on a clinical pharmacology study in 24 patients with mild, moderate, and severe
1277
liver dysfunction (see CLINICAL PHARMACOLOGY), the following general
1278
recommendations can be made. No dosage adjustment is needed in patients with mild liver
1279
impairment. Initial, escalation, and maintenance doses should generally be reduced by
1280
approximately 25% in patients with moderate and severe liver impairment without ascites and
1281
50% in patients with severe liver impairment with ascites. Escalation and maintenance doses
1282
may be adjusted according to clinical response.
1283
Patients With Renal Functional Impairment: Initial doses of LAMICTAL should be
1284
based on patients' AED regimen (see above); reduced maintenance doses may be effective for
1285
patients with significant renal functional impairment (see CLINICAL PHARMACOLOGY).
1286
Few patients with severe renal impairment have been evaluated during chronic treatment with
1287
LAMICTAL. Because there is inadequate experience in this population, LAMICTAL should be
1288
used with caution in these patients.
1289
Epilepsy:
1290
Adjunctive Therapy With LAMICTAL for Epilepsy: This section provides specific
1291
dosing recommendations for patients 2 to 12 years of age and patients greater than 12 years of
1292
age. Within each of these age-groups, specific dosing recommendations are provided depending
1293
upon concomitant AED (Table 9 for patients 2 to 12 years of age and Table 11 for patients
1294
greater than 12 years of age). A weight based dosing guide for pediatric patients on concomitant
1295
valproate is provided in Table 10.
1296
Patients 2 to 12 Years of Age: Recommended dosing guidelines are summarized in Table 9.
1297
Note that some of the starting doses and dose escalations listed in Table 9 are different than
1298
those used in clinical trials; however, the maintenance doses are the same as in clinical trials.
1299
Smaller starting doses and slower dose escalations than those used in clinical trials are
1300
recommended because of the suggestions that the risk of rash may be decreased by smaller
1301
starting doses and slower dose escalations. Therefore, maintenance doses will take longer to
1302
reach in clinical practice than in clinical trials. It may take several weeks to months to achieve an
1303
individualized maintenance dose. Maintenance doses in patients weighing less than 30 kg,
1304
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
43
regardless of age or concomitant AED, may need to be increased as much as 50%, based on
1305
clinical response.
1306
The smallest available strength of LAMICTAL Chewable Dispersible Tablets is 2 mg,
1307
and only whole tablets should be administered. If the calculated dose cannot be achieved
1308
using whole tablets, the dose should be rounded down to the nearest whole tablet (see
1309
HOW SUPPLIED and PATIENT INFORMATION for a description of the available sizes
1310
of LAMICTAL Chewable Dispersible Tablets).
1311
1312
Table 9. Escalation Regimen for LAMICTAL in Patients 2 to 12 Years of Age With
1313
Epilepsy
1314
For Patients Taking
Valproate (see Table 10 for
weight-based dosing guide)
For Patients Taking AEDs
Other Than
Carbamazepine,
Phenytoin, Phenobarbital,
Primidone, or Valproate*
For Patients Taking
Carbamazepine,
Phenytoin,
Phenobarbital,
Primidone* and Not
Taking Valproate
Weeks 1 and 2
0.15 mg/kg/day
in 1 or 2 divided doses,
rounded down to the
nearest whole tablet (see
Table 10 for weight-based
dosing guide).
0.3 mg/kg/day
in 1 or 2 divided doses,
rounded down to the
nearest whole tablet.
0.6 mg/kg/day
in 2 divided doses,
rounded down to the
nearest whole tablet.
Weeks 3 and 4
0.3 mg/kg/day
in 1 or 2 divided doses,
rounded down to the
nearest whole tablet (see
Table 10 for weight-based
dosing guide).
0.6 mg/kg/day
in 2 divided doses,
rounded down to the
nearest whole tablet.
1.2 mg/kg/day
in 2 divided doses,
rounded down to the
nearest whole tablet.
Weeks 5
onwards to
maintenance
The dose should be
increased every 1 to 2
weeks as follows: calculate
0.3 mg/kg/day, round this
amount down to the nearest
whole tablet, and add this
amount to the previously
administered daily dose.
The dose should be
increased every 1 to 2
weeks as follows:
calculate 0.6 mg/kg/day,
round this amount down
to the nearest whole
tablet, and add this
amount to the previously
administered daily dose
The dose should be
increased every 1 to
2 weeks as follows:
calculate
1.2 mg/kg/day,
round this amount
down to the nearest
whole tablet, and
add this amount to
the previously
administered daily
dose
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
44
Usual
Maintenance
Dose
1 to 5 mg/kg/day
(maximum 200 mg/day in
1 or 2 divided doses).
1 to 3 mg/kg/day with
valproate alone
4.5 to 7.5 mg/kg/day
(maximum 300 mg/day in
2 divided doses)
5 to 15 mg/kg/day
(maximum
400 mg/day in 2
divided doses)
Maintenance
dose in
patients less
than 30 kg
May need to be increased
by as much as 50%, based
on clinical response
May need to be increased
by as much as 50%, based
on clinical response
May need to be
increased by as
much as 50%, based
on clinical response
Note: Only whole tablets should be used for dosing
1315
* Rifampin and estrogen-containing oral contraceptives have also been shown to increase the
1316
apparent clearance of lamotrigine (see PRECAUTIONS: Drug Interactions).
1317
1318
1319
Table 10. The Initial Weight-Based Dosing Guide for Patients 2 to 12 Years Taking
1320
Valproate (Weeks 1 to 4) With Epilepsy
1321
:
If the patient’s weight is
Give this daily dose, using the most appropriate
combination of LAMICTAL 2-mg and 5-mg tablets
Greater than
And less than
Weeks 1 and 2
Weeks 3 and 4
6.7 kg
14 kg
2 mg every other day
2 mg every day
14.1 kg
27 kg
2 mg every day
4 mg every day
27.1 kg
34 kg
4 mg every day
8 mg every day
34.1 kg
40 kg
5 mg every day
10 mg every day
1322
Patients Over 12 Years of Age: Recommended dosing guidelines are summarized in
1323
Table 11.
1324
1325
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
45
Table 11. Escalation Regimen for LAMICTAL in Patients Over 12 Years of Age With
1326
Epilepsy
1327
For Patients Taking
Valproate
For Patients Taking
AEDs Other Than
Carbamazepine,
Phenytoin,
Phenobarbital,
Primidone, or
Valproate*
For Patients Taking
Carbamazepine,
Phenytoin,
Phenobarbital,
Primidone* and Not
Taking Valproate
Weeks 1 and 2
25 mg every other day
25 mg every day
50 mg/day
Weeks 3 and 4
25 mg every day
50 mg/day
100 mg/day
(in 2 divided doses)
Weeks 5 onwards
to maintenance
Increase by 25 to
50 mg/day every 1 to
2 weeks
Increase by 50 mg/day
every 1 to 2 weeks
Increase by
100 mg/day every 1 to
2 weeks.
Usual Maintenance
Dose
100 to 400 mg/day
(1 or 2 divided doses)
100 to 200 mg/day with
valproate alone
225 to 375 mg/day
(in 2 divided doses).
300 to 500 mg/day
(in 2 divided doses).
* Rifampin and estrogen-containing oral contraceptives have also been shown to increase the
1328
apparent clearance of lamotrigine (see PRECAUTIONS: Drug Interactions).
1329
1330
1331
Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin,
1332
Phenobarbital, Primidone, or Valproate as the Single AED to Monotherapy With
1333
LAMICTAL in Patients ≥16 Years of Age With Epilepsy: The goal of the transition
1334
regimen is to effect the conversion to monotherapy with LAMICTAL under conditions that
1335
ensure adequate seizure control while mitigating the risk of serious rash associated with the rapid
1336
titration of LAMICTAL.
1337
The recommended maintenance dose of LAMICTAL as monotherapy is 500 mg/day given in
1338
2 divided doses.
1339
To avoid an increased risk of rash, the recommended initial dose and subsequent dose
1340
escalations of LAMICTAL should not be exceeded (see BOX WARNING).
1341
Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin,
1342
Phenobarbital, or Primidone to Monotherapy With LAMICTAL: After achieving a dose
1343
of 500 mg/day of LAMICTAL according to Table 11, the concomitant AED should be
1344
withdrawn by 20% decrements each week over a 4-week period. The regimen for the withdrawal
1345
of the concomitant AED is based on experience gained in the controlled monotherapy clinical
1346
trial.
1347
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
46
Conversion from Adjunctive Therapy With Valproate to Monotherapy With
1348
LAMICTAL: The conversion regimen involves 4 steps (see Table 12).
1349
1350
Table 12. Conversion From Adjunctive Therapy With Valproate to Monotherapy With
1351
LAMICTAL in Patients ≥16 Years of Age With Epilepsy
1352
LAMICTAL
Valproate
Step 1
Achieve a dose of 200 mg/day
according to guidelines in Table 11
(if not already on 200 mg/day).
Maintain previous stable dose.
Step 2
Maintain at 200 mg/day.
Decrease to 500 mg/day by decrements no
greater than 500 mg/day per week and then
maintain the dose of 500 mg/day for 1 week.
Step 3
Increase to 300 mg/day and maintain
for 1 week.
Simultaneously decrease to 250 mg/day and
maintain for 1 week.
Step 4
Increase by 100 mg/day every week
to achieve maintenance dose of
500 mg/day.
Discontinue.
1353
Conversion from Adjunctive Therapy With Antiepileptic Drugs Other Than
1354
Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to
1355
Monotherapy With LAMICTAL: No specific dosing guidelines can be provided for
1356
conversion to monotherapy with LAMICTAL with AEDs other than carbamazepine,
1357
phenobarbital, phenytoin, primidone, or valproate.
1358
Usual Maintenance Dose for Epilepsy: The usual maintenance doses identified in
1359
Tables 9-11 are derived from dosing regimens employed in the placebo-controlled adjunctive
1360
studies in which the efficacy of LAMICTAL was established. In patients receiving multidrug
1361
regimens employing carbamazepine, phenytoin, phenobarbital, or primidone without valproate,
1362
maintenance doses of adjunctive LAMICTAL as high as 700 mg/day have been used. In patients
1363
receiving valproate alone, maintenance doses of adjunctive LAMICTAL as high as 200 mg/day
1364
have been used. The advantage of using doses above those recommended in Tables 9-12 has not
1365
been established in controlled trials.
1366
Discontinuation Strategy for Patients With Epilepsy: For patients receiving
1367
LAMICTAL in combination with other AEDs, a reevaluation of all AEDs in the regimen should
1368
be considered if a change in seizure control or an appearance or worsening of adverse
1369
experiences is observed.
1370
If a decision is made to discontinue therapy with LAMICTAL, a step-wise reduction of dose
1371
over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns
1372
require a more rapid withdrawal (see PRECAUTIONS).
1373
Discontinuing carbamazepine, phenytoin, phenobarbital, or primidone should prolong the
1374
half-life of lamotrigine; discontinuing valproate should shorten the half-life of lamotrigine.
1375
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
47
.
1376
Bipolar Disorder: The goal of maintenance treatment with LAMICTAL is to delay the time to
1377
occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated
1378
for acute mood episodes with standard therapy. The target dose of LAMICTAL is 200 mg/day
1379
(100 mg/day in patients taking valproate,which decreases the apparent clearance of lamotrigine,
1380
and 400 mg/day in patients not taking valproate and taking either Carbamazepine, phenytoin,
1381
phenobarbital, primidone, or rifampin, which increase the apparent clearance of lamotrigine). In
1382
the clinical trials, doses up to 400 mg/day as monotherapy were evaluated, however, no
1383
additional benefit was seen at 400 mg/day compared to 200 mg/day (see CLINICAL STUDIES:
1384
Bipolar Disorder). Accordingly, doses above 200 mg/day are not recommended. Treatment with
1385
LAMICTAL is introduced, based on concurrent medications, according to the regimen outlined
1386
in Table 13. If other psychotropic medications are withdrawn following stabilization, the dose of
1387
LAMICTAL should be adjusted. For patients discontinuing valproate, the dose of LAMICTAL
1388
should be doubled over a 2-week period in equal weekly increments (see Table 14). For patients
1389
discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, the dose of
1390
LAMICTAL should remain constant for the first week and then should be decreased by half over
1391
a 2-week period in equal weekly decrements (see Table 14). The dose of LAMICTAL may then
1392
be further adjusted to the target dose (200 mg) as clinically indicated.
1393
Dosage adjustments will be necessary in most patients who start or stop estrogen-containing
1394
oral contraceptives while taking LAMICTAL (see DOSAGE AND ADMINISTRATION:
1395
Special Populations: Women and Oral Contraceptives: Adjustments to the Maintenance Dose of
1396
LAMICTAL).
1397
If other drugs are subsequently introduced, the dose of LAMICTAL may need to be adjusted.
1398
In particular, the introduction of valproate requires reduction in the dose of LAMICTAL (see
1399
CLINICAL PHARMACOLOGY: Drug Interactions).
1400
To avoid an increased risk of rash, the recommended initial dose and subsequent dose
1401
escalations of LAMICTAL should not be exceeded (see BOX WARNING).
1402
1403
Table 13. Escalation Regimen for LAMICTAL for Patients With Bipolar Disorder*
1404
For Patients Not Taking
Carbamazepine (or
Other Enzyme-Inducing
Drugs†) or Valproate‡
For Patients
Taking
Valproate‡
For Patients Taking
Carbamazepine (or Other
Enzyme-Inducing Drugs)
and Not Taking Valproate‡
Weeks 1 and 2
25 mg daily
25 mg every
other day
50 mg daily
Weeks 3 and 4
50 mg daily
25 mg daily
100 mg daily, in divided
doses
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
48
Week 5
100 mg daily
50 mg daily
200 mg daily, in divided
doses
Week 6
200 mg daily
100 mg daily
300 mg daily, in divided
doses
Week 7
200 mg daily
100 mg daily
up to 400 mg daily, in
divided doses
*See CLINICAL PHARMACOLOGY: Drug Interactions and PRECAUTIONS: Drug
1405
Interactions for a description of known drug interactions.
1406
†Carbamazepine, phenytoin, phenobarbital, primidone, rifampin, have been shown to increase
1407
the apparent clearance of lamotrigine.
1408
‡Valproate has been shown to decrease the apparent clearance of lamotrigine.
1409
1410
Table 14. Adjustments to LAMICTAL Dosing for Patients With Bipolar Disorder
1411
Following Discontinuation of Psychotropic Medications*
1412
After Discontinuation
of Valproate‡
After Discontinuation of
Carbamazepine or Other
Enzyme-Inducing Drugs†
Discontinuation of
Psychotropic Drugs
(excluding Valproate‡,
Carbamazepine, or Other
Enzyme-Inducing
Drugs†)
Current LAMICTAL
dose (mg/day)
100
Current LAMICTAL dose
(mg/day)
400
Week 1 Maintain current
LAMICTAL dose
150
400
Week 2
Maintain current
LAMICTAL dose
200
300
Week 3
onward
Maintain current
LAMICTAL dose
200
200
*See CLINICAL PHARMACOLOGY: Drug Interactions and PRECAUTIONS: Drug
1413
Interactions for a description of known drug interactions.
1414
†Carbamazepine, phenytoin, phenobarbital, primidone, rifampin, have been shown to increase
1415
the apparent clearance of lamotrigine.
1416
‡Valproate has been shown to decrease the apparent clearance of lamotrigine.
1417
1418
There is no body of evidence available to answer the question of how long the patient should
1419
remain on LAMICTAL therapy. Systematic evaluation of the efficacy of LAMICTAL in patients
1420
with either depression or mania who responded to standard therapy during an acute 8 to 16 week
1421
treatment phase and were then randomized to LAMICTAL or placebo for up to 76 weeks of
1422
observation for affective relapse demonstrated a benefit of such maintenance treatment (see
1423
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
49
CLINICAL STUDIES: Bipolar Disorder). Nevertheless, patients should be periodically
1424
reassessed to determine the need for maintenance treatment.
1425
Discontinuation Strategy in Bipolar Disorder: As with other AEDs, LAMICTAL
1426
should not be abruptly discontinued. In the controlled clinical trials, there was no increase in the
1427
incidence, type, or severity of adverse experiences following abrupt termination of LAMICTAL.
1428
In clinical trials in patients with bipolar disorder, 2 patients experienced seizures shortly after
1429
abrupt withdrawal of LAMICTAL. However, there were confounding factors that may have
1430
contributed to the occurrence of seizures in these bipolar patients. Discontinuation of
1431
LAMICTAL should involve a step-wise reduction of dose over at least 2 weeks (approximately
1432
50% per week) unless safety concerns require a more rapid withdrawal.
1433
1434
Administration of LAMICTAL Chewable Dispersible Tablets: LAMICTAL Chewable
1435
Dispersible Tablets may be swallowed whole, chewed, or dispersed in water or diluted fruit
1436
juice. If the tablets are chewed, consume a small amount of water or diluted fruit juice to aid in
1437
swallowing.
1438
To disperse LAMICTAL Chewable Dispersible Tablets, add the tablets to a small amount of
1439
liquid (1 teaspoon, or enough to cover the medication). Approximately 1 minute later, when the
1440
tablets are completely dispersed, swirl the solution and consume the entire quantity immediately.
1441
No attempt should be made to administer partial quantities of the dispersed tablets.
1442
HOW SUPPLIED
1443
LAMICTAL Tablets, 25-mg
1444
White, scored, shield-shaped tablets debossed with "LAMICTAL" and "25", bottles of 100
1445
(NDC 0173-0633-02).
1446
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled
1447
Room Temperature] in a dry place.
1448
LAMICTAL Tablets, 100-mg
1449
Peach, scored, shield-shaped tablets debossed with "LAMICTAL" and "100", bottles of 100
1450
(NDC 0173-0642-55).
1451
LAMICTAL Tablets, 150-mg
1452
Cream, scored, shield-shaped tablets debossed with "LAMICTAL" and "150", bottles of 60
1453
(NDC 0173-0643-60).
1454
LAMICTAL Tablets, 200-mg
1455
Blue, scored, shield-shaped tablets debossed with "LAMICTAL" and "200", bottles of 60
1456
(NDC 0173-0644-60).
1457
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled
1458
Room Temperature] in a dry place and protect from light.
1459
1460
LAMICTAL Chewable Dispersible Tablets, 2-mg
1461
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
50
White to off-white, round tablets debossed with “LTG” over “2”, bottles of 30 (NDC 0173-
1462
0699-00). ORDER DIRECTLY FROM GlaxoSmithKline 1-800-334-4153.
1463
LAMICTAL Chewable Dispersible Tablets, 5-mg
1464
White to off-white, caplet-shaped tablets debossed with “GX CL2”, bottles of 100 (NDC
1465
0173-0526-00).
1466
LAMICTAL Chewable Dispersible Tablets, 25-mg
1467
White, super elliptical-shaped tablets debossed with “GX CL5”, bottles of 100 (NDC 0173-
1468
0527-00).
1469
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled
1470
Room Temperature] in a dry place.
1471
1472
LAMICTAL Starter Kit for Patients Taking Valproate
1473
25-mg, white, scored, shield-shaped tablets debossed with "LAMICTAL" and "25",
1474
blisterpack of 35 tablets (NDC 0173-0633-10).
1475
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled
1476
Room Temperature] in a dry place.
1477
1478
LAMICTAL Starter Kit for Patients Taking Carbamazepine, Phenytoin, Phenobarbital,
1479
Primidone, or Rifampin and Not Taking Valproate
1480
25-mg, white, scored, shield-shaped tablets debossed with "LAMICTAL" and "25" and
1481
100-mg, peach, scored, shield-shaped tablets debossed with "LAMICTAL" and “100”,
1482
blisterpack of 84, 25-mg tablets and 14, 100-mg tablets (NDC 0173-0594-01)
1483
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled
1484
Room Temperature] in a dry place and protect from light.
1485
1486
LAMICTAL Starter Kit for Patients Not Taking Carbamazepine, Phenytoin,
1487
Phenobarbital, Primidone, Rifampin, or Valproate
1488
1489
25-mg, white, scored, shield-shaped tablets debossed with "LAMICTAL" and "25" and
1490
100-mg, peach, scored, shield-shaped tablets debossed with "LAMICTAL" and “100”,
1491
blisterpack of 42, 25-mg tablets and 7, 100-mg tablets (NDC 0173-0594-02).
1492
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled
1493
Room Temperature] in a dry place and protect from light.
1494
PATIENT INFORMATION
1495
The following wording is contained in a separate leaflet provided for patients.
1496
1497
Information for the Patient
1498
1499
LAMICTAL® (lamotrigine) Tablets
1500
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
51
LAMICTAL® (lamotrigine) Chewable Dispersible Tablets
1501
1502
ALWAYS CHECK THAT YOU RECEIVE LAMICTAL
1503
Patients prescribed LAMICTAL (lah-MICK-tall) have sometimes been given the wrong
1504
medicine in error because many medicines have names similar to LAMICTAL. Taking the
1505
wrong medication can cause serious health problems. When your healthcare provider gives you a
1506
prescription for LAMICTAL
1507
• make sure you can read it clearly.
1508
• talk to your pharmacist to check that you are given the correct medicine.
1509
• check the tablets you receive against the pictures of the tablets below. The pictures show
1510
actual tablet shape and size and the wording describes the color and printing that is on each
1511
strength of LAMICTAL Tablets and Chewable Dispersible Tablets.
1512
1513
LAMICTAL (lamotrigine) Tablets
1514
1515
25 mg, white
Imprinted with
LAMICTAL 25
100 mg, peach
Imprinted with
LAMICTAL 100
150 mg, cream
Imprinted with
LAMICTAL 150
200 mg, blue
Imprinted with
LAMICTAL 200
1516
LAMICTAL (lamotrigine) Chewable Dispersible Tablets
1517
1518
2 mg, white
Imprinted with
LTG 2
5 mg, white
Imprinted with
GX CL2
25 mg, white
Imprinted with
GX CL5
1519
Please read this leaflet carefully before you take LAMICTAL and read the leaflet provided
1520
with any refill, in case any information has changed. This leaflet provides a summary of the
1521
information about your medicine. Please do not throw away this leaflet until you have finished
1522
your medicine. This leaflet does not contain all the information about LAMICTAL and is not
1523
meant to take the place of talking with your doctor. If you have any questions about
1524
LAMICTAL, ask your doctor or pharmacist.
1525
1526
Information About Your Medicine:
1527
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
52
The name of your medicine is LAMICTAL (lamotrigine). The decision to use LAMICTAL is
1528
one that you and your doctor should make together. When taking lamotrigine, it is important to
1529
follow your doctor's instructions.
1530
1531
1. The Purpose of Your Medicine:
1532
For Patients With Epilepsy: LAMICTAL is intended to be used either alone or in
1533
combination with other medicines to treat seizures in people aged 2 years or older.
1534
For Patients With Bipolar Disorder: LAMICTAL is used as maintenance treatment of
1535
Bipolar I Disorder to delay the time to occurrence of mood episodes in people aged 18 years or
1536
older treated for acute mood episodes with standard therapy.
1537
If you are taking LAMICTAL to help prevent extreme mood swings, you may not experience
1538
the full effect for several weeks. Occasionally, the symptoms of depression or bipolar disorder
1539
may include thoughts of harming yourself or committing suicide. Tell your doctor immediately
1540
or go to the nearest hospital if you have any distressing thoughts or experiences during this initial
1541
period or at any other time. Also contact your doctor if you experience any worsening of your
1542
condition or develop other new symptoms at any time during your treatment.
1543
Some medicines used to treat depression have been associated with suicidal thoughts and
1544
suicidal behavior in children or teenagers. LAMICTAL is not approved for treating children or
1545
teenagers with mood disorders such as bipolar disorder or depression.
1546
2. Who Should Not Take LAMICTAL:
1547
You should not take LAMICTAL if you had an allergic reaction to it in the past.
1548
3. Side Effects to Watch for:
1549
• Most people who take LAMICTAL tolerate it well. Common side effects with LAMICTAL
1550
include dizziness, headache, blurred or double vision, lack of coordination, sleepiness,
1551
nausea, vomiting, insomnia, and rash. LAMICTAL may cause other side effects not listed in
1552
this leaflet. If you develop any side effects or symptoms you are concerned about or need
1553
more information, call your doctor.
1554
• Although most patients who develop rash while receiving LAMICTAL have mild to
1555
moderate symptoms, some individuals may develop a serious skin reaction that requires
1556
hospitalization. Rarely, deaths have been reported. These serious skin reactions are most
1557
likely to happen within the first 8 weeks of treatment with LAMICTAL. Serious skin
1558
reactions occur more often in children than in adults.
1559
• Rashes may be more likely to occur if you: (1) take LAMICTAL in combination with
1560
valproate [DEPAKENE® (valproic acid) or DEPAKOTE® (divalproex sodium)], (2) take a
1561
higher starting dose of LAMICTAL than your doctor prescribed, or (3) increase your dose of
1562
LAMICTAL faster than prescribed.
1563
• It is not possible to predict whether a mild rash will develop into a more serious reaction.
1564
Therefore, if you experience a skin rash, hives, fever, swollen lymph glands, painful
1565
sores in the mouth or around the eyes, or swelling of lips or tongue, tell a doctor
1566
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
53
immediately, since these symptoms may be the first signs of a serious reaction. A doctor
1567
should evaluate your condition and decide if you should continue taking LAMICTAL.
1568
4. The Use of LAMICTAL During Pregnancy and Breastfeeding:
1569
The effects of LAMICTAL during pregnancy are not known at this time. If you are pregnant
1570
or are planning to become pregnant, talk to your doctor. Some LAMICTAL passes into breast
1571
milk and the effects of this on infants are unknown. Therefore, if you are breast-feeding, you
1572
should discuss this with your doctor to determine if you should continue to take LAMICTAL.
1573
5. Use of Birth Control Pills or Other Female Hormonal Products:
1574
• Do not start or stop using birth control pills or other female hormonal products until you
1575
have consulted your doctor. Stopping or starting these products may cause side effects
1576
(such as dizziness, lack of coordination, or double vision) or decrease the effectiveness
1577
of LAMICTAL.
1578
• Tell your doctor as soon as possible if you experience side effects or changes in your menstrual
1579
pattern (e.g., break-through bleeding) while taking LAMICTAL and birth control pills or
1580
other female hormonal products.
1581
6. How to Use LAMICTAL:
1582
• It is important to take LAMICTAL exactly as instructed by your doctor. The dose of
1583
LAMICTAL must be increased slowly. It may take several weeks or months before your
1584
final dosage can be determined by your doctor, based on your response.
1585
• Do not increase your dose of LAMICTAL or take more frequent doses than those indicated
1586
by your doctor. Contact your doctor, if you stop taking LAMICTAL for any reason. Do not
1587
restart without consulting your doctor.
1588
• If you miss a dose of LAMICTAL, do not double your next dose.
1589
• Always tell your doctor and pharmacist if you are taking any other prescription or
1590
over-the-counter medicines. Tell your doctor before you start any other medicines.
1591
• Do NOT stop taking LAMICTAL or any of your other medicines unless instructed by your
1592
doctor.
1593
• Use caution before driving a car or operating complex, hazardous machinery until you know
1594
if LAMICTAL affects your ability to perform these tasks.
1595
• If you have epilepsy, tell your doctor if your seizures get worse or if you have any new types
1596
of seizures.
1597
7. How to Take LAMICTAL:
1598
LAMICTAL Tablets should be swallowed whole. Chewing the tablets may leave a bitter taste.
1599
LAMICTAL Chewable Dispersible Tablets may be swallowed whole, chewed, or mixed in
1600
water or diluted fruit juice. If the tablets are chewed, consume a small amount of water or diluted
1601
fruit juice to aid in swallowing.
1602
To disperse LAMICTAL Chewable Dispersible Tablets, add the tablets to a small amount of
1603
liquid (1 teaspoon, or enough to cover the medication) in a glass or spoon. Approximately
1604
1 minute later, when the tablets are completely dispersed, mix the solution and take the entire
1605
amount immediately.
1606
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
54
8. Storing Your Medicine:
1607
Store LAMICTAL at room temperature away from heat and light. Always keep your
1608
medicines out of the reach of children.
1609
This medicine was prescribed for your use only to treat seizures or to treat Bipolar Disorder.
1610
Do not give the drug to others.
1611
If your doctor decides to stop your treatment, do not keep any leftover medicine unless your
1612
doctor tells you to. Throw away your medicine as instructed.
1613
1614
1615
Manufactured for
1616
GlaxoSmithKline
1617
Research Triangle Park, NC 27709
1618
by DSM Pharmaceuticals, Inc.
1619
Greenville, NC 27834 or
1620
GlaxoSmithKline
1621
Research Triangle Park, NC 27709
1622
1623
DEPAKENE and DEPAKOTE are registered trademarks of Abbott Laboratories.
1624
1625
©2005, GlaxoSmithKline. All rights reserved.
1626
1627
(Date of Issue)
RL-
1628
1629
PHARMACIST--DETACH HERE AND GIVE INSTRUCTIONS TO PATIENT
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
1630
1631
Information for the Patient
1632
1633
LAMICTAL® (lamotrigine) Tablets
1634
LAMICTAL® (lamotrigine) Chewable Dispersible Tablets
1635
1636
ALWAYS CHECK THAT YOU RECEIVE LAMICTAL
1637
Patients prescribed LAMICTAL (lah-MICK-tall) have sometimes been given the wrong
1638
medicine in error because many medicines have names similar to LAMICTAL. Taking the
1639
wrong medication can cause serious health problems. When your healthcare provider gives you a
1640
prescription for LAMICTAL
1641
• make sure you can read it clearly.
1642
• talk to your pharmacist to check that you are given the correct medicine.
1643
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
55
• check the tablets you receive against the pictures of the tablets below. The pictures show
1644
actual tablet shape and size and the wording describes the color and printing that is on each
1645
strength of LAMICTAL Tablets and Chewable Dispersible Tablets.
1646
1647
LAMICTAL (lamotrigine) Tablets
1648
1649
25 mg, white
Imprinted with
LAMICTAL 25
100 mg, peach
Imprinted with
LAMICTAL 100
150 mg, cream
Imprinted with
LAMICTAL 150
200 mg, blue
Imprinted with
LAMICTAL 200
1650
LAMICTAL (lamotrigine) Chewable Dispersible Tablets
1651
1652
2 mg, white
Imprinted with
LTG 2
5 mg, white
Imprinted with
GX CL2
25 mg, white
Imprinted with
GX CL5
1653
Please read this leaflet carefully before you take LAMICTAL and read the leaflet provided
1654
with any refill, in case any information has changed. This leaflet provides a summary of the
1655
information about your medicine. Please do not throw away this leaflet until you have finished
1656
your medicine. This leaflet does not contain all the information about LAMICTAL and is not
1657
meant to take the place of talking with your doctor. If you have any questions about
1658
LAMICTAL, ask your doctor or pharmacist.
1659
1660
Information About Your Medicine:
1661
The name of your medicine is LAMICTAL (lamotrigine). The decision to use LAMICTAL is
1662
one that you and your doctor should make together. When taking lamotrigine, it is important to
1663
follow your doctor's instructions.
1664
1665
1. The Purpose of Your Medicine:
1666
For Patients With Epilepsy: LAMICTAL is intended to be used either alone or in
1667
combination with other medicines to treat seizures in people aged 2 years or older.
1668
For Patients With Bipolar Disorder: LAMICTAL is used as maintenance treatment of
1669
Bipolar I Disorder to delay the time to occurrence of mood episodes in people aged 18 years or
1670
older treated for acute mood episodes with standard therapy.
1671
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
56
If you are taking LAMICTAL to help prevent extreme mood swings, you may not experience
1672
the full effect for several weeks. Occasionally, the symptoms of depression or bipolar disorder
1673
may include thoughts of harming yourself or committing suicide. Tell your doctor immediately
1674
or go to the nearest hospital if you have any distressing thoughts or experiences during this initial
1675
period or at any other time. Also contact your doctor if you experience any worsening of your
1676
condition or develop other new symptoms at any time during your treatment.
1677
Some medicines used to treat depression have been associated with suicidal thoughts and
1678
suicidal behavior in children or teenagers. LAMICTAL is not approved for treating children or
1679
teenagers with mood disorders such as bipolar disorder or depression.
1680
2. Who Should Not Take LAMICTAL:
1681
You should not take LAMICTAL if you had an allergic reaction to it in the past.
1682
3. Side Effects to Watch for:
1683
• Most people who take LAMICTAL tolerate it well. Common side effects with
1684
LAMICTAL include dizziness, headache, blurred or double vision, lack of coordination,
1685
sleepiness, nausea, vomiting, insomnia, and rash. LAMICTAL may cause other side effects
1686
not listed in this leaflet. If you develop any side effects or symptoms you are concerned about
1687
or need more information, call your doctor.
1688
• Although most patients who develop rash while receiving LAMICTAL have mild to
1689
moderate symptoms, some individuals may develop a serious skin reaction that requires
1690
hospitalization. Rarely, deaths have been reported. These serious skin reactions are most
1691
likely to happen within the first 8 weeks of treatment with LAMICTAL. Serious skin
1692
reactions occur more often in children than in adults.
1693
• Rashes may be more likely to occur if you: (1) take LAMICTAL in combination with
1694
valproate [DEPAKENE® (valproic acid) or DEPAKOTE® (divalproex sodium)], (2) take a
1695
higher starting dose of LAMICTAL than your doctor prescribed, or (3) increase your dose of
1696
LAMICTAL faster than prescribed.
1697
• It is not possible to predict whether a mild rash will develop into a more serious reaction.
1698
Therefore, if you experience a skin rash, hives, fever, swollen lymph glands, painful
1699
sores in the mouth or around the eyes, or swelling of lips or tongue, tell a doctor
1700
immediately, since these symptoms may be the first signs of a serious reaction. A doctor
1701
should evaluate your condition and decide if you should continue taking LAMICTAL.
1702
4. The Use of LAMICTAL During Pregnancy and Breastfeeding:
1703
The effects of LAMICTAL during pregnancy are not known at this time. If you are pregnant
1704
or are planning to become pregnant, talk to your doctor. Some LAMICTAL passes into breast
1705
milk and the effects of this on infants are unknown. Therefore, if you are breastfeeding, you
1706
should discuss this with your doctor to determine if you should continue to take LAMICTAL.
1707
5. Use of Birth Control Pills or Other Female Hormonal Products:
1708
• Do not start or stop using birth control pills or other female hormonal products until you
1709
have consulted your doctor. Stopping or starting these products may cause side effects
1710
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
57
(such as dizziness, lack of coordination, or double vision) or to decrease the
1711
effectiveness of LAMICTAL.
1712
1713
1714
• Tell your doctor as soon as possible if you experience side effects changes in your menstrual
1715
pattern (e.g., break-through bleeding) while taking LAMICTAL and birth control pills or
1716
other female hormonal products.
1717
6. How to Use LAMICTAL:
1718
• It is important to take LAMICTAL exactly as instructed by your doctor. The dose of
1719
LAMICTAL must be increased slowly. It may take several weeks or months before your
1720
final dosage can be determined by your doctor, based on your response.
1721
• Do not increase your dose of LAMICTAL or take more frequent doses than those indicated
1722
by your doctor. Contact your doctor, if you stop taking LAMICTAL for any reason. Do not
1723
restart without consulting your doctor.
1724
• If you miss a dose of LAMICTAL, do not double your next dose.
1725
• Always tell your doctor and pharmacist if you are taking any other prescription or
1726
over-the-counter medicines. Tell your doctor before you start any other medicines.
1727
• Do NOT stop taking LAMICTAL or any of your other medicines unless instructed by your
1728
doctor.
1729
• Use caution before driving a car or operating complex, hazardous machinery until you know
1730
if LAMICTAL affects your ability to perform these tasks.
1731
• If you have epilepsy, tell your doctor if your seizures get worse or if you have any new types
1732
of seizures.
1733
7. How to Take LAMICTAL:
1734
LAMICTAL Tablets should be swallowed whole. Chewing the tablets may leave a bitter taste.
1735
LAMICTAL Chewable Dispersible Tablets may be swallowed whole, chewed, or mixed in
1736
water or diluted fruit juice. If the tablets are chewed, consume a small amount of water or diluted
1737
fruit juice to aid in swallowing.
1738
To disperse LAMICTAL Chewable Dispersible Tablets, add the tablets to a small amount of
1739
liquid (1 teaspoon, or enough to cover the medication) in a glass or spoon. Approximately
1740
1 minute later, when the tablets are completely dispersed, mix the solution and take the entire
1741
amount immediately.
1742
8. Storing Your Medicine:
1743
Store LAMICTAL at room temperature away from heat and light. Always keep your
1744
medicines out of the reach of children.
1745
This medicine was prescribed for your use only to treat seizures or to treat Bipolar Disorder.
1746
Do not give the drug to others.
1747
If your doctor decides to stop your treatment, do not keep any leftover medicine unless your
1748
doctor tells you to. Throw away your medicine as instructed.
1749
1750
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
58
1751
Manufactured for
1752
GlaxoSmithKline
1753
Research Triangle Park, NC 27709
1754
by DSM Pharmaceuticals, Inc.
1755
Greenville, NC 27834 or
1756
GlaxoSmithKline
1757
Research Triangle Park, NC 27709
1758
1759
DEPAKENE and DEPAKOTE are registered trademarks of Abbott Laboratories.
1760
1761
©2005, GlaxoSmithKline. All rights reserved.
1762
1763
(Date of Issue)
RL-
1764
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:47:11.348361
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/020241s10s21s25s26s27,020764s3s14s18s19s20lbl.pdf', 'application_number': 20241, 'submission_type': 'SUPPL ', 'submission_number': 21}
|
12,360
|
1
PRESCRIBING INFORMATION
1
LAMICTAL®
2
(lamotrigine)
3
Tablets
4
5
LAMICTAL®
6
(lamotrigine)
7
Chewable Dispersible Tablets
8
9
SERIOUS RASHES REQUIRING HOSPITALIZATION AND DISCONTINUATION
10
OF TREATMENT HAVE BEEN REPORTED IN ASSOCIATION WITH THE USE OF
11
LAMICTAL. THE INCIDENCE OF THESE RASHES, WHICH HAVE INCLUDED
12
STEVENS-JOHNSON SYNDROME, IS APPROXIMATELY 0.8% (8 PER 1,000) IN
13
PEDIATRIC PATIENTS (AGE <16 YEARS) RECEIVING LAMICTAL AS
14
ADJUNCTIVE THERAPY FOR EPILEPSY AND 0.3% (3 PER 1,000) IN ADULTS ON
15
ADJUNCTIVE THERAPY FOR EPILEPSY. IN CLINICAL TRIALS OF BIPOLAR AND
16
OTHER MOOD DISORDERS, THE RATE OF SERIOUS RASH WAS 0.08% (0.8 PER
17
1,000) IN ADULT PATIENTS RECEIVING LAMICTAL AS INITIAL MONOTHERAPY
18
AND 0.13% (1.3 PER 1,000) IN ADULT PATIENTS RECEIVING LAMICTAL AS
19
ADJUNCTIVE THERAPY. IN A PROSPECTIVELY FOLLOWED COHORT OF
20
1,983 PEDIATRIC PATIENTS WITH EPILEPSY TAKING ADJUNCTIVE LAMICTAL,
21
THERE WAS 1 RASH-RELATED DEATH. IN WORLDWIDE POSTMARKETING
22
EXPERIENCE, RARE CASES OF TOXIC EPIDERMAL NECROLYSIS AND/OR
23
RASH-RELATED DEATH HAVE BEEN REPORTED IN ADULT AND PEDIATRIC
24
PATIENTS, BUT THEIR NUMBERS ARE TOO FEW TO PERMIT A PRECISE
25
ESTIMATE OF THE RATE.
26
OTHER THAN AGE, THERE ARE AS YET NO FACTORS IDENTIFIED THAT ARE
27
KNOWN TO PREDICT THE RISK OF OCCURRENCE OR THE SEVERITY OF RASH
28
ASSOCIATED WITH LAMICTAL. THERE ARE SUGGESTIONS, YET TO BE
29
PROVEN, THAT THE RISK OF RASH MAY ALSO BE INCREASED BY (1)
30
COADMINISTRATION OF LAMICTAL WITH VALPROATE (INCLUDES VALPROIC
31
ACID AND DIVALPROEX SODIUM), (2) EXCEEDING THE RECOMMENDED
32
INITIAL DOSE OF LAMICTAL, OR (3) EXCEEDING THE RECOMMENDED DOSE
33
ESCALATION FOR LAMICTAL. HOWEVER, CASES HAVE BEEN REPORTED IN
34
THE ABSENCE OF THESE FACTORS.
35
NEARLY ALL CASES OF LIFE-THREATENING RASHES ASSOCIATED WITH
36
LAMICTAL HAVE OCCURRED WITHIN 2 TO 8 WEEKS OF TREATMENT
37
INITIATION. HOWEVER, ISOLATED CASES HAVE BEEN REPORTED AFTER
38
PROLONGED TREATMENT (E.G., 6 MONTHS). ACCORDINGLY, DURATION OF
39
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2
THERAPY CANNOT BE RELIED UPON AS A MEANS TO PREDICT THE
40
POTENTIAL RISK HERALDED BY THE FIRST APPEARANCE OF A RASH.
41
ALTHOUGH BENIGN RASHES ALSO OCCUR WITH LAMICTAL, IT IS NOT
42
POSSIBLE TO PREDICT RELIABLY WHICH RASHES WILL PROVE TO BE
43
SERIOUS OR LIFE THREATENING. ACCORDINGLY, LAMICTAL SHOULD
44
ORDINARILY BE DISCONTINUED AT THE FIRST SIGN OF RASH, UNLESS THE
45
RASH IS CLEARLY NOT DRUG RELATED. DISCONTINUATION OF TREATMENT
46
MAY NOT PREVENT A RASH FROM BECOMING LIFE THREATENING OR
47
PERMANENTLY DISABLING OR DISFIGURING.
48
49
DESCRIPTION
50
LAMICTAL (lamotrigine), an antiepileptic drug (AED) of the phenyltriazine class, is
51
chemically unrelated to existing antiepileptic drugs. Its chemical name is 3,5-diamino-6-(2,3-
52
dichlorophenyl)-as-triazine, its molecular formula is C9H7N5Cl2, and its molecular weight is
53
256.09. Lamotrigine is a white to pale cream-colored powder and has a pKa of 5.7. Lamotrigine
54
is very slightly soluble in water (0.17 mg/mL at 25°C) and slightly soluble in 0.1 M HCl
55
(4.1 mg/mL at 25°C). The structural formula is:
56
57
58
59
LAMICTAL Tablets are supplied for oral administration as 25-mg (white), 100-mg (peach),
60
150-mg (cream), and 200-mg (blue) tablets. Each tablet contains the labeled amount of
61
lamotrigine and the following inactive ingredients: lactose; magnesium stearate; microcrystalline
62
cellulose; povidone; sodium starch glycolate; FD&C Yellow No. 6 Lake (100-mg tablet only);
63
ferric oxide, yellow (150-mg tablet only); and FD&C Blue No. 2 Lake (200-mg tablet only).
64
LAMICTAL Chewable Dispersible Tablets are supplied for oral administration. The tablets
65
contain 2 mg (white), 5 mg (white), or 25 mg (white) of lamotrigine and the following inactive
66
ingredients: blackcurrant flavor, calcium carbonate, low-substituted hydroxypropylcellulose,
67
magnesium aluminum silicate, magnesium stearate, povidone, saccharin sodium, and sodium
68
starch glycolate.
69
CLINICAL PHARMACOLOGY
70
Mechanism of Action: The precise mechanism(s) by which lamotrigine exerts its
71
anticonvulsant action are unknown. In animal models designed to detect anticonvulsant activity,
72
lamotrigine was effective in preventing seizure spread in the maximum electroshock (MES) and
73
pentylenetetrazol (scMet) tests, and prevented seizures in the visually and electrically evoked
74
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
3
after-discharge (EEAD) tests for antiepileptic activity. LAMICTAL also displayed inhibitory
75
properties in the kindling model in rats both during kindling development and in the fully
76
kindled state. The relevance of these models to human epilepsy, however, is not known.
77
One proposed mechanism of action of LAMICTAL, the relevance of which remains to be
78
established in humans, involves an effect on sodium channels. In vitro pharmacological studies
79
suggest that lamotrigine inhibits voltage-sensitive sodium channels, thereby stabilizing neuronal
80
membranes and consequently modulating presynaptic transmitter release of excitatory amino
81
acids (e.g., glutamate and aspartate).
82
The mechanisms by which lamotrigine exerts its therapeutic action in Bipolar Disorder have
83
not been established.
84
Pharmacological Properties: Although the relevance for human use is unknown, the
85
following data characterize the performance of LAMICTAL in receptor binding assays.
86
Lamotrigine had a weak inhibitory effect on the serotonin 5-HT3 receptor (IC50 = 18 µM). It does
87
not exhibit high affinity binding (IC50>100 µM) to the following neurotransmitter receptors:
88
adenosine A1 and A2; adrenergic α1, α2, and β; dopamine D1 and D2; γ-aminobutyric acid
89
(GABA) A and B; histamine H1; kappa opioid; muscarinic acetylcholine; and serotonin 5-HT2.
90
Studies have failed to detect an effect of lamotrigine on dihydropyridine-sensitive calcium
91
channels. It had weak effects at sigma opioid receptors (IC50 = 145 µM). Lamotrigine did not
92
inhibit the uptake of norepinephrine, dopamine, or serotonin, (IC50>200 µM) when tested in rat
93
synaptosomes and/or human platelets in vitro.
94
Effect of Lamotrigine on N-Methyl d-Aspartate-Receptor Mediated Activity:
95
Lamotrigine did not inhibit N-methyl d-aspartate (NMDA)-induced depolarizations in rat cortical
96
slices or NMDA-induced cyclic GMP formation in immature rat cerebellum, nor did lamotrigine
97
displace compounds that are either competitive or noncompetitive ligands at this glutamate
98
receptor complex (CNQX, CGS, TCHP). The IC50 for lamotrigine effects on NMDA-induced
99
currents (in the presence of 3 µM of glycine) in cultured hippocampal neurons exceeded
100
100 µM.
101
Folate Metabolism: In vitro, lamotrigine was shown to be an inhibitor of dihydrofolate
102
reductase, the enzyme that catalyzes the reduction of dihydrofolate to tetrahydrofolate. Inhibition
103
of this enzyme may interfere with the biosynthesis of nucleic acids and proteins. When oral daily
104
doses of lamotrigine were given to pregnant rats during organogenesis, fetal, placental, and
105
maternal folate concentrations were reduced. Significantly reduced concentrations of folate are
106
associated with teratogenesis (see PRECAUTIONS: Pregnancy). Folate concentrations were also
107
reduced in male rats given repeated oral doses of lamotrigine. Reduced concentrations were
108
partially returned to normal when supplemented with folinic acid.
109
Accumulation in Kidneys: Lamotrigine was found to accumulate in the kidney of the
110
male rat, causing chronic progressive nephrosis, necrosis, and mineralization. These findings are
111
attributed to α-2 microglobulin, a species- and sex-specific protein that has not been detected in
112
humans or other animal species.
113
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
4
Melanin Binding: Lamotrigine binds to melanin-containing tissues, e.g., in the eye and
114
pigmented skin. It has been found in the uveal tract up to 52 weeks after a single dose in rodents.
115
Cardiovascular: In dogs, lamotrigine is extensively metabolized to a 2-N-methyl
116
metabolite. This metabolite causes dose-dependent prolongations of the PR interval, widening of
117
the QRS complex, and, at higher doses, complete AV conduction block. Similar cardiovascular
118
effects are not anticipated in humans because only trace amounts of the 2-N-methyl metabolite
119
(<0.6% of lamotrigine dose) have been found in human urine (see Drug Disposition). However,
120
it is conceivable that plasma concentrations of this metabolite could be increased in patients with
121
a reduced capacity to glucuronidate lamotrigine (e.g., in patients with liver disease).
122
Pharmacokinetics and Drug Metabolism: The pharmacokinetics of lamotrigine have been
123
studied in patients with epilepsy, healthy young and elderly volunteers, and volunteers with
124
chronic renal failure. Lamotrigine pharmacokinetic parameters for adult and pediatric patients
125
and healthy normal volunteers are summarized in Tables 1 and 2.
126
127
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5
Table 1. Mean* Pharmacokinetic Parameters in Healthy Volunteers and Adult Patients
128
With Epilepsy
129
Adult Study Population
Number of
Subjects
Tmax: Time of
Maximum
Plasma
Concentration
(h)
t½:
Elimination
Half-life
(h)
Cl/F:
Apparent Plasma
Clearance
(mL/min/kg)
Healthy volunteers taking
no other medications:
Single-dose LAMICTAL
Multiple-dose LAMICTAL
179
36
2.2
(0.25-12.0)
1.7
(0.5-4.0)
32.8
(14.0-103.0)
25.4
(11.6-61.6)
0.44
(0.12-1.10)
0.58
(0.24-1.15)
Healthy volunteers taking
valproate:
Single-dose LAMICTAL
Multiple-dose LAMICTAL
6
18
1.8
(1.0-4.0)
1.9
(0.5-3.5)
48.3
(31.5-88.6)
70.3
(41.9-113.5)
0.30
(0.14-0.42)
0.18
(0.12-0.33)
Patients with epilepsy taking
valproate only:
Single-dose LAMICTAL
4
4.8
(1.8-8.4)
58.8
(30.5-88.8)
0.28
(0.16-0.40)
Patients with epilepsy taking
carbamazepine, phenytoin,
phenobarbital, or primidone†
plus valproate:
Single-dose LAMICTAL
25
3.8
(1.0-10.0)
27.2
(11.2-51.6)
0.53
(0.27-1.04)
Patients with epilepsy taking
carbamazepine, phenytoin,
phenobarbital, or primidone†:
Single-dose LAMICTAL
Multiple-dose LAMICTAL
24
17
2.3
(0.5-5.0)
2.0
(0.75-5.93)
14.4
(6.4-30.4)
12.6
(7.5-23.1)
1.10
(0.51-2.22)
1.21
(0.66-1.82)
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
6
*The majority of parameter means determined in each study had coefficients of variation
130
between 20% and 40% for half-life and Cl/F and between 30% and 70% for Tmax. The
131
overall mean values were calculated from individual study means that were weighted based
132
on the number of volunteers/patients in each study. The numbers in parentheses below each
133
parameter mean represent the range of individual volunteer/patient values across studies.
134
† Carbamazepine, phenobarbital, phenytoin, and primidone have been shown to increase the
135
apparent clearance of lamotrigine. Estrogen-containing oral contraceptives and rifampin have
136
also been shown to increase the apparent clearance of lamotrigine (see CLINICAL
137
PHARMACOLOGY: Drug Interactions and PRECAUTIONS: Drug Interactions).
138
139
Absorption: Lamotrigine is rapidly and completely absorbed after oral administration with
140
negligible first-pass metabolism (absolute bioavailability is 98%). The bioavailability is not
141
affected by food. Peak plasma concentrations occur anywhere from 1.4 to 4.8 hours following
142
drug administration. The lamotrigine chewable/dispersible tablets were found to be equivalent,
143
whether they were administered as dispersed in water, chewed and swallowed, or swallowed as
144
whole, to the lamotrigine compressed tablets in terms of rate and extent of absorption.
145
Distribution: Estimates of the mean apparent volume of distribution (Vd/F) of lamotrigine
146
following oral administration ranged from 0.9 to 1.3 L/kg. Vd/F is independent of dose and is
147
similar following single and multiple doses in both patients with epilepsy and in healthy
148
volunteers.
149
Protein Binding: Data from in vitro studies indicate that lamotrigine is approximately 55%
150
bound to human plasma proteins at plasma lamotrigine concentrations from 1 to 10 mcg/mL
151
(10 mcg/mL is 4 to 6 times the trough plasma concentration observed in the controlled efficacy
152
trials). Because lamotrigine is not highly bound to plasma proteins, clinically significant
153
interactions with other drugs through competition for protein binding sites are unlikely. The
154
binding of lamotrigine to plasma proteins did not change in the presence of therapeutic
155
concentrations of phenytoin, phenobarbital, or valproate. Lamotrigine did not displace other
156
AEDs (carbamazepine, phenytoin, phenobarbital) from protein binding sites.
157
Drug Disposition: Lamotrigine is metabolized predominantly by glucuronic acid
158
conjugation; the major metabolite is an inactive 2-N-glucuronide conjugate. After oral
159
administration of 240 mg of 14C-lamotrigine (15 μCi) to 6 healthy volunteers, 94% was
160
recovered in the urine and 2% was recovered in the feces. The radioactivity in the urine consisted
161
of unchanged lamotrigine (10%), the 2-N-glucuronide (76%), a 5-N-glucuronide (10%), a
162
2-N-methyl metabolite (0.14%), and other unidentified minor metabolites (4%).
163
Drug Interactions: The apparent clearance of lamotrigine is affected by the
164
coadministration of certain medications. Because lamotrigine is metabolized predominantly
165
by glucuronic acid conjugation, drugs that induce or inhibit glucuronidation may affect the
166
apparent clearance of lamotrigine.
167
Carbamazepine, phenytoin, phenobarbital, and primidone have been shown to increase the
168
apparent clearance of lamotrigine (see DOSAGE AND ADMINISTRATION and
169
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
7
PRECAUTIONS: Drug Interactions). Most clinical experience is derived from patients taking
170
these AEDs.
171
Estrogen-containing oral contraceptives and rifampin have also been shown to increase the
172
apparent clearance of lamotrigine (see PRECAUTIONS: Drug Interactions).
173
Valproate decreases the apparent clearance of lamotrigine (i.e., more than doubles the
174
elimination half-life of lamotrigine), whether given with or without carbamazepine,
175
phenytoin, phenobarbital, or primidone. Accordingly, if lamotrigine is to be administered to a
176
patient receiving valproate, lamotrigine must be given at a reduced dosage, of no more than half
177
the dose used in patients not receiving valproate, even in the presence of drugs that increase the
178
apparent clearance of lamotrigine (see DOSAGE AND ADMINISTRATION and
179
PRECAUTIONS: Drug Interactions).
180
The following drugs were shown not to increase the apparent clearance of lamotrigine:
181
felbamate, gabapentin, levetiracetam, oxcarbazepine, pregabalin, and topiramate. Zonisamide
182
does not appear to change the pharmacokinetic profile of lamotrigine (see PRECAUTIONS:
183
Drug Interactions).
184
In vitro inhibition experiments indicated that the formation of the primary metabolite of
185
lamotrigine, the 2-N-glucuronide, was not significantly affected by co-incubation with clozapine,
186
fluoxetine, phenelzine, risperidone, sertraline, or trazodone, and was minimally affected by co-
187
incubation with amitriptyline, bupropion, clonazepam, haloperidol, or lorazepam. In addition,
188
bufuralol metabolism data from human liver microsomes suggested that lamotrigine does not
189
inhibit the metabolism of drugs eliminated predominantly by CYP2D6.
190
LAMICTAL has no effects on the pharmacokinetics of lithium (see PRECAUTIONS: Drug
191
Interactions).
192
The pharmacokinetics of LAMICTAL were not changed by co-administration of bupropion
193
(see PRECAUTIONS: Drug Interactions).
194
Co-administration of olanzapine did not have a clinically relevant effect on LAMICTAL
195
pharmacokinetics (see PRECAUTIONS: Drug Interactions).
196
Enzyme Induction: The effects of lamotrigine on the induction of specific families of
197
mixed-function oxidase isozymes have not been systematically evaluated.
198
Following multiple administrations (150 mg twice daily) to normal volunteers taking no other
199
medications, lamotrigine induced its own metabolism, resulting in a 25% decrease in t½ and a
200
37% increase in Cl/F at steady state compared to values obtained in the same volunteers
201
following a single dose. Evidence gathered from other sources suggests that self-induction by
202
LAMICTAL may not occur when LAMICTAL is given as adjunctive therapy in patients
203
receiving carbamazepine, phenytoin, phenobarbital, primidone, or rifampin.
204
Dose Proportionality: In healthy volunteers not receiving any other medications and given
205
single doses, the plasma concentrations of lamotrigine increased in direct proportion to the dose
206
administered over the range of 50 to 400 mg. In 2 small studies (n = 7 and 8) of patients with
207
epilepsy who were maintained on other AEDs, there also was a linear relationship between dose
208
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
8
and lamotrigine plasma concentrations at steady state following doses of 50 to 350 mg twice
209
daily.
210
Elimination: (see Table 1).
211
Special Populations: Patients With Renal Insufficiency: Twelve volunteers with
212
chronic renal failure (mean creatinine clearance = 13 mL/min; range = 6 to 23) and another
213
6 individuals undergoing hemodialysis were each given a single 100-mg dose of LAMICTAL.
214
The mean plasma half-lives determined in the study were 42.9 hours (chronic renal failure),
215
13.0 hours (during hemodialysis), and 57.4 hours (between hemodialysis) compared to
216
26.2 hours in healthy volunteers. On average, approximately 20% (range = 5.6 to 35.1) of the
217
amount of lamotrigine present in the body was eliminated by hemodialysis during a 4-hour
218
session.
219
Hepatic Disease: The pharmacokinetics of lamotrigine following a single 100-mg dose
220
of LAMICTAL were evaluated in 24 subjects with mild, moderate, and severe hepatic
221
dysfunction (Child-Pugh Classification system) and compared with 12 subjects without hepatic
222
impairment. The patients with severe hepatic impairment were without ascites (n = 2) or with
223
ascites (n = 5). The mean apparent clearance of lamotrigine in patients with mild (n = 12),
224
moderate (n = 5), severe without ascites (n = 2), and severe with ascites (n = 5) liver impairment
225
was 0.30 ± 0.09, 0.24 ± 0.1, 0.21 ± 0.04, and 0.15 ± 0.09 mL/min/kg, respectively, as compared
226
to 0.37 ± 0.1 mL/min/kg in the healthy controls. Mean half-life of lamotrigine in patients with
227
mild, moderate, severe without ascites, and severe with ascites liver impairment was 46 ± 20,
228
72 ± 44, 67 ± 11, and 100 ± 48 hours, respectively, as compared to 33 ± 7 hours in healthy
229
controls (for dosing guidelines, see DOSAGE AND ADMINISTRATION: Patient With Hepatic
230
Impairment).
231
Age: Pediatric Patients: The pharmacokinetics of LAMICTAL following a single
232
2-mg/kg dose were evaluated in 2 studies of pediatric patients (n = 29 for patients aged
233
10 months to 5.9 years and n = 26 for patients aged 5 to 11 years). Forty-three patients received
234
concomitant therapy with other AEDs and 12 patients received LAMICTAL as monotherapy.
235
Lamotrigine pharmacokinetic parameters for pediatric patients are summarized in Table 2.
236
Population pharmacokinetic analyses involving patients aged 2 to 18 years demonstrated that
237
lamotrigine clearance was influenced predominantly by total body weight and concurrent AED
238
therapy. The oral clearance of lamotrigine was higher, on a body weight basis, in pediatric
239
patients than in adults. Weight-normalized lamotrigine clearance was higher in those subjects
240
weighing less than 30 kg, compared with those weighing greater than 30 kg. Accordingly,
241
patients weighing less than 30 kg may need an increase of as much as 50% in maintenance doses,
242
based on clinical response, as compared with subjects weighing more than 30 kg being
243
administered the same AEDs (see DOSAGE AND ADMINISTRATION). These analyses also
244
revealed that, after accounting for body weight, lamotrigine clearance was not significantly
245
influenced by age. Thus, the same weight-adjusted doses should be administered to children
246
irrespective of differences in age. Concomitant AEDs which influence lamotrigine clearance in
247
adults were found to have similar effects in children.
248
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For current labeling information, please visit https://www.fda.gov/drugsatfda
9
249
Table 2. Mean Pharmacokinetic Parameters in Pediatric Patients With Epilepsy
250
Pediatric Study Population
Number
of
Subjects
Tmax
(h)
t½
(h)
Cl/F
(mL/min/kg)
Ages 10 months-5.3 years
Patients taking carbamazepine,
phenytoin, phenobarbital, or
primidone*
10
3.0
(1.0-5.9)
7.7
(5.7-11.4)
3.62
(2.44-5.28)
Patients taking antiepileptic drugs
(AEDs) with no known effect on
the apparent clearance of
lamotrigine
7
5.2
(2.9-6.1)
19.0
(12.9-27.1)
1.2
(0.75-2.42)
Patients taking valproate only
8
2.9
(1.0-6.0)
44.9
(29.5-52.5)
0.47
(0.23-0.77)
Ages 5-11 years
Patients taking carbamazepine,
phenytoin, phenobarbital, or
primidone*
7
1.6
(1.0-3.0)
7.0
(3.8-9.8)
2.54
(1.35-5.58)
Patients taking carbamazepine,
phenytoin, phenobarbital, or
primidone* plus valproate
8
3.3
(1.0-6.4)
19.1
(7.0-31.2)
0.89
(0.39-1.93)
Patients taking valproate only
†
3
4.5
(3.0-6.0)
65.8
(50.7-73.7)
0.24
(0.21-0.26)
Ages 13-18 years
Patients taking carbamazepine,
phenytoin, phenobarbital, or
primidone*
11
‡
‡
1.3
Patients taking carbamazepine,
phenytoin, phenobarbital, or
primidone*plus valproate
8
‡
‡
0.5
Patients taking valproate only
4
‡
‡
0.3
*Carbamazepine, phenobarbital, phenytoin, and primidone have been shown to increase the
251
apparent clearance of lamotrigine. Estrogen-containing oral contraceptives and rifampin have
252
also been shown to increase the apparent clearance of lamotrigine (see CLINICAL
253
PHARMACOLOGY: Drug Interactions and PRECAUTIONS: Drug Interactions).
254
†Two subjects were included in the calculation for mean Tmax.
255
‡Parameter not estimated.
256
257
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10
Elderly: The pharmacokinetics of lamotrigine following a single 150-mg dose of
258
LAMICTAL were evaluated in 12 elderly volunteers between the ages of 65 and 76 years (mean
259
creatinine clearance = 61 mL/min, range = 33 to 108 mL/min). The mean half-life of lamotrigine
260
in these subjects was 31.2 hours (range, 24.5 to 43.4 hours), and the mean clearance was
261
0.40 mL/min/kg (range, 0.26 to 0.48 mL/min/kg).
262
Gender: The clearance of lamotrigine is not affected by gender. However, during dose
263
escalation of LAMICTAL in one clinical trial in patients with epilepsy on a stable dose of
264
valproate (n = 77), mean trough lamotrigine concentrations, unadjusted for weight, were 24% to
265
45% higher (0.3 to 1.7 mcg/mL) in females than in males.
266
Race: The apparent oral clearance of lamotrigine was 25% lower in non-Caucasians than
267
Caucasians.
268
CLINICAL STUDIES
269
Epilepsy: The results of controlled clinical trials established the efficacy of LAMICTAL as
270
monotherapy in adults with partial onset seizures already receiving treatment with
271
carbamazepine, phenytoin, phenobarbital, or primidone as the single antiepileptic drug (AED), as
272
adjunctive therapy in adults and pediatric patients age 2 to 16 with partial seizures, and as
273
adjunctive therapy in the generalized seizures of Lennox-Gastaut syndrome in pediatric and adult
274
patients.
275
Monotherapy With LAMICTAL in Adults With Partial Seizures Already Receiving
276
Treatment With Carbamazepine, Phenytoin, Phenobarbital, or Primidone as the
277
Single AED: The effectiveness of monotherapy with LAMICTAL was established in a
278
multicenter, double-blind clinical trial enrolling 156 adult outpatients with partial seizures. The
279
patients experienced at least 4 simple partial, complex partial, and/or secondarily generalized
280
seizures during each of 2 consecutive 4-week periods while receiving carbamazepine or
281
phenytoin monotherapy during baseline. LAMICTAL (target dose of 500 mg/day) or valproate
282
(1,000 mg/day) was added to either carbamazepine or phenytoin monotherapy over a 4-week
283
period. Patients were then converted to monotherapy with LAMICTAL or valproate during the
284
next 4 weeks, then continued on monotherapy for an additional 12-week period.
285
Study endpoints were completion of all weeks of study treatment or meeting an escape
286
criterion. Criteria for escape relative to baseline were: (1) doubling of average monthly seizure
287
count, (2) doubling of highest consecutive 2-day seizure frequency, (3) emergence of a new
288
seizure type (defined as a seizure that did not occur during the 8-week baseline) that is more
289
severe than seizure types that occur during study treatment, or (4) clinically significant
290
prolongation of generalized-tonic-clonic (GTC) seizures. The primary efficacy variable was the
291
proportion of patients in each treatment group who met escape criteria.
292
The percentage of patients who met escape criteria was 42% (32/76) in the LAMICTAL
293
group and 69% (55/80) in the valproate group. The difference in the percentage of patients
294
meeting escape criteria was statistically significant (p = 0.0012) in favor of LAMICTAL. No
295
differences in efficacy based on age, sex, or race were detected.
296
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11
Patients in the control group were intentionally treated with a relatively low dose of valproate;
297
as such, the sole objective of this study was to demonstrate the effectiveness and safety of
298
monotherapy with LAMICTAL, and cannot be interpreted to imply the superiority of
299
LAMICTAL to an adequate dose of valproate.
300
Adjunctive Therapy With LAMICTAL in Adults With Partial Seizures: The
301
effectiveness of LAMICTAL as adjunctive therapy (added to other AEDs) was established in
302
3 multicenter, placebo-controlled, double-blind clinical trials in 355 adults with refractory partial
303
seizures. The patients had a history of at least 4 partial seizures per month in spite of receiving
304
one or more AEDs at therapeutic concentrations and, in 2 of the studies, were observed on their
305
established AED regimen during baselines that varied between 8 to 12 weeks. In the third,
306
patients were not observed in a prospective baseline. In patients continuing to have at least
307
4 seizures per month during the baseline, LAMICTAL or placebo was then added to the existing
308
therapy. In all 3 studies, change from baseline in seizure frequency was the primary measure of
309
effectiveness. The results given below are for all partial seizures in the intent-to-treat population
310
(all patients who received at least one dose of treatment) in each study, unless otherwise
311
indicated. The median seizure frequency at baseline was 3 per week while the mean at baseline
312
was 6.6 per week for all patients enrolled in efficacy studies.
313
One study (n = 216) was a double-blind, placebo-controlled, parallel trial consisting of a
314
24-week treatment period. Patients could not be on more than 2 other anticonvulsants and
315
valproate was not allowed. Patients were randomized to receive placebo, a target dose of
316
300 mg/day of LAMICTAL, or a target dose of 500 mg/day of LAMICTAL. The median
317
reductions in the frequency of all partial seizures relative to baseline were 8% in patients
318
receiving placebo, 20% in patients receiving 300 mg/day of LAMICTAL, and 36% in patients
319
receiving 500 mg/day of LAMICTAL. The seizure frequency reduction was statistically
320
significant in the 500-mg/day group compared to the placebo group, but not in the 300-mg/day
321
group.
322
A second study (n = 98) was a double-blind, placebo-controlled, randomized, crossover trial
323
consisting of two 14-week treatment periods (the last 2 weeks of which consisted of dose
324
tapering) separated by a 4-week washout period. Patients could not be on more than 2 other
325
anticonvulsants and valproate was not allowed. The target dose of LAMICTAL was 400 mg/day.
326
When the first 12 weeks of the treatment periods were analyzed, the median change in seizure
327
frequency was a 25% reduction on LAMICTAL compared to placebo (p<0.001).
328
The third study (n = 41) was a double-blind, placebo-controlled, crossover trial consisting of
329
two 12-week treatment periods separated by a 4-week washout period. Patients could not be on
330
more than 2 other anticonvulsants. Thirteen patients were on concomitant valproate; these
331
patients received 150 mg/day of LAMICTAL. The 28 other patients had a target dose of
332
300 mg/day of LAMICTAL. The median change in seizure frequency was a 26% reduction on
333
LAMICTAL compared to placebo (p<0.01).
334
No differences in efficacy based on age, sex, or race, as measured by change in seizure
335
frequency, were detected.
336
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12
Adjunctive Therapy With LAMICTAL in Pediatric Patients With Partial Seizures:
337
The effectiveness of LAMICTAL as adjunctive therapy in pediatric patients with partial seizures
338
was established in a multicenter, double-blind, placebo-controlled trial in 199 patients aged 2 to
339
16 years (n = 98 on LAMICTAL, n = 101 on placebo). Following an 8-week baseline phase,
340
patients were randomized to 18 weeks of treatment with LAMICTAL or placebo added to their
341
current AED regimen of up to 2 drugs. Patients were dosed based on body weight and valproate
342
use. Target doses were designed to approximate 5 mg/kg per day for patients taking valproate
343
(maximum dose, 250 mg/day) and 15 mg/kg per day for the patients not taking valproate
344
(maximum dose, 750 mg per day). The primary efficacy endpoint was percentage change from
345
baseline in all partial seizures. For the intent-to-treat population, the median reduction of all
346
partial seizures was 36% in patients treated with LAMICTAL and 7% on placebo, a difference
347
that was statistically significant (p<0.01).
348
Adjunctive Therapy With LAMICTAL in Pediatric and Adult Patients With
349
Lennox-Gastaut Syndrome: The effectiveness of LAMICTAL as adjunctive therapy in
350
patients with Lennox-Gastaut syndrome was established in a multicenter, double-blind,
351
placebo-controlled trial in 169 patients aged 3 to 25 years (n = 79 on LAMICTAL, n = 90 on
352
placebo). Following a 4-week single-blind, placebo phase, patients were randomized to 16 weeks
353
of treatment with LAMICTAL or placebo added to their current AED regimen of up to 3 drugs.
354
Patients were dosed on a fixed-dose regimen based on body weight and valproate use. Target
355
doses were designed to approximate 5 mg/kg per day for patients taking valproate (maximum
356
dose, 200 mg/day) and 15 mg/kg per day for patients not taking valproate (maximum dose,
357
400 mg/day). The primary efficacy endpoint was percentage change from baseline in major
358
motor seizures (atonic, tonic, major myoclonic, and tonic-clonic seizures). For the intent-to-treat
359
population, the median reduction of major motor seizures was 32% in patients treated with
360
LAMICTAL and 9% on placebo, a difference that was statistically significant (p<0.05). Drop
361
attacks were significantly reduced by LAMICTAL (34%) compared to placebo (9%), as were
362
tonic-clonic seizures (36% reduction versus 10% increase for LAMICTAL and placebo,
363
respectively).
364
Adjunctive Therapy With LAMICTAL in Pediatric and Adult Patients With
365
Primary Generalized Tonic-Clonic Seizures: The effectiveness of LAMICTAL as
366
adjunctive therapy in patients with primary generalized tonic-clonic seizures was established in a
367
multicenter, double-blind, placebo-controlled trial in 117 pediatric and adult patients ≥ 2 years
368
(n = 58 on LAMICTAL, n = 59 on placebo). Patients with at least 3 primary generalized tonic-
369
clonic seizures during an 8-week baseline phase were randomized to 19 to 24 weeks of treatment
370
with LAMICTAL or placebo added to their current AED regimen of up to 2 drugs. Patients were
371
dosed on a fixed-dose regimen, with target doses ranging from 3 mg/kg/day to 12 mg/kg/day for
372
pediatric patients and from 200 mg/day to 400 mg/day for adult patients based on concomitant
373
AED.
374
The primary efficacy endpoint was percentage change from baseline in primary generalized
375
tonic-clonic seizures. For the intent-to-treat population, the median percent reduction of primary
376
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13
generalized tonic-clonic seizures was 66% in patients treated with LAMICTAL and 34% on
377
placebo, a difference that was statistically significant (p=0.006).
378
379
Bipolar Disorder: The effectiveness of LAMICTAL in the maintenance treatment of Bipolar I
380
Disorder was established in 2 multicenter, double-blind, placebo-controlled studies in adult
381
patients who met DSM-IV criteria for Bipolar I Disorder. Study 1 enrolled patients with a current
382
or recent (within 60 days) depressive episode as defined by DSM-IV and Study 2 included
383
patients with a current or recent (within 60 days) episode of mania or hypomania as defined by
384
DSM-IV. Both studies included a cohort of patients (30% of 404 patients in Study 1 and 28% of
385
171 patients in Study 2) with rapid cycling Bipolar Disorder (4 to 6 episodes per year).
386
In both studies, patients were titrated to a target dose of 200 mg of LAMICTAL, as add-on
387
therapy or as monotherapy, with gradual withdrawal of any psychotropic medications during an
388
8- to 16-week open-label period. Overall 81% of 1,305 patients participating in the open-label
389
period were receiving 1 or more other psychotropic medications, including benzodiazepines,
390
selective serotonin reuptake inhibitors (SSRIs), atypical antipsychotics (including olanzapine),
391
valproate, or lithium, during titration of LAMICTAL. Patients with a CGI-severity score of 3 or
392
less maintained for at least 4 continuous weeks, including at least the final week on monotherapy
393
with LAMICTAL, were randomized to a placebo-controlled, double-blind treatment period for
394
up to 18 months. The primary endpoint was TIME (time to intervention for a mood episode or
395
one that was emerging, time to discontinuation for either an adverse event that was judged to be
396
related to Bipolar Disorder, or for lack of efficacy). The mood episode could be depression,
397
mania, hypomania, or a mixed episode.
398
In Study 1, patients received double-blind monotherapy with LAMICTAL, 50 mg/day
399
(n = 50), LAMICTAL 200 mg/day (n = 124), LAMICTAL 400 mg/day (n = 47), or placebo
400
(n = 121). LAMICTAL (200- and 400-mg/day treatment groups combined) was superior to
401
placebo in delaying the time to occurrence of a mood episode. Separate analyses of the 200 and
402
400 mg/day dose groups revealed no added benefit from the higher dose.
403
In Study 2, patients received double-blind monotherapy with LAMICTAL (100 to
404
400 mg/day, n = 59), or placebo (n = 70). LAMICTAL was superior to placebo in delaying time
405
to occurrence of a mood episode. The mean LAMICTAL dose was about 211 mg/day.
406
Although these studies were not designed to separately evaluate time to the occurrence of
407
depression or mania, a combined analysis for the 2 studies revealed a statistically significant
408
benefit for LAMICTAL over placebo in delaying the time to occurrence of both depression and
409
mania, although the finding was more robust for depression.
410
INDICATIONS AND USAGE
411
Epilepsy:
412
Adjunctive Use: LAMICTAL is indicated as adjunctive therapy for partial seizures, the
413
generalized seizures of Lennox-Gastaut syndrome, and primary generalized tonic-clonic seizures
414
in adults and pediatric patients (≥2 years of age).
415
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For current labeling information, please visit https://www.fda.gov/drugsatfda
14
416
Monotherapy Use: LAMICTAL is indicated for conversion to monotherapy in adults with
417
partial seizures.who are receiving treatment with carbamazepine, phenytoin, phenobarbital,
418
primidone, or valproate as the single AED.
419
Safety and effectiveness of LAMICTAL have not been established (1) as initial monotherapy,
420
(2) for conversion to monotherapy from AEDs other than carbamazepine, phenytoin,
421
phenobarbital, primidone, or valproate, or (3) for simultaneous conversion to monotherapy from
422
2 or more concomitant AEDs (see DOSAGE AND ADMINISTRATION).
423
424
Bipolar Disorder: LAMICTAL is indicated for the maintenance treatment of Bipolar I
425
Disorder to delay the time to occurrence of mood episodes (depression, mania, hypomania,
426
mixed episodes) in patients treated for acute mood episodes with standard therapy. The
427
effectiveness of LAMICTAL in the acute treatment of mood episodes has not been established.
428
The effectiveness of LAMICTAL as maintenance treatment was established in
429
2 placebo-controlled trials of 18 months’ duration in patients with Bipolar I Disorder as defined
430
by DSM-IV (see CLINICAL STUDIES, Bipolar Disorder). The physician who elects to use
431
LAMICTAL for periods extending beyond 18 months should periodically re-evaluate the
432
long-term usefulness of the drug for the individual patient.
433
CONTRAINDICATIONS
434
LAMICTAL is contraindicated in patients who have demonstrated hypersensitivity to the drug
435
or its ingredients.
436
WARNINGS
437
SEE BOX WARNING REGARDING THE RISK OF SERIOUS RASHES REQUIRING
438
HOSPITALIZATION AND DISCONTINUATION OF LAMICTAL.
439
ALTHOUGH BENIGN RASHES ALSO OCCUR WITH LAMICTAL, IT IS NOT
440
POSSIBLE TO PREDICT RELIABLY WHICH RASHES WILL PROVE TO BE
441
SERIOUS OR LIFE THREATENING. ACCORDINGLY, LAMICTAL SHOULD
442
ORDINARILY BE DISCONTINUED AT THE FIRST SIGN OF RASH, UNLESS THE
443
RASH IS CLEARLY NOT DRUG RELATED. DISCONTINUATION OF TREATMENT
444
MAY NOT PREVENT A RASH FROM BECOMING LIFE THREATENING OR
445
PERMANENTLY DISABLING OR DISFIGURING.
446
Serious Rash: Pediatric Population: The incidence of serious rash associated with
447
hospitalization and discontinuation of LAMICTAL in a prospectively followed cohort of
448
pediatric patients with epilepsy receiving adjunctive therapy was approximately 0.8% (16 of
449
1,983). When 14 of these cases were reviewed by 3 expert dermatologists, there was
450
considerable disagreement as to their proper classification. To illustrate, one dermatologist
451
considered none of the cases to be Stevens-Johnson syndrome; another assigned 7 of the 14 to
452
this diagnosis. There was 1 rash-related death in this 1,983 patient cohort. Additionally, there
453
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
15
have been rare cases of toxic epidermal necrolysis with and without permanent sequelae and/or
454
death in US and foreign postmarketing experience.
455
There is evidence that the inclusion of valproate in a multidrug regimen increases the risk of
456
serious, potentially life-threatening rash in pediatric patients. In pediatric patients who used
457
valproate concomitantly, 1.2% (6 of 482) experienced a serious rash compared to 0.6% (6 of
458
952) patients not taking valproate.
459
Adult Population: Serious rash associated with hospitalization and discontinuation of
460
LAMICTAL occurred in 0.3% (11 of 3,348) of adult patients who received LAMICTAL in
461
premarketing clinical trials of epilepsy. In the bipolar and other mood disorders clinical trials, the
462
rate of serious rash was 0.08% (1 of 1,233) of adult patients who received LAMICTAL as initial
463
monotherapy and 0.13% (2 of 1,538) of adult patients who received LAMICTAL as adjunctive
464
therapy. No fatalities occurred among these individuals. However, in worldwide postmarketing
465
experience, rare cases of rash-related death have been reported, but their numbers are too few to
466
permit a precise estimate of the rate.
467
Among the rashes leading to hospitalization were Stevens-Johnson syndrome, toxic epidermal
468
necrolysis, angioedema, and a rash associated with a variable number of the following systemic
469
manifestations: fever, lymphadenopathy, facial swelling, hematologic, and hepatologic
470
abnormalities.
471
There is evidence that the inclusion of valproate in a multidrug regimen increases the risk of
472
serious, potentially life-threatening rash in adults. Specifically, of 584 patients administered
473
LAMICTAL with valproate in epilepsy clinical trials, 6 (1%) were hospitalized in association
474
with rash; in contrast, 4 (0.16%) of 2,398 clinical trial patients and volunteers administered
475
LAMICTAL in the absence of valproate were hospitalized.
476
Other examples of serious and potentially life-threatening rash that did not lead to
477
hospitalization also occurred in premarketing development. Among these, 1 case was reported to
478
be Stevens-Johnson–like.
479
Hypersensitivity Reactions: Hypersensitivity reactions, some fatal or life threatening, have
480
also occurred. Some of these reactions have included clinical features of multiorgan
481
failure/dysfunction, including hepatic abnormalities and evidence of disseminated intravascular
482
coagulation. It is important to note that early manifestations of hypersensitivity (e.g., fever,
483
lymphadenopathy) may be present even though a rash is not evident. If such signs or symptoms
484
are present, the patient should be evaluated immediately. LAMICTAL should be discontinued if
485
an alternative etiology for the signs or symptoms cannot be established.
486
Prior to initiation of treatment with LAMICTAL, the patient should be instructed that a
487
rash or other signs or symptoms of hypersensitivity (e.g., fever, lymphadenopathy) may
488
herald a serious medical event and that the patient should report any such occurrence to a
489
physician immediately.
490
Acute Multiorgan Failure: Multiorgan failure, which in some cases has been fatal or
491
irreversible, has been observed in patients receiving LAMICTAL. Fatalities associated with
492
multiorgan failure and various degrees of hepatic failure have been reported in 2 of 3,796 adult
493
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For current labeling information, please visit https://www.fda.gov/drugsatfda
16
patients and 4 of 2,435 pediatric patients who received LAMICTAL in clinical trials. No such
494
fatalities have been reported in bipolar patients in clinical trials. Rare fatalities from multiorgan
495
failure have also been reported in compassionate plea and postmarketing use. The majority of
496
these deaths occurred in association with other serious medical events, including status
497
epilepticus and overwhelming sepsis, and hantavirus making it difficult to identify the initial
498
cause.
499
Additionally, 3 patients (a 45-year-old woman, a 3.5-year-old boy, and an 11-year-old girl)
500
developed multiorgan dysfunction and disseminated intravascular coagulation 9 to 14 days after
501
LAMICTAL was added to their AED regimens. Rash and elevated transaminases were also
502
present in all patients and rhabdomyolysis was noted in 2 patients. Both pediatric patients were
503
receiving concomitant therapy with valproate, while the adult patient was being treated with
504
carbamazepine and clonazepam. All patients subsequently recovered with supportive care after
505
treatment with LAMICTAL was discontinued.
506
Blood Dyscrasias: There have been reports of blood dyscrasias that may or may not be
507
associated with the hypersensitivity syndrome. These have included neutropenia, leukopenia,
508
anemia, thrombocytopenia, pancytopenia, and, rarely, aplastic anemia and pure red cell aplasia.
509
Withdrawal Seizures: As with other AEDs, LAMICTAL should not be abruptly discontinued.
510
In patients with epilepsy there is a possibility of increasing seizure frequency. In clinical trials in
511
patients with Bipolar Disorder, 2 patients experienced seizures shortly after abrupt withdrawal of
512
LAMICTAL. However, there were confounding factors that may have contributed to the
513
occurrence of seizures in these bipolar patients. Unless safety concerns require a more rapid
514
withdrawal, the dose of LAMICTAL should be tapered over a period of at least 2 weeks (see
515
DOSAGE AND ADMINISTRATION).
516
PRECAUTIONS
517
518
Concomitant Use With Oral Contraceptives: Some estrogen-containing oral
519
contraceptives have been shown to decrease serum concentrations of lamotrigine (see
520
PRECAUTIONS: Drug Interactions). Dosage adjustments will be necessary in most patients
521
who start or stop estrogen-containing oral contraceptives while taking LAMICTAL (see
522
DOSAGE AND ADMINISTRATION: Special Populations: Women and Oral
523
Contraceptives: Adjustments to the Maintenance Dose of LAMICTAL). During the week of
524
inactive hormone preparation (“pill-free” week) of oral contraceptive therapy, plasma levels are
525
expected to rise, as much as doubling by the end of the week. Adverse events consistent with
526
elevated levels of lamotrigine, such as dizziness, ataxia, and diplopia, could occur.
527
Dermatological Events (see BOX WARNING, WARNINGS): Serious rashes associated
528
with hospitalization and discontinuation of LAMICTAL have been reported. Rare deaths have
529
been reported, but their numbers are too few to permit a precise estimate of the rate. There are
530
suggestions, yet to be proven, that the risk of rash may also be increased by (1) coadministration
531
of LAMICTAL with valproate, (2) exceeding the recommended initial dose of LAMICTAL, or
532
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
17
(3) exceeding the recommended dose escalation for LAMICTAL. However, cases have been
533
reported in the absence of these factors.
534
In epilepsy clinical trials, approximately 10% of all patients exposed to LAMICTAL
535
developed a rash. In the Bipolar Disorder clinical trials, 14% of patients exposed to LAMICTAL
536
developed a rash. Rashes associated with LAMICTAL do not appear to have unique identifying
537
features. Typically, rash occurs in the first 2 to 8 weeks following treatment initiation. However,
538
isolated cases have been reported after prolonged treatment (e.g., 6 months). Accordingly,
539
duration of therapy cannot be relied upon as a means to predict the potential risk heralded by the
540
first appearance of a rash.
541
Although most rashes resolved even with continuation of treatment with LAMICTAL, it is not
542
possible to predict reliably which rashes will prove to be serious or life threatening.
543
ACCORDINGLY, LAMICTAL SHOULD ORDINARILY BE DISCONTINUED AT THE
544
FIRST SIGN OF RASH, UNLESS THE RASH IS CLEARLY NOT DRUG RELATED.
545
DISCONTINUATION OF TREATMENT MAY NOT PREVENT A RASH FROM
546
BECOMING LIFE THREATENING OR PERMANENTLY DISABLING OR
547
DISFIGURING.
548
It is recommended that LAMICTAL not be restarted in patients who discontinued due to rash
549
associated with prior treatment with LAMICTAL unless the potential benefits clearly outweigh
550
the risks. If the decision is made to restart a patient who has discontinued LAMICTAL, the need
551
to restart with the initial dosing recommendations should be assessed. The greater the interval of
552
time since the previous dose, the greater consideration should be given to restarting with the
553
initial dosing recommendations. If a patient has discontinued LAMICTAL for a period of more
554
than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be
555
followed. The half-life of LAMICTAL is affected by other concomitant medications (see
556
CLINICAL PHARMACOLOGY: Pharmacokinetics and Drug Metabolism, and DOSAGE AND
557
ADMINISTRATION).
558
Use in Patients With Epilepsy:
559
Sudden Unexplained Death in Epilepsy (SUDEP): During the premarketing
560
development of LAMICTAL, 20 sudden and unexplained deaths were recorded among a cohort
561
of 4,700 patients with epilepsy (5,747 patient-years of exposure).
562
Some of these could represent seizure-related deaths in which the seizure was not observed,
563
e.g., at night. This represents an incidence of 0.0035 deaths per patient-year. Although this rate
564
exceeds that expected in a healthy population matched for age and sex, it is within the range of
565
estimates for the incidence of sudden unexplained deaths in patients with epilepsy not receiving
566
LAMICTAL (ranging from 0.0005 for the general population of patients with epilepsy, to 0.004
567
for a recently studied clinical trial population similar to that in the clinical development program
568
for LAMICTAL, to 0.005 for patients with refractory epilepsy). Consequently, whether these
569
figures are reassuring or suggest concern depends on the comparability of the populations
570
reported upon to the cohort receiving LAMICTAL and the accuracy of the estimates provided.
571
Probably most reassuring is the similarity of estimated SUDEP rates in patients receiving
572
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
18
LAMICTAL and those receiving another antiepileptic drug that underwent clinical testing in a
573
similar population at about the same time. Importantly, that drug is chemically unrelated to
574
LAMICTAL. This evidence suggests, although it certainly does not prove, that the high SUDEP
575
rates reflect population rates, not a drug effect.
576
Status Epilepticus: Valid estimates of the incidence of treatment emergent status
577
epilepticus among patients treated with LAMICTAL are difficult to obtain because reporters
578
participating in clinical trials did not all employ identical rules for identifying cases. At a
579
minimum, 7 of 2,343 adult patients had episodes that could unequivocally be described as status.
580
In addition, a number of reports of variably defined episodes of seizure exacerbation (e.g.,
581
seizure clusters, seizure flurries, etc.) were made.
582
Use in Patients With Bipolar Disorder:
583
Acute Treatment of Mood Episodes: Safety and effectiveness of LAMICTAL in the
584
acute treatment of mood episodes has not been established.
585
Children and Adolescents (less than 18 years of age): Treatment with
586
antidepressants is associated with an increased risk of suicidal thinking and behavior in children
587
and adolescents with major depressive disorder and other psychiatric disorders. It is not known
588
whether LAMICTAL is associated with a similar risk in this population (see PRECAUTIONS:
589
Clinical Worsening and Suicide Risk Associated With Bipolar Disorder).
590
Safety and effectiveness of LAMICTAL in patients below the age of 18 years with mood
591
disorders have not been established.
592
Clinical Worsening and Suicide Risk Associated with Bipolar Disorder:
593
Patients with bipolar disorder may experience worsening of their depressive symptoms and/or
594
the emergence of suicidal ideation and behaviors (suicidality) whether or not they are taking
595
medications for bipolar disorder. Patients should be closely monitored for clinical worsening
596
(including development of new symptoms) and suicidality, especially at the beginning of a
597
course of treatment, or at the time of dose changes.
598
In addition, patients with a history of suicidal behavior or thoughts, those patients exhibiting a
599
significant degree of suicidal ideation prior to commencement of treatment, and young adults,
600
are at an increased risk of suicidal thoughts or suicide attempts, and should receive careful
601
monitoring during treatment.
602
Patients (and caregivers of patients) should be alerted about the need to monitor for any
603
worsening of their condition (including development of new symptoms) and /or the emergence
604
of suicidal ideation/behavior or thoughts of harming themselves and to seek medical advice
605
immediately if these symptoms present.
606
Consideration should be given to changing the therapeutic regimen, including possibly
607
discontinuing the medication, in patients who experience clinical worsening (including
608
development of new symptoms) and/or the emergence of suicidal ideation/behavior especially if
609
these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting
610
symptoms.
611
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
19
Prescriptions for LAMICTAL should be written for the smallest quantity of tablets consistent
612
with good patient management, in order to reduce the risk of overdose. Overdoses have been
613
reported for LAMICTAL, some of which have been fatal (see OVERDOSAGE).
614
Addition of LAMICTAL to a Multidrug Regimen That Includes Valproate (Dosage
615
Reduction): Because valproate reduces the clearance of lamotrigine, the dosage of lamotrigine
616
in the presence of valproate is less than half of that required in its absence (see DOSAGE AND
617
ADMINISTRATION).
618
Use in Patients With Concomitant Illness: Clinical experience with LAMICTAL in
619
patients with concomitant illness is limited. Caution is advised when using LAMICTAL in
620
patients with diseases or conditions that could affect metabolism or elimination of the drug, such
621
as renal, hepatic, or cardiac functional impairment.
622
Hepatic metabolism to the glucuronide followed by renal excretion is the principal route of
623
elimination of lamotrigine (see CLINICAL PHARMACOLOGY).
624
A study in individuals with severe chronic renal failure (mean creatinine
625
clearance = 13 mL/min) not receiving other AEDs indicated that the elimination half-life of
626
unchanged lamotrigine is prolonged relative to individuals with normal renal function. Until
627
adequate numbers of patients with severe renal impairment have been evaluated during chronic
628
treatment with LAMICTAL, it should be used with caution in these patients, generally using a
629
reduced maintenance dose for patients with significant impairment.
630
Because there is limited experience with the use of LAMICTAL in patients with impaired
631
liver function, the use in such patients may be associated with as yet unrecognized risks (see
632
CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).
633
Binding in the Eye and Other Melanin-Containing Tissues: Because lamotrigine binds
634
to melanin, it could accumulate in melanin-rich tissues over time. This raises the possibility that
635
lamotrigine may cause toxicity in these tissues after extended use. Although ophthalmological
636
testing was performed in one controlled clinical trial, the testing was inadequate to exclude
637
subtle effects or injury occurring after long-term exposure. Moreover, the capacity of available
638
tests to detect potentially adverse consequences, if any, of lamotrigine's binding to melanin is
639
unknown.
640
Accordingly, although there are no specific recommendations for periodic ophthalmological
641
monitoring, prescribers should be aware of the possibility of long-term ophthalmologic effects.
642
Information for Patients: Prior to initiation of treatment with LAMICTAL, the patient should
643
be instructed that a rash or other signs or symptoms of hypersensitivity (e.g., fever,
644
lymphadenopathy) may herald a serious medical event and that the patient should report any
645
such occurrence to a physician immediately. In addition, the patient should notify his or her
646
physician if worsening of seizure control occurs.
647
Patients should be advised that LAMICTAL may cause dizziness, somnolence, and other
648
symptoms and signs of central nervous system (CNS) depression. Accordingly, they should be
649
advised neither to drive a car nor to operate other complex machinery until they have gained
650
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
20
sufficient experience on LAMICTAL to gauge whether or not it adversely affects their mental
651
and/or motor performance.
652
Patients should be advised to notify their physicians if they become pregnant or intend to
653
become pregnant during therapy. Patients should be advised to notify their physicians if they
654
intend to breast-feed or are breast-feeding an infant.
655
Women should be advised to notify their physician if they plan to start or stop use of oral
656
contraceptives or other female hormonal preparations. Starting estrogen-containing oral
657
contraceptives may significantly decrease lamotrigine plasma levels and stopping estrogen-
658
containing oral contraceptives (including the “pill-free” week) may significantly increase
659
lamotrigine plasma levels (see PRECAUTIONS: Drug Interactions). Women should also be
660
advised to promptly notify their physician if they experience adverse events or changes in
661
menstrual pattern (e.g., break-through bleeding) while receiving LAMICTAL in combination
662
with these medications.
663
Patients should be advised to notify their physician if they stop taking LAMICTAL for any
664
reason and not to resume LAMICTAL without consulting their physician.
665
Patients should be informed of the availability of a patient information leaflet, and they should
666
be instructed to read the leaflet prior to taking LAMICTAL. See PATIENT INFORMATION at
667
the end of this labeling for the text of the leaflet provided for patients.
668
Laboratory Tests: The value of monitoring plasma concentrations of LAMICTAL has not
669
been established. Because of the possible pharmacokinetic interactions between LAMICTAL
670
and other drugs including AEDs (see Table 3), monitoring of the plasma levels of LAMICTAL
671
and concomitant drugs may be indicated, particularly during dosage adjustments. In general,
672
clinical judgment should be exercised regarding monitoring of plasma levels of LAMICTAL and
673
other drugs and whether or not dosage adjustments are necessary.
674
675
Drug Interactions:
676
677
The net effects of drug interactions with LAMICTAL are summarized in Table 3 (see also
678
DOSAGE AND ADMINISTRATION).
679
680
Oral Contraceptives: In 16 female volunteers, an oral contraceptive preparation containing
681
30 mcg ethinylestradiol and 150 mcg levonorgestrel increased the apparent clearance of
682
lamotrigine (300 mg/day) by approximately 2-fold with a mean decrease in AUC of 52% and in
683
Cmax of 39%. In this study, trough serum lamotrigine concentrations gradually increased and
684
were approximately 2-fold higher on average at the end of the week of the inactive preparation
685
compared to trough lamotrigine concentrations at the end of the active hormone cycle.
686
Gradual transient increases in lamotrigine plasma levels (approximate 2-fold increase)
687
occurred during the week of inactive hormone preparation (“pill-free” week) for women not also
688
taking a drug that increased the clearance of lamotrigine (carbamazepine, phenytoin,
689
phenobarbital, primidone, or rifampin). The increase in lamotrigine plasma levels will be greater
690
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
21
if the dose of LAMICTAL is increased in the few days before or during the “pill-free” week.
691
Increases in lamotrigine plasma levels could result in dose-dependent adverse effects (see
692
PRECAUTIONS: Concomitant Use With Oral Contraceptives).
693
In the same study, co-administration of LAMICTAL (300 mg/day) in 16 female volunteers
694
did not affect the pharmacokinetics of the ethinylestradiol component of the oral contraceptive
695
preparation. There was a mean decrease in the AUC and Cmax of the levonorgestrel component of
696
19% and 12%, respectively. Measurement of serum progesterone indicated that there was no
697
hormonal evidence of ovulation in any of the 16 volunteers, although measurement of serum
698
FSH, LH, and estradiol indicated that there was some loss of suppression of the hypothalamic-
699
pituitary-ovarian axis.
700
The effects of doses of LAMICTAL other than 300 mg/day have not been studied in clinical
701
trials.
702
The clinical significance of the observed hormonal changes on ovulatory activity is unknown.
703
However, the possibility of decreased contraceptive efficacy in some patients cannot be
704
excluded. Therefore, patients should be instructed to promptly report changes in their menstrual
705
pattern (e.g., break-through bleeding).
706
Dosage adjustments will be necessary for most women receiving estrogen-containing oral
707
contraceptive preparations (see DOSAGE AND ADMINISTRATION: Special Populations:
708
Women and Oral Contraceptives).
709
Other Hormonal Contraceptives or Hormone Replacement Therapy: The effect of
710
other hormonal contraceptive preparations or hormone replacement therapy on the
711
pharmacokinetics of lamotrigine has not been systematically evaluated, It has been reported that
712
ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the
713
progestin only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the
714
dosage of LAMICTAL in the presence of progestogens alone will likely not be needed.
715
716
Bupropion: The pharmacokinetics of a 100-mg single dose of LAMICTAL in healthy
717
volunteers (n = 12) were not changed by co-administration of bupropion sustained-release
718
formulation (150 mg twice a day) starting 11 days before LAMICTAL.
719
Carbamazepine: LAMICTAL has no appreciable effect on steady-state carbamazepine
720
plasma concentration. Limited clinical data suggest there is a higher incidence of dizziness,
721
diplopia, ataxia, and blurred vision in patients receiving carbamazepine with LAMICTAL than in
722
patients receiving other AEDs with LAMICTAL (see ADVERSE REACTIONS). The
723
mechanism of this interaction is unclear. The effect of LAMICTAL on plasma concentrations of
724
carbamazepine-epoxide is unclear. In a small subset of patients (n = 7) studied in a
725
placebo-controlled trial, LAMICTAL had no effect on carbamazepine-epoxide plasma
726
concentrations, but in a small, uncontrolled study (n = 9), carbamazepine-epoxide levels
727
increased.
728
The addition of carbamazepine decreases lamotrigine steady-state concentrations by
729
approximately 40%.
730
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
22
Felbamate: In a study of 21 healthy volunteers, coadministration of felbamate (1,200 mg
731
twice daily) with LAMICTAL (100 mg twice daily for 10 days) appeared to have no clinically
732
relevant effects on the pharmacokinetics of lamotrigine.
733
Folate Inhibitors: Lamotrigine is a weak inhibitor of dihydrofolate reductase. Prescribers
734
should be aware of this action when prescribing other medications that inhibit folate metabolism.
735
Gabapentin: Based on a retrospective analysis of plasma levels in 34 patients who received
736
LAMICTAL both with and without gabapentin, gabapentin does not appear to change the
737
apparent clearance of lamotrigine.
738
Levetiracetam: Potential drug interactions between levetiracetam and LAMICTAL were
739
assessed by evaluating serum concentrations of both agents during placebo-controlled clinical
740
trials. These data indicate that LAMICTAL does not influence the pharmacokinetics of
741
levetiracetam and that levetiracetam does not influence the pharmacokinetics of LAMICTAL.
742
Lithium: The pharmacokinetics of lithium were not altered in healthy subjects (n = 20) by
743
co-administration of LAMICTAL (100 mg/day) for 6 days.
744
Olanzapine: The AUC and Cmax of olanzapine were similar following the addition of
745
olanzapine (15 mg once daily) to LAMICTAL (200 mg once daily) in healthy male volunteers
746
(n = 16) compared to the AUC and Cmax in healthy male volunteers receiving olanzapine alone
747
(n = 16).
748
In the same study, the AUC and Cmax of lamotrigine was reduced on average by 24% and
749
20%, respectively, following the addition of olanzapine to LAMICTAL in healthy male
750
volunteers compared to those receiving LAMICTAL alone. This reduction in lamotrigine plasma
751
concentrations is not expected to be clinically relevant.
752
Oxcarbazepine: The AUC and Cmax of oxcarbazepine and its active 10-monohydroxy
753
oxcarbazepine metabolite were not significantly different following the addition of
754
oxcarbazepine (600 mg twice daily) to LAMICTAL (200 mg once daily) in healthy male
755
volunteers (n = 13) compared to healthy male volunteers receiving oxcarbazepine alone (n = 13).
756
In the same study, the AUC and Cmax of lamotrigine were similar following the addition of
757
oxcarbazepine (600 mg twice daily) to LAMICTAL in healthy male volunteers compared to
758
those receiving LAMICTAL alone. Limited clinical data suggest a higher incidence of headache,
759
dizziness, nausea, and somnolence with coadministration of LAMICTAL and oxcarbazepine
760
compared to LAMICTAL alone or oxcarbazepine alone.
761
Phenobarbital, Primidone: The addition of phenobarbital or primidone decreases
762
lamotrigine steady-state concentrations by approximately 40%.
763
Phenytoin: LAMICTAL has no appreciable effect on steady-state phenytoin plasma
764
concentrations in patients with epilepsy. The addition of phenytoin decreases lamotrigine steady-
765
state concentrations by approximately 40%.
766
Pregabalin: Steady-state trough plasma concentrations of lamotrigine were not affected by
767
concomitant pregabalin (200 mg 3 times daily) administration. There are no pharmacokinetic
768
interactions between LAMICTAL and pregabalin.
769
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
23
Rifampin: In 10 male volunteers, rifampin (600 mg/day for 5 days) significantly increased
770
the apparent clearance of a single 25 mg dose of LAMICTAL by approximately 2-fold (AUC
771
decreased by approximately 40%).
772
Topiramate: Topiramate resulted in no change in plasma concentrations of lamotrigine.
773
Administration of LAMICTAL resulted in a 15% increase in topiramate concentrations.
774
Valproate: When LAMICTAL was administered to healthy volunteers (n = 18) receiving
775
valproate, the trough steady-state valproate plasma concentrations decreased by an average of
776
25% over a 3-week period, and then stabilized. However, adding LAMICTAL to the existing
777
therapy did not cause a change in valproate plasma concentrations in either adult or pediatric
778
patients in controlled clinical trials.
779
The addition of valproate increased lamotrigine steady-state concentrations in normal
780
volunteers by slightly more than 2-fold. In one study, maximal inhibition of lamotrigine
781
clearance was reached at valproate doses between 250 mg/day and 500 mg/day and did not
782
increase as the valproate dose was further increased.
783
Zonisamide: In a study of 18 patients with epilepsy, coadministration of zonisamide (200 to
784
400 mg/day) with LAMICTAL (150 to 500 mg/day) for 35 days had no significant effect on the
785
pharmacokinetics of lamotrigine.
786
Known Inducers or Inhibitors of Glucuronidation: Drugs other than those listed above
787
have not been systematically evaluated in combination with LAMICTAL. Since lamotrigine is
788
metabolized predominately by glucuronic acid conjugation, drugs that are known to induce or
789
inhibit glucuronidation may affect the apparent clearance of lamotrigine, and doses of
790
LAMICTAL may require adjustment based on clinical response.
791
Other: Results of in vitro experiments suggest that clearance of lamotrigine is unlikely to be
792
reduced by concomitant administration of amitriptyline, clonazepam, clozapine, fluoxetine,
793
haloperidol, lorazepam, phenelzine, risperidone, sertraline, or trazodone (see CLINICAL
794
PHARMACOLOGY: Pharmacokinetics and Drug Metabolism).
Results of in vitro
795
experiments suggest that lamotrigine does not reduce the clearance of drugs eliminated
796
predominantly by CYP2D6 (see CLINICAL PHARMACOLOGY).
797
.
798
Table 3. Summary of Drug Interactions With LAMICTAL
799
Drug
Drug Plasma
Concentration With
Adjunctive
LAMICTAL*
Lamotrigine Plasma
Concentration With Adjunctive
Drugs†
Oral contraceptives (e.g.,
ethinylestradiol/levonorgestrel)‡
↔§
↓
Bupropion
Not assessed
↔
Carbamazepine (CBZ)
↔
↓
CBZ epoxide║
?
Felbamate
Not assessed
↔
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
24
Gabapentin
Not assessed
↔
Levetiracetam
↔
↔
Lithium
↔
Not assessed
Olanzapine
↔
↔¶
Oxcarbazepine
↔
↔
10-monohydroxy oxcarbazepine
metabolite#
↔
Phenobarbital/primidone
↔
↓
Phenytoin (PHT)
↔
↓
Pregabalin
↔
↔
Rifampin
Not assessed
↓
Topiramate
↔**
↔
Valproate
↓
↑
Valproate + PHT and/or CBZ
Not assessed
↔
Zonisamide
Not assessed
↔
* From adjunctive clinical trials and volunteer studies.
800
† Net effects were estimated by comparing the mean clearance values obtained in adjunctive
801
clinical trials and volunteers studies.
802
‡ The effect of other hormonal contraceptive preparations or hormone replacement therapy on the
803
pharmacokinetics of lamotrigine has not been systematically evaluated in clinical trials and
804
the effect may not be similar to that seen with the ethinylestradiol/levonorgestrel
805
combinations.
806
§Modest decrease in levonorgestrel (see PRECAUTIONS: Drug Interactions: Effect of
807
LAMICTAL on Oral Contraceptives).
808
║Not administered, but an active metabolite of carbamazepine.
809
¶Slight decrease, not expected to be clinically relevant.
810
#Not administered, but an active metabolite of oxcarbazepine.
811
** Slight increase not expected to be clinically relevant.
812
↔ = No significant effect.
813
814
Drug/Laboratory Test Interactions: None known.
815
Carcinogenesis, Mutagenesis, Impairment of Fertility: No evidence of carcinogenicity
816
was seen in 1 mouse study or 2 rat studies following oral administration of lamotrigine for up to
817
2 years at maximum tolerated doses (30 mg/kg per day for mice and 10 to 15 mg/kg per day for
818
rats, doses that are equivalent to 90 mg/m2 and 60 to 90 mg/m2, respectively). Steady-state
819
plasma concentrations ranged from 1 to 4 mcg/mL in the mouse study and 1 to 10 mcg/mL in the
820
rat study. Plasma concentrations associated with the recommended human doses of 300 to
821
500 mg/day are generally in the range of 2 to 5 mcg/mL, but concentrations as high as
822
19 mcg/mL have been recorded.
823
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
25
Lamotrigine was not mutagenic in the presence or absence of metabolic activation when
824
tested in 2 gene mutation assays (the Ames test and the in vitro mammalian mouse lymphoma
825
assay). In 2 cytogenetic assays (the in vitro human lymphocyte assay and the in vivo rat bone
826
marrow assay), lamotrigine did not increase the incidence of structural or numerical
827
chromosomal abnormalities.
828
No evidence of impairment of fertility was detected in rats given oral doses of lamotrigine up
829
to 2.4 times the highest usual human maintenance dose of 8.33 mg/kg per day or 0.4 times the
830
human dose on a mg/m2 basis. The effect of lamotrigine on human fertility is unknown.
831
Pregnancy: Teratogenic Effects: Pregnancy Category C. No evidence of teratogenicity was
832
found in mice, rats, or rabbits when lamotrigine was orally administered to pregnant animals
833
during the period of organogenesis at doses up to 1.2, 0.5, and 1.1 times, respectively, on a
834
mg/m2 basis, the highest usual human maintenance dose (i.e., 500 mg/day). However, maternal
835
toxicity and secondary fetal toxicity producing reduced fetal weight and/or delayed ossification
836
were seen in mice and rats, but not in rabbits at these doses. Teratology studies were also
837
conducted using bolus intravenous administration of the isethionate salt of lamotrigine in rats
838
and rabbits. In rat dams administered an intravenous dose at 0.6 times the highest usual human
839
maintenance dose, the incidence of intrauterine death without signs of teratogenicity was
840
increased.
841
A behavioral teratology study was conducted in rats dosed during the period of organogenesis.
842
At day 21 postpartum, offspring of dams receiving 5 mg/kg per day or higher displayed a
843
significantly longer latent period for open field exploration and a lower frequency of rearing. In a
844
swimming maze test performed on days 39 to 44 postpartum, time to completion was increased
845
in offspring of dams receiving 25 mg/kg per day. These doses represent 0.1 and 0.5 times the
846
clinical dose on a mg/m2 basis, respectively.
847
Lamotrigine did not affect fertility, teratogenesis, or postnatal development when rats were
848
dosed prior to and during mating, and throughout gestation and lactation at doses equivalent to
849
0.4 times the highest usual human maintenance dose on a mg/m2 basis.
850
When pregnant rats were orally dosed at 0.1, 0.14, or 0.3 times the highest human
851
maintenance dose (on a mg/m2 basis) during the latter part of gestation (days 15 to 20), maternal
852
toxicity and fetal death were seen. In dams, food consumption and weight gain were reduced,
853
and the gestation period was slightly prolonged (22.6 vs. 22.0 days in the control group).
854
Stillborn pups were found in all 3 drug-treated groups with the highest number in the high-dose
855
group. Postnatal death was also seen, but only in the 2 highest doses, and occurred between day 1
856
and 20. Some of these deaths appear to be drug-related and not secondary to the maternal
857
toxicity. A no-observed-effect level (NOEL) could not be determined for this study.
858
Although LAMICTAL was not found to be teratogenic in the above studies, lamotrigine
859
decreases fetal folate concentrations in rats, an effect known to be associated with teratogenesis
860
in animals and humans. There are no adequate and well-controlled studies in pregnant women.
861
Because animal reproduction studies are not always predictive of human response, this drug
862
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
26
should be used during pregnancy only if the potential benefit justifies the potential risk to the
863
fetus.
864
Non-Teratogenic Effects: As with other antiepileptic drugs, physiological changes during
865
pregnancy may affect lamotrigine concentrations and/or therapeutic effect. There have been
866
reports of decreased lamotrigine concentrations during pregnancy and restoration of pre-partum
867
concentrations after delivery. Dosage adjustments may be necessary to maintain clinical
868
response.
869
Pregnancy Exposure Registry: To facilitate monitoring fetal outcomes of pregnant women
870
exposed to lamotrigine, physicians are encouraged to register patients, before fetal outcome
871
(e.g., ultrasound, results of amniocentesis, birth, etc.) is known, and can obtain information
872
by calling the Lamotrigine Pregnancy Registry at (800) 336-2176 (toll-free). Patients can enroll
873
themselves in the North American Antiepileptic Drug Pregnancy Registry by calling (888) 233-
874
2334 (toll-free).
875
Labor and Delivery: The effect of LAMICTAL on labor and delivery in humans is unknown.
876
Use in Nursing Mothers: Preliminary data indicate that lamotrigine passes into human milk.
877
Because the effects on the infant exposed to LAMICTAL by this route are unknown,
878
breast-feeding while taking LAMICTAL is not recommended.
879
Pediatric Use: LAMICTAL is indicated as adjunctive therapy for partial seizures, for the
880
generalized seizures of Lennox-Gastaut syndrome, and primary generalized tonic-clonic seizures
881
in patients above 2 years of age. .
882
Safety and effectiveness in patients below the age of 18 years with Bipolar Disorder has not
883
been established.
884
Geriatric Use: Clinical studies of LAMICTAL for epilepsy and in Bipolar Disorder did not
885
include sufficient numbers of subjects aged 65 and over to determine whether they respond
886
differently from younger subjects. In general, dose selection for an elderly patient should be
887
cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of
888
decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
889
ADVERSE REACTIONS
890
SERIOUS RASH REQUIRING HOSPITALIZATION AND DISCONTINUATION OF
891
LAMICTAL, INCLUDING STEVENS-JOHNSON SYNDROME AND TOXIC
892
EPIDERMAL NECROLYSIS, HAVE OCCURRED IN ASSOCIATION WITH
893
THERAPY WITH LAMICTAL. RARE DEATHS HAVE BEEN REPORTED, BUT
894
THEIR NUMBERS ARE TOO FEW TO PERMIT A PRECISE ESTIMATE OF THE
895
RATE (see BOX WARNING).
896
Epilepsy:
897
Most Common Adverse Events in All Clinical Studies: Adjunctive Therapy in
898
Adults With Epilepsy: The most commonly observed (≥5%) adverse experiences seen in
899
association with LAMICTAL during adjunctive therapy in adults and not seen at an equivalent
900
frequency among placebo-treated patients were: dizziness, ataxia, somnolence, headache,
901
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
27
diplopia, blurred vision, nausea, vomiting, and rash. Dizziness, diplopia, ataxia, blurred vision,
902
nausea, and vomiting were dose related. Dizziness, diplopia, ataxia, and blurred vision occurred
903
more commonly in patients receiving carbamazepine with LAMICTAL than in patients receiving
904
other AEDs with LAMICTAL. Clinical data suggest a higher incidence of rash, including serious
905
rash, in patients receiving concomitant valproate than in patients not receiving valproate (see
906
WARNINGS).
907
Approximately 11% of the 3,378 adult patients who received LAMICTAL as adjunctive
908
therapy in premarketing clinical trials discontinued treatment because of an adverse experience.
909
The adverse events most commonly associated with discontinuation were rash (3.0%), dizziness
910
(2.8%), and headache (2.5%).
911
In a dose response study in adults, the rate of discontinuation of LAMICTAL for dizziness,
912
ataxia, diplopia, blurred vision, nausea, and vomiting was dose related.
913
Monotherapy in Adults With Epilepsy: The most commonly observed (≥5%) adverse
914
experiences seen in association with the use of LAMICTAL during the monotherapy phase of the
915
controlled trial in adults not seen at an equivalent rate in the control group were vomiting,
916
coordination abnormality, dyspepsia, nausea, dizziness, rhinitis, anxiety, insomnia, infection,
917
pain, weight decrease, chest pain, and dysmenorrhea. The most commonly observed (≥5%)
918
adverse experiences associated with the use of LAMICTAL during the conversion to
919
monotherapy (add-on) period, not seen at an equivalent frequency among low-dose
920
valproate-treated patients, were dizziness, headache, nausea, asthenia, coordination abnormality,
921
vomiting, rash, somnolence, diplopia, ataxia, accidental injury, tremor, blurred vision, insomnia,
922
nystagmus, diarrhea, lymphadenopathy, pruritus, and sinusitis.
923
Approximately 10% of the 420 adult patients who received LAMICTAL as monotherapy in
924
premarketing clinical trials discontinued treatment because of an adverse experience. The
925
adverse events most commonly associated with discontinuation were rash (4.5%), headache
926
(3.1%), and asthenia (2.4%).
927
Adjunctive Therapy in Pediatric Patients With Epilepsy: The most commonly
928
observed (≥5%) adverse experiences seen in association with the use of LAMICTAL as
929
adjunctive treatment in pediatric patients and not seen at an equivalent rate in the control group
930
were infection, vomiting, rash, fever, somnolence, accidental injury, dizziness, diarrhea,
931
abdominal pain, nausea, ataxia, tremor, asthenia, bronchitis, flu syndrome, and diplopia.
932
In 339 patients age 2 to 16 years with partial seizures or generalized seizures of Lennox-
933
Gastaut syndrome, 4.2% of patients on LAMICTAL and 2.9% of patients on placebo
934
discontinued due to adverse experiences. The most commonly reported adverse experiences that
935
led to discontinuation were rash for patients treated with LAMICTAL and deterioration of
936
seizure control for patients treated with placebo.
937
Approximately 11.5% of the 1,081 pediatric patients who received LAMICTAL as adjunctive
938
therapy in premarketing clinical trials discontinued treatment because of an adverse experience.
939
The adverse events most commonly associated with discontinuation were rash (4.4%), reaction
940
aggravated (1.7%), and ataxia (0.6%).
941
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
28
Incidence in Controlled Clinical Studies of Epilepsy: The prescriber should be aware
942
that the figures in Tables 4, 5, 6, and 7 cannot be used to predict the frequency of adverse
943
experiences in the course of usual medical practice where patient characteristics and other factors
944
may differ from those prevailing during clinical studies. Similarly, the cited frequencies cannot
945
be directly compared with figures obtained from other clinical investigations involving different
946
treatments, uses, or investigators. An inspection of these frequencies, however, does provide the
947
prescriber with one basis to estimate the relative contribution of drug and nondrug factors to the
948
adverse event incidences in the population studied.
949
Incidence in Controlled Adjunctive Clinical Studies in Adults With Epilepsy:
950
Table 4 lists treatment-emergent signs and symptoms that occurred in at least 2% of adult
951
patients with epilepsy treated with LAMICTAL in placebo-controlled trials and were
952
numerically more common in the patients treated with LAMICTAL. In these studies, either
953
LAMICTAL or placebo was added to the patient's current AED therapy. Adverse events were
954
usually mild to moderate in intensity.
955
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
29
Table 4. Treatment-Emergent Adverse Event Incidence in Placebo-Controlled
956
Adjunctive Trials in Adult Patients With Epilepsy* (Events in at least 2% of patients
957
treated with LAMICTAL and numerically more frequent than in the placebo group.)
958
Body System/
Adverse Experience†
Percent of Patients
Receiving Adjunctive
LAMICTAL
(n = 711)
Percent of Patients
Receiving Adjunctive Placebo
(n = 419)
Body as a whole
Headache
29
19
Flu syndrome
7
6
Fever
6
4
Abdominal pain
5
4
Neck pain
2
1
Reaction aggravated
(seizure exacerbation)
2
1
Digestive
Nausea
19
10
Vomiting
9
4
Diarrhea
6
4
Dyspepsia
5
2
Constipation
4
3
Tooth disorder
3
2
Anorexia
2
1
Musculoskeletal
Arthralgia
2
0
Nervous
Dizziness
38
13
Ataxia
22
6
Somnolence
14
7
Incoordination
6
2
Insomnia
6
2
Tremor
4
1
Depression
4
3
Anxiety
4
3
Convulsion
3
1
Irritability
3
2
Speech disorder
3
0
Concentration
disturbance
2
1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
30
Respiratory
Rhinitis
14
9
Pharyngitis
10
9
Cough increased
8
6
Skin and appendages
Rash
10
5
Pruritus
3
2
Special senses
Diplopia
28
7
Blurred vision
16
5
Vision abnormality
3
1
Urogenital
Female patients only
(n = 365)
(n = 207)
Dysmenorrhea
7
6
Vaginitis
4
1
Amenorrhea
2
1
* Patients in these adjunctive studies were receiving 1 to 3 of the following concomitant
959
AEDs (carbamazepine, phenytoin, phenobarbital, or primidone) in addition to LAMICTAL
960
or placebo. Patients may have reported multiple adverse experiences during the study or at
961
discontinuation; thus, patients may be included in more than one category.
962
† Adverse experiences reported by at least 2% of patients treated with LAMICTAL are
963
included.
964
965
In a randomized, parallel study comparing placebo and 300 and 500 mg/day of LAMICTAL,
966
some of the more common drug-related adverse events were dose related (see Table 5).
967
968
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
31
Table 5. Dose-Related Adverse Events From a Randomized, Placebo-Controlled Trial
969
in Adults With Epilepsy
970
Percent of Patients Experiencing Adverse Experiences
Adverse Experience
Placebo
(n = 73)
LAMICTAL
300 mg
(n = 71)
LAMICTAL
500 mg
(n = 72)
Ataxia
10
10
28*†
Blurred vision
10
11
25*†
Diplopia
8
24*
49*†
Dizziness
27
31
54*†
Nausea
11
18
25*
Vomiting
4
11
18*
*Significantly greater than placebo group (p<0.05).
971
†Significantly greater than group receiving LAMICTAL 300 mg (p<0.05).
972
973
Other events that occurred in more than 1% of patients but equally or more frequently in the
974
placebo group included: asthenia, back pain, chest pain, flatulence, menstrual disorder, myalgia,
975
paresthesia, respiratory disorder, and urinary tract infection.
976
The overall adverse experience profile for LAMICTAL was similar between females and
977
males, and was independent of age. Because the largest non-Caucasian racial subgroup was only
978
6% of patients exposed to LAMICTAL in placebo-controlled trials, there are insufficient data to
979
support a statement regarding the distribution of adverse experience reports by race. Generally,
980
females receiving either adjunctive LAMICTAL or placebo were more likely to report adverse
981
experiences than males. The only adverse experience for which the reports on LAMICTAL were
982
greater than 10% more frequent in females than males (without a corresponding difference by
983
gender on placebo) was dizziness (difference = 16.5%). There was little difference between
984
females and males in the rates of discontinuation of LAMICTAL for individual adverse
985
experiences.
986
Incidence in a Controlled Monotherapy Trial in Adults With Partial Seizures:
987
Table 6 lists treatment-emergent signs and symptoms that occurred in at least 5% of patients with
988
epilepsy treated with monotherapy with LAMICTAL in a double-blind trial following
989
discontinuation of either concomitant carbamazepine or phenytoin not seen at an equivalent
990
frequency in the control group.
991
992
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
32
Table 6. Treatment-Emergent Adverse Event Incidence in Adults With Partial Seizures in
993
a Controlled Monotherapy Trial* (Events in at least 5% of patients treated with
994
LAMICTAL and numerically more frequent than in the valproate group.)
995
Body System/
Adverse Experience†
Percent of Patients Receiving
LAMICTAL Monotherapy‡
(n = 43)
Percent of Patients Receiving
Low-Dose Valproate§
Monotherapy
(n = 44)
Body as a whole
Pain
5
0
Infection
5
2
Chest pain
5
2
Digestive
Vomiting
9
0
Dyspepsia
7
2
Nausea
7
2
Metabolic and nutritional
Weight decrease
5
2
Nervous
Coordination
abnormality
7
0
Dizziness
7
0
Anxiety
5
0
Insomnia
5
2
Respiratory
Rhinitis
7
2
Urogenital (female
patients only)
(n = 21)
(n = 28)
Dysmenorrhea
5
0
* Patients in these studies were converted to LAMICTAL or valproate monotherapy from
996
adjunctive therapy with carbamazepine or phenytoin. Patients may have reported multiple
997
adverse experiences during the study; thus, patients may be included in more than one
998
category.
999
† Adverse experiences reported by at least 5% of patients are included.
1000
‡ Up to 500 mg/day.
1001
§ 1,000 mg/day.
1002
1003
Adverse events that occurred with a frequency of less than 5% and greater than 2% of patients
1004
receiving LAMICTAL and numerically more frequent than placebo were:
1005
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
33
Body as a Whole: Asthenia, fever.
1006
Digestive: Anorexia, dry mouth, rectal hemorrhage, peptic ulcer.
1007
Metabolic and Nutritional: Peripheral edema.
1008
Nervous System: Amnesia, ataxia, depression, hypesthesia, libido increase, decreased
1009
reflexes, increased reflexes, nystagmus, irritability, suicidal ideation.
1010
Respiratory: Epistaxis, bronchitis, dyspnea.
1011
Skin and Appendages: Contact dermatitis, dry skin, sweating.
1012
Special Senses: Vision abnormality.
1013
Incidence in Controlled Adjunctive Trials in Pediatric Patients With Epilepsy:
1014
Table 7 lists adverse events that occurred in at least 2% of 339 pediatric patients with partial
1015
seizures or generalized seizures of Lennox-Gastaut syndrome, who received LAMICTAL up to
1016
15 mg/kg per day or a maximum of 750 mg per day. Reported adverse events were classified
1017
using COSTART terminology.
1018
1019
Table 7. Treatment-Emergent Adverse Event Incidence in Placebo-Controlled Adjunctive
1020
Trials in Pediatric Patients With Epilepsy (Events in at least 2% of patients treated with
1021
LAMICTAL and numerically more frequent than in the placebo group.)
1022
Body System/
Adverse Experience
Percent of Patients
Receiving LAMICTAL
(n = 168)
Percent of Patients
Receiving Placebo
(n = 171)
Body as a whole
Infection
20
17
Fever
15
14
Accidental injury
14
12
Abdominal pain
10
5
Asthenia
8
4
Flu syndrome
7
6
Pain
5
4
Facial edema
2
1
Photosensitivity
2
0
Cardiovascular
Hemorrhage
2
1
Digestive
Vomiting
20
16
Diarrhea
11
9
Nausea
10
2
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
34
Constipation
4
2
Dyspepsia
2
1
Tooth disorder
2
1
Hemic and lymphatic
Lymphadenopathy
2
1
Metabolic and nutritional
Edema
2
0
Nervous system
Somnolence
17
15
Dizziness
14
4
Ataxia
11
3
Tremor
10
1
Emotional lability
4
2
Gait abnormality
4
2
Thinking abnormality
3
2
Convulsions
2
1
Nervousness
2
1
Vertigo
2
1
Respiratory
Pharyngitis
14
11
Bronchitis
7
5
Increased cough
7
6
Sinusitis
2
1
Bronchospasm
2
1
Skin
Rash
14
12
Eczema
2
1
Pruritus
2
1
Special senses
Diplopia
5
1
Blurred vision
4
1
Ear disorder
2
1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
35
Visual abnormality
2
0
Urogenital
Male and female patients
Urinary tract infection
3
0
Male patients only
n = 93
n = 92
Penis disorder
2
0
1023
Bipolar Disorder: The most commonly observed (≥5%) adverse experiences seen in
1024
association with the use of LAMICTAL as monotherapy (100 to 400 mg/day) in Bipolar
1025
Disorder in the 2 double-blind, placebo-controlled trials of 18 months’ duration, and numerically
1026
more frequent than in placebo-treated patients are included in Table 8. Adverse events that
1027
occurred in at least 5% of patients and were numerically more common during the dose
1028
escalation phase of LAMICTAL in these trials (when patients may have been receiving
1029
concomitant medications) compared to the monotherapy phase were: headache (25%), rash
1030
(11%), dizziness (10%), diarrhea (8%), dream abnormality (6%), and pruritus (6%).
1031
During the monotherapy phase of the double-blind, placebo-controlled trials of 18 months’
1032
duration, 13% of 227 patients who received LAMICTAL (100 to 400 mg/day), 16% of
1033
190 patients who received placebo, and 23% of 166 patients who received lithium discontinued
1034
therapy because of an adverse experience. The adverse events which most commonly led to
1035
discontinuation of LAMICTAL were rash (3%) and mania/hypomania/mixed mood adverse
1036
events (2%). Approximately 16% of 2,401 patients who received LAMICTAL (50 to
1037
500 mg/day) for Bipolar Disorder in premarketing trials discontinued therapy because of an
1038
adverse experience; most commonly due to rash (5%) and mania/hypomania/mixed mood
1039
adverse events (2%).
1040
Incidence in Controlled Clinical Studies of LAMICTAL for the Maintenance
1041
Treatment of Bipolar I Disorder: Table 8 lists treatment-emergent signs and symptoms that
1042
occurred in at least 5% of patients with Bipolar Disorder treated with LAMICTAL monotherapy
1043
(100 to 400 mg/day), following the discontinuation of other psychotropic drugs, in
1044
2 double-blind, placebo-controlled trials of 18 months’ duration and were numerically more
1045
frequent than in the placebo group.
1046
1047
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
36
Table 8. Treatment-Emergent Adverse Event Incidence in 2 Placebo-Controlled Trials
1048
in Adults With Bipolar I Disorder* (Events in at least 5% of patients treated with
1049
LAMICTAL monotherapy and numerically more frequent than in the placebo group.)
1050
Body System/
Adverse Experience†
Percent of Patients
Receiving LAMICTAL
n = 227
Percent of Patients
Receiving Placebo
n = 190
General
Back pain
8
6
Fatigue
8
5
Abdominal pain
6
3
Digestive
Nausea
14
11
Constipation
5
2
Vomiting
5
2
Nervous System
Insomnia
10
6
Somnolence
9
7
Xerostomia (dry mouth)
6
4
Respiratory
Rhinitis
7
4
Exacerbation of cough
5
3
Pharyngitis
5
4
Skin
Rash (nonserious)‡
7
5
* Patients in these studies were converted to LAMICTAL (100 to 400 mg/day) or placebo
1051
monotherapy from add-on therapy with other psychotropic medications. Patients may
1052
have reported multiple adverse experiences during the study; thus, patients may be
1053
included in more than one category.
1054
† Adverse experiences reported by at least 5% of patients are included.
1055
‡ In the overall bipolar and other mood disorders clinical trials, the rate of serious rash
1056
was 0.08% (1 of 1,233) of adult patients who received LAMICTAL as initial
1057
monotherapy and 0.13% (2 of 1,538) of adult patients who received LAMICTAL as
1058
adjunctive therapy (see WARNINGS).
1059
1060
These adverse events were usually mild to moderate in intensity.
1061
Other events that occurred in 5% or more patients but equally or more frequently in the
1062
placebo group included: dizziness, mania, headache, infection, influenza, pain, accidental injury,
1063
diarrhea, and dyspepsia.
1064
Adverse events that occurred with a frequency of less than 5% and greater than 1% of patients
1065
receiving LAMICTAL and numerically more frequent than placebo were:
1066
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
37
General: Fever, neck pain.
1067
Cardiovascular: Migraine.
1068
Digestive: Flatulence.
1069
Metabolic and Nutritional: Weight gain, edema.
1070
Musculoskeletal: Arthralgia, myalgia.
1071
Nervous System: Amnesia, depression, agitation, emotional lability, dyspraxia, abnormal
1072
thoughts, dream abnormality, hypoesthesia.
1073
Respiratory: Sinusitis.
1074
Urogenital: Urinary frequency.
1075
Adverse Events Following Abrupt Discontinuation: In the 2 maintenance trials, there
1076
was no increase in the incidence, severity or type of adverse events in Bipolar Disorder patients
1077
after abruptly terminating LAMICTAL therapy. In clinical trials in patients with Bipolar
1078
Disorder, 2 patients experienced seizures shortly after abrupt withdrawal of LAMICTAL.
1079
However, there were confounding factors that may have contributed to the occurrence of seizures
1080
in these bipolar patients (see DOSAGE AND ADMINISTRATION).
1081
Mania/Hypomania/Mixed Episodes: During the double-blind, placebo-controlled clinical
1082
trials in Bipolar I Disorder in which patients were converted to LAMICTAL monotherapy (100
1083
to 400 mg/day) from other psychotropic medications and followed for durations up to 18 months,
1084
the rate of manic or hypomanic or mixed mood episodes reported as adverse experiences was 5%
1085
for patients treated with LAMICTAL (n = 227), 4% for patients treated with lithium (n = 166),
1086
and 7% for patients treated with placebo (n = 190). In all bipolar controlled trials combined,
1087
adverse events of mania (including hypomania and mixed mood episodes) were reported in 5%
1088
of patients treated with LAMICTAL (n = 956), 3% of patients treated with lithium (n = 280), and
1089
4% of patients treated with placebo (n = 803).
1090
The overall adverse event profile for LAMICTAL was similar between females and males,
1091
between elderly and nonelderly patients, and among racial groups.
1092
Other Adverse Events Observed During All Clinical Trials For Pediatric and Adult
1093
Patients With Epilepsy or Bipolar Disorder and Other Mood Disorders: LAMICTAL
1094
has been administered to 6,694 individuals for whom complete adverse event data was captured
1095
during all clinical trials, only some of which were placebo controlled. During these trials, all
1096
adverse events were recorded by the clinical investigators using terminology of their own
1097
choosing. To provide a meaningful estimate of the proportion of individuals having adverse
1098
events, similar types of events were grouped into a smaller number of standardized categories
1099
using modified COSTART dictionary terminology. The frequencies presented represent the
1100
proportion of the 6,694 individuals exposed to LAMICTAL who experienced an event of the
1101
type cited on at least one occasion while receiving LAMICTAL. All reported events are included
1102
except those already listed in the previous tables or elsewhere in the labeling, those too general
1103
to be informative, and those not reasonably associated with the use of the drug.
1104
Events are further classified within body system categories and enumerated in order of
1105
decreasing frequency using the following definitions: frequent adverse events are defined as
1106
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
38
those occurring in at least 1/100 patients; infrequent adverse events are those occurring in 1/100
1107
to 1/1,000 patients; rare adverse events are those occurring in fewer than 1/1,000 patients.
1108
Body as a Whole: Infrequent: Allergic reaction, chills, halitosis, and malaise. Rare:
1109
Abdomen enlarged, abscess, and suicide/suicide attempt.
1110
Cardiovascular System: Infrequent: Flushing, hot flashes, hypertension, palpitations,
1111
postural hypotension, syncope, tachycardia, and vasodilation. Rare: Angina pectoris, atrial
1112
fibrillation, deep thrombophlebitis, ECG abnormality, and myocardial infarction.
1113
Dermatological: Infrequent: Acne, alopecia, hirsutism, maculopapular rash, skin
1114
discoloration, and urticaria. Rare: Angioedema, erythema, exfoliative dermatitis, fungal
1115
dermatitis, herpes zoster, leukoderma, multiforme erythema, petechial rash, pustular rash,
1116
seborrhea, Stevens-Johnson syndrome, and vesiculobullous rash.
1117
Digestive System: Infrequent: Dysphagia, eructation, gastritis, gingivitis, increased
1118
appetite, increased salivation, liver function tests abnormal, and mouth ulceration. Rare:
1119
Gastrointestinal hemorrhage, glossitis, gum hemorrhage, gum hyperplasia, hematemesis,
1120
hemorrhagic colitis, hepatitis, melena, stomach ulcer, stomatitis, thirst, and tongue edema.
1121
Endocrine System: Rare: Goiter and hypothyroidism.
1122
Hematologic and Lymphatic System: Infrequent: Ecchymosis and leukopenia. Rare:
1123
Anemia, eosinophilia, fibrin decrease, fibrinogen decrease, iron deficiency anemia, leukocytosis,
1124
lymphocytosis, macrocytic anemia, petechia, and thrombocytopenia.
1125
Metabolic and Nutritional Disorders: Infrequent: Aspartate transaminase increased.
1126
Rare: Alcohol intolerance, alkaline phosphatase increase, alanine transaminase increase,
1127
bilirubinemia, general edema, gamma glutamyl transpeptidase increase, and hyperglycemia.
1128
Musculoskeletal System: Infrequent: Arthritis, leg cramps, myasthenia, and twitching.
1129
Rare: Bursitis, joint disorder, muscle atrophy, pathological fracture, and tendinous contracture.
1130
Nervous System: Frequent: Confusion and paresthesia. Infrequent: Akathisia, apathy,
1131
aphasia, CNS depression, depersonalization, dysarthria, dyskinesia, euphoria, hallucinations,
1132
hostility, hyperkinesia, hypertonia, libido decreased, memory decrease, mind racing, movement
1133
disorder, myoclonus, panic attack, paranoid reaction, personality disorder, psychosis, sleep
1134
disorder, stupor, and suicidal ideation. Rare: Cerebellar syndrome, cerebrovascular accident,
1135
cerebral sinus thrombosis, choreoathetosis, CNS stimulation, delirium, delusions, dysphoria,
1136
dystonia, extrapyramidal syndrome, faintness, grand mal convulsions, hemiplegia, hyperalgesia,
1137
hyperesthesia, hypokinesia, hypotonia, manic depression reaction, muscle spasm, neuralgia,
1138
neurosis, paralysis, and peripheral neuritis.
1139
Respiratory System: Infrequent: Yawn. Rare: Hiccup and hyperventilation.
1140
Special Senses: Frequent: Amblyopia. Infrequent: Abnormality of accommodation,
1141
conjunctivitis, dry eyes, ear pain, photophobia, taste perversion, and tinnitus. Rare: Deafness,
1142
lacrimation disorder, oscillopsia, parosmia, ptosis, strabismus, taste loss, uveitis, and visual field
1143
defect.
1144
Urogenital System: Infrequent: Abnormal ejaculation, breast pain, hematuria, impotence,
1145
menorrhagia, polyuria, urinary incontinence, and urine abnormality. Rare: Acute kidney failure,
1146
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
39
anorgasmia, breast abscess, breast neoplasm, creatinine increase, cystitis, dysuria, epididymitis,
1147
female lactation, kidney failure, kidney pain, nocturia, urinary retention, urinary urgency, and
1148
vaginal moniliasis.
1149
Postmarketing and Other Experience: In addition to the adverse experiences reported
1150
during clinical testing of LAMICTAL, the following adverse experiences have been reported in
1151
patients receiving marketed LAMICTAL and from worldwide noncontrolled investigational use.
1152
These adverse experiences have not been listed above, and data are insufficient to support an
1153
estimate of their incidence or to establish causation.
1154
Blood and Lymphatic: Agranulocytosis, aplastic anemia, disseminated intravascular
1155
coagulation, hemolytic anemia, neutropenia, pancytopenia, red cell aplasia.
1156
Gastrointestinal: Esophagitis.
1157
Hepatobiliary Tract and Pancreas: Pancreatitis.
1158
Immunologic: Lupus-like reaction, vasculitis.
1159
Lower Respiratory: Apnea.
1160
Musculoskeletal: Rhabdomyolysis has been observed in patients experiencing
1161
hypersensitivity reactions.
1162
Neurology: Exacerbation of parkinsonian symptoms in patients with pre-existing
1163
Parkinson’s disease, tics.
1164
Non-site Specific: Hypersensitivity reaction, multiorgan failure, progressive
1165
immunosuppression.
1166
DRUG ABUSE AND DEPENDENCE
1167
The abuse and dependence potential of LAMICTAL have not been evaluated in human
1168
studies.
1169
OVERDOSAGE
1170
Human Overdose Experience: Overdoses involving quantities up to 15 g have been
1171
reported for LAMICTAL, some of which have been fatal. Overdose has resulted in ataxia,
1172
nystagmus, increased seizures, decreased level of consciousness, coma, and intraventricular
1173
conduction delay.
1174
Management of Overdose: There are no specific antidotes for LAMICTAL. Following a
1175
suspected overdose, hospitalization of the patient is advised. General supportive care is
1176
indicated, including frequent monitoring of vital signs and close observation of the patient. If
1177
indicated, emesis should be induced or gastric lavage should be performed; usual precautions
1178
should be taken to protect the airway. It should be kept in mind that lamotrigine is rapidly
1179
absorbed (see CLINICAL PHARMACOLOGY). It is uncertain whether hemodialysis is an
1180
effective means of removing lamotrigine from the blood. In 6 renal failure patients, about 20% of
1181
the amount of lamotrigine in the body was removed by hemodialysis during a 4-hour session. A
1182
Poison Control Center should be contacted for information on the management of overdosage of
1183
LAMICTAL.
1184
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
40
DOSAGE AND ADMINISTRATION
1185
Epilepsy:
1186
Adjunctive Use: LAMICTAL is indicated as adjunctive therapy for partial seizures, the
1187
generalized seizures of Lennox-Gastaut syndrome, and primary generalized tonic-clonic seizures
1188
in adult and pediatric patients (≥2 years of age).
1189
Monotherapy Use: LAMICTAL is indicated for conversion to monotherapy in adults with
1190
partial seizures who are receiving treatment with carbamazepine, phenytoin, phenobarbital,
1191
primidone, or valproate as the single AED.
1192
Safety and effectiveness of LAMICTAL have not been established. (1) as initial
1193
monotherapy, (2) for conversion to monotherapy from AEDs other than carbamazepine,
1194
phenytoin, phenobarbital, primidone, or valproate, or (3) for simultaneous conversion to
1195
monotherapy from 2 or more concomitant AEDs.
1196
1197
Bipolar Disorder: LAMICTAL is indicated for the maintenance treatment of Bipolar I
1198
Disorder to delay the time to occurrence of mood episodes (depression, mania, hypomania,
1199
mixed episodes) in patients treated for acute mood episodes with standard therapy. The
1200
effectiveness of LAMICTAL in the acute treatment of mood episodes has not been established.
1201
General Dosing Considerations for Epilepsy and Bipolar Disorder Patients: The
1202
risk of nonserious rash is increased when the recommended initial dose and/or the rate of dose
1203
escalation of LAMICTAL is exceeded. There are suggestions, yet to be proven, that the risk of
1204
severe, potentially life-threatening rash may be increased by (1) coadministration of LAMICTAL
1205
with valproate, (2) exceeding the recommended initial dose of LAMICTAL, or (3) exceeding the
1206
recommended dose escalation for LAMICTAL. However, cases have been reported in the
1207
absence of these factors (see BOX WARNING). Therefore, it is important that the dosing
1208
recommendations be followed closely.
1209
It is recommended that LAMICTAL not be restarted in patients who discontinued due to rash
1210
associated with prior treatment with LAMICTAL, unless the potential benefits clearly outweigh
1211
the risks. If the decision is made to restart a patient who has discontinued LAMICTAL, the need
1212
to restart with the initial dosing recommendations should be assessed. The greater the interval of
1213
time since the previous dose, the greater consideration should be given to restarting with the
1214
initial dosing recommendations. If a patient has discontinued LAMICTAL for a period of more
1215
than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be
1216
followed.
1217
1218
LAMICTAL Added to Drugs Known to Induce or Inhibit Glucuronidation: Drugs
1219
other than those listed in PRECAUTIONS: Drug Interactions have not been systematically
1220
evaluated in combination with LAMICTAL. Since lamotrigine is metabolized predominantly by
1221
glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may
1222
affect the apparent clearance of lamotrigine, and doses of LAMICTAL may require adjustment
1223
based on clinical response.
1224
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
41
Target Plasma Levels for Patients With Epilepsy or Bipolar Disorder: A
1225
therapeutic plasma concentration range has not been established for lamotrigine. Dosing of
1226
LAMICTAL should be based on therapeutic response.
1227
The half-life of LAMICTAL is affected by other concomitant medications (see CLINICAL
1228
PHARMACOLOGY: Pharmacokinetics and Drug Metabolism).
1229
See also DOSAGE AND ADMINISTRATION: Special Populations.
1230
Special Populations: Women and Oral Contraceptives: Starting LAMICTAL in
1231
Women Taking Oral Contraceptives: Although estrogen-containing oral contraceptives
1232
have been shown to increase the clearance of lamotrigine (see PRECAUTIONS: Drug
1233
Interactions), no adjustments to the recommended dose escalation guidelines for LAMICTAL
1234
should be necessary solely based on the use of estrogen-containing oral contraceptives.
1235
Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive
1236
therapy with LAMICTAL based on the concomitant AED (see Table 11). See below for
1237
adjustments to maintenance doses of LAMICTAL in women taking estrogen-containing oral
1238
contraceptives.
1239
Adjustments to the Maintenance Dose of LAMICTAL: (1) Taking Estrogen-
1240
Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin,
1241
phenobarbital, primidone, or rifampin, the maintenance dose of LAMICTAL will in most cases
1242
need to be increased, by as much as 2-fold over the recommended target maintenance dose, in
1243
order to maintain a consistent lamotrigine plasma level (see PRECAUTIONS: Drug
1244
Interactions). (2) Starting Estrogen-Containing Oral Contraceptives: In women taking a stable
1245
dose of LAMICTAL and not taking carbamazepine, phenytoin, phenobarbital, primidone, or
1246
rifampin, the maintenance dose will in most cases need to be increased by as much as 2-fold, in
1247
order to maintain a consistent lamotrigine plasma level. The dose increases should begin at the
1248
same time that the oral contraceptive is introduced and continue, based on clinical response, no
1249
more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the
1250
recommended rate unless lamotrigine plasma levels or clinical response support larger increases
1251
(see Table 11, column 2). Gradual transient increases in lamotrigine plasma levels may occur
1252
during the week of inactive hormonal preparation (“pill-free” week), and these increases will be
1253
greater if dose increases are made in the days before or during the week of inactive hormonal
1254
preparation. Increased lamotrigine plasma levels could result in additional adverse events, such
1255
as dizziness, ataxia, and diplopia (see PRECAUTIONS: Drug Interactions). If adverse events
1256
attributable to LAMICTAL consistently occur during the “pill-free” week, dose adjustments to
1257
the overall maintenance dose may be necessary. Dose adjustments limited to the “pill-free” week
1258
are not recommended. For women taking LAMICTAL in addition to carbamazepine, phenytoin,
1259
phenobarbital, primidone, or rifampin, no adjustment should be necessary to the dose of
1260
LAMICTAL. (3) Stopping Estrogen-Containing Oral Contraceptives: For women not taking
1261
carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, the maintenance dose of
1262
LAMICTAL will in most cases need to be decreased by as much as 50%, in order to maintain a
1263
consistent lamotrigine plasma level. The decrease in dose of LAMICTAL should not exceed
1264
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
42
25% of the total daily dose per week over a 2-week period, unless clinical response or
1265
lamotrigine plasma levels indicate otherwise (see PRECAUTIONS: Drug Interactions). For
1266
women taking LAMICTAL in addition to carbamazepine, phenytoin, phenobarbital, primidone,
1267
or rifampin, no adjustment to the dose of LAMICTAL should be necessary.
1268
Women and Other Hormonal Contraceptive Preparations or Hormone
1269
Replacement Therapy: The effect of other hormonal contraceptive preparations or hormone
1270
replacement therapy on the pharmacokinetics of lamotrigine has not been systematically
1271
evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of
1272
lamotrigine up to 2-fold, and the progestin only pills had no effect on lamotrigine plasma levels.
1273
Therefore, adjustments to the dosage of LAMICTAL in the presence of progestogens alone will
1274
likely not be needed.
1275
Patients With Hepatic Impairment: Experience in patients with hepatic impairment is
1276
limited. Based on a clinical pharmacology study in 24 patients with mild, moderate, and severe
1277
liver dysfunction (see CLINICAL PHARMACOLOGY), the following general
1278
recommendations can be made. No dosage adjustment is needed in patients with mild liver
1279
impairment. Initial, escalation, and maintenance doses should generally be reduced by
1280
approximately 25% in patients with moderate and severe liver impairment without ascites and
1281
50% in patients with severe liver impairment with ascites. Escalation and maintenance doses
1282
may be adjusted according to clinical response.
1283
Patients With Renal Functional Impairment: Initial doses of LAMICTAL should be
1284
based on patients' AED regimen (see above); reduced maintenance doses may be effective for
1285
patients with significant renal functional impairment (see CLINICAL PHARMACOLOGY).
1286
Few patients with severe renal impairment have been evaluated during chronic treatment with
1287
LAMICTAL. Because there is inadequate experience in this population, LAMICTAL should be
1288
used with caution in these patients.
1289
Epilepsy:
1290
Adjunctive Therapy With LAMICTAL for Epilepsy: This section provides specific
1291
dosing recommendations for patients 2 to 12 years of age and patients greater than 12 years of
1292
age. Within each of these age-groups, specific dosing recommendations are provided depending
1293
upon concomitant AED (Table 9 for patients 2 to 12 years of age and Table 11 for patients
1294
greater than 12 years of age). A weight based dosing guide for pediatric patients on concomitant
1295
valproate is provided in Table 10.
1296
Patients 2 to 12 Years of Age: Recommended dosing guidelines are summarized in Table 9.
1297
Note that some of the starting doses and dose escalations listed in Table 9 are different than
1298
those used in clinical trials; however, the maintenance doses are the same as in clinical trials.
1299
Smaller starting doses and slower dose escalations than those used in clinical trials are
1300
recommended because of the suggestions that the risk of rash may be decreased by smaller
1301
starting doses and slower dose escalations. Therefore, maintenance doses will take longer to
1302
reach in clinical practice than in clinical trials. It may take several weeks to months to achieve an
1303
individualized maintenance dose. Maintenance doses in patients weighing less than 30 kg,
1304
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
43
regardless of age or concomitant AED, may need to be increased as much as 50%, based on
1305
clinical response.
1306
The smallest available strength of LAMICTAL Chewable Dispersible Tablets is 2 mg,
1307
and only whole tablets should be administered. If the calculated dose cannot be achieved
1308
using whole tablets, the dose should be rounded down to the nearest whole tablet (see
1309
HOW SUPPLIED and PATIENT INFORMATION for a description of the available sizes
1310
of LAMICTAL Chewable Dispersible Tablets).
1311
1312
Table 9. Escalation Regimen for LAMICTAL in Patients 2 to 12 Years of Age With
1313
Epilepsy
1314
For Patients Taking
Valproate (see Table 10 for
weight-based dosing guide)
For Patients Taking AEDs
Other Than
Carbamazepine,
Phenytoin, Phenobarbital,
Primidone, or Valproate*
For Patients Taking
Carbamazepine,
Phenytoin,
Phenobarbital,
Primidone* and Not
Taking Valproate
Weeks 1 and 2
0.15 mg/kg/day
in 1 or 2 divided doses,
rounded down to the
nearest whole tablet (see
Table 10 for weight-based
dosing guide).
0.3 mg/kg/day
in 1 or 2 divided doses,
rounded down to the
nearest whole tablet.
0.6 mg/kg/day
in 2 divided doses,
rounded down to the
nearest whole tablet.
Weeks 3 and 4
0.3 mg/kg/day
in 1 or 2 divided doses,
rounded down to the
nearest whole tablet (see
Table 10 for weight-based
dosing guide).
0.6 mg/kg/day
in 2 divided doses,
rounded down to the
nearest whole tablet.
1.2 mg/kg/day
in 2 divided doses,
rounded down to the
nearest whole tablet.
Weeks 5
onwards to
maintenance
The dose should be
increased every 1 to 2
weeks as follows: calculate
0.3 mg/kg/day, round this
amount down to the nearest
whole tablet, and add this
amount to the previously
administered daily dose.
The dose should be
increased every 1 to 2
weeks as follows:
calculate 0.6 mg/kg/day,
round this amount down
to the nearest whole
tablet, and add this
amount to the previously
administered daily dose
The dose should be
increased every 1 to
2 weeks as follows:
calculate
1.2 mg/kg/day,
round this amount
down to the nearest
whole tablet, and
add this amount to
the previously
administered daily
dose
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
44
Usual
Maintenance
Dose
1 to 5 mg/kg/day
(maximum 200 mg/day in
1 or 2 divided doses).
1 to 3 mg/kg/day with
valproate alone
4.5 to 7.5 mg/kg/day
(maximum 300 mg/day in
2 divided doses)
5 to 15 mg/kg/day
(maximum
400 mg/day in 2
divided doses)
Maintenance
dose in
patients less
than 30 kg
May need to be increased
by as much as 50%, based
on clinical response
May need to be increased
by as much as 50%, based
on clinical response
May need to be
increased by as
much as 50%, based
on clinical response
Note: Only whole tablets should be used for dosing
1315
* Rifampin and estrogen-containing oral contraceptives have also been shown to increase the
1316
apparent clearance of lamotrigine (see PRECAUTIONS: Drug Interactions).
1317
1318
1319
Table 10. The Initial Weight-Based Dosing Guide for Patients 2 to 12 Years Taking
1320
Valproate (Weeks 1 to 4) With Epilepsy
1321
:
If the patient’s weight is
Give this daily dose, using the most appropriate
combination of LAMICTAL 2-mg and 5-mg tablets
Greater than
And less than
Weeks 1 and 2
Weeks 3 and 4
6.7 kg
14 kg
2 mg every other day
2 mg every day
14.1 kg
27 kg
2 mg every day
4 mg every day
27.1 kg
34 kg
4 mg every day
8 mg every day
34.1 kg
40 kg
5 mg every day
10 mg every day
1322
Patients Over 12 Years of Age: Recommended dosing guidelines are summarized in
1323
Table 11.
1324
1325
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
45
Table 11. Escalation Regimen for LAMICTAL in Patients Over 12 Years of Age With
1326
Epilepsy
1327
For Patients Taking
Valproate
For Patients Taking
AEDs Other Than
Carbamazepine,
Phenytoin,
Phenobarbital,
Primidone, or
Valproate*
For Patients Taking
Carbamazepine,
Phenytoin,
Phenobarbital,
Primidone* and Not
Taking Valproate
Weeks 1 and 2
25 mg every other day
25 mg every day
50 mg/day
Weeks 3 and 4
25 mg every day
50 mg/day
100 mg/day
(in 2 divided doses)
Weeks 5 onwards
to maintenance
Increase by 25 to
50 mg/day every 1 to
2 weeks
Increase by 50 mg/day
every 1 to 2 weeks
Increase by
100 mg/day every 1 to
2 weeks.
Usual Maintenance
Dose
100 to 400 mg/day
(1 or 2 divided doses)
100 to 200 mg/day with
valproate alone
225 to 375 mg/day
(in 2 divided doses).
300 to 500 mg/day
(in 2 divided doses).
* Rifampin and estrogen-containing oral contraceptives have also been shown to increase the
1328
apparent clearance of lamotrigine (see PRECAUTIONS: Drug Interactions).
1329
1330
1331
Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin,
1332
Phenobarbital, Primidone, or Valproate as the Single AED to Monotherapy With
1333
LAMICTAL in Patients ≥16 Years of Age With Epilepsy: The goal of the transition
1334
regimen is to effect the conversion to monotherapy with LAMICTAL under conditions that
1335
ensure adequate seizure control while mitigating the risk of serious rash associated with the rapid
1336
titration of LAMICTAL.
1337
The recommended maintenance dose of LAMICTAL as monotherapy is 500 mg/day given in
1338
2 divided doses.
1339
To avoid an increased risk of rash, the recommended initial dose and subsequent dose
1340
escalations of LAMICTAL should not be exceeded (see BOX WARNING).
1341
Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin,
1342
Phenobarbital, or Primidone to Monotherapy With LAMICTAL: After achieving a dose
1343
of 500 mg/day of LAMICTAL according to Table 11, the concomitant AED should be
1344
withdrawn by 20% decrements each week over a 4-week period. The regimen for the withdrawal
1345
of the concomitant AED is based on experience gained in the controlled monotherapy clinical
1346
trial.
1347
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
46
Conversion from Adjunctive Therapy With Valproate to Monotherapy With
1348
LAMICTAL: The conversion regimen involves 4 steps (see Table 12).
1349
1350
Table 12. Conversion From Adjunctive Therapy With Valproate to Monotherapy With
1351
LAMICTAL in Patients ≥16 Years of Age With Epilepsy
1352
LAMICTAL
Valproate
Step 1
Achieve a dose of 200 mg/day
according to guidelines in Table 11
(if not already on 200 mg/day).
Maintain previous stable dose.
Step 2
Maintain at 200 mg/day.
Decrease to 500 mg/day by decrements no
greater than 500 mg/day per week and then
maintain the dose of 500 mg/day for 1 week.
Step 3
Increase to 300 mg/day and maintain
for 1 week.
Simultaneously decrease to 250 mg/day and
maintain for 1 week.
Step 4
Increase by 100 mg/day every week
to achieve maintenance dose of
500 mg/day.
Discontinue.
1353
Conversion from Adjunctive Therapy With Antiepileptic Drugs Other Than
1354
Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to
1355
Monotherapy With LAMICTAL: No specific dosing guidelines can be provided for
1356
conversion to monotherapy with LAMICTAL with AEDs other than carbamazepine,
1357
phenobarbital, phenytoin, primidone, or valproate.
1358
Usual Maintenance Dose for Epilepsy: The usual maintenance doses identified in
1359
Tables 9-11 are derived from dosing regimens employed in the placebo-controlled adjunctive
1360
studies in which the efficacy of LAMICTAL was established. In patients receiving multidrug
1361
regimens employing carbamazepine, phenytoin, phenobarbital, or primidone without valproate,
1362
maintenance doses of adjunctive LAMICTAL as high as 700 mg/day have been used. In patients
1363
receiving valproate alone, maintenance doses of adjunctive LAMICTAL as high as 200 mg/day
1364
have been used. The advantage of using doses above those recommended in Tables 9-12 has not
1365
been established in controlled trials.
1366
Discontinuation Strategy for Patients With Epilepsy: For patients receiving
1367
LAMICTAL in combination with other AEDs, a reevaluation of all AEDs in the regimen should
1368
be considered if a change in seizure control or an appearance or worsening of adverse
1369
experiences is observed.
1370
If a decision is made to discontinue therapy with LAMICTAL, a step-wise reduction of dose
1371
over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns
1372
require a more rapid withdrawal (see PRECAUTIONS).
1373
Discontinuing carbamazepine, phenytoin, phenobarbital, or primidone should prolong the
1374
half-life of lamotrigine; discontinuing valproate should shorten the half-life of lamotrigine.
1375
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
47
.
1376
Bipolar Disorder: The goal of maintenance treatment with LAMICTAL is to delay the time to
1377
occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated
1378
for acute mood episodes with standard therapy. The target dose of LAMICTAL is 200 mg/day
1379
(100 mg/day in patients taking valproate,which decreases the apparent clearance of lamotrigine,
1380
and 400 mg/day in patients not taking valproate and taking either Carbamazepine, phenytoin,
1381
phenobarbital, primidone, or rifampin, which increase the apparent clearance of lamotrigine). In
1382
the clinical trials, doses up to 400 mg/day as monotherapy were evaluated, however, no
1383
additional benefit was seen at 400 mg/day compared to 200 mg/day (see CLINICAL STUDIES:
1384
Bipolar Disorder). Accordingly, doses above 200 mg/day are not recommended. Treatment with
1385
LAMICTAL is introduced, based on concurrent medications, according to the regimen outlined
1386
in Table 13. If other psychotropic medications are withdrawn following stabilization, the dose of
1387
LAMICTAL should be adjusted. For patients discontinuing valproate, the dose of LAMICTAL
1388
should be doubled over a 2-week period in equal weekly increments (see Table 14). For patients
1389
discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, the dose of
1390
LAMICTAL should remain constant for the first week and then should be decreased by half over
1391
a 2-week period in equal weekly decrements (see Table 14). The dose of LAMICTAL may then
1392
be further adjusted to the target dose (200 mg) as clinically indicated.
1393
Dosage adjustments will be necessary in most patients who start or stop estrogen-containing
1394
oral contraceptives while taking LAMICTAL (see DOSAGE AND ADMINISTRATION:
1395
Special Populations: Women and Oral Contraceptives: Adjustments to the Maintenance Dose of
1396
LAMICTAL).
1397
If other drugs are subsequently introduced, the dose of LAMICTAL may need to be adjusted.
1398
In particular, the introduction of valproate requires reduction in the dose of LAMICTAL (see
1399
CLINICAL PHARMACOLOGY: Drug Interactions).
1400
To avoid an increased risk of rash, the recommended initial dose and subsequent dose
1401
escalations of LAMICTAL should not be exceeded (see BOX WARNING).
1402
1403
Table 13. Escalation Regimen for LAMICTAL for Patients With Bipolar Disorder*
1404
For Patients Not Taking
Carbamazepine (or
Other Enzyme-Inducing
Drugs†) or Valproate‡
For Patients
Taking
Valproate‡
For Patients Taking
Carbamazepine (or Other
Enzyme-Inducing Drugs)
and Not Taking Valproate‡
Weeks 1 and 2
25 mg daily
25 mg every
other day
50 mg daily
Weeks 3 and 4
50 mg daily
25 mg daily
100 mg daily, in divided
doses
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
48
Week 5
100 mg daily
50 mg daily
200 mg daily, in divided
doses
Week 6
200 mg daily
100 mg daily
300 mg daily, in divided
doses
Week 7
200 mg daily
100 mg daily
up to 400 mg daily, in
divided doses
*See CLINICAL PHARMACOLOGY: Drug Interactions and PRECAUTIONS: Drug
1405
Interactions for a description of known drug interactions.
1406
†Carbamazepine, phenytoin, phenobarbital, primidone, rifampin, have been shown to increase
1407
the apparent clearance of lamotrigine.
1408
‡Valproate has been shown to decrease the apparent clearance of lamotrigine.
1409
1410
Table 14. Adjustments to LAMICTAL Dosing for Patients With Bipolar Disorder
1411
Following Discontinuation of Psychotropic Medications*
1412
After Discontinuation
of Valproate‡
After Discontinuation of
Carbamazepine or Other
Enzyme-Inducing Drugs†
Discontinuation of
Psychotropic Drugs
(excluding Valproate‡,
Carbamazepine, or Other
Enzyme-Inducing
Drugs†)
Current LAMICTAL
dose (mg/day)
100
Current LAMICTAL dose
(mg/day)
400
Week 1 Maintain current
LAMICTAL dose
150
400
Week 2
Maintain current
LAMICTAL dose
200
300
Week 3
onward
Maintain current
LAMICTAL dose
200
200
*See CLINICAL PHARMACOLOGY: Drug Interactions and PRECAUTIONS: Drug
1413
Interactions for a description of known drug interactions.
1414
†Carbamazepine, phenytoin, phenobarbital, primidone, rifampin, have been shown to increase
1415
the apparent clearance of lamotrigine.
1416
‡Valproate has been shown to decrease the apparent clearance of lamotrigine.
1417
1418
There is no body of evidence available to answer the question of how long the patient should
1419
remain on LAMICTAL therapy. Systematic evaluation of the efficacy of LAMICTAL in patients
1420
with either depression or mania who responded to standard therapy during an acute 8 to 16 week
1421
treatment phase and were then randomized to LAMICTAL or placebo for up to 76 weeks of
1422
observation for affective relapse demonstrated a benefit of such maintenance treatment (see
1423
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
49
CLINICAL STUDIES: Bipolar Disorder). Nevertheless, patients should be periodically
1424
reassessed to determine the need for maintenance treatment.
1425
Discontinuation Strategy in Bipolar Disorder: As with other AEDs, LAMICTAL
1426
should not be abruptly discontinued. In the controlled clinical trials, there was no increase in the
1427
incidence, type, or severity of adverse experiences following abrupt termination of LAMICTAL.
1428
In clinical trials in patients with bipolar disorder, 2 patients experienced seizures shortly after
1429
abrupt withdrawal of LAMICTAL. However, there were confounding factors that may have
1430
contributed to the occurrence of seizures in these bipolar patients. Discontinuation of
1431
LAMICTAL should involve a step-wise reduction of dose over at least 2 weeks (approximately
1432
50% per week) unless safety concerns require a more rapid withdrawal.
1433
1434
Administration of LAMICTAL Chewable Dispersible Tablets: LAMICTAL Chewable
1435
Dispersible Tablets may be swallowed whole, chewed, or dispersed in water or diluted fruit
1436
juice. If the tablets are chewed, consume a small amount of water or diluted fruit juice to aid in
1437
swallowing.
1438
To disperse LAMICTAL Chewable Dispersible Tablets, add the tablets to a small amount of
1439
liquid (1 teaspoon, or enough to cover the medication). Approximately 1 minute later, when the
1440
tablets are completely dispersed, swirl the solution and consume the entire quantity immediately.
1441
No attempt should be made to administer partial quantities of the dispersed tablets.
1442
HOW SUPPLIED
1443
LAMICTAL Tablets, 25-mg
1444
White, scored, shield-shaped tablets debossed with "LAMICTAL" and "25", bottles of 100
1445
(NDC 0173-0633-02).
1446
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled
1447
Room Temperature] in a dry place.
1448
LAMICTAL Tablets, 100-mg
1449
Peach, scored, shield-shaped tablets debossed with "LAMICTAL" and "100", bottles of 100
1450
(NDC 0173-0642-55).
1451
LAMICTAL Tablets, 150-mg
1452
Cream, scored, shield-shaped tablets debossed with "LAMICTAL" and "150", bottles of 60
1453
(NDC 0173-0643-60).
1454
LAMICTAL Tablets, 200-mg
1455
Blue, scored, shield-shaped tablets debossed with "LAMICTAL" and "200", bottles of 60
1456
(NDC 0173-0644-60).
1457
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled
1458
Room Temperature] in a dry place and protect from light.
1459
1460
LAMICTAL Chewable Dispersible Tablets, 2-mg
1461
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
50
White to off-white, round tablets debossed with “LTG” over “2”, bottles of 30 (NDC 0173-
1462
0699-00). ORDER DIRECTLY FROM GlaxoSmithKline 1-800-334-4153.
1463
LAMICTAL Chewable Dispersible Tablets, 5-mg
1464
White to off-white, caplet-shaped tablets debossed with “GX CL2”, bottles of 100 (NDC
1465
0173-0526-00).
1466
LAMICTAL Chewable Dispersible Tablets, 25-mg
1467
White, super elliptical-shaped tablets debossed with “GX CL5”, bottles of 100 (NDC 0173-
1468
0527-00).
1469
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled
1470
Room Temperature] in a dry place.
1471
1472
LAMICTAL Starter Kit for Patients Taking Valproate
1473
25-mg, white, scored, shield-shaped tablets debossed with "LAMICTAL" and "25",
1474
blisterpack of 35 tablets (NDC 0173-0633-10).
1475
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled
1476
Room Temperature] in a dry place.
1477
1478
LAMICTAL Starter Kit for Patients Taking Carbamazepine, Phenytoin, Phenobarbital,
1479
Primidone, or Rifampin and Not Taking Valproate
1480
25-mg, white, scored, shield-shaped tablets debossed with "LAMICTAL" and "25" and
1481
100-mg, peach, scored, shield-shaped tablets debossed with "LAMICTAL" and “100”,
1482
blisterpack of 84, 25-mg tablets and 14, 100-mg tablets (NDC 0173-0594-01)
1483
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled
1484
Room Temperature] in a dry place and protect from light.
1485
1486
LAMICTAL Starter Kit for Patients Not Taking Carbamazepine, Phenytoin,
1487
Phenobarbital, Primidone, Rifampin, or Valproate
1488
1489
25-mg, white, scored, shield-shaped tablets debossed with "LAMICTAL" and "25" and
1490
100-mg, peach, scored, shield-shaped tablets debossed with "LAMICTAL" and “100”,
1491
blisterpack of 42, 25-mg tablets and 7, 100-mg tablets (NDC 0173-0594-02).
1492
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled
1493
Room Temperature] in a dry place and protect from light.
1494
PATIENT INFORMATION
1495
The following wording is contained in a separate leaflet provided for patients.
1496
1497
Information for the Patient
1498
1499
LAMICTAL® (lamotrigine) Tablets
1500
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
51
LAMICTAL® (lamotrigine) Chewable Dispersible Tablets
1501
1502
ALWAYS CHECK THAT YOU RECEIVE LAMICTAL
1503
Patients prescribed LAMICTAL (lah-MICK-tall) have sometimes been given the wrong
1504
medicine in error because many medicines have names similar to LAMICTAL. Taking the
1505
wrong medication can cause serious health problems. When your healthcare provider gives you a
1506
prescription for LAMICTAL
1507
• make sure you can read it clearly.
1508
• talk to your pharmacist to check that you are given the correct medicine.
1509
• check the tablets you receive against the pictures of the tablets below. The pictures show
1510
actual tablet shape and size and the wording describes the color and printing that is on each
1511
strength of LAMICTAL Tablets and Chewable Dispersible Tablets.
1512
1513
LAMICTAL (lamotrigine) Tablets
1514
1515
25 mg, white
Imprinted with
LAMICTAL 25
100 mg, peach
Imprinted with
LAMICTAL 100
150 mg, cream
Imprinted with
LAMICTAL 150
200 mg, blue
Imprinted with
LAMICTAL 200
1516
LAMICTAL (lamotrigine) Chewable Dispersible Tablets
1517
1518
2 mg, white
Imprinted with
LTG 2
5 mg, white
Imprinted with
GX CL2
25 mg, white
Imprinted with
GX CL5
1519
Please read this leaflet carefully before you take LAMICTAL and read the leaflet provided
1520
with any refill, in case any information has changed. This leaflet provides a summary of the
1521
information about your medicine. Please do not throw away this leaflet until you have finished
1522
your medicine. This leaflet does not contain all the information about LAMICTAL and is not
1523
meant to take the place of talking with your doctor. If you have any questions about
1524
LAMICTAL, ask your doctor or pharmacist.
1525
1526
Information About Your Medicine:
1527
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
52
The name of your medicine is LAMICTAL (lamotrigine). The decision to use LAMICTAL is
1528
one that you and your doctor should make together. When taking lamotrigine, it is important to
1529
follow your doctor's instructions.
1530
1531
1. The Purpose of Your Medicine:
1532
For Patients With Epilepsy: LAMICTAL is intended to be used either alone or in
1533
combination with other medicines to treat seizures in people aged 2 years or older.
1534
For Patients With Bipolar Disorder: LAMICTAL is used as maintenance treatment of
1535
Bipolar I Disorder to delay the time to occurrence of mood episodes in people aged 18 years or
1536
older treated for acute mood episodes with standard therapy.
1537
If you are taking LAMICTAL to help prevent extreme mood swings, you may not experience
1538
the full effect for several weeks. Occasionally, the symptoms of depression or bipolar disorder
1539
may include thoughts of harming yourself or committing suicide. Tell your doctor immediately
1540
or go to the nearest hospital if you have any distressing thoughts or experiences during this initial
1541
period or at any other time. Also contact your doctor if you experience any worsening of your
1542
condition or develop other new symptoms at any time during your treatment.
1543
Some medicines used to treat depression have been associated with suicidal thoughts and
1544
suicidal behavior in children or teenagers. LAMICTAL is not approved for treating children or
1545
teenagers with mood disorders such as bipolar disorder or depression.
1546
2. Who Should Not Take LAMICTAL:
1547
You should not take LAMICTAL if you had an allergic reaction to it in the past.
1548
3. Side Effects to Watch for:
1549
• Most people who take LAMICTAL tolerate it well. Common side effects with LAMICTAL
1550
include dizziness, headache, blurred or double vision, lack of coordination, sleepiness,
1551
nausea, vomiting, insomnia, and rash. LAMICTAL may cause other side effects not listed in
1552
this leaflet. If you develop any side effects or symptoms you are concerned about or need
1553
more information, call your doctor.
1554
• Although most patients who develop rash while receiving LAMICTAL have mild to
1555
moderate symptoms, some individuals may develop a serious skin reaction that requires
1556
hospitalization. Rarely, deaths have been reported. These serious skin reactions are most
1557
likely to happen within the first 8 weeks of treatment with LAMICTAL. Serious skin
1558
reactions occur more often in children than in adults.
1559
• Rashes may be more likely to occur if you: (1) take LAMICTAL in combination with
1560
valproate [DEPAKENE® (valproic acid) or DEPAKOTE® (divalproex sodium)], (2) take a
1561
higher starting dose of LAMICTAL than your doctor prescribed, or (3) increase your dose of
1562
LAMICTAL faster than prescribed.
1563
• It is not possible to predict whether a mild rash will develop into a more serious reaction.
1564
Therefore, if you experience a skin rash, hives, fever, swollen lymph glands, painful
1565
sores in the mouth or around the eyes, or swelling of lips or tongue, tell a doctor
1566
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
53
immediately, since these symptoms may be the first signs of a serious reaction. A doctor
1567
should evaluate your condition and decide if you should continue taking LAMICTAL.
1568
4. The Use of LAMICTAL During Pregnancy and Breastfeeding:
1569
The effects of LAMICTAL during pregnancy are not known at this time. If you are pregnant
1570
or are planning to become pregnant, talk to your doctor. Some LAMICTAL passes into breast
1571
milk and the effects of this on infants are unknown. Therefore, if you are breast-feeding, you
1572
should discuss this with your doctor to determine if you should continue to take LAMICTAL.
1573
5. Use of Birth Control Pills or Other Female Hormonal Products:
1574
• Do not start or stop using birth control pills or other female hormonal products until you
1575
have consulted your doctor. Stopping or starting these products may cause side effects
1576
(such as dizziness, lack of coordination, or double vision) or decrease the effectiveness
1577
of LAMICTAL.
1578
• Tell your doctor as soon as possible if you experience side effects or changes in your menstrual
1579
pattern (e.g., break-through bleeding) while taking LAMICTAL and birth control pills or
1580
other female hormonal products.
1581
6. How to Use LAMICTAL:
1582
• It is important to take LAMICTAL exactly as instructed by your doctor. The dose of
1583
LAMICTAL must be increased slowly. It may take several weeks or months before your
1584
final dosage can be determined by your doctor, based on your response.
1585
• Do not increase your dose of LAMICTAL or take more frequent doses than those indicated
1586
by your doctor. Contact your doctor, if you stop taking LAMICTAL for any reason. Do not
1587
restart without consulting your doctor.
1588
• If you miss a dose of LAMICTAL, do not double your next dose.
1589
• Always tell your doctor and pharmacist if you are taking any other prescription or
1590
over-the-counter medicines. Tell your doctor before you start any other medicines.
1591
• Do NOT stop taking LAMICTAL or any of your other medicines unless instructed by your
1592
doctor.
1593
• Use caution before driving a car or operating complex, hazardous machinery until you know
1594
if LAMICTAL affects your ability to perform these tasks.
1595
• If you have epilepsy, tell your doctor if your seizures get worse or if you have any new types
1596
of seizures.
1597
7. How to Take LAMICTAL:
1598
LAMICTAL Tablets should be swallowed whole. Chewing the tablets may leave a bitter taste.
1599
LAMICTAL Chewable Dispersible Tablets may be swallowed whole, chewed, or mixed in
1600
water or diluted fruit juice. If the tablets are chewed, consume a small amount of water or diluted
1601
fruit juice to aid in swallowing.
1602
To disperse LAMICTAL Chewable Dispersible Tablets, add the tablets to a small amount of
1603
liquid (1 teaspoon, or enough to cover the medication) in a glass or spoon. Approximately
1604
1 minute later, when the tablets are completely dispersed, mix the solution and take the entire
1605
amount immediately.
1606
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
54
8. Storing Your Medicine:
1607
Store LAMICTAL at room temperature away from heat and light. Always keep your
1608
medicines out of the reach of children.
1609
This medicine was prescribed for your use only to treat seizures or to treat Bipolar Disorder.
1610
Do not give the drug to others.
1611
If your doctor decides to stop your treatment, do not keep any leftover medicine unless your
1612
doctor tells you to. Throw away your medicine as instructed.
1613
1614
1615
Manufactured for
1616
GlaxoSmithKline
1617
Research Triangle Park, NC 27709
1618
by DSM Pharmaceuticals, Inc.
1619
Greenville, NC 27834 or
1620
GlaxoSmithKline
1621
Research Triangle Park, NC 27709
1622
1623
DEPAKENE and DEPAKOTE are registered trademarks of Abbott Laboratories.
1624
1625
©2005, GlaxoSmithKline. All rights reserved.
1626
1627
(Date of Issue)
RL-
1628
1629
PHARMACIST--DETACH HERE AND GIVE INSTRUCTIONS TO PATIENT
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
1630
1631
Information for the Patient
1632
1633
LAMICTAL® (lamotrigine) Tablets
1634
LAMICTAL® (lamotrigine) Chewable Dispersible Tablets
1635
1636
ALWAYS CHECK THAT YOU RECEIVE LAMICTAL
1637
Patients prescribed LAMICTAL (lah-MICK-tall) have sometimes been given the wrong
1638
medicine in error because many medicines have names similar to LAMICTAL. Taking the
1639
wrong medication can cause serious health problems. When your healthcare provider gives you a
1640
prescription for LAMICTAL
1641
• make sure you can read it clearly.
1642
• talk to your pharmacist to check that you are given the correct medicine.
1643
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
55
• check the tablets you receive against the pictures of the tablets below. The pictures show
1644
actual tablet shape and size and the wording describes the color and printing that is on each
1645
strength of LAMICTAL Tablets and Chewable Dispersible Tablets.
1646
1647
LAMICTAL (lamotrigine) Tablets
1648
1649
25 mg, white
Imprinted with
LAMICTAL 25
100 mg, peach
Imprinted with
LAMICTAL 100
150 mg, cream
Imprinted with
LAMICTAL 150
200 mg, blue
Imprinted with
LAMICTAL 200
1650
LAMICTAL (lamotrigine) Chewable Dispersible Tablets
1651
1652
2 mg, white
Imprinted with
LTG 2
5 mg, white
Imprinted with
GX CL2
25 mg, white
Imprinted with
GX CL5
1653
Please read this leaflet carefully before you take LAMICTAL and read the leaflet provided
1654
with any refill, in case any information has changed. This leaflet provides a summary of the
1655
information about your medicine. Please do not throw away this leaflet until you have finished
1656
your medicine. This leaflet does not contain all the information about LAMICTAL and is not
1657
meant to take the place of talking with your doctor. If you have any questions about
1658
LAMICTAL, ask your doctor or pharmacist.
1659
1660
Information About Your Medicine:
1661
The name of your medicine is LAMICTAL (lamotrigine). The decision to use LAMICTAL is
1662
one that you and your doctor should make together. When taking lamotrigine, it is important to
1663
follow your doctor's instructions.
1664
1665
1. The Purpose of Your Medicine:
1666
For Patients With Epilepsy: LAMICTAL is intended to be used either alone or in
1667
combination with other medicines to treat seizures in people aged 2 years or older.
1668
For Patients With Bipolar Disorder: LAMICTAL is used as maintenance treatment of
1669
Bipolar I Disorder to delay the time to occurrence of mood episodes in people aged 18 years or
1670
older treated for acute mood episodes with standard therapy.
1671
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
56
If you are taking LAMICTAL to help prevent extreme mood swings, you may not experience
1672
the full effect for several weeks. Occasionally, the symptoms of depression or bipolar disorder
1673
may include thoughts of harming yourself or committing suicide. Tell your doctor immediately
1674
or go to the nearest hospital if you have any distressing thoughts or experiences during this initial
1675
period or at any other time. Also contact your doctor if you experience any worsening of your
1676
condition or develop other new symptoms at any time during your treatment.
1677
Some medicines used to treat depression have been associated with suicidal thoughts and
1678
suicidal behavior in children or teenagers. LAMICTAL is not approved for treating children or
1679
teenagers with mood disorders such as bipolar disorder or depression.
1680
2. Who Should Not Take LAMICTAL:
1681
You should not take LAMICTAL if you had an allergic reaction to it in the past.
1682
3. Side Effects to Watch for:
1683
• Most people who take LAMICTAL tolerate it well. Common side effects with
1684
LAMICTAL include dizziness, headache, blurred or double vision, lack of coordination,
1685
sleepiness, nausea, vomiting, insomnia, and rash. LAMICTAL may cause other side effects
1686
not listed in this leaflet. If you develop any side effects or symptoms you are concerned about
1687
or need more information, call your doctor.
1688
• Although most patients who develop rash while receiving LAMICTAL have mild to
1689
moderate symptoms, some individuals may develop a serious skin reaction that requires
1690
hospitalization. Rarely, deaths have been reported. These serious skin reactions are most
1691
likely to happen within the first 8 weeks of treatment with LAMICTAL. Serious skin
1692
reactions occur more often in children than in adults.
1693
• Rashes may be more likely to occur if you: (1) take LAMICTAL in combination with
1694
valproate [DEPAKENE® (valproic acid) or DEPAKOTE® (divalproex sodium)], (2) take a
1695
higher starting dose of LAMICTAL than your doctor prescribed, or (3) increase your dose of
1696
LAMICTAL faster than prescribed.
1697
• It is not possible to predict whether a mild rash will develop into a more serious reaction.
1698
Therefore, if you experience a skin rash, hives, fever, swollen lymph glands, painful
1699
sores in the mouth or around the eyes, or swelling of lips or tongue, tell a doctor
1700
immediately, since these symptoms may be the first signs of a serious reaction. A doctor
1701
should evaluate your condition and decide if you should continue taking LAMICTAL.
1702
4. The Use of LAMICTAL During Pregnancy and Breastfeeding:
1703
The effects of LAMICTAL during pregnancy are not known at this time. If you are pregnant
1704
or are planning to become pregnant, talk to your doctor. Some LAMICTAL passes into breast
1705
milk and the effects of this on infants are unknown. Therefore, if you are breastfeeding, you
1706
should discuss this with your doctor to determine if you should continue to take LAMICTAL.
1707
5. Use of Birth Control Pills or Other Female Hormonal Products:
1708
• Do not start or stop using birth control pills or other female hormonal products until you
1709
have consulted your doctor. Stopping or starting these products may cause side effects
1710
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
57
(such as dizziness, lack of coordination, or double vision) or to decrease the
1711
effectiveness of LAMICTAL.
1712
1713
1714
• Tell your doctor as soon as possible if you experience side effects changes in your menstrual
1715
pattern (e.g., break-through bleeding) while taking LAMICTAL and birth control pills or
1716
other female hormonal products.
1717
6. How to Use LAMICTAL:
1718
• It is important to take LAMICTAL exactly as instructed by your doctor. The dose of
1719
LAMICTAL must be increased slowly. It may take several weeks or months before your
1720
final dosage can be determined by your doctor, based on your response.
1721
• Do not increase your dose of LAMICTAL or take more frequent doses than those indicated
1722
by your doctor. Contact your doctor, if you stop taking LAMICTAL for any reason. Do not
1723
restart without consulting your doctor.
1724
• If you miss a dose of LAMICTAL, do not double your next dose.
1725
• Always tell your doctor and pharmacist if you are taking any other prescription or
1726
over-the-counter medicines. Tell your doctor before you start any other medicines.
1727
• Do NOT stop taking LAMICTAL or any of your other medicines unless instructed by your
1728
doctor.
1729
• Use caution before driving a car or operating complex, hazardous machinery until you know
1730
if LAMICTAL affects your ability to perform these tasks.
1731
• If you have epilepsy, tell your doctor if your seizures get worse or if you have any new types
1732
of seizures.
1733
7. How to Take LAMICTAL:
1734
LAMICTAL Tablets should be swallowed whole. Chewing the tablets may leave a bitter taste.
1735
LAMICTAL Chewable Dispersible Tablets may be swallowed whole, chewed, or mixed in
1736
water or diluted fruit juice. If the tablets are chewed, consume a small amount of water or diluted
1737
fruit juice to aid in swallowing.
1738
To disperse LAMICTAL Chewable Dispersible Tablets, add the tablets to a small amount of
1739
liquid (1 teaspoon, or enough to cover the medication) in a glass or spoon. Approximately
1740
1 minute later, when the tablets are completely dispersed, mix the solution and take the entire
1741
amount immediately.
1742
8. Storing Your Medicine:
1743
Store LAMICTAL at room temperature away from heat and light. Always keep your
1744
medicines out of the reach of children.
1745
This medicine was prescribed for your use only to treat seizures or to treat Bipolar Disorder.
1746
Do not give the drug to others.
1747
If your doctor decides to stop your treatment, do not keep any leftover medicine unless your
1748
doctor tells you to. Throw away your medicine as instructed.
1749
1750
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
58
1751
Manufactured for
1752
GlaxoSmithKline
1753
Research Triangle Park, NC 27709
1754
by DSM Pharmaceuticals, Inc.
1755
Greenville, NC 27834 or
1756
GlaxoSmithKline
1757
Research Triangle Park, NC 27709
1758
1759
DEPAKENE and DEPAKOTE are registered trademarks of Abbott Laboratories.
1760
1761
©2005, GlaxoSmithKline. All rights reserved.
1762
1763
(Date of Issue)
RL-
1764
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:47:11.400932
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/020241s10s21s25s26s27,020764s3s14s18s19s20lbl.pdf', 'application_number': 20241, 'submission_type': 'SUPPL ', 'submission_number': 26}
|
12,361
|
1
PRESCRIBING INFORMATION
1
LAMICTAL®
2
(lamotrigine)
3
Tablets
4
5
LAMICTAL®
6
(lamotrigine)
7
Chewable Dispersible Tablets
8
9
SERIOUS RASHES REQUIRING HOSPITALIZATION AND DISCONTINUATION
10
OF TREATMENT HAVE BEEN REPORTED IN ASSOCIATION WITH THE USE OF
11
LAMICTAL. THE INCIDENCE OF THESE RASHES, WHICH HAVE INCLUDED
12
STEVENS-JOHNSON SYNDROME, IS APPROXIMATELY 0.8% (8 PER 1,000) IN
13
PEDIATRIC PATIENTS (AGE <16 YEARS) RECEIVING LAMICTAL AS
14
ADJUNCTIVE THERAPY FOR EPILEPSY AND 0.3% (3 PER 1,000) IN ADULTS ON
15
ADJUNCTIVE THERAPY FOR EPILEPSY. IN CLINICAL TRIALS OF BIPOLAR AND
16
OTHER MOOD DISORDERS, THE RATE OF SERIOUS RASH WAS 0.08% (0.8 PER
17
1,000) IN ADULT PATIENTS RECEIVING LAMICTAL AS INITIAL MONOTHERAPY
18
AND 0.13% (1.3 PER 1,000) IN ADULT PATIENTS RECEIVING LAMICTAL AS
19
ADJUNCTIVE THERAPY. IN A PROSPECTIVELY FOLLOWED COHORT OF
20
1,983 PEDIATRIC PATIENTS WITH EPILEPSY TAKING ADJUNCTIVE LAMICTAL,
21
THERE WAS 1 RASH-RELATED DEATH. IN WORLDWIDE POSTMARKETING
22
EXPERIENCE, RARE CASES OF TOXIC EPIDERMAL NECROLYSIS AND/OR
23
RASH-RELATED DEATH HAVE BEEN REPORTED IN ADULT AND PEDIATRIC
24
PATIENTS, BUT THEIR NUMBERS ARE TOO FEW TO PERMIT A PRECISE
25
ESTIMATE OF THE RATE.
26
OTHER THAN AGE, THERE ARE AS YET NO FACTORS IDENTIFIED THAT ARE
27
KNOWN TO PREDICT THE RISK OF OCCURRENCE OR THE SEVERITY OF RASH
28
ASSOCIATED WITH LAMICTAL. THERE ARE SUGGESTIONS, YET TO BE
29
PROVEN, THAT THE RISK OF RASH MAY ALSO BE INCREASED BY (1)
30
COADMINISTRATION OF LAMICTAL WITH VALPROATE (INCLUDES VALPROIC
31
ACID AND DIVALPROEX SODIUM), (2) EXCEEDING THE RECOMMENDED
32
INITIAL DOSE OF LAMICTAL, OR (3) EXCEEDING THE RECOMMENDED DOSE
33
ESCALATION FOR LAMICTAL. HOWEVER, CASES HAVE BEEN REPORTED IN
34
THE ABSENCE OF THESE FACTORS.
35
NEARLY ALL CASES OF LIFE-THREATENING RASHES ASSOCIATED WITH
36
LAMICTAL HAVE OCCURRED WITHIN 2 TO 8 WEEKS OF TREATMENT
37
INITIATION. HOWEVER, ISOLATED CASES HAVE BEEN REPORTED AFTER
38
PROLONGED TREATMENT (E.G., 6 MONTHS). ACCORDINGLY, DURATION OF
39
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2
THERAPY CANNOT BE RELIED UPON AS A MEANS TO PREDICT THE
40
POTENTIAL RISK HERALDED BY THE FIRST APPEARANCE OF A RASH.
41
ALTHOUGH BENIGN RASHES ALSO OCCUR WITH LAMICTAL, IT IS NOT
42
POSSIBLE TO PREDICT RELIABLY WHICH RASHES WILL PROVE TO BE
43
SERIOUS OR LIFE THREATENING. ACCORDINGLY, LAMICTAL SHOULD
44
ORDINARILY BE DISCONTINUED AT THE FIRST SIGN OF RASH, UNLESS THE
45
RASH IS CLEARLY NOT DRUG RELATED. DISCONTINUATION OF TREATMENT
46
MAY NOT PREVENT A RASH FROM BECOMING LIFE THREATENING OR
47
PERMANENTLY DISABLING OR DISFIGURING.
48
49
DESCRIPTION
50
LAMICTAL (lamotrigine), an antiepileptic drug (AED) of the phenyltriazine class, is
51
chemically unrelated to existing antiepileptic drugs. Its chemical name is 3,5-diamino-6-(2,3-
52
dichlorophenyl)-as-triazine, its molecular formula is C9H7N5Cl2, and its molecular weight is
53
256.09. Lamotrigine is a white to pale cream-colored powder and has a pKa of 5.7. Lamotrigine
54
is very slightly soluble in water (0.17 mg/mL at 25°C) and slightly soluble in 0.1 M HCl
55
(4.1 mg/mL at 25°C). The structural formula is:
56
57
58
59
LAMICTAL Tablets are supplied for oral administration as 25-mg (white), 100-mg (peach),
60
150-mg (cream), and 200-mg (blue) tablets. Each tablet contains the labeled amount of
61
lamotrigine and the following inactive ingredients: lactose; magnesium stearate; microcrystalline
62
cellulose; povidone; sodium starch glycolate; FD&C Yellow No. 6 Lake (100-mg tablet only);
63
ferric oxide, yellow (150-mg tablet only); and FD&C Blue No. 2 Lake (200-mg tablet only).
64
LAMICTAL Chewable Dispersible Tablets are supplied for oral administration. The tablets
65
contain 2 mg (white), 5 mg (white), or 25 mg (white) of lamotrigine and the following inactive
66
ingredients: blackcurrant flavor, calcium carbonate, low-substituted hydroxypropylcellulose,
67
magnesium aluminum silicate, magnesium stearate, povidone, saccharin sodium, and sodium
68
starch glycolate.
69
CLINICAL PHARMACOLOGY
70
Mechanism of Action: The precise mechanism(s) by which lamotrigine exerts its
71
anticonvulsant action are unknown. In animal models designed to detect anticonvulsant activity,
72
lamotrigine was effective in preventing seizure spread in the maximum electroshock (MES) and
73
pentylenetetrazol (scMet) tests, and prevented seizures in the visually and electrically evoked
74
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3
after-discharge (EEAD) tests for antiepileptic activity. LAMICTAL also displayed inhibitory
75
properties in the kindling model in rats both during kindling development and in the fully
76
kindled state. The relevance of these models to human epilepsy, however, is not known.
77
One proposed mechanism of action of LAMICTAL, the relevance of which remains to be
78
established in humans, involves an effect on sodium channels. In vitro pharmacological studies
79
suggest that lamotrigine inhibits voltage-sensitive sodium channels, thereby stabilizing neuronal
80
membranes and consequently modulating presynaptic transmitter release of excitatory amino
81
acids (e.g., glutamate and aspartate).
82
The mechanisms by which lamotrigine exerts its therapeutic action in Bipolar Disorder have
83
not been established.
84
Pharmacological Properties: Although the relevance for human use is unknown, the
85
following data characterize the performance of LAMICTAL in receptor binding assays.
86
Lamotrigine had a weak inhibitory effect on the serotonin 5-HT3 receptor (IC50 = 18 µM). It does
87
not exhibit high affinity binding (IC50>100 µM) to the following neurotransmitter receptors:
88
adenosine A1 and A2; adrenergic α1, α2, and β; dopamine D1 and D2; γ-aminobutyric acid
89
(GABA) A and B; histamine H1; kappa opioid; muscarinic acetylcholine; and serotonin 5-HT2.
90
Studies have failed to detect an effect of lamotrigine on dihydropyridine-sensitive calcium
91
channels. It had weak effects at sigma opioid receptors (IC50 = 145 µM). Lamotrigine did not
92
inhibit the uptake of norepinephrine, dopamine, or serotonin, (IC50>200 µM) when tested in rat
93
synaptosomes and/or human platelets in vitro.
94
Effect of Lamotrigine on N-Methyl d-Aspartate-Receptor Mediated Activity:
95
Lamotrigine did not inhibit N-methyl d-aspartate (NMDA)-induced depolarizations in rat cortical
96
slices or NMDA-induced cyclic GMP formation in immature rat cerebellum, nor did lamotrigine
97
displace compounds that are either competitive or noncompetitive ligands at this glutamate
98
receptor complex (CNQX, CGS, TCHP). The IC50 for lamotrigine effects on NMDA-induced
99
currents (in the presence of 3 µM of glycine) in cultured hippocampal neurons exceeded
100
100 µM.
101
Folate Metabolism: In vitro, lamotrigine was shown to be an inhibitor of dihydrofolate
102
reductase, the enzyme that catalyzes the reduction of dihydrofolate to tetrahydrofolate. Inhibition
103
of this enzyme may interfere with the biosynthesis of nucleic acids and proteins. When oral daily
104
doses of lamotrigine were given to pregnant rats during organogenesis, fetal, placental, and
105
maternal folate concentrations were reduced. Significantly reduced concentrations of folate are
106
associated with teratogenesis (see PRECAUTIONS: Pregnancy). Folate concentrations were also
107
reduced in male rats given repeated oral doses of lamotrigine. Reduced concentrations were
108
partially returned to normal when supplemented with folinic acid.
109
Accumulation in Kidneys: Lamotrigine was found to accumulate in the kidney of the
110
male rat, causing chronic progressive nephrosis, necrosis, and mineralization. These findings are
111
attributed to α-2 microglobulin, a species- and sex-specific protein that has not been detected in
112
humans or other animal species.
113
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4
Melanin Binding: Lamotrigine binds to melanin-containing tissues, e.g., in the eye and
114
pigmented skin. It has been found in the uveal tract up to 52 weeks after a single dose in rodents.
115
Cardiovascular: In dogs, lamotrigine is extensively metabolized to a 2-N-methyl
116
metabolite. This metabolite causes dose-dependent prolongations of the PR interval, widening of
117
the QRS complex, and, at higher doses, complete AV conduction block. Similar cardiovascular
118
effects are not anticipated in humans because only trace amounts of the 2-N-methyl metabolite
119
(<0.6% of lamotrigine dose) have been found in human urine (see Drug Disposition). However,
120
it is conceivable that plasma concentrations of this metabolite could be increased in patients with
121
a reduced capacity to glucuronidate lamotrigine (e.g., in patients with liver disease).
122
Pharmacokinetics and Drug Metabolism: The pharmacokinetics of lamotrigine have been
123
studied in patients with epilepsy, healthy young and elderly volunteers, and volunteers with
124
chronic renal failure. Lamotrigine pharmacokinetic parameters for adult and pediatric patients
125
and healthy normal volunteers are summarized in Tables 1 and 2.
126
127
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5
Table 1. Mean* Pharmacokinetic Parameters in Healthy Volunteers and Adult Patients
128
With Epilepsy
129
Adult Study Population
Number of
Subjects
Tmax: Time of
Maximum
Plasma
Concentration
(h)
t½:
Elimination
Half-life
(h)
Cl/F:
Apparent Plasma
Clearance
(mL/min/kg)
Healthy volunteers taking
no other medications:
Single-dose LAMICTAL
Multiple-dose LAMICTAL
179
36
2.2
(0.25-12.0)
1.7
(0.5-4.0)
32.8
(14.0-103.0)
25.4
(11.6-61.6)
0.44
(0.12-1.10)
0.58
(0.24-1.15)
Healthy volunteers taking
valproate:
Single-dose LAMICTAL
Multiple-dose LAMICTAL
6
18
1.8
(1.0-4.0)
1.9
(0.5-3.5)
48.3
(31.5-88.6)
70.3
(41.9-113.5)
0.30
(0.14-0.42)
0.18
(0.12-0.33)
Patients with epilepsy taking
valproate only:
Single-dose LAMICTAL
4
4.8
(1.8-8.4)
58.8
(30.5-88.8)
0.28
(0.16-0.40)
Patients with epilepsy taking
carbamazepine, phenytoin,
phenobarbital, or primidone†
plus valproate:
Single-dose LAMICTAL
25
3.8
(1.0-10.0)
27.2
(11.2-51.6)
0.53
(0.27-1.04)
Patients with epilepsy taking
carbamazepine, phenytoin,
phenobarbital, or primidone†:
Single-dose LAMICTAL
Multiple-dose LAMICTAL
24
17
2.3
(0.5-5.0)
2.0
(0.75-5.93)
14.4
(6.4-30.4)
12.6
(7.5-23.1)
1.10
(0.51-2.22)
1.21
(0.66-1.82)
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6
*The majority of parameter means determined in each study had coefficients of variation
130
between 20% and 40% for half-life and Cl/F and between 30% and 70% for Tmax. The
131
overall mean values were calculated from individual study means that were weighted based
132
on the number of volunteers/patients in each study. The numbers in parentheses below each
133
parameter mean represent the range of individual volunteer/patient values across studies.
134
† Carbamazepine, phenobarbital, phenytoin, and primidone have been shown to increase the
135
apparent clearance of lamotrigine. Estrogen-containing oral contraceptives and rifampin have
136
also been shown to increase the apparent clearance of lamotrigine (see CLINICAL
137
PHARMACOLOGY: Drug Interactions and PRECAUTIONS: Drug Interactions).
138
139
Absorption: Lamotrigine is rapidly and completely absorbed after oral administration with
140
negligible first-pass metabolism (absolute bioavailability is 98%). The bioavailability is not
141
affected by food. Peak plasma concentrations occur anywhere from 1.4 to 4.8 hours following
142
drug administration. The lamotrigine chewable/dispersible tablets were found to be equivalent,
143
whether they were administered as dispersed in water, chewed and swallowed, or swallowed as
144
whole, to the lamotrigine compressed tablets in terms of rate and extent of absorption.
145
Distribution: Estimates of the mean apparent volume of distribution (Vd/F) of lamotrigine
146
following oral administration ranged from 0.9 to 1.3 L/kg. Vd/F is independent of dose and is
147
similar following single and multiple doses in both patients with epilepsy and in healthy
148
volunteers.
149
Protein Binding: Data from in vitro studies indicate that lamotrigine is approximately 55%
150
bound to human plasma proteins at plasma lamotrigine concentrations from 1 to 10 mcg/mL
151
(10 mcg/mL is 4 to 6 times the trough plasma concentration observed in the controlled efficacy
152
trials). Because lamotrigine is not highly bound to plasma proteins, clinically significant
153
interactions with other drugs through competition for protein binding sites are unlikely. The
154
binding of lamotrigine to plasma proteins did not change in the presence of therapeutic
155
concentrations of phenytoin, phenobarbital, or valproate. Lamotrigine did not displace other
156
AEDs (carbamazepine, phenytoin, phenobarbital) from protein binding sites.
157
Drug Disposition: Lamotrigine is metabolized predominantly by glucuronic acid
158
conjugation; the major metabolite is an inactive 2-N-glucuronide conjugate. After oral
159
administration of 240 mg of 14C-lamotrigine (15 μCi) to 6 healthy volunteers, 94% was
160
recovered in the urine and 2% was recovered in the feces. The radioactivity in the urine consisted
161
of unchanged lamotrigine (10%), the 2-N-glucuronide (76%), a 5-N-glucuronide (10%), a
162
2-N-methyl metabolite (0.14%), and other unidentified minor metabolites (4%).
163
Drug Interactions: The apparent clearance of lamotrigine is affected by the
164
coadministration of certain medications. Because lamotrigine is metabolized predominantly
165
by glucuronic acid conjugation, drugs that induce or inhibit glucuronidation may affect the
166
apparent clearance of lamotrigine.
167
Carbamazepine, phenytoin, phenobarbital, and primidone have been shown to increase the
168
apparent clearance of lamotrigine (see DOSAGE AND ADMINISTRATION and
169
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7
PRECAUTIONS: Drug Interactions). Most clinical experience is derived from patients taking
170
these AEDs.
171
Estrogen-containing oral contraceptives and rifampin have also been shown to increase the
172
apparent clearance of lamotrigine (see PRECAUTIONS: Drug Interactions).
173
Valproate decreases the apparent clearance of lamotrigine (i.e., more than doubles the
174
elimination half-life of lamotrigine), whether given with or without carbamazepine,
175
phenytoin, phenobarbital, or primidone. Accordingly, if lamotrigine is to be administered to a
176
patient receiving valproate, lamotrigine must be given at a reduced dosage, of no more than half
177
the dose used in patients not receiving valproate, even in the presence of drugs that increase the
178
apparent clearance of lamotrigine (see DOSAGE AND ADMINISTRATION and
179
PRECAUTIONS: Drug Interactions).
180
The following drugs were shown not to increase the apparent clearance of lamotrigine:
181
felbamate, gabapentin, levetiracetam, oxcarbazepine, pregabalin, and topiramate. Zonisamide
182
does not appear to change the pharmacokinetic profile of lamotrigine (see PRECAUTIONS:
183
Drug Interactions).
184
In vitro inhibition experiments indicated that the formation of the primary metabolite of
185
lamotrigine, the 2-N-glucuronide, was not significantly affected by co-incubation with clozapine,
186
fluoxetine, phenelzine, risperidone, sertraline, or trazodone, and was minimally affected by co-
187
incubation with amitriptyline, bupropion, clonazepam, haloperidol, or lorazepam. In addition,
188
bufuralol metabolism data from human liver microsomes suggested that lamotrigine does not
189
inhibit the metabolism of drugs eliminated predominantly by CYP2D6.
190
LAMICTAL has no effects on the pharmacokinetics of lithium (see PRECAUTIONS: Drug
191
Interactions).
192
The pharmacokinetics of LAMICTAL were not changed by co-administration of bupropion
193
(see PRECAUTIONS: Drug Interactions).
194
Co-administration of olanzapine did not have a clinically relevant effect on LAMICTAL
195
pharmacokinetics (see PRECAUTIONS: Drug Interactions).
196
Enzyme Induction: The effects of lamotrigine on the induction of specific families of
197
mixed-function oxidase isozymes have not been systematically evaluated.
198
Following multiple administrations (150 mg twice daily) to normal volunteers taking no other
199
medications, lamotrigine induced its own metabolism, resulting in a 25% decrease in t½ and a
200
37% increase in Cl/F at steady state compared to values obtained in the same volunteers
201
following a single dose. Evidence gathered from other sources suggests that self-induction by
202
LAMICTAL may not occur when LAMICTAL is given as adjunctive therapy in patients
203
receiving carbamazepine, phenytoin, phenobarbital, primidone, or rifampin.
204
Dose Proportionality: In healthy volunteers not receiving any other medications and given
205
single doses, the plasma concentrations of lamotrigine increased in direct proportion to the dose
206
administered over the range of 50 to 400 mg. In 2 small studies (n = 7 and 8) of patients with
207
epilepsy who were maintained on other AEDs, there also was a linear relationship between dose
208
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8
and lamotrigine plasma concentrations at steady state following doses of 50 to 350 mg twice
209
daily.
210
Elimination: (see Table 1).
211
Special Populations: Patients With Renal Insufficiency: Twelve volunteers with
212
chronic renal failure (mean creatinine clearance = 13 mL/min; range = 6 to 23) and another
213
6 individuals undergoing hemodialysis were each given a single 100-mg dose of LAMICTAL.
214
The mean plasma half-lives determined in the study were 42.9 hours (chronic renal failure),
215
13.0 hours (during hemodialysis), and 57.4 hours (between hemodialysis) compared to
216
26.2 hours in healthy volunteers. On average, approximately 20% (range = 5.6 to 35.1) of the
217
amount of lamotrigine present in the body was eliminated by hemodialysis during a 4-hour
218
session.
219
Hepatic Disease: The pharmacokinetics of lamotrigine following a single 100-mg dose
220
of LAMICTAL were evaluated in 24 subjects with mild, moderate, and severe hepatic
221
dysfunction (Child-Pugh Classification system) and compared with 12 subjects without hepatic
222
impairment. The patients with severe hepatic impairment were without ascites (n = 2) or with
223
ascites (n = 5). The mean apparent clearance of lamotrigine in patients with mild (n = 12),
224
moderate (n = 5), severe without ascites (n = 2), and severe with ascites (n = 5) liver impairment
225
was 0.30 ± 0.09, 0.24 ± 0.1, 0.21 ± 0.04, and 0.15 ± 0.09 mL/min/kg, respectively, as compared
226
to 0.37 ± 0.1 mL/min/kg in the healthy controls. Mean half-life of lamotrigine in patients with
227
mild, moderate, severe without ascites, and severe with ascites liver impairment was 46 ± 20,
228
72 ± 44, 67 ± 11, and 100 ± 48 hours, respectively, as compared to 33 ± 7 hours in healthy
229
controls (for dosing guidelines, see DOSAGE AND ADMINISTRATION: Patient With Hepatic
230
Impairment).
231
Age: Pediatric Patients: The pharmacokinetics of LAMICTAL following a single
232
2-mg/kg dose were evaluated in 2 studies of pediatric patients (n = 29 for patients aged
233
10 months to 5.9 years and n = 26 for patients aged 5 to 11 years). Forty-three patients received
234
concomitant therapy with other AEDs and 12 patients received LAMICTAL as monotherapy.
235
Lamotrigine pharmacokinetic parameters for pediatric patients are summarized in Table 2.
236
Population pharmacokinetic analyses involving patients aged 2 to 18 years demonstrated that
237
lamotrigine clearance was influenced predominantly by total body weight and concurrent AED
238
therapy. The oral clearance of lamotrigine was higher, on a body weight basis, in pediatric
239
patients than in adults. Weight-normalized lamotrigine clearance was higher in those subjects
240
weighing less than 30 kg, compared with those weighing greater than 30 kg. Accordingly,
241
patients weighing less than 30 kg may need an increase of as much as 50% in maintenance doses,
242
based on clinical response, as compared with subjects weighing more than 30 kg being
243
administered the same AEDs (see DOSAGE AND ADMINISTRATION). These analyses also
244
revealed that, after accounting for body weight, lamotrigine clearance was not significantly
245
influenced by age. Thus, the same weight-adjusted doses should be administered to children
246
irrespective of differences in age. Concomitant AEDs which influence lamotrigine clearance in
247
adults were found to have similar effects in children.
248
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9
249
Table 2. Mean Pharmacokinetic Parameters in Pediatric Patients With Epilepsy
250
Pediatric Study Population
Number
of
Subjects
Tmax
(h)
t½
(h)
Cl/F
(mL/min/kg)
Ages 10 months-5.3 years
Patients taking carbamazepine,
phenytoin, phenobarbital, or
primidone*
10
3.0
(1.0-5.9)
7.7
(5.7-11.4)
3.62
(2.44-5.28)
Patients taking antiepileptic drugs
(AEDs) with no known effect on
the apparent clearance of
lamotrigine
7
5.2
(2.9-6.1)
19.0
(12.9-27.1)
1.2
(0.75-2.42)
Patients taking valproate only
8
2.9
(1.0-6.0)
44.9
(29.5-52.5)
0.47
(0.23-0.77)
Ages 5-11 years
Patients taking carbamazepine,
phenytoin, phenobarbital, or
primidone*
7
1.6
(1.0-3.0)
7.0
(3.8-9.8)
2.54
(1.35-5.58)
Patients taking carbamazepine,
phenytoin, phenobarbital, or
primidone* plus valproate
8
3.3
(1.0-6.4)
19.1
(7.0-31.2)
0.89
(0.39-1.93)
Patients taking valproate only
†
3
4.5
(3.0-6.0)
65.8
(50.7-73.7)
0.24
(0.21-0.26)
Ages 13-18 years
Patients taking carbamazepine,
phenytoin, phenobarbital, or
primidone*
11
‡
‡
1.3
Patients taking carbamazepine,
phenytoin, phenobarbital, or
primidone*plus valproate
8
‡
‡
0.5
Patients taking valproate only
4
‡
‡
0.3
*Carbamazepine, phenobarbital, phenytoin, and primidone have been shown to increase the
251
apparent clearance of lamotrigine. Estrogen-containing oral contraceptives and rifampin have
252
also been shown to increase the apparent clearance of lamotrigine (see CLINICAL
253
PHARMACOLOGY: Drug Interactions and PRECAUTIONS: Drug Interactions).
254
†Two subjects were included in the calculation for mean Tmax.
255
‡Parameter not estimated.
256
257
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10
Elderly: The pharmacokinetics of lamotrigine following a single 150-mg dose of
258
LAMICTAL were evaluated in 12 elderly volunteers between the ages of 65 and 76 years (mean
259
creatinine clearance = 61 mL/min, range = 33 to 108 mL/min). The mean half-life of lamotrigine
260
in these subjects was 31.2 hours (range, 24.5 to 43.4 hours), and the mean clearance was
261
0.40 mL/min/kg (range, 0.26 to 0.48 mL/min/kg).
262
Gender: The clearance of lamotrigine is not affected by gender. However, during dose
263
escalation of LAMICTAL in one clinical trial in patients with epilepsy on a stable dose of
264
valproate (n = 77), mean trough lamotrigine concentrations, unadjusted for weight, were 24% to
265
45% higher (0.3 to 1.7 mcg/mL) in females than in males.
266
Race: The apparent oral clearance of lamotrigine was 25% lower in non-Caucasians than
267
Caucasians.
268
CLINICAL STUDIES
269
Epilepsy: The results of controlled clinical trials established the efficacy of LAMICTAL as
270
monotherapy in adults with partial onset seizures already receiving treatment with
271
carbamazepine, phenytoin, phenobarbital, or primidone as the single antiepileptic drug (AED), as
272
adjunctive therapy in adults and pediatric patients age 2 to 16 with partial seizures, and as
273
adjunctive therapy in the generalized seizures of Lennox-Gastaut syndrome in pediatric and adult
274
patients.
275
Monotherapy With LAMICTAL in Adults With Partial Seizures Already Receiving
276
Treatment With Carbamazepine, Phenytoin, Phenobarbital, or Primidone as the
277
Single AED: The effectiveness of monotherapy with LAMICTAL was established in a
278
multicenter, double-blind clinical trial enrolling 156 adult outpatients with partial seizures. The
279
patients experienced at least 4 simple partial, complex partial, and/or secondarily generalized
280
seizures during each of 2 consecutive 4-week periods while receiving carbamazepine or
281
phenytoin monotherapy during baseline. LAMICTAL (target dose of 500 mg/day) or valproate
282
(1,000 mg/day) was added to either carbamazepine or phenytoin monotherapy over a 4-week
283
period. Patients were then converted to monotherapy with LAMICTAL or valproate during the
284
next 4 weeks, then continued on monotherapy for an additional 12-week period.
285
Study endpoints were completion of all weeks of study treatment or meeting an escape
286
criterion. Criteria for escape relative to baseline were: (1) doubling of average monthly seizure
287
count, (2) doubling of highest consecutive 2-day seizure frequency, (3) emergence of a new
288
seizure type (defined as a seizure that did not occur during the 8-week baseline) that is more
289
severe than seizure types that occur during study treatment, or (4) clinically significant
290
prolongation of generalized-tonic-clonic (GTC) seizures. The primary efficacy variable was the
291
proportion of patients in each treatment group who met escape criteria.
292
The percentage of patients who met escape criteria was 42% (32/76) in the LAMICTAL
293
group and 69% (55/80) in the valproate group. The difference in the percentage of patients
294
meeting escape criteria was statistically significant (p = 0.0012) in favor of LAMICTAL. No
295
differences in efficacy based on age, sex, or race were detected.
296
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11
Patients in the control group were intentionally treated with a relatively low dose of valproate;
297
as such, the sole objective of this study was to demonstrate the effectiveness and safety of
298
monotherapy with LAMICTAL, and cannot be interpreted to imply the superiority of
299
LAMICTAL to an adequate dose of valproate.
300
Adjunctive Therapy With LAMICTAL in Adults With Partial Seizures: The
301
effectiveness of LAMICTAL as adjunctive therapy (added to other AEDs) was established in
302
3 multicenter, placebo-controlled, double-blind clinical trials in 355 adults with refractory partial
303
seizures. The patients had a history of at least 4 partial seizures per month in spite of receiving
304
one or more AEDs at therapeutic concentrations and, in 2 of the studies, were observed on their
305
established AED regimen during baselines that varied between 8 to 12 weeks. In the third,
306
patients were not observed in a prospective baseline. In patients continuing to have at least
307
4 seizures per month during the baseline, LAMICTAL or placebo was then added to the existing
308
therapy. In all 3 studies, change from baseline in seizure frequency was the primary measure of
309
effectiveness. The results given below are for all partial seizures in the intent-to-treat population
310
(all patients who received at least one dose of treatment) in each study, unless otherwise
311
indicated. The median seizure frequency at baseline was 3 per week while the mean at baseline
312
was 6.6 per week for all patients enrolled in efficacy studies.
313
One study (n = 216) was a double-blind, placebo-controlled, parallel trial consisting of a
314
24-week treatment period. Patients could not be on more than 2 other anticonvulsants and
315
valproate was not allowed. Patients were randomized to receive placebo, a target dose of
316
300 mg/day of LAMICTAL, or a target dose of 500 mg/day of LAMICTAL. The median
317
reductions in the frequency of all partial seizures relative to baseline were 8% in patients
318
receiving placebo, 20% in patients receiving 300 mg/day of LAMICTAL, and 36% in patients
319
receiving 500 mg/day of LAMICTAL. The seizure frequency reduction was statistically
320
significant in the 500-mg/day group compared to the placebo group, but not in the 300-mg/day
321
group.
322
A second study (n = 98) was a double-blind, placebo-controlled, randomized, crossover trial
323
consisting of two 14-week treatment periods (the last 2 weeks of which consisted of dose
324
tapering) separated by a 4-week washout period. Patients could not be on more than 2 other
325
anticonvulsants and valproate was not allowed. The target dose of LAMICTAL was 400 mg/day.
326
When the first 12 weeks of the treatment periods were analyzed, the median change in seizure
327
frequency was a 25% reduction on LAMICTAL compared to placebo (p<0.001).
328
The third study (n = 41) was a double-blind, placebo-controlled, crossover trial consisting of
329
two 12-week treatment periods separated by a 4-week washout period. Patients could not be on
330
more than 2 other anticonvulsants. Thirteen patients were on concomitant valproate; these
331
patients received 150 mg/day of LAMICTAL. The 28 other patients had a target dose of
332
300 mg/day of LAMICTAL. The median change in seizure frequency was a 26% reduction on
333
LAMICTAL compared to placebo (p<0.01).
334
No differences in efficacy based on age, sex, or race, as measured by change in seizure
335
frequency, were detected.
336
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For current labeling information, please visit https://www.fda.gov/drugsatfda
12
Adjunctive Therapy With LAMICTAL in Pediatric Patients With Partial Seizures:
337
The effectiveness of LAMICTAL as adjunctive therapy in pediatric patients with partial seizures
338
was established in a multicenter, double-blind, placebo-controlled trial in 199 patients aged 2 to
339
16 years (n = 98 on LAMICTAL, n = 101 on placebo). Following an 8-week baseline phase,
340
patients were randomized to 18 weeks of treatment with LAMICTAL or placebo added to their
341
current AED regimen of up to 2 drugs. Patients were dosed based on body weight and valproate
342
use. Target doses were designed to approximate 5 mg/kg per day for patients taking valproate
343
(maximum dose, 250 mg/day) and 15 mg/kg per day for the patients not taking valproate
344
(maximum dose, 750 mg per day). The primary efficacy endpoint was percentage change from
345
baseline in all partial seizures. For the intent-to-treat population, the median reduction of all
346
partial seizures was 36% in patients treated with LAMICTAL and 7% on placebo, a difference
347
that was statistically significant (p<0.01).
348
Adjunctive Therapy With LAMICTAL in Pediatric and Adult Patients With
349
Lennox-Gastaut Syndrome: The effectiveness of LAMICTAL as adjunctive therapy in
350
patients with Lennox-Gastaut syndrome was established in a multicenter, double-blind,
351
placebo-controlled trial in 169 patients aged 3 to 25 years (n = 79 on LAMICTAL, n = 90 on
352
placebo). Following a 4-week single-blind, placebo phase, patients were randomized to 16 weeks
353
of treatment with LAMICTAL or placebo added to their current AED regimen of up to 3 drugs.
354
Patients were dosed on a fixed-dose regimen based on body weight and valproate use. Target
355
doses were designed to approximate 5 mg/kg per day for patients taking valproate (maximum
356
dose, 200 mg/day) and 15 mg/kg per day for patients not taking valproate (maximum dose,
357
400 mg/day). The primary efficacy endpoint was percentage change from baseline in major
358
motor seizures (atonic, tonic, major myoclonic, and tonic-clonic seizures). For the intent-to-treat
359
population, the median reduction of major motor seizures was 32% in patients treated with
360
LAMICTAL and 9% on placebo, a difference that was statistically significant (p<0.05). Drop
361
attacks were significantly reduced by LAMICTAL (34%) compared to placebo (9%), as were
362
tonic-clonic seizures (36% reduction versus 10% increase for LAMICTAL and placebo,
363
respectively).
364
Adjunctive Therapy With LAMICTAL in Pediatric and Adult Patients With
365
Primary Generalized Tonic-Clonic Seizures: The effectiveness of LAMICTAL as
366
adjunctive therapy in patients with primary generalized tonic-clonic seizures was established in a
367
multicenter, double-blind, placebo-controlled trial in 117 pediatric and adult patients ≥ 2 years
368
(n = 58 on LAMICTAL, n = 59 on placebo). Patients with at least 3 primary generalized tonic-
369
clonic seizures during an 8-week baseline phase were randomized to 19 to 24 weeks of treatment
370
with LAMICTAL or placebo added to their current AED regimen of up to 2 drugs. Patients were
371
dosed on a fixed-dose regimen, with target doses ranging from 3 mg/kg/day to 12 mg/kg/day for
372
pediatric patients and from 200 mg/day to 400 mg/day for adult patients based on concomitant
373
AED.
374
The primary efficacy endpoint was percentage change from baseline in primary generalized
375
tonic-clonic seizures. For the intent-to-treat population, the median percent reduction of primary
376
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For current labeling information, please visit https://www.fda.gov/drugsatfda
13
generalized tonic-clonic seizures was 66% in patients treated with LAMICTAL and 34% on
377
placebo, a difference that was statistically significant (p=0.006).
378
379
Bipolar Disorder: The effectiveness of LAMICTAL in the maintenance treatment of Bipolar I
380
Disorder was established in 2 multicenter, double-blind, placebo-controlled studies in adult
381
patients who met DSM-IV criteria for Bipolar I Disorder. Study 1 enrolled patients with a current
382
or recent (within 60 days) depressive episode as defined by DSM-IV and Study 2 included
383
patients with a current or recent (within 60 days) episode of mania or hypomania as defined by
384
DSM-IV. Both studies included a cohort of patients (30% of 404 patients in Study 1 and 28% of
385
171 patients in Study 2) with rapid cycling Bipolar Disorder (4 to 6 episodes per year).
386
In both studies, patients were titrated to a target dose of 200 mg of LAMICTAL, as add-on
387
therapy or as monotherapy, with gradual withdrawal of any psychotropic medications during an
388
8- to 16-week open-label period. Overall 81% of 1,305 patients participating in the open-label
389
period were receiving 1 or more other psychotropic medications, including benzodiazepines,
390
selective serotonin reuptake inhibitors (SSRIs), atypical antipsychotics (including olanzapine),
391
valproate, or lithium, during titration of LAMICTAL. Patients with a CGI-severity score of 3 or
392
less maintained for at least 4 continuous weeks, including at least the final week on monotherapy
393
with LAMICTAL, were randomized to a placebo-controlled, double-blind treatment period for
394
up to 18 months. The primary endpoint was TIME (time to intervention for a mood episode or
395
one that was emerging, time to discontinuation for either an adverse event that was judged to be
396
related to Bipolar Disorder, or for lack of efficacy). The mood episode could be depression,
397
mania, hypomania, or a mixed episode.
398
In Study 1, patients received double-blind monotherapy with LAMICTAL, 50 mg/day
399
(n = 50), LAMICTAL 200 mg/day (n = 124), LAMICTAL 400 mg/day (n = 47), or placebo
400
(n = 121). LAMICTAL (200- and 400-mg/day treatment groups combined) was superior to
401
placebo in delaying the time to occurrence of a mood episode. Separate analyses of the 200 and
402
400 mg/day dose groups revealed no added benefit from the higher dose.
403
In Study 2, patients received double-blind monotherapy with LAMICTAL (100 to
404
400 mg/day, n = 59), or placebo (n = 70). LAMICTAL was superior to placebo in delaying time
405
to occurrence of a mood episode. The mean LAMICTAL dose was about 211 mg/day.
406
Although these studies were not designed to separately evaluate time to the occurrence of
407
depression or mania, a combined analysis for the 2 studies revealed a statistically significant
408
benefit for LAMICTAL over placebo in delaying the time to occurrence of both depression and
409
mania, although the finding was more robust for depression.
410
INDICATIONS AND USAGE
411
Epilepsy:
412
Adjunctive Use: LAMICTAL is indicated as adjunctive therapy for partial seizures, the
413
generalized seizures of Lennox-Gastaut syndrome, and primary generalized tonic-clonic seizures
414
in adults and pediatric patients (≥2 years of age).
415
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
14
416
Monotherapy Use: LAMICTAL is indicated for conversion to monotherapy in adults with
417
partial seizures.who are receiving treatment with carbamazepine, phenytoin, phenobarbital,
418
primidone, or valproate as the single AED.
419
Safety and effectiveness of LAMICTAL have not been established (1) as initial monotherapy,
420
(2) for conversion to monotherapy from AEDs other than carbamazepine, phenytoin,
421
phenobarbital, primidone, or valproate, or (3) for simultaneous conversion to monotherapy from
422
2 or more concomitant AEDs (see DOSAGE AND ADMINISTRATION).
423
424
Bipolar Disorder: LAMICTAL is indicated for the maintenance treatment of Bipolar I
425
Disorder to delay the time to occurrence of mood episodes (depression, mania, hypomania,
426
mixed episodes) in patients treated for acute mood episodes with standard therapy. The
427
effectiveness of LAMICTAL in the acute treatment of mood episodes has not been established.
428
The effectiveness of LAMICTAL as maintenance treatment was established in
429
2 placebo-controlled trials of 18 months’ duration in patients with Bipolar I Disorder as defined
430
by DSM-IV (see CLINICAL STUDIES, Bipolar Disorder). The physician who elects to use
431
LAMICTAL for periods extending beyond 18 months should periodically re-evaluate the
432
long-term usefulness of the drug for the individual patient.
433
CONTRAINDICATIONS
434
LAMICTAL is contraindicated in patients who have demonstrated hypersensitivity to the drug
435
or its ingredients.
436
WARNINGS
437
SEE BOX WARNING REGARDING THE RISK OF SERIOUS RASHES REQUIRING
438
HOSPITALIZATION AND DISCONTINUATION OF LAMICTAL.
439
ALTHOUGH BENIGN RASHES ALSO OCCUR WITH LAMICTAL, IT IS NOT
440
POSSIBLE TO PREDICT RELIABLY WHICH RASHES WILL PROVE TO BE
441
SERIOUS OR LIFE THREATENING. ACCORDINGLY, LAMICTAL SHOULD
442
ORDINARILY BE DISCONTINUED AT THE FIRST SIGN OF RASH, UNLESS THE
443
RASH IS CLEARLY NOT DRUG RELATED. DISCONTINUATION OF TREATMENT
444
MAY NOT PREVENT A RASH FROM BECOMING LIFE THREATENING OR
445
PERMANENTLY DISABLING OR DISFIGURING.
446
Serious Rash: Pediatric Population: The incidence of serious rash associated with
447
hospitalization and discontinuation of LAMICTAL in a prospectively followed cohort of
448
pediatric patients with epilepsy receiving adjunctive therapy was approximately 0.8% (16 of
449
1,983). When 14 of these cases were reviewed by 3 expert dermatologists, there was
450
considerable disagreement as to their proper classification. To illustrate, one dermatologist
451
considered none of the cases to be Stevens-Johnson syndrome; another assigned 7 of the 14 to
452
this diagnosis. There was 1 rash-related death in this 1,983 patient cohort. Additionally, there
453
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
15
have been rare cases of toxic epidermal necrolysis with and without permanent sequelae and/or
454
death in US and foreign postmarketing experience.
455
There is evidence that the inclusion of valproate in a multidrug regimen increases the risk of
456
serious, potentially life-threatening rash in pediatric patients. In pediatric patients who used
457
valproate concomitantly, 1.2% (6 of 482) experienced a serious rash compared to 0.6% (6 of
458
952) patients not taking valproate.
459
Adult Population: Serious rash associated with hospitalization and discontinuation of
460
LAMICTAL occurred in 0.3% (11 of 3,348) of adult patients who received LAMICTAL in
461
premarketing clinical trials of epilepsy. In the bipolar and other mood disorders clinical trials, the
462
rate of serious rash was 0.08% (1 of 1,233) of adult patients who received LAMICTAL as initial
463
monotherapy and 0.13% (2 of 1,538) of adult patients who received LAMICTAL as adjunctive
464
therapy. No fatalities occurred among these individuals. However, in worldwide postmarketing
465
experience, rare cases of rash-related death have been reported, but their numbers are too few to
466
permit a precise estimate of the rate.
467
Among the rashes leading to hospitalization were Stevens-Johnson syndrome, toxic epidermal
468
necrolysis, angioedema, and a rash associated with a variable number of the following systemic
469
manifestations: fever, lymphadenopathy, facial swelling, hematologic, and hepatologic
470
abnormalities.
471
There is evidence that the inclusion of valproate in a multidrug regimen increases the risk of
472
serious, potentially life-threatening rash in adults. Specifically, of 584 patients administered
473
LAMICTAL with valproate in epilepsy clinical trials, 6 (1%) were hospitalized in association
474
with rash; in contrast, 4 (0.16%) of 2,398 clinical trial patients and volunteers administered
475
LAMICTAL in the absence of valproate were hospitalized.
476
Other examples of serious and potentially life-threatening rash that did not lead to
477
hospitalization also occurred in premarketing development. Among these, 1 case was reported to
478
be Stevens-Johnson–like.
479
Hypersensitivity Reactions: Hypersensitivity reactions, some fatal or life threatening, have
480
also occurred. Some of these reactions have included clinical features of multiorgan
481
failure/dysfunction, including hepatic abnormalities and evidence of disseminated intravascular
482
coagulation. It is important to note that early manifestations of hypersensitivity (e.g., fever,
483
lymphadenopathy) may be present even though a rash is not evident. If such signs or symptoms
484
are present, the patient should be evaluated immediately. LAMICTAL should be discontinued if
485
an alternative etiology for the signs or symptoms cannot be established.
486
Prior to initiation of treatment with LAMICTAL, the patient should be instructed that a
487
rash or other signs or symptoms of hypersensitivity (e.g., fever, lymphadenopathy) may
488
herald a serious medical event and that the patient should report any such occurrence to a
489
physician immediately.
490
Acute Multiorgan Failure: Multiorgan failure, which in some cases has been fatal or
491
irreversible, has been observed in patients receiving LAMICTAL. Fatalities associated with
492
multiorgan failure and various degrees of hepatic failure have been reported in 2 of 3,796 adult
493
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
16
patients and 4 of 2,435 pediatric patients who received LAMICTAL in clinical trials. No such
494
fatalities have been reported in bipolar patients in clinical trials. Rare fatalities from multiorgan
495
failure have also been reported in compassionate plea and postmarketing use. The majority of
496
these deaths occurred in association with other serious medical events, including status
497
epilepticus and overwhelming sepsis, and hantavirus making it difficult to identify the initial
498
cause.
499
Additionally, 3 patients (a 45-year-old woman, a 3.5-year-old boy, and an 11-year-old girl)
500
developed multiorgan dysfunction and disseminated intravascular coagulation 9 to 14 days after
501
LAMICTAL was added to their AED regimens. Rash and elevated transaminases were also
502
present in all patients and rhabdomyolysis was noted in 2 patients. Both pediatric patients were
503
receiving concomitant therapy with valproate, while the adult patient was being treated with
504
carbamazepine and clonazepam. All patients subsequently recovered with supportive care after
505
treatment with LAMICTAL was discontinued.
506
Blood Dyscrasias: There have been reports of blood dyscrasias that may or may not be
507
associated with the hypersensitivity syndrome. These have included neutropenia, leukopenia,
508
anemia, thrombocytopenia, pancytopenia, and, rarely, aplastic anemia and pure red cell aplasia.
509
Withdrawal Seizures: As with other AEDs, LAMICTAL should not be abruptly discontinued.
510
In patients with epilepsy there is a possibility of increasing seizure frequency. In clinical trials in
511
patients with Bipolar Disorder, 2 patients experienced seizures shortly after abrupt withdrawal of
512
LAMICTAL. However, there were confounding factors that may have contributed to the
513
occurrence of seizures in these bipolar patients. Unless safety concerns require a more rapid
514
withdrawal, the dose of LAMICTAL should be tapered over a period of at least 2 weeks (see
515
DOSAGE AND ADMINISTRATION).
516
PRECAUTIONS
517
518
Concomitant Use With Oral Contraceptives: Some estrogen-containing oral
519
contraceptives have been shown to decrease serum concentrations of lamotrigine (see
520
PRECAUTIONS: Drug Interactions). Dosage adjustments will be necessary in most patients
521
who start or stop estrogen-containing oral contraceptives while taking LAMICTAL (see
522
DOSAGE AND ADMINISTRATION: Special Populations: Women and Oral
523
Contraceptives: Adjustments to the Maintenance Dose of LAMICTAL). During the week of
524
inactive hormone preparation (“pill-free” week) of oral contraceptive therapy, plasma levels are
525
expected to rise, as much as doubling by the end of the week. Adverse events consistent with
526
elevated levels of lamotrigine, such as dizziness, ataxia, and diplopia, could occur.
527
Dermatological Events (see BOX WARNING, WARNINGS): Serious rashes associated
528
with hospitalization and discontinuation of LAMICTAL have been reported. Rare deaths have
529
been reported, but their numbers are too few to permit a precise estimate of the rate. There are
530
suggestions, yet to be proven, that the risk of rash may also be increased by (1) coadministration
531
of LAMICTAL with valproate, (2) exceeding the recommended initial dose of LAMICTAL, or
532
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
17
(3) exceeding the recommended dose escalation for LAMICTAL. However, cases have been
533
reported in the absence of these factors.
534
In epilepsy clinical trials, approximately 10% of all patients exposed to LAMICTAL
535
developed a rash. In the Bipolar Disorder clinical trials, 14% of patients exposed to LAMICTAL
536
developed a rash. Rashes associated with LAMICTAL do not appear to have unique identifying
537
features. Typically, rash occurs in the first 2 to 8 weeks following treatment initiation. However,
538
isolated cases have been reported after prolonged treatment (e.g., 6 months). Accordingly,
539
duration of therapy cannot be relied upon as a means to predict the potential risk heralded by the
540
first appearance of a rash.
541
Although most rashes resolved even with continuation of treatment with LAMICTAL, it is not
542
possible to predict reliably which rashes will prove to be serious or life threatening.
543
ACCORDINGLY, LAMICTAL SHOULD ORDINARILY BE DISCONTINUED AT THE
544
FIRST SIGN OF RASH, UNLESS THE RASH IS CLEARLY NOT DRUG RELATED.
545
DISCONTINUATION OF TREATMENT MAY NOT PREVENT A RASH FROM
546
BECOMING LIFE THREATENING OR PERMANENTLY DISABLING OR
547
DISFIGURING.
548
It is recommended that LAMICTAL not be restarted in patients who discontinued due to rash
549
associated with prior treatment with LAMICTAL unless the potential benefits clearly outweigh
550
the risks. If the decision is made to restart a patient who has discontinued LAMICTAL, the need
551
to restart with the initial dosing recommendations should be assessed. The greater the interval of
552
time since the previous dose, the greater consideration should be given to restarting with the
553
initial dosing recommendations. If a patient has discontinued LAMICTAL for a period of more
554
than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be
555
followed. The half-life of LAMICTAL is affected by other concomitant medications (see
556
CLINICAL PHARMACOLOGY: Pharmacokinetics and Drug Metabolism, and DOSAGE AND
557
ADMINISTRATION).
558
Use in Patients With Epilepsy:
559
Sudden Unexplained Death in Epilepsy (SUDEP): During the premarketing
560
development of LAMICTAL, 20 sudden and unexplained deaths were recorded among a cohort
561
of 4,700 patients with epilepsy (5,747 patient-years of exposure).
562
Some of these could represent seizure-related deaths in which the seizure was not observed,
563
e.g., at night. This represents an incidence of 0.0035 deaths per patient-year. Although this rate
564
exceeds that expected in a healthy population matched for age and sex, it is within the range of
565
estimates for the incidence of sudden unexplained deaths in patients with epilepsy not receiving
566
LAMICTAL (ranging from 0.0005 for the general population of patients with epilepsy, to 0.004
567
for a recently studied clinical trial population similar to that in the clinical development program
568
for LAMICTAL, to 0.005 for patients with refractory epilepsy). Consequently, whether these
569
figures are reassuring or suggest concern depends on the comparability of the populations
570
reported upon to the cohort receiving LAMICTAL and the accuracy of the estimates provided.
571
Probably most reassuring is the similarity of estimated SUDEP rates in patients receiving
572
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
18
LAMICTAL and those receiving another antiepileptic drug that underwent clinical testing in a
573
similar population at about the same time. Importantly, that drug is chemically unrelated to
574
LAMICTAL. This evidence suggests, although it certainly does not prove, that the high SUDEP
575
rates reflect population rates, not a drug effect.
576
Status Epilepticus: Valid estimates of the incidence of treatment emergent status
577
epilepticus among patients treated with LAMICTAL are difficult to obtain because reporters
578
participating in clinical trials did not all employ identical rules for identifying cases. At a
579
minimum, 7 of 2,343 adult patients had episodes that could unequivocally be described as status.
580
In addition, a number of reports of variably defined episodes of seizure exacerbation (e.g.,
581
seizure clusters, seizure flurries, etc.) were made.
582
Use in Patients With Bipolar Disorder:
583
Acute Treatment of Mood Episodes: Safety and effectiveness of LAMICTAL in the
584
acute treatment of mood episodes has not been established.
585
Children and Adolescents (less than 18 years of age): Treatment with
586
antidepressants is associated with an increased risk of suicidal thinking and behavior in children
587
and adolescents with major depressive disorder and other psychiatric disorders. It is not known
588
whether LAMICTAL is associated with a similar risk in this population (see PRECAUTIONS:
589
Clinical Worsening and Suicide Risk Associated With Bipolar Disorder).
590
Safety and effectiveness of LAMICTAL in patients below the age of 18 years with mood
591
disorders have not been established.
592
Clinical Worsening and Suicide Risk Associated with Bipolar Disorder:
593
Patients with bipolar disorder may experience worsening of their depressive symptoms and/or
594
the emergence of suicidal ideation and behaviors (suicidality) whether or not they are taking
595
medications for bipolar disorder. Patients should be closely monitored for clinical worsening
596
(including development of new symptoms) and suicidality, especially at the beginning of a
597
course of treatment, or at the time of dose changes.
598
In addition, patients with a history of suicidal behavior or thoughts, those patients exhibiting a
599
significant degree of suicidal ideation prior to commencement of treatment, and young adults,
600
are at an increased risk of suicidal thoughts or suicide attempts, and should receive careful
601
monitoring during treatment.
602
Patients (and caregivers of patients) should be alerted about the need to monitor for any
603
worsening of their condition (including development of new symptoms) and /or the emergence
604
of suicidal ideation/behavior or thoughts of harming themselves and to seek medical advice
605
immediately if these symptoms present.
606
Consideration should be given to changing the therapeutic regimen, including possibly
607
discontinuing the medication, in patients who experience clinical worsening (including
608
development of new symptoms) and/or the emergence of suicidal ideation/behavior especially if
609
these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting
610
symptoms.
611
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
19
Prescriptions for LAMICTAL should be written for the smallest quantity of tablets consistent
612
with good patient management, in order to reduce the risk of overdose. Overdoses have been
613
reported for LAMICTAL, some of which have been fatal (see OVERDOSAGE).
614
Addition of LAMICTAL to a Multidrug Regimen That Includes Valproate (Dosage
615
Reduction): Because valproate reduces the clearance of lamotrigine, the dosage of lamotrigine
616
in the presence of valproate is less than half of that required in its absence (see DOSAGE AND
617
ADMINISTRATION).
618
Use in Patients With Concomitant Illness: Clinical experience with LAMICTAL in
619
patients with concomitant illness is limited. Caution is advised when using LAMICTAL in
620
patients with diseases or conditions that could affect metabolism or elimination of the drug, such
621
as renal, hepatic, or cardiac functional impairment.
622
Hepatic metabolism to the glucuronide followed by renal excretion is the principal route of
623
elimination of lamotrigine (see CLINICAL PHARMACOLOGY).
624
A study in individuals with severe chronic renal failure (mean creatinine
625
clearance = 13 mL/min) not receiving other AEDs indicated that the elimination half-life of
626
unchanged lamotrigine is prolonged relative to individuals with normal renal function. Until
627
adequate numbers of patients with severe renal impairment have been evaluated during chronic
628
treatment with LAMICTAL, it should be used with caution in these patients, generally using a
629
reduced maintenance dose for patients with significant impairment.
630
Because there is limited experience with the use of LAMICTAL in patients with impaired
631
liver function, the use in such patients may be associated with as yet unrecognized risks (see
632
CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).
633
Binding in the Eye and Other Melanin-Containing Tissues: Because lamotrigine binds
634
to melanin, it could accumulate in melanin-rich tissues over time. This raises the possibility that
635
lamotrigine may cause toxicity in these tissues after extended use. Although ophthalmological
636
testing was performed in one controlled clinical trial, the testing was inadequate to exclude
637
subtle effects or injury occurring after long-term exposure. Moreover, the capacity of available
638
tests to detect potentially adverse consequences, if any, of lamotrigine's binding to melanin is
639
unknown.
640
Accordingly, although there are no specific recommendations for periodic ophthalmological
641
monitoring, prescribers should be aware of the possibility of long-term ophthalmologic effects.
642
Information for Patients: Prior to initiation of treatment with LAMICTAL, the patient should
643
be instructed that a rash or other signs or symptoms of hypersensitivity (e.g., fever,
644
lymphadenopathy) may herald a serious medical event and that the patient should report any
645
such occurrence to a physician immediately. In addition, the patient should notify his or her
646
physician if worsening of seizure control occurs.
647
Patients should be advised that LAMICTAL may cause dizziness, somnolence, and other
648
symptoms and signs of central nervous system (CNS) depression. Accordingly, they should be
649
advised neither to drive a car nor to operate other complex machinery until they have gained
650
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
20
sufficient experience on LAMICTAL to gauge whether or not it adversely affects their mental
651
and/or motor performance.
652
Patients should be advised to notify their physicians if they become pregnant or intend to
653
become pregnant during therapy. Patients should be advised to notify their physicians if they
654
intend to breast-feed or are breast-feeding an infant.
655
Women should be advised to notify their physician if they plan to start or stop use of oral
656
contraceptives or other female hormonal preparations. Starting estrogen-containing oral
657
contraceptives may significantly decrease lamotrigine plasma levels and stopping estrogen-
658
containing oral contraceptives (including the “pill-free” week) may significantly increase
659
lamotrigine plasma levels (see PRECAUTIONS: Drug Interactions). Women should also be
660
advised to promptly notify their physician if they experience adverse events or changes in
661
menstrual pattern (e.g., break-through bleeding) while receiving LAMICTAL in combination
662
with these medications.
663
Patients should be advised to notify their physician if they stop taking LAMICTAL for any
664
reason and not to resume LAMICTAL without consulting their physician.
665
Patients should be informed of the availability of a patient information leaflet, and they should
666
be instructed to read the leaflet prior to taking LAMICTAL. See PATIENT INFORMATION at
667
the end of this labeling for the text of the leaflet provided for patients.
668
Laboratory Tests: The value of monitoring plasma concentrations of LAMICTAL has not
669
been established. Because of the possible pharmacokinetic interactions between LAMICTAL
670
and other drugs including AEDs (see Table 3), monitoring of the plasma levels of LAMICTAL
671
and concomitant drugs may be indicated, particularly during dosage adjustments. In general,
672
clinical judgment should be exercised regarding monitoring of plasma levels of LAMICTAL and
673
other drugs and whether or not dosage adjustments are necessary.
674
675
Drug Interactions:
676
677
The net effects of drug interactions with LAMICTAL are summarized in Table 3 (see also
678
DOSAGE AND ADMINISTRATION).
679
680
Oral Contraceptives: In 16 female volunteers, an oral contraceptive preparation containing
681
30 mcg ethinylestradiol and 150 mcg levonorgestrel increased the apparent clearance of
682
lamotrigine (300 mg/day) by approximately 2-fold with a mean decrease in AUC of 52% and in
683
Cmax of 39%. In this study, trough serum lamotrigine concentrations gradually increased and
684
were approximately 2-fold higher on average at the end of the week of the inactive preparation
685
compared to trough lamotrigine concentrations at the end of the active hormone cycle.
686
Gradual transient increases in lamotrigine plasma levels (approximate 2-fold increase)
687
occurred during the week of inactive hormone preparation (“pill-free” week) for women not also
688
taking a drug that increased the clearance of lamotrigine (carbamazepine, phenytoin,
689
phenobarbital, primidone, or rifampin). The increase in lamotrigine plasma levels will be greater
690
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
21
if the dose of LAMICTAL is increased in the few days before or during the “pill-free” week.
691
Increases in lamotrigine plasma levels could result in dose-dependent adverse effects (see
692
PRECAUTIONS: Concomitant Use With Oral Contraceptives).
693
In the same study, co-administration of LAMICTAL (300 mg/day) in 16 female volunteers
694
did not affect the pharmacokinetics of the ethinylestradiol component of the oral contraceptive
695
preparation. There was a mean decrease in the AUC and Cmax of the levonorgestrel component of
696
19% and 12%, respectively. Measurement of serum progesterone indicated that there was no
697
hormonal evidence of ovulation in any of the 16 volunteers, although measurement of serum
698
FSH, LH, and estradiol indicated that there was some loss of suppression of the hypothalamic-
699
pituitary-ovarian axis.
700
The effects of doses of LAMICTAL other than 300 mg/day have not been studied in clinical
701
trials.
702
The clinical significance of the observed hormonal changes on ovulatory activity is unknown.
703
However, the possibility of decreased contraceptive efficacy in some patients cannot be
704
excluded. Therefore, patients should be instructed to promptly report changes in their menstrual
705
pattern (e.g., break-through bleeding).
706
Dosage adjustments will be necessary for most women receiving estrogen-containing oral
707
contraceptive preparations (see DOSAGE AND ADMINISTRATION: Special Populations:
708
Women and Oral Contraceptives).
709
Other Hormonal Contraceptives or Hormone Replacement Therapy: The effect of
710
other hormonal contraceptive preparations or hormone replacement therapy on the
711
pharmacokinetics of lamotrigine has not been systematically evaluated, It has been reported that
712
ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the
713
progestin only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the
714
dosage of LAMICTAL in the presence of progestogens alone will likely not be needed.
715
716
Bupropion: The pharmacokinetics of a 100-mg single dose of LAMICTAL in healthy
717
volunteers (n = 12) were not changed by co-administration of bupropion sustained-release
718
formulation (150 mg twice a day) starting 11 days before LAMICTAL.
719
Carbamazepine: LAMICTAL has no appreciable effect on steady-state carbamazepine
720
plasma concentration. Limited clinical data suggest there is a higher incidence of dizziness,
721
diplopia, ataxia, and blurred vision in patients receiving carbamazepine with LAMICTAL than in
722
patients receiving other AEDs with LAMICTAL (see ADVERSE REACTIONS). The
723
mechanism of this interaction is unclear. The effect of LAMICTAL on plasma concentrations of
724
carbamazepine-epoxide is unclear. In a small subset of patients (n = 7) studied in a
725
placebo-controlled trial, LAMICTAL had no effect on carbamazepine-epoxide plasma
726
concentrations, but in a small, uncontrolled study (n = 9), carbamazepine-epoxide levels
727
increased.
728
The addition of carbamazepine decreases lamotrigine steady-state concentrations by
729
approximately 40%.
730
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
22
Felbamate: In a study of 21 healthy volunteers, coadministration of felbamate (1,200 mg
731
twice daily) with LAMICTAL (100 mg twice daily for 10 days) appeared to have no clinically
732
relevant effects on the pharmacokinetics of lamotrigine.
733
Folate Inhibitors: Lamotrigine is a weak inhibitor of dihydrofolate reductase. Prescribers
734
should be aware of this action when prescribing other medications that inhibit folate metabolism.
735
Gabapentin: Based on a retrospective analysis of plasma levels in 34 patients who received
736
LAMICTAL both with and without gabapentin, gabapentin does not appear to change the
737
apparent clearance of lamotrigine.
738
Levetiracetam: Potential drug interactions between levetiracetam and LAMICTAL were
739
assessed by evaluating serum concentrations of both agents during placebo-controlled clinical
740
trials. These data indicate that LAMICTAL does not influence the pharmacokinetics of
741
levetiracetam and that levetiracetam does not influence the pharmacokinetics of LAMICTAL.
742
Lithium: The pharmacokinetics of lithium were not altered in healthy subjects (n = 20) by
743
co-administration of LAMICTAL (100 mg/day) for 6 days.
744
Olanzapine: The AUC and Cmax of olanzapine were similar following the addition of
745
olanzapine (15 mg once daily) to LAMICTAL (200 mg once daily) in healthy male volunteers
746
(n = 16) compared to the AUC and Cmax in healthy male volunteers receiving olanzapine alone
747
(n = 16).
748
In the same study, the AUC and Cmax of lamotrigine was reduced on average by 24% and
749
20%, respectively, following the addition of olanzapine to LAMICTAL in healthy male
750
volunteers compared to those receiving LAMICTAL alone. This reduction in lamotrigine plasma
751
concentrations is not expected to be clinically relevant.
752
Oxcarbazepine: The AUC and Cmax of oxcarbazepine and its active 10-monohydroxy
753
oxcarbazepine metabolite were not significantly different following the addition of
754
oxcarbazepine (600 mg twice daily) to LAMICTAL (200 mg once daily) in healthy male
755
volunteers (n = 13) compared to healthy male volunteers receiving oxcarbazepine alone (n = 13).
756
In the same study, the AUC and Cmax of lamotrigine were similar following the addition of
757
oxcarbazepine (600 mg twice daily) to LAMICTAL in healthy male volunteers compared to
758
those receiving LAMICTAL alone. Limited clinical data suggest a higher incidence of headache,
759
dizziness, nausea, and somnolence with coadministration of LAMICTAL and oxcarbazepine
760
compared to LAMICTAL alone or oxcarbazepine alone.
761
Phenobarbital, Primidone: The addition of phenobarbital or primidone decreases
762
lamotrigine steady-state concentrations by approximately 40%.
763
Phenytoin: LAMICTAL has no appreciable effect on steady-state phenytoin plasma
764
concentrations in patients with epilepsy. The addition of phenytoin decreases lamotrigine steady-
765
state concentrations by approximately 40%.
766
Pregabalin: Steady-state trough plasma concentrations of lamotrigine were not affected by
767
concomitant pregabalin (200 mg 3 times daily) administration. There are no pharmacokinetic
768
interactions between LAMICTAL and pregabalin.
769
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
23
Rifampin: In 10 male volunteers, rifampin (600 mg/day for 5 days) significantly increased
770
the apparent clearance of a single 25 mg dose of LAMICTAL by approximately 2-fold (AUC
771
decreased by approximately 40%).
772
Topiramate: Topiramate resulted in no change in plasma concentrations of lamotrigine.
773
Administration of LAMICTAL resulted in a 15% increase in topiramate concentrations.
774
Valproate: When LAMICTAL was administered to healthy volunteers (n = 18) receiving
775
valproate, the trough steady-state valproate plasma concentrations decreased by an average of
776
25% over a 3-week period, and then stabilized. However, adding LAMICTAL to the existing
777
therapy did not cause a change in valproate plasma concentrations in either adult or pediatric
778
patients in controlled clinical trials.
779
The addition of valproate increased lamotrigine steady-state concentrations in normal
780
volunteers by slightly more than 2-fold. In one study, maximal inhibition of lamotrigine
781
clearance was reached at valproate doses between 250 mg/day and 500 mg/day and did not
782
increase as the valproate dose was further increased.
783
Zonisamide: In a study of 18 patients with epilepsy, coadministration of zonisamide (200 to
784
400 mg/day) with LAMICTAL (150 to 500 mg/day) for 35 days had no significant effect on the
785
pharmacokinetics of lamotrigine.
786
Known Inducers or Inhibitors of Glucuronidation: Drugs other than those listed above
787
have not been systematically evaluated in combination with LAMICTAL. Since lamotrigine is
788
metabolized predominately by glucuronic acid conjugation, drugs that are known to induce or
789
inhibit glucuronidation may affect the apparent clearance of lamotrigine, and doses of
790
LAMICTAL may require adjustment based on clinical response.
791
Other: Results of in vitro experiments suggest that clearance of lamotrigine is unlikely to be
792
reduced by concomitant administration of amitriptyline, clonazepam, clozapine, fluoxetine,
793
haloperidol, lorazepam, phenelzine, risperidone, sertraline, or trazodone (see CLINICAL
794
PHARMACOLOGY: Pharmacokinetics and Drug Metabolism).
Results of in vitro
795
experiments suggest that lamotrigine does not reduce the clearance of drugs eliminated
796
predominantly by CYP2D6 (see CLINICAL PHARMACOLOGY).
797
.
798
Table 3. Summary of Drug Interactions With LAMICTAL
799
Drug
Drug Plasma
Concentration With
Adjunctive
LAMICTAL*
Lamotrigine Plasma
Concentration With Adjunctive
Drugs†
Oral contraceptives (e.g.,
ethinylestradiol/levonorgestrel)‡
↔§
↓
Bupropion
Not assessed
↔
Carbamazepine (CBZ)
↔
↓
CBZ epoxide║
?
Felbamate
Not assessed
↔
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
24
Gabapentin
Not assessed
↔
Levetiracetam
↔
↔
Lithium
↔
Not assessed
Olanzapine
↔
↔¶
Oxcarbazepine
↔
↔
10-monohydroxy oxcarbazepine
metabolite#
↔
Phenobarbital/primidone
↔
↓
Phenytoin (PHT)
↔
↓
Pregabalin
↔
↔
Rifampin
Not assessed
↓
Topiramate
↔**
↔
Valproate
↓
↑
Valproate + PHT and/or CBZ
Not assessed
↔
Zonisamide
Not assessed
↔
* From adjunctive clinical trials and volunteer studies.
800
† Net effects were estimated by comparing the mean clearance values obtained in adjunctive
801
clinical trials and volunteers studies.
802
‡ The effect of other hormonal contraceptive preparations or hormone replacement therapy on the
803
pharmacokinetics of lamotrigine has not been systematically evaluated in clinical trials and
804
the effect may not be similar to that seen with the ethinylestradiol/levonorgestrel
805
combinations.
806
§Modest decrease in levonorgestrel (see PRECAUTIONS: Drug Interactions: Effect of
807
LAMICTAL on Oral Contraceptives).
808
║Not administered, but an active metabolite of carbamazepine.
809
¶Slight decrease, not expected to be clinically relevant.
810
#Not administered, but an active metabolite of oxcarbazepine.
811
** Slight increase not expected to be clinically relevant.
812
↔ = No significant effect.
813
814
Drug/Laboratory Test Interactions: None known.
815
Carcinogenesis, Mutagenesis, Impairment of Fertility: No evidence of carcinogenicity
816
was seen in 1 mouse study or 2 rat studies following oral administration of lamotrigine for up to
817
2 years at maximum tolerated doses (30 mg/kg per day for mice and 10 to 15 mg/kg per day for
818
rats, doses that are equivalent to 90 mg/m2 and 60 to 90 mg/m2, respectively). Steady-state
819
plasma concentrations ranged from 1 to 4 mcg/mL in the mouse study and 1 to 10 mcg/mL in the
820
rat study. Plasma concentrations associated with the recommended human doses of 300 to
821
500 mg/day are generally in the range of 2 to 5 mcg/mL, but concentrations as high as
822
19 mcg/mL have been recorded.
823
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
25
Lamotrigine was not mutagenic in the presence or absence of metabolic activation when
824
tested in 2 gene mutation assays (the Ames test and the in vitro mammalian mouse lymphoma
825
assay). In 2 cytogenetic assays (the in vitro human lymphocyte assay and the in vivo rat bone
826
marrow assay), lamotrigine did not increase the incidence of structural or numerical
827
chromosomal abnormalities.
828
No evidence of impairment of fertility was detected in rats given oral doses of lamotrigine up
829
to 2.4 times the highest usual human maintenance dose of 8.33 mg/kg per day or 0.4 times the
830
human dose on a mg/m2 basis. The effect of lamotrigine on human fertility is unknown.
831
Pregnancy: Teratogenic Effects: Pregnancy Category C. No evidence of teratogenicity was
832
found in mice, rats, or rabbits when lamotrigine was orally administered to pregnant animals
833
during the period of organogenesis at doses up to 1.2, 0.5, and 1.1 times, respectively, on a
834
mg/m2 basis, the highest usual human maintenance dose (i.e., 500 mg/day). However, maternal
835
toxicity and secondary fetal toxicity producing reduced fetal weight and/or delayed ossification
836
were seen in mice and rats, but not in rabbits at these doses. Teratology studies were also
837
conducted using bolus intravenous administration of the isethionate salt of lamotrigine in rats
838
and rabbits. In rat dams administered an intravenous dose at 0.6 times the highest usual human
839
maintenance dose, the incidence of intrauterine death without signs of teratogenicity was
840
increased.
841
A behavioral teratology study was conducted in rats dosed during the period of organogenesis.
842
At day 21 postpartum, offspring of dams receiving 5 mg/kg per day or higher displayed a
843
significantly longer latent period for open field exploration and a lower frequency of rearing. In a
844
swimming maze test performed on days 39 to 44 postpartum, time to completion was increased
845
in offspring of dams receiving 25 mg/kg per day. These doses represent 0.1 and 0.5 times the
846
clinical dose on a mg/m2 basis, respectively.
847
Lamotrigine did not affect fertility, teratogenesis, or postnatal development when rats were
848
dosed prior to and during mating, and throughout gestation and lactation at doses equivalent to
849
0.4 times the highest usual human maintenance dose on a mg/m2 basis.
850
When pregnant rats were orally dosed at 0.1, 0.14, or 0.3 times the highest human
851
maintenance dose (on a mg/m2 basis) during the latter part of gestation (days 15 to 20), maternal
852
toxicity and fetal death were seen. In dams, food consumption and weight gain were reduced,
853
and the gestation period was slightly prolonged (22.6 vs. 22.0 days in the control group).
854
Stillborn pups were found in all 3 drug-treated groups with the highest number in the high-dose
855
group. Postnatal death was also seen, but only in the 2 highest doses, and occurred between day 1
856
and 20. Some of these deaths appear to be drug-related and not secondary to the maternal
857
toxicity. A no-observed-effect level (NOEL) could not be determined for this study.
858
Although LAMICTAL was not found to be teratogenic in the above studies, lamotrigine
859
decreases fetal folate concentrations in rats, an effect known to be associated with teratogenesis
860
in animals and humans. There are no adequate and well-controlled studies in pregnant women.
861
Because animal reproduction studies are not always predictive of human response, this drug
862
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
26
should be used during pregnancy only if the potential benefit justifies the potential risk to the
863
fetus.
864
Non-Teratogenic Effects: As with other antiepileptic drugs, physiological changes during
865
pregnancy may affect lamotrigine concentrations and/or therapeutic effect. There have been
866
reports of decreased lamotrigine concentrations during pregnancy and restoration of pre-partum
867
concentrations after delivery. Dosage adjustments may be necessary to maintain clinical
868
response.
869
Pregnancy Exposure Registry: To facilitate monitoring fetal outcomes of pregnant women
870
exposed to lamotrigine, physicians are encouraged to register patients, before fetal outcome
871
(e.g., ultrasound, results of amniocentesis, birth, etc.) is known, and can obtain information
872
by calling the Lamotrigine Pregnancy Registry at (800) 336-2176 (toll-free). Patients can enroll
873
themselves in the North American Antiepileptic Drug Pregnancy Registry by calling (888) 233-
874
2334 (toll-free).
875
Labor and Delivery: The effect of LAMICTAL on labor and delivery in humans is unknown.
876
Use in Nursing Mothers: Preliminary data indicate that lamotrigine passes into human milk.
877
Because the effects on the infant exposed to LAMICTAL by this route are unknown,
878
breast-feeding while taking LAMICTAL is not recommended.
879
Pediatric Use: LAMICTAL is indicated as adjunctive therapy for partial seizures, for the
880
generalized seizures of Lennox-Gastaut syndrome, and primary generalized tonic-clonic seizures
881
in patients above 2 years of age. .
882
Safety and effectiveness in patients below the age of 18 years with Bipolar Disorder has not
883
been established.
884
Geriatric Use: Clinical studies of LAMICTAL for epilepsy and in Bipolar Disorder did not
885
include sufficient numbers of subjects aged 65 and over to determine whether they respond
886
differently from younger subjects. In general, dose selection for an elderly patient should be
887
cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of
888
decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
889
ADVERSE REACTIONS
890
SERIOUS RASH REQUIRING HOSPITALIZATION AND DISCONTINUATION OF
891
LAMICTAL, INCLUDING STEVENS-JOHNSON SYNDROME AND TOXIC
892
EPIDERMAL NECROLYSIS, HAVE OCCURRED IN ASSOCIATION WITH
893
THERAPY WITH LAMICTAL. RARE DEATHS HAVE BEEN REPORTED, BUT
894
THEIR NUMBERS ARE TOO FEW TO PERMIT A PRECISE ESTIMATE OF THE
895
RATE (see BOX WARNING).
896
Epilepsy:
897
Most Common Adverse Events in All Clinical Studies: Adjunctive Therapy in
898
Adults With Epilepsy: The most commonly observed (≥5%) adverse experiences seen in
899
association with LAMICTAL during adjunctive therapy in adults and not seen at an equivalent
900
frequency among placebo-treated patients were: dizziness, ataxia, somnolence, headache,
901
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
27
diplopia, blurred vision, nausea, vomiting, and rash. Dizziness, diplopia, ataxia, blurred vision,
902
nausea, and vomiting were dose related. Dizziness, diplopia, ataxia, and blurred vision occurred
903
more commonly in patients receiving carbamazepine with LAMICTAL than in patients receiving
904
other AEDs with LAMICTAL. Clinical data suggest a higher incidence of rash, including serious
905
rash, in patients receiving concomitant valproate than in patients not receiving valproate (see
906
WARNINGS).
907
Approximately 11% of the 3,378 adult patients who received LAMICTAL as adjunctive
908
therapy in premarketing clinical trials discontinued treatment because of an adverse experience.
909
The adverse events most commonly associated with discontinuation were rash (3.0%), dizziness
910
(2.8%), and headache (2.5%).
911
In a dose response study in adults, the rate of discontinuation of LAMICTAL for dizziness,
912
ataxia, diplopia, blurred vision, nausea, and vomiting was dose related.
913
Monotherapy in Adults With Epilepsy: The most commonly observed (≥5%) adverse
914
experiences seen in association with the use of LAMICTAL during the monotherapy phase of the
915
controlled trial in adults not seen at an equivalent rate in the control group were vomiting,
916
coordination abnormality, dyspepsia, nausea, dizziness, rhinitis, anxiety, insomnia, infection,
917
pain, weight decrease, chest pain, and dysmenorrhea. The most commonly observed (≥5%)
918
adverse experiences associated with the use of LAMICTAL during the conversion to
919
monotherapy (add-on) period, not seen at an equivalent frequency among low-dose
920
valproate-treated patients, were dizziness, headache, nausea, asthenia, coordination abnormality,
921
vomiting, rash, somnolence, diplopia, ataxia, accidental injury, tremor, blurred vision, insomnia,
922
nystagmus, diarrhea, lymphadenopathy, pruritus, and sinusitis.
923
Approximately 10% of the 420 adult patients who received LAMICTAL as monotherapy in
924
premarketing clinical trials discontinued treatment because of an adverse experience. The
925
adverse events most commonly associated with discontinuation were rash (4.5%), headache
926
(3.1%), and asthenia (2.4%).
927
Adjunctive Therapy in Pediatric Patients With Epilepsy: The most commonly
928
observed (≥5%) adverse experiences seen in association with the use of LAMICTAL as
929
adjunctive treatment in pediatric patients and not seen at an equivalent rate in the control group
930
were infection, vomiting, rash, fever, somnolence, accidental injury, dizziness, diarrhea,
931
abdominal pain, nausea, ataxia, tremor, asthenia, bronchitis, flu syndrome, and diplopia.
932
In 339 patients age 2 to 16 years with partial seizures or generalized seizures of Lennox-
933
Gastaut syndrome, 4.2% of patients on LAMICTAL and 2.9% of patients on placebo
934
discontinued due to adverse experiences. The most commonly reported adverse experiences that
935
led to discontinuation were rash for patients treated with LAMICTAL and deterioration of
936
seizure control for patients treated with placebo.
937
Approximately 11.5% of the 1,081 pediatric patients who received LAMICTAL as adjunctive
938
therapy in premarketing clinical trials discontinued treatment because of an adverse experience.
939
The adverse events most commonly associated with discontinuation were rash (4.4%), reaction
940
aggravated (1.7%), and ataxia (0.6%).
941
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
28
Incidence in Controlled Clinical Studies of Epilepsy: The prescriber should be aware
942
that the figures in Tables 4, 5, 6, and 7 cannot be used to predict the frequency of adverse
943
experiences in the course of usual medical practice where patient characteristics and other factors
944
may differ from those prevailing during clinical studies. Similarly, the cited frequencies cannot
945
be directly compared with figures obtained from other clinical investigations involving different
946
treatments, uses, or investigators. An inspection of these frequencies, however, does provide the
947
prescriber with one basis to estimate the relative contribution of drug and nondrug factors to the
948
adverse event incidences in the population studied.
949
Incidence in Controlled Adjunctive Clinical Studies in Adults With Epilepsy:
950
Table 4 lists treatment-emergent signs and symptoms that occurred in at least 2% of adult
951
patients with epilepsy treated with LAMICTAL in placebo-controlled trials and were
952
numerically more common in the patients treated with LAMICTAL. In these studies, either
953
LAMICTAL or placebo was added to the patient's current AED therapy. Adverse events were
954
usually mild to moderate in intensity.
955
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
29
Table 4. Treatment-Emergent Adverse Event Incidence in Placebo-Controlled
956
Adjunctive Trials in Adult Patients With Epilepsy* (Events in at least 2% of patients
957
treated with LAMICTAL and numerically more frequent than in the placebo group.)
958
Body System/
Adverse Experience†
Percent of Patients
Receiving Adjunctive
LAMICTAL
(n = 711)
Percent of Patients
Receiving Adjunctive Placebo
(n = 419)
Body as a whole
Headache
29
19
Flu syndrome
7
6
Fever
6
4
Abdominal pain
5
4
Neck pain
2
1
Reaction aggravated
(seizure exacerbation)
2
1
Digestive
Nausea
19
10
Vomiting
9
4
Diarrhea
6
4
Dyspepsia
5
2
Constipation
4
3
Tooth disorder
3
2
Anorexia
2
1
Musculoskeletal
Arthralgia
2
0
Nervous
Dizziness
38
13
Ataxia
22
6
Somnolence
14
7
Incoordination
6
2
Insomnia
6
2
Tremor
4
1
Depression
4
3
Anxiety
4
3
Convulsion
3
1
Irritability
3
2
Speech disorder
3
0
Concentration
disturbance
2
1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
30
Respiratory
Rhinitis
14
9
Pharyngitis
10
9
Cough increased
8
6
Skin and appendages
Rash
10
5
Pruritus
3
2
Special senses
Diplopia
28
7
Blurred vision
16
5
Vision abnormality
3
1
Urogenital
Female patients only
(n = 365)
(n = 207)
Dysmenorrhea
7
6
Vaginitis
4
1
Amenorrhea
2
1
* Patients in these adjunctive studies were receiving 1 to 3 of the following concomitant
959
AEDs (carbamazepine, phenytoin, phenobarbital, or primidone) in addition to LAMICTAL
960
or placebo. Patients may have reported multiple adverse experiences during the study or at
961
discontinuation; thus, patients may be included in more than one category.
962
† Adverse experiences reported by at least 2% of patients treated with LAMICTAL are
963
included.
964
965
In a randomized, parallel study comparing placebo and 300 and 500 mg/day of LAMICTAL,
966
some of the more common drug-related adverse events were dose related (see Table 5).
967
968
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
31
Table 5. Dose-Related Adverse Events From a Randomized, Placebo-Controlled Trial
969
in Adults With Epilepsy
970
Percent of Patients Experiencing Adverse Experiences
Adverse Experience
Placebo
(n = 73)
LAMICTAL
300 mg
(n = 71)
LAMICTAL
500 mg
(n = 72)
Ataxia
10
10
28*†
Blurred vision
10
11
25*†
Diplopia
8
24*
49*†
Dizziness
27
31
54*†
Nausea
11
18
25*
Vomiting
4
11
18*
*Significantly greater than placebo group (p<0.05).
971
†Significantly greater than group receiving LAMICTAL 300 mg (p<0.05).
972
973
Other events that occurred in more than 1% of patients but equally or more frequently in the
974
placebo group included: asthenia, back pain, chest pain, flatulence, menstrual disorder, myalgia,
975
paresthesia, respiratory disorder, and urinary tract infection.
976
The overall adverse experience profile for LAMICTAL was similar between females and
977
males, and was independent of age. Because the largest non-Caucasian racial subgroup was only
978
6% of patients exposed to LAMICTAL in placebo-controlled trials, there are insufficient data to
979
support a statement regarding the distribution of adverse experience reports by race. Generally,
980
females receiving either adjunctive LAMICTAL or placebo were more likely to report adverse
981
experiences than males. The only adverse experience for which the reports on LAMICTAL were
982
greater than 10% more frequent in females than males (without a corresponding difference by
983
gender on placebo) was dizziness (difference = 16.5%). There was little difference between
984
females and males in the rates of discontinuation of LAMICTAL for individual adverse
985
experiences.
986
Incidence in a Controlled Monotherapy Trial in Adults With Partial Seizures:
987
Table 6 lists treatment-emergent signs and symptoms that occurred in at least 5% of patients with
988
epilepsy treated with monotherapy with LAMICTAL in a double-blind trial following
989
discontinuation of either concomitant carbamazepine or phenytoin not seen at an equivalent
990
frequency in the control group.
991
992
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
32
Table 6. Treatment-Emergent Adverse Event Incidence in Adults With Partial Seizures in
993
a Controlled Monotherapy Trial* (Events in at least 5% of patients treated with
994
LAMICTAL and numerically more frequent than in the valproate group.)
995
Body System/
Adverse Experience†
Percent of Patients Receiving
LAMICTAL Monotherapy‡
(n = 43)
Percent of Patients Receiving
Low-Dose Valproate§
Monotherapy
(n = 44)
Body as a whole
Pain
5
0
Infection
5
2
Chest pain
5
2
Digestive
Vomiting
9
0
Dyspepsia
7
2
Nausea
7
2
Metabolic and nutritional
Weight decrease
5
2
Nervous
Coordination
abnormality
7
0
Dizziness
7
0
Anxiety
5
0
Insomnia
5
2
Respiratory
Rhinitis
7
2
Urogenital (female
patients only)
(n = 21)
(n = 28)
Dysmenorrhea
5
0
* Patients in these studies were converted to LAMICTAL or valproate monotherapy from
996
adjunctive therapy with carbamazepine or phenytoin. Patients may have reported multiple
997
adverse experiences during the study; thus, patients may be included in more than one
998
category.
999
† Adverse experiences reported by at least 5% of patients are included.
1000
‡ Up to 500 mg/day.
1001
§ 1,000 mg/day.
1002
1003
Adverse events that occurred with a frequency of less than 5% and greater than 2% of patients
1004
receiving LAMICTAL and numerically more frequent than placebo were:
1005
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
33
Body as a Whole: Asthenia, fever.
1006
Digestive: Anorexia, dry mouth, rectal hemorrhage, peptic ulcer.
1007
Metabolic and Nutritional: Peripheral edema.
1008
Nervous System: Amnesia, ataxia, depression, hypesthesia, libido increase, decreased
1009
reflexes, increased reflexes, nystagmus, irritability, suicidal ideation.
1010
Respiratory: Epistaxis, bronchitis, dyspnea.
1011
Skin and Appendages: Contact dermatitis, dry skin, sweating.
1012
Special Senses: Vision abnormality.
1013
Incidence in Controlled Adjunctive Trials in Pediatric Patients With Epilepsy:
1014
Table 7 lists adverse events that occurred in at least 2% of 339 pediatric patients with partial
1015
seizures or generalized seizures of Lennox-Gastaut syndrome, who received LAMICTAL up to
1016
15 mg/kg per day or a maximum of 750 mg per day. Reported adverse events were classified
1017
using COSTART terminology.
1018
1019
Table 7. Treatment-Emergent Adverse Event Incidence in Placebo-Controlled Adjunctive
1020
Trials in Pediatric Patients With Epilepsy (Events in at least 2% of patients treated with
1021
LAMICTAL and numerically more frequent than in the placebo group.)
1022
Body System/
Adverse Experience
Percent of Patients
Receiving LAMICTAL
(n = 168)
Percent of Patients
Receiving Placebo
(n = 171)
Body as a whole
Infection
20
17
Fever
15
14
Accidental injury
14
12
Abdominal pain
10
5
Asthenia
8
4
Flu syndrome
7
6
Pain
5
4
Facial edema
2
1
Photosensitivity
2
0
Cardiovascular
Hemorrhage
2
1
Digestive
Vomiting
20
16
Diarrhea
11
9
Nausea
10
2
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
34
Constipation
4
2
Dyspepsia
2
1
Tooth disorder
2
1
Hemic and lymphatic
Lymphadenopathy
2
1
Metabolic and nutritional
Edema
2
0
Nervous system
Somnolence
17
15
Dizziness
14
4
Ataxia
11
3
Tremor
10
1
Emotional lability
4
2
Gait abnormality
4
2
Thinking abnormality
3
2
Convulsions
2
1
Nervousness
2
1
Vertigo
2
1
Respiratory
Pharyngitis
14
11
Bronchitis
7
5
Increased cough
7
6
Sinusitis
2
1
Bronchospasm
2
1
Skin
Rash
14
12
Eczema
2
1
Pruritus
2
1
Special senses
Diplopia
5
1
Blurred vision
4
1
Ear disorder
2
1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
35
Visual abnormality
2
0
Urogenital
Male and female patients
Urinary tract infection
3
0
Male patients only
n = 93
n = 92
Penis disorder
2
0
1023
Bipolar Disorder: The most commonly observed (≥5%) adverse experiences seen in
1024
association with the use of LAMICTAL as monotherapy (100 to 400 mg/day) in Bipolar
1025
Disorder in the 2 double-blind, placebo-controlled trials of 18 months’ duration, and numerically
1026
more frequent than in placebo-treated patients are included in Table 8. Adverse events that
1027
occurred in at least 5% of patients and were numerically more common during the dose
1028
escalation phase of LAMICTAL in these trials (when patients may have been receiving
1029
concomitant medications) compared to the monotherapy phase were: headache (25%), rash
1030
(11%), dizziness (10%), diarrhea (8%), dream abnormality (6%), and pruritus (6%).
1031
During the monotherapy phase of the double-blind, placebo-controlled trials of 18 months’
1032
duration, 13% of 227 patients who received LAMICTAL (100 to 400 mg/day), 16% of
1033
190 patients who received placebo, and 23% of 166 patients who received lithium discontinued
1034
therapy because of an adverse experience. The adverse events which most commonly led to
1035
discontinuation of LAMICTAL were rash (3%) and mania/hypomania/mixed mood adverse
1036
events (2%). Approximately 16% of 2,401 patients who received LAMICTAL (50 to
1037
500 mg/day) for Bipolar Disorder in premarketing trials discontinued therapy because of an
1038
adverse experience; most commonly due to rash (5%) and mania/hypomania/mixed mood
1039
adverse events (2%).
1040
Incidence in Controlled Clinical Studies of LAMICTAL for the Maintenance
1041
Treatment of Bipolar I Disorder: Table 8 lists treatment-emergent signs and symptoms that
1042
occurred in at least 5% of patients with Bipolar Disorder treated with LAMICTAL monotherapy
1043
(100 to 400 mg/day), following the discontinuation of other psychotropic drugs, in
1044
2 double-blind, placebo-controlled trials of 18 months’ duration and were numerically more
1045
frequent than in the placebo group.
1046
1047
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
36
Table 8. Treatment-Emergent Adverse Event Incidence in 2 Placebo-Controlled Trials
1048
in Adults With Bipolar I Disorder* (Events in at least 5% of patients treated with
1049
LAMICTAL monotherapy and numerically more frequent than in the placebo group.)
1050
Body System/
Adverse Experience†
Percent of Patients
Receiving LAMICTAL
n = 227
Percent of Patients
Receiving Placebo
n = 190
General
Back pain
8
6
Fatigue
8
5
Abdominal pain
6
3
Digestive
Nausea
14
11
Constipation
5
2
Vomiting
5
2
Nervous System
Insomnia
10
6
Somnolence
9
7
Xerostomia (dry mouth)
6
4
Respiratory
Rhinitis
7
4
Exacerbation of cough
5
3
Pharyngitis
5
4
Skin
Rash (nonserious)‡
7
5
* Patients in these studies were converted to LAMICTAL (100 to 400 mg/day) or placebo
1051
monotherapy from add-on therapy with other psychotropic medications. Patients may
1052
have reported multiple adverse experiences during the study; thus, patients may be
1053
included in more than one category.
1054
† Adverse experiences reported by at least 5% of patients are included.
1055
‡ In the overall bipolar and other mood disorders clinical trials, the rate of serious rash
1056
was 0.08% (1 of 1,233) of adult patients who received LAMICTAL as initial
1057
monotherapy and 0.13% (2 of 1,538) of adult patients who received LAMICTAL as
1058
adjunctive therapy (see WARNINGS).
1059
1060
These adverse events were usually mild to moderate in intensity.
1061
Other events that occurred in 5% or more patients but equally or more frequently in the
1062
placebo group included: dizziness, mania, headache, infection, influenza, pain, accidental injury,
1063
diarrhea, and dyspepsia.
1064
Adverse events that occurred with a frequency of less than 5% and greater than 1% of patients
1065
receiving LAMICTAL and numerically more frequent than placebo were:
1066
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
37
General: Fever, neck pain.
1067
Cardiovascular: Migraine.
1068
Digestive: Flatulence.
1069
Metabolic and Nutritional: Weight gain, edema.
1070
Musculoskeletal: Arthralgia, myalgia.
1071
Nervous System: Amnesia, depression, agitation, emotional lability, dyspraxia, abnormal
1072
thoughts, dream abnormality, hypoesthesia.
1073
Respiratory: Sinusitis.
1074
Urogenital: Urinary frequency.
1075
Adverse Events Following Abrupt Discontinuation: In the 2 maintenance trials, there
1076
was no increase in the incidence, severity or type of adverse events in Bipolar Disorder patients
1077
after abruptly terminating LAMICTAL therapy. In clinical trials in patients with Bipolar
1078
Disorder, 2 patients experienced seizures shortly after abrupt withdrawal of LAMICTAL.
1079
However, there were confounding factors that may have contributed to the occurrence of seizures
1080
in these bipolar patients (see DOSAGE AND ADMINISTRATION).
1081
Mania/Hypomania/Mixed Episodes: During the double-blind, placebo-controlled clinical
1082
trials in Bipolar I Disorder in which patients were converted to LAMICTAL monotherapy (100
1083
to 400 mg/day) from other psychotropic medications and followed for durations up to 18 months,
1084
the rate of manic or hypomanic or mixed mood episodes reported as adverse experiences was 5%
1085
for patients treated with LAMICTAL (n = 227), 4% for patients treated with lithium (n = 166),
1086
and 7% for patients treated with placebo (n = 190). In all bipolar controlled trials combined,
1087
adverse events of mania (including hypomania and mixed mood episodes) were reported in 5%
1088
of patients treated with LAMICTAL (n = 956), 3% of patients treated with lithium (n = 280), and
1089
4% of patients treated with placebo (n = 803).
1090
The overall adverse event profile for LAMICTAL was similar between females and males,
1091
between elderly and nonelderly patients, and among racial groups.
1092
Other Adverse Events Observed During All Clinical Trials For Pediatric and Adult
1093
Patients With Epilepsy or Bipolar Disorder and Other Mood Disorders: LAMICTAL
1094
has been administered to 6,694 individuals for whom complete adverse event data was captured
1095
during all clinical trials, only some of which were placebo controlled. During these trials, all
1096
adverse events were recorded by the clinical investigators using terminology of their own
1097
choosing. To provide a meaningful estimate of the proportion of individuals having adverse
1098
events, similar types of events were grouped into a smaller number of standardized categories
1099
using modified COSTART dictionary terminology. The frequencies presented represent the
1100
proportion of the 6,694 individuals exposed to LAMICTAL who experienced an event of the
1101
type cited on at least one occasion while receiving LAMICTAL. All reported events are included
1102
except those already listed in the previous tables or elsewhere in the labeling, those too general
1103
to be informative, and those not reasonably associated with the use of the drug.
1104
Events are further classified within body system categories and enumerated in order of
1105
decreasing frequency using the following definitions: frequent adverse events are defined as
1106
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
38
those occurring in at least 1/100 patients; infrequent adverse events are those occurring in 1/100
1107
to 1/1,000 patients; rare adverse events are those occurring in fewer than 1/1,000 patients.
1108
Body as a Whole: Infrequent: Allergic reaction, chills, halitosis, and malaise. Rare:
1109
Abdomen enlarged, abscess, and suicide/suicide attempt.
1110
Cardiovascular System: Infrequent: Flushing, hot flashes, hypertension, palpitations,
1111
postural hypotension, syncope, tachycardia, and vasodilation. Rare: Angina pectoris, atrial
1112
fibrillation, deep thrombophlebitis, ECG abnormality, and myocardial infarction.
1113
Dermatological: Infrequent: Acne, alopecia, hirsutism, maculopapular rash, skin
1114
discoloration, and urticaria. Rare: Angioedema, erythema, exfoliative dermatitis, fungal
1115
dermatitis, herpes zoster, leukoderma, multiforme erythema, petechial rash, pustular rash,
1116
seborrhea, Stevens-Johnson syndrome, and vesiculobullous rash.
1117
Digestive System: Infrequent: Dysphagia, eructation, gastritis, gingivitis, increased
1118
appetite, increased salivation, liver function tests abnormal, and mouth ulceration. Rare:
1119
Gastrointestinal hemorrhage, glossitis, gum hemorrhage, gum hyperplasia, hematemesis,
1120
hemorrhagic colitis, hepatitis, melena, stomach ulcer, stomatitis, thirst, and tongue edema.
1121
Endocrine System: Rare: Goiter and hypothyroidism.
1122
Hematologic and Lymphatic System: Infrequent: Ecchymosis and leukopenia. Rare:
1123
Anemia, eosinophilia, fibrin decrease, fibrinogen decrease, iron deficiency anemia, leukocytosis,
1124
lymphocytosis, macrocytic anemia, petechia, and thrombocytopenia.
1125
Metabolic and Nutritional Disorders: Infrequent: Aspartate transaminase increased.
1126
Rare: Alcohol intolerance, alkaline phosphatase increase, alanine transaminase increase,
1127
bilirubinemia, general edema, gamma glutamyl transpeptidase increase, and hyperglycemia.
1128
Musculoskeletal System: Infrequent: Arthritis, leg cramps, myasthenia, and twitching.
1129
Rare: Bursitis, joint disorder, muscle atrophy, pathological fracture, and tendinous contracture.
1130
Nervous System: Frequent: Confusion and paresthesia. Infrequent: Akathisia, apathy,
1131
aphasia, CNS depression, depersonalization, dysarthria, dyskinesia, euphoria, hallucinations,
1132
hostility, hyperkinesia, hypertonia, libido decreased, memory decrease, mind racing, movement
1133
disorder, myoclonus, panic attack, paranoid reaction, personality disorder, psychosis, sleep
1134
disorder, stupor, and suicidal ideation. Rare: Cerebellar syndrome, cerebrovascular accident,
1135
cerebral sinus thrombosis, choreoathetosis, CNS stimulation, delirium, delusions, dysphoria,
1136
dystonia, extrapyramidal syndrome, faintness, grand mal convulsions, hemiplegia, hyperalgesia,
1137
hyperesthesia, hypokinesia, hypotonia, manic depression reaction, muscle spasm, neuralgia,
1138
neurosis, paralysis, and peripheral neuritis.
1139
Respiratory System: Infrequent: Yawn. Rare: Hiccup and hyperventilation.
1140
Special Senses: Frequent: Amblyopia. Infrequent: Abnormality of accommodation,
1141
conjunctivitis, dry eyes, ear pain, photophobia, taste perversion, and tinnitus. Rare: Deafness,
1142
lacrimation disorder, oscillopsia, parosmia, ptosis, strabismus, taste loss, uveitis, and visual field
1143
defect.
1144
Urogenital System: Infrequent: Abnormal ejaculation, breast pain, hematuria, impotence,
1145
menorrhagia, polyuria, urinary incontinence, and urine abnormality. Rare: Acute kidney failure,
1146
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
39
anorgasmia, breast abscess, breast neoplasm, creatinine increase, cystitis, dysuria, epididymitis,
1147
female lactation, kidney failure, kidney pain, nocturia, urinary retention, urinary urgency, and
1148
vaginal moniliasis.
1149
Postmarketing and Other Experience: In addition to the adverse experiences reported
1150
during clinical testing of LAMICTAL, the following adverse experiences have been reported in
1151
patients receiving marketed LAMICTAL and from worldwide noncontrolled investigational use.
1152
These adverse experiences have not been listed above, and data are insufficient to support an
1153
estimate of their incidence or to establish causation.
1154
Blood and Lymphatic: Agranulocytosis, aplastic anemia, disseminated intravascular
1155
coagulation, hemolytic anemia, neutropenia, pancytopenia, red cell aplasia.
1156
Gastrointestinal: Esophagitis.
1157
Hepatobiliary Tract and Pancreas: Pancreatitis.
1158
Immunologic: Lupus-like reaction, vasculitis.
1159
Lower Respiratory: Apnea.
1160
Musculoskeletal: Rhabdomyolysis has been observed in patients experiencing
1161
hypersensitivity reactions.
1162
Neurology: Exacerbation of parkinsonian symptoms in patients with pre-existing
1163
Parkinson’s disease, tics.
1164
Non-site Specific: Hypersensitivity reaction, multiorgan failure, progressive
1165
immunosuppression.
1166
DRUG ABUSE AND DEPENDENCE
1167
The abuse and dependence potential of LAMICTAL have not been evaluated in human
1168
studies.
1169
OVERDOSAGE
1170
Human Overdose Experience: Overdoses involving quantities up to 15 g have been
1171
reported for LAMICTAL, some of which have been fatal. Overdose has resulted in ataxia,
1172
nystagmus, increased seizures, decreased level of consciousness, coma, and intraventricular
1173
conduction delay.
1174
Management of Overdose: There are no specific antidotes for LAMICTAL. Following a
1175
suspected overdose, hospitalization of the patient is advised. General supportive care is
1176
indicated, including frequent monitoring of vital signs and close observation of the patient. If
1177
indicated, emesis should be induced or gastric lavage should be performed; usual precautions
1178
should be taken to protect the airway. It should be kept in mind that lamotrigine is rapidly
1179
absorbed (see CLINICAL PHARMACOLOGY). It is uncertain whether hemodialysis is an
1180
effective means of removing lamotrigine from the blood. In 6 renal failure patients, about 20% of
1181
the amount of lamotrigine in the body was removed by hemodialysis during a 4-hour session. A
1182
Poison Control Center should be contacted for information on the management of overdosage of
1183
LAMICTAL.
1184
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
40
DOSAGE AND ADMINISTRATION
1185
Epilepsy:
1186
Adjunctive Use: LAMICTAL is indicated as adjunctive therapy for partial seizures, the
1187
generalized seizures of Lennox-Gastaut syndrome, and primary generalized tonic-clonic seizures
1188
in adult and pediatric patients (≥2 years of age).
1189
Monotherapy Use: LAMICTAL is indicated for conversion to monotherapy in adults with
1190
partial seizures who are receiving treatment with carbamazepine, phenytoin, phenobarbital,
1191
primidone, or valproate as the single AED.
1192
Safety and effectiveness of LAMICTAL have not been established. (1) as initial
1193
monotherapy, (2) for conversion to monotherapy from AEDs other than carbamazepine,
1194
phenytoin, phenobarbital, primidone, or valproate, or (3) for simultaneous conversion to
1195
monotherapy from 2 or more concomitant AEDs.
1196
1197
Bipolar Disorder: LAMICTAL is indicated for the maintenance treatment of Bipolar I
1198
Disorder to delay the time to occurrence of mood episodes (depression, mania, hypomania,
1199
mixed episodes) in patients treated for acute mood episodes with standard therapy. The
1200
effectiveness of LAMICTAL in the acute treatment of mood episodes has not been established.
1201
General Dosing Considerations for Epilepsy and Bipolar Disorder Patients: The
1202
risk of nonserious rash is increased when the recommended initial dose and/or the rate of dose
1203
escalation of LAMICTAL is exceeded. There are suggestions, yet to be proven, that the risk of
1204
severe, potentially life-threatening rash may be increased by (1) coadministration of LAMICTAL
1205
with valproate, (2) exceeding the recommended initial dose of LAMICTAL, or (3) exceeding the
1206
recommended dose escalation for LAMICTAL. However, cases have been reported in the
1207
absence of these factors (see BOX WARNING). Therefore, it is important that the dosing
1208
recommendations be followed closely.
1209
It is recommended that LAMICTAL not be restarted in patients who discontinued due to rash
1210
associated with prior treatment with LAMICTAL, unless the potential benefits clearly outweigh
1211
the risks. If the decision is made to restart a patient who has discontinued LAMICTAL, the need
1212
to restart with the initial dosing recommendations should be assessed. The greater the interval of
1213
time since the previous dose, the greater consideration should be given to restarting with the
1214
initial dosing recommendations. If a patient has discontinued LAMICTAL for a period of more
1215
than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be
1216
followed.
1217
1218
LAMICTAL Added to Drugs Known to Induce or Inhibit Glucuronidation: Drugs
1219
other than those listed in PRECAUTIONS: Drug Interactions have not been systematically
1220
evaluated in combination with LAMICTAL. Since lamotrigine is metabolized predominantly by
1221
glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may
1222
affect the apparent clearance of lamotrigine, and doses of LAMICTAL may require adjustment
1223
based on clinical response.
1224
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
41
Target Plasma Levels for Patients With Epilepsy or Bipolar Disorder: A
1225
therapeutic plasma concentration range has not been established for lamotrigine. Dosing of
1226
LAMICTAL should be based on therapeutic response.
1227
The half-life of LAMICTAL is affected by other concomitant medications (see CLINICAL
1228
PHARMACOLOGY: Pharmacokinetics and Drug Metabolism).
1229
See also DOSAGE AND ADMINISTRATION: Special Populations.
1230
Special Populations: Women and Oral Contraceptives: Starting LAMICTAL in
1231
Women Taking Oral Contraceptives: Although estrogen-containing oral contraceptives
1232
have been shown to increase the clearance of lamotrigine (see PRECAUTIONS: Drug
1233
Interactions), no adjustments to the recommended dose escalation guidelines for LAMICTAL
1234
should be necessary solely based on the use of estrogen-containing oral contraceptives.
1235
Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive
1236
therapy with LAMICTAL based on the concomitant AED (see Table 11). See below for
1237
adjustments to maintenance doses of LAMICTAL in women taking estrogen-containing oral
1238
contraceptives.
1239
Adjustments to the Maintenance Dose of LAMICTAL: (1) Taking Estrogen-
1240
Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin,
1241
phenobarbital, primidone, or rifampin, the maintenance dose of LAMICTAL will in most cases
1242
need to be increased, by as much as 2-fold over the recommended target maintenance dose, in
1243
order to maintain a consistent lamotrigine plasma level (see PRECAUTIONS: Drug
1244
Interactions). (2) Starting Estrogen-Containing Oral Contraceptives: In women taking a stable
1245
dose of LAMICTAL and not taking carbamazepine, phenytoin, phenobarbital, primidone, or
1246
rifampin, the maintenance dose will in most cases need to be increased by as much as 2-fold, in
1247
order to maintain a consistent lamotrigine plasma level. The dose increases should begin at the
1248
same time that the oral contraceptive is introduced and continue, based on clinical response, no
1249
more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the
1250
recommended rate unless lamotrigine plasma levels or clinical response support larger increases
1251
(see Table 11, column 2). Gradual transient increases in lamotrigine plasma levels may occur
1252
during the week of inactive hormonal preparation (“pill-free” week), and these increases will be
1253
greater if dose increases are made in the days before or during the week of inactive hormonal
1254
preparation. Increased lamotrigine plasma levels could result in additional adverse events, such
1255
as dizziness, ataxia, and diplopia (see PRECAUTIONS: Drug Interactions). If adverse events
1256
attributable to LAMICTAL consistently occur during the “pill-free” week, dose adjustments to
1257
the overall maintenance dose may be necessary. Dose adjustments limited to the “pill-free” week
1258
are not recommended. For women taking LAMICTAL in addition to carbamazepine, phenytoin,
1259
phenobarbital, primidone, or rifampin, no adjustment should be necessary to the dose of
1260
LAMICTAL. (3) Stopping Estrogen-Containing Oral Contraceptives: For women not taking
1261
carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, the maintenance dose of
1262
LAMICTAL will in most cases need to be decreased by as much as 50%, in order to maintain a
1263
consistent lamotrigine plasma level. The decrease in dose of LAMICTAL should not exceed
1264
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
42
25% of the total daily dose per week over a 2-week period, unless clinical response or
1265
lamotrigine plasma levels indicate otherwise (see PRECAUTIONS: Drug Interactions). For
1266
women taking LAMICTAL in addition to carbamazepine, phenytoin, phenobarbital, primidone,
1267
or rifampin, no adjustment to the dose of LAMICTAL should be necessary.
1268
Women and Other Hormonal Contraceptive Preparations or Hormone
1269
Replacement Therapy: The effect of other hormonal contraceptive preparations or hormone
1270
replacement therapy on the pharmacokinetics of lamotrigine has not been systematically
1271
evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of
1272
lamotrigine up to 2-fold, and the progestin only pills had no effect on lamotrigine plasma levels.
1273
Therefore, adjustments to the dosage of LAMICTAL in the presence of progestogens alone will
1274
likely not be needed.
1275
Patients With Hepatic Impairment: Experience in patients with hepatic impairment is
1276
limited. Based on a clinical pharmacology study in 24 patients with mild, moderate, and severe
1277
liver dysfunction (see CLINICAL PHARMACOLOGY), the following general
1278
recommendations can be made. No dosage adjustment is needed in patients with mild liver
1279
impairment. Initial, escalation, and maintenance doses should generally be reduced by
1280
approximately 25% in patients with moderate and severe liver impairment without ascites and
1281
50% in patients with severe liver impairment with ascites. Escalation and maintenance doses
1282
may be adjusted according to clinical response.
1283
Patients With Renal Functional Impairment: Initial doses of LAMICTAL should be
1284
based on patients' AED regimen (see above); reduced maintenance doses may be effective for
1285
patients with significant renal functional impairment (see CLINICAL PHARMACOLOGY).
1286
Few patients with severe renal impairment have been evaluated during chronic treatment with
1287
LAMICTAL. Because there is inadequate experience in this population, LAMICTAL should be
1288
used with caution in these patients.
1289
Epilepsy:
1290
Adjunctive Therapy With LAMICTAL for Epilepsy: This section provides specific
1291
dosing recommendations for patients 2 to 12 years of age and patients greater than 12 years of
1292
age. Within each of these age-groups, specific dosing recommendations are provided depending
1293
upon concomitant AED (Table 9 for patients 2 to 12 years of age and Table 11 for patients
1294
greater than 12 years of age). A weight based dosing guide for pediatric patients on concomitant
1295
valproate is provided in Table 10.
1296
Patients 2 to 12 Years of Age: Recommended dosing guidelines are summarized in Table 9.
1297
Note that some of the starting doses and dose escalations listed in Table 9 are different than
1298
those used in clinical trials; however, the maintenance doses are the same as in clinical trials.
1299
Smaller starting doses and slower dose escalations than those used in clinical trials are
1300
recommended because of the suggestions that the risk of rash may be decreased by smaller
1301
starting doses and slower dose escalations. Therefore, maintenance doses will take longer to
1302
reach in clinical practice than in clinical trials. It may take several weeks to months to achieve an
1303
individualized maintenance dose. Maintenance doses in patients weighing less than 30 kg,
1304
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
43
regardless of age or concomitant AED, may need to be increased as much as 50%, based on
1305
clinical response.
1306
The smallest available strength of LAMICTAL Chewable Dispersible Tablets is 2 mg,
1307
and only whole tablets should be administered. If the calculated dose cannot be achieved
1308
using whole tablets, the dose should be rounded down to the nearest whole tablet (see
1309
HOW SUPPLIED and PATIENT INFORMATION for a description of the available sizes
1310
of LAMICTAL Chewable Dispersible Tablets).
1311
1312
Table 9. Escalation Regimen for LAMICTAL in Patients 2 to 12 Years of Age With
1313
Epilepsy
1314
For Patients Taking
Valproate (see Table 10 for
weight-based dosing guide)
For Patients Taking AEDs
Other Than
Carbamazepine,
Phenytoin, Phenobarbital,
Primidone, or Valproate*
For Patients Taking
Carbamazepine,
Phenytoin,
Phenobarbital,
Primidone* and Not
Taking Valproate
Weeks 1 and 2
0.15 mg/kg/day
in 1 or 2 divided doses,
rounded down to the
nearest whole tablet (see
Table 10 for weight-based
dosing guide).
0.3 mg/kg/day
in 1 or 2 divided doses,
rounded down to the
nearest whole tablet.
0.6 mg/kg/day
in 2 divided doses,
rounded down to the
nearest whole tablet.
Weeks 3 and 4
0.3 mg/kg/day
in 1 or 2 divided doses,
rounded down to the
nearest whole tablet (see
Table 10 for weight-based
dosing guide).
0.6 mg/kg/day
in 2 divided doses,
rounded down to the
nearest whole tablet.
1.2 mg/kg/day
in 2 divided doses,
rounded down to the
nearest whole tablet.
Weeks 5
onwards to
maintenance
The dose should be
increased every 1 to 2
weeks as follows: calculate
0.3 mg/kg/day, round this
amount down to the nearest
whole tablet, and add this
amount to the previously
administered daily dose.
The dose should be
increased every 1 to 2
weeks as follows:
calculate 0.6 mg/kg/day,
round this amount down
to the nearest whole
tablet, and add this
amount to the previously
administered daily dose
The dose should be
increased every 1 to
2 weeks as follows:
calculate
1.2 mg/kg/day,
round this amount
down to the nearest
whole tablet, and
add this amount to
the previously
administered daily
dose
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
44
Usual
Maintenance
Dose
1 to 5 mg/kg/day
(maximum 200 mg/day in
1 or 2 divided doses).
1 to 3 mg/kg/day with
valproate alone
4.5 to 7.5 mg/kg/day
(maximum 300 mg/day in
2 divided doses)
5 to 15 mg/kg/day
(maximum
400 mg/day in 2
divided doses)
Maintenance
dose in
patients less
than 30 kg
May need to be increased
by as much as 50%, based
on clinical response
May need to be increased
by as much as 50%, based
on clinical response
May need to be
increased by as
much as 50%, based
on clinical response
Note: Only whole tablets should be used for dosing
1315
* Rifampin and estrogen-containing oral contraceptives have also been shown to increase the
1316
apparent clearance of lamotrigine (see PRECAUTIONS: Drug Interactions).
1317
1318
1319
Table 10. The Initial Weight-Based Dosing Guide for Patients 2 to 12 Years Taking
1320
Valproate (Weeks 1 to 4) With Epilepsy
1321
:
If the patient’s weight is
Give this daily dose, using the most appropriate
combination of LAMICTAL 2-mg and 5-mg tablets
Greater than
And less than
Weeks 1 and 2
Weeks 3 and 4
6.7 kg
14 kg
2 mg every other day
2 mg every day
14.1 kg
27 kg
2 mg every day
4 mg every day
27.1 kg
34 kg
4 mg every day
8 mg every day
34.1 kg
40 kg
5 mg every day
10 mg every day
1322
Patients Over 12 Years of Age: Recommended dosing guidelines are summarized in
1323
Table 11.
1324
1325
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
45
Table 11. Escalation Regimen for LAMICTAL in Patients Over 12 Years of Age With
1326
Epilepsy
1327
For Patients Taking
Valproate
For Patients Taking
AEDs Other Than
Carbamazepine,
Phenytoin,
Phenobarbital,
Primidone, or
Valproate*
For Patients Taking
Carbamazepine,
Phenytoin,
Phenobarbital,
Primidone* and Not
Taking Valproate
Weeks 1 and 2
25 mg every other day
25 mg every day
50 mg/day
Weeks 3 and 4
25 mg every day
50 mg/day
100 mg/day
(in 2 divided doses)
Weeks 5 onwards
to maintenance
Increase by 25 to
50 mg/day every 1 to
2 weeks
Increase by 50 mg/day
every 1 to 2 weeks
Increase by
100 mg/day every 1 to
2 weeks.
Usual Maintenance
Dose
100 to 400 mg/day
(1 or 2 divided doses)
100 to 200 mg/day with
valproate alone
225 to 375 mg/day
(in 2 divided doses).
300 to 500 mg/day
(in 2 divided doses).
* Rifampin and estrogen-containing oral contraceptives have also been shown to increase the
1328
apparent clearance of lamotrigine (see PRECAUTIONS: Drug Interactions).
1329
1330
1331
Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin,
1332
Phenobarbital, Primidone, or Valproate as the Single AED to Monotherapy With
1333
LAMICTAL in Patients ≥16 Years of Age With Epilepsy: The goal of the transition
1334
regimen is to effect the conversion to monotherapy with LAMICTAL under conditions that
1335
ensure adequate seizure control while mitigating the risk of serious rash associated with the rapid
1336
titration of LAMICTAL.
1337
The recommended maintenance dose of LAMICTAL as monotherapy is 500 mg/day given in
1338
2 divided doses.
1339
To avoid an increased risk of rash, the recommended initial dose and subsequent dose
1340
escalations of LAMICTAL should not be exceeded (see BOX WARNING).
1341
Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin,
1342
Phenobarbital, or Primidone to Monotherapy With LAMICTAL: After achieving a dose
1343
of 500 mg/day of LAMICTAL according to Table 11, the concomitant AED should be
1344
withdrawn by 20% decrements each week over a 4-week period. The regimen for the withdrawal
1345
of the concomitant AED is based on experience gained in the controlled monotherapy clinical
1346
trial.
1347
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
46
Conversion from Adjunctive Therapy With Valproate to Monotherapy With
1348
LAMICTAL: The conversion regimen involves 4 steps (see Table 12).
1349
1350
Table 12. Conversion From Adjunctive Therapy With Valproate to Monotherapy With
1351
LAMICTAL in Patients ≥16 Years of Age With Epilepsy
1352
LAMICTAL
Valproate
Step 1
Achieve a dose of 200 mg/day
according to guidelines in Table 11
(if not already on 200 mg/day).
Maintain previous stable dose.
Step 2
Maintain at 200 mg/day.
Decrease to 500 mg/day by decrements no
greater than 500 mg/day per week and then
maintain the dose of 500 mg/day for 1 week.
Step 3
Increase to 300 mg/day and maintain
for 1 week.
Simultaneously decrease to 250 mg/day and
maintain for 1 week.
Step 4
Increase by 100 mg/day every week
to achieve maintenance dose of
500 mg/day.
Discontinue.
1353
Conversion from Adjunctive Therapy With Antiepileptic Drugs Other Than
1354
Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to
1355
Monotherapy With LAMICTAL: No specific dosing guidelines can be provided for
1356
conversion to monotherapy with LAMICTAL with AEDs other than carbamazepine,
1357
phenobarbital, phenytoin, primidone, or valproate.
1358
Usual Maintenance Dose for Epilepsy: The usual maintenance doses identified in
1359
Tables 9-11 are derived from dosing regimens employed in the placebo-controlled adjunctive
1360
studies in which the efficacy of LAMICTAL was established. In patients receiving multidrug
1361
regimens employing carbamazepine, phenytoin, phenobarbital, or primidone without valproate,
1362
maintenance doses of adjunctive LAMICTAL as high as 700 mg/day have been used. In patients
1363
receiving valproate alone, maintenance doses of adjunctive LAMICTAL as high as 200 mg/day
1364
have been used. The advantage of using doses above those recommended in Tables 9-12 has not
1365
been established in controlled trials.
1366
Discontinuation Strategy for Patients With Epilepsy: For patients receiving
1367
LAMICTAL in combination with other AEDs, a reevaluation of all AEDs in the regimen should
1368
be considered if a change in seizure control or an appearance or worsening of adverse
1369
experiences is observed.
1370
If a decision is made to discontinue therapy with LAMICTAL, a step-wise reduction of dose
1371
over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns
1372
require a more rapid withdrawal (see PRECAUTIONS).
1373
Discontinuing carbamazepine, phenytoin, phenobarbital, or primidone should prolong the
1374
half-life of lamotrigine; discontinuing valproate should shorten the half-life of lamotrigine.
1375
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
47
.
1376
Bipolar Disorder: The goal of maintenance treatment with LAMICTAL is to delay the time to
1377
occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated
1378
for acute mood episodes with standard therapy. The target dose of LAMICTAL is 200 mg/day
1379
(100 mg/day in patients taking valproate,which decreases the apparent clearance of lamotrigine,
1380
and 400 mg/day in patients not taking valproate and taking either Carbamazepine, phenytoin,
1381
phenobarbital, primidone, or rifampin, which increase the apparent clearance of lamotrigine). In
1382
the clinical trials, doses up to 400 mg/day as monotherapy were evaluated, however, no
1383
additional benefit was seen at 400 mg/day compared to 200 mg/day (see CLINICAL STUDIES:
1384
Bipolar Disorder). Accordingly, doses above 200 mg/day are not recommended. Treatment with
1385
LAMICTAL is introduced, based on concurrent medications, according to the regimen outlined
1386
in Table 13. If other psychotropic medications are withdrawn following stabilization, the dose of
1387
LAMICTAL should be adjusted. For patients discontinuing valproate, the dose of LAMICTAL
1388
should be doubled over a 2-week period in equal weekly increments (see Table 14). For patients
1389
discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, the dose of
1390
LAMICTAL should remain constant for the first week and then should be decreased by half over
1391
a 2-week period in equal weekly decrements (see Table 14). The dose of LAMICTAL may then
1392
be further adjusted to the target dose (200 mg) as clinically indicated.
1393
Dosage adjustments will be necessary in most patients who start or stop estrogen-containing
1394
oral contraceptives while taking LAMICTAL (see DOSAGE AND ADMINISTRATION:
1395
Special Populations: Women and Oral Contraceptives: Adjustments to the Maintenance Dose of
1396
LAMICTAL).
1397
If other drugs are subsequently introduced, the dose of LAMICTAL may need to be adjusted.
1398
In particular, the introduction of valproate requires reduction in the dose of LAMICTAL (see
1399
CLINICAL PHARMACOLOGY: Drug Interactions).
1400
To avoid an increased risk of rash, the recommended initial dose and subsequent dose
1401
escalations of LAMICTAL should not be exceeded (see BOX WARNING).
1402
1403
Table 13. Escalation Regimen for LAMICTAL for Patients With Bipolar Disorder*
1404
For Patients Not Taking
Carbamazepine (or
Other Enzyme-Inducing
Drugs†) or Valproate‡
For Patients
Taking
Valproate‡
For Patients Taking
Carbamazepine (or Other
Enzyme-Inducing Drugs)
and Not Taking Valproate‡
Weeks 1 and 2
25 mg daily
25 mg every
other day
50 mg daily
Weeks 3 and 4
50 mg daily
25 mg daily
100 mg daily, in divided
doses
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
48
Week 5
100 mg daily
50 mg daily
200 mg daily, in divided
doses
Week 6
200 mg daily
100 mg daily
300 mg daily, in divided
doses
Week 7
200 mg daily
100 mg daily
up to 400 mg daily, in
divided doses
*See CLINICAL PHARMACOLOGY: Drug Interactions and PRECAUTIONS: Drug
1405
Interactions for a description of known drug interactions.
1406
†Carbamazepine, phenytoin, phenobarbital, primidone, rifampin, have been shown to increase
1407
the apparent clearance of lamotrigine.
1408
‡Valproate has been shown to decrease the apparent clearance of lamotrigine.
1409
1410
Table 14. Adjustments to LAMICTAL Dosing for Patients With Bipolar Disorder
1411
Following Discontinuation of Psychotropic Medications*
1412
After Discontinuation
of Valproate‡
After Discontinuation of
Carbamazepine or Other
Enzyme-Inducing Drugs†
Discontinuation of
Psychotropic Drugs
(excluding Valproate‡,
Carbamazepine, or Other
Enzyme-Inducing
Drugs†)
Current LAMICTAL
dose (mg/day)
100
Current LAMICTAL dose
(mg/day)
400
Week 1 Maintain current
LAMICTAL dose
150
400
Week 2
Maintain current
LAMICTAL dose
200
300
Week 3
onward
Maintain current
LAMICTAL dose
200
200
*See CLINICAL PHARMACOLOGY: Drug Interactions and PRECAUTIONS: Drug
1413
Interactions for a description of known drug interactions.
1414
†Carbamazepine, phenytoin, phenobarbital, primidone, rifampin, have been shown to increase
1415
the apparent clearance of lamotrigine.
1416
‡Valproate has been shown to decrease the apparent clearance of lamotrigine.
1417
1418
There is no body of evidence available to answer the question of how long the patient should
1419
remain on LAMICTAL therapy. Systematic evaluation of the efficacy of LAMICTAL in patients
1420
with either depression or mania who responded to standard therapy during an acute 8 to 16 week
1421
treatment phase and were then randomized to LAMICTAL or placebo for up to 76 weeks of
1422
observation for affective relapse demonstrated a benefit of such maintenance treatment (see
1423
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
49
CLINICAL STUDIES: Bipolar Disorder). Nevertheless, patients should be periodically
1424
reassessed to determine the need for maintenance treatment.
1425
Discontinuation Strategy in Bipolar Disorder: As with other AEDs, LAMICTAL
1426
should not be abruptly discontinued. In the controlled clinical trials, there was no increase in the
1427
incidence, type, or severity of adverse experiences following abrupt termination of LAMICTAL.
1428
In clinical trials in patients with bipolar disorder, 2 patients experienced seizures shortly after
1429
abrupt withdrawal of LAMICTAL. However, there were confounding factors that may have
1430
contributed to the occurrence of seizures in these bipolar patients. Discontinuation of
1431
LAMICTAL should involve a step-wise reduction of dose over at least 2 weeks (approximately
1432
50% per week) unless safety concerns require a more rapid withdrawal.
1433
1434
Administration of LAMICTAL Chewable Dispersible Tablets: LAMICTAL Chewable
1435
Dispersible Tablets may be swallowed whole, chewed, or dispersed in water or diluted fruit
1436
juice. If the tablets are chewed, consume a small amount of water or diluted fruit juice to aid in
1437
swallowing.
1438
To disperse LAMICTAL Chewable Dispersible Tablets, add the tablets to a small amount of
1439
liquid (1 teaspoon, or enough to cover the medication). Approximately 1 minute later, when the
1440
tablets are completely dispersed, swirl the solution and consume the entire quantity immediately.
1441
No attempt should be made to administer partial quantities of the dispersed tablets.
1442
HOW SUPPLIED
1443
LAMICTAL Tablets, 25-mg
1444
White, scored, shield-shaped tablets debossed with "LAMICTAL" and "25", bottles of 100
1445
(NDC 0173-0633-02).
1446
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled
1447
Room Temperature] in a dry place.
1448
LAMICTAL Tablets, 100-mg
1449
Peach, scored, shield-shaped tablets debossed with "LAMICTAL" and "100", bottles of 100
1450
(NDC 0173-0642-55).
1451
LAMICTAL Tablets, 150-mg
1452
Cream, scored, shield-shaped tablets debossed with "LAMICTAL" and "150", bottles of 60
1453
(NDC 0173-0643-60).
1454
LAMICTAL Tablets, 200-mg
1455
Blue, scored, shield-shaped tablets debossed with "LAMICTAL" and "200", bottles of 60
1456
(NDC 0173-0644-60).
1457
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled
1458
Room Temperature] in a dry place and protect from light.
1459
1460
LAMICTAL Chewable Dispersible Tablets, 2-mg
1461
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
50
White to off-white, round tablets debossed with “LTG” over “2”, bottles of 30 (NDC 0173-
1462
0699-00). ORDER DIRECTLY FROM GlaxoSmithKline 1-800-334-4153.
1463
LAMICTAL Chewable Dispersible Tablets, 5-mg
1464
White to off-white, caplet-shaped tablets debossed with “GX CL2”, bottles of 100 (NDC
1465
0173-0526-00).
1466
LAMICTAL Chewable Dispersible Tablets, 25-mg
1467
White, super elliptical-shaped tablets debossed with “GX CL5”, bottles of 100 (NDC 0173-
1468
0527-00).
1469
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled
1470
Room Temperature] in a dry place.
1471
1472
LAMICTAL Starter Kit for Patients Taking Valproate
1473
25-mg, white, scored, shield-shaped tablets debossed with "LAMICTAL" and "25",
1474
blisterpack of 35 tablets (NDC 0173-0633-10).
1475
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled
1476
Room Temperature] in a dry place.
1477
1478
LAMICTAL Starter Kit for Patients Taking Carbamazepine, Phenytoin, Phenobarbital,
1479
Primidone, or Rifampin and Not Taking Valproate
1480
25-mg, white, scored, shield-shaped tablets debossed with "LAMICTAL" and "25" and
1481
100-mg, peach, scored, shield-shaped tablets debossed with "LAMICTAL" and “100”,
1482
blisterpack of 84, 25-mg tablets and 14, 100-mg tablets (NDC 0173-0594-01)
1483
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled
1484
Room Temperature] in a dry place and protect from light.
1485
1486
LAMICTAL Starter Kit for Patients Not Taking Carbamazepine, Phenytoin,
1487
Phenobarbital, Primidone, Rifampin, or Valproate
1488
1489
25-mg, white, scored, shield-shaped tablets debossed with "LAMICTAL" and "25" and
1490
100-mg, peach, scored, shield-shaped tablets debossed with "LAMICTAL" and “100”,
1491
blisterpack of 42, 25-mg tablets and 7, 100-mg tablets (NDC 0173-0594-02).
1492
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled
1493
Room Temperature] in a dry place and protect from light.
1494
PATIENT INFORMATION
1495
The following wording is contained in a separate leaflet provided for patients.
1496
1497
Information for the Patient
1498
1499
LAMICTAL® (lamotrigine) Tablets
1500
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
51
LAMICTAL® (lamotrigine) Chewable Dispersible Tablets
1501
1502
ALWAYS CHECK THAT YOU RECEIVE LAMICTAL
1503
Patients prescribed LAMICTAL (lah-MICK-tall) have sometimes been given the wrong
1504
medicine in error because many medicines have names similar to LAMICTAL. Taking the
1505
wrong medication can cause serious health problems. When your healthcare provider gives you a
1506
prescription for LAMICTAL
1507
• make sure you can read it clearly.
1508
• talk to your pharmacist to check that you are given the correct medicine.
1509
• check the tablets you receive against the pictures of the tablets below. The pictures show
1510
actual tablet shape and size and the wording describes the color and printing that is on each
1511
strength of LAMICTAL Tablets and Chewable Dispersible Tablets.
1512
1513
LAMICTAL (lamotrigine) Tablets
1514
1515
25 mg, white
Imprinted with
LAMICTAL 25
100 mg, peach
Imprinted with
LAMICTAL 100
150 mg, cream
Imprinted with
LAMICTAL 150
200 mg, blue
Imprinted with
LAMICTAL 200
1516
LAMICTAL (lamotrigine) Chewable Dispersible Tablets
1517
1518
2 mg, white
Imprinted with
LTG 2
5 mg, white
Imprinted with
GX CL2
25 mg, white
Imprinted with
GX CL5
1519
Please read this leaflet carefully before you take LAMICTAL and read the leaflet provided
1520
with any refill, in case any information has changed. This leaflet provides a summary of the
1521
information about your medicine. Please do not throw away this leaflet until you have finished
1522
your medicine. This leaflet does not contain all the information about LAMICTAL and is not
1523
meant to take the place of talking with your doctor. If you have any questions about
1524
LAMICTAL, ask your doctor or pharmacist.
1525
1526
Information About Your Medicine:
1527
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
52
The name of your medicine is LAMICTAL (lamotrigine). The decision to use LAMICTAL is
1528
one that you and your doctor should make together. When taking lamotrigine, it is important to
1529
follow your doctor's instructions.
1530
1531
1. The Purpose of Your Medicine:
1532
For Patients With Epilepsy: LAMICTAL is intended to be used either alone or in
1533
combination with other medicines to treat seizures in people aged 2 years or older.
1534
For Patients With Bipolar Disorder: LAMICTAL is used as maintenance treatment of
1535
Bipolar I Disorder to delay the time to occurrence of mood episodes in people aged 18 years or
1536
older treated for acute mood episodes with standard therapy.
1537
If you are taking LAMICTAL to help prevent extreme mood swings, you may not experience
1538
the full effect for several weeks. Occasionally, the symptoms of depression or bipolar disorder
1539
may include thoughts of harming yourself or committing suicide. Tell your doctor immediately
1540
or go to the nearest hospital if you have any distressing thoughts or experiences during this initial
1541
period or at any other time. Also contact your doctor if you experience any worsening of your
1542
condition or develop other new symptoms at any time during your treatment.
1543
Some medicines used to treat depression have been associated with suicidal thoughts and
1544
suicidal behavior in children or teenagers. LAMICTAL is not approved for treating children or
1545
teenagers with mood disorders such as bipolar disorder or depression.
1546
2. Who Should Not Take LAMICTAL:
1547
You should not take LAMICTAL if you had an allergic reaction to it in the past.
1548
3. Side Effects to Watch for:
1549
• Most people who take LAMICTAL tolerate it well. Common side effects with LAMICTAL
1550
include dizziness, headache, blurred or double vision, lack of coordination, sleepiness,
1551
nausea, vomiting, insomnia, and rash. LAMICTAL may cause other side effects not listed in
1552
this leaflet. If you develop any side effects or symptoms you are concerned about or need
1553
more information, call your doctor.
1554
• Although most patients who develop rash while receiving LAMICTAL have mild to
1555
moderate symptoms, some individuals may develop a serious skin reaction that requires
1556
hospitalization. Rarely, deaths have been reported. These serious skin reactions are most
1557
likely to happen within the first 8 weeks of treatment with LAMICTAL. Serious skin
1558
reactions occur more often in children than in adults.
1559
• Rashes may be more likely to occur if you: (1) take LAMICTAL in combination with
1560
valproate [DEPAKENE® (valproic acid) or DEPAKOTE® (divalproex sodium)], (2) take a
1561
higher starting dose of LAMICTAL than your doctor prescribed, or (3) increase your dose of
1562
LAMICTAL faster than prescribed.
1563
• It is not possible to predict whether a mild rash will develop into a more serious reaction.
1564
Therefore, if you experience a skin rash, hives, fever, swollen lymph glands, painful
1565
sores in the mouth or around the eyes, or swelling of lips or tongue, tell a doctor
1566
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
53
immediately, since these symptoms may be the first signs of a serious reaction. A doctor
1567
should evaluate your condition and decide if you should continue taking LAMICTAL.
1568
4. The Use of LAMICTAL During Pregnancy and Breastfeeding:
1569
The effects of LAMICTAL during pregnancy are not known at this time. If you are pregnant
1570
or are planning to become pregnant, talk to your doctor. Some LAMICTAL passes into breast
1571
milk and the effects of this on infants are unknown. Therefore, if you are breast-feeding, you
1572
should discuss this with your doctor to determine if you should continue to take LAMICTAL.
1573
5. Use of Birth Control Pills or Other Female Hormonal Products:
1574
• Do not start or stop using birth control pills or other female hormonal products until you
1575
have consulted your doctor. Stopping or starting these products may cause side effects
1576
(such as dizziness, lack of coordination, or double vision) or decrease the effectiveness
1577
of LAMICTAL.
1578
• Tell your doctor as soon as possible if you experience side effects or changes in your menstrual
1579
pattern (e.g., break-through bleeding) while taking LAMICTAL and birth control pills or
1580
other female hormonal products.
1581
6. How to Use LAMICTAL:
1582
• It is important to take LAMICTAL exactly as instructed by your doctor. The dose of
1583
LAMICTAL must be increased slowly. It may take several weeks or months before your
1584
final dosage can be determined by your doctor, based on your response.
1585
• Do not increase your dose of LAMICTAL or take more frequent doses than those indicated
1586
by your doctor. Contact your doctor, if you stop taking LAMICTAL for any reason. Do not
1587
restart without consulting your doctor.
1588
• If you miss a dose of LAMICTAL, do not double your next dose.
1589
• Always tell your doctor and pharmacist if you are taking any other prescription or
1590
over-the-counter medicines. Tell your doctor before you start any other medicines.
1591
• Do NOT stop taking LAMICTAL or any of your other medicines unless instructed by your
1592
doctor.
1593
• Use caution before driving a car or operating complex, hazardous machinery until you know
1594
if LAMICTAL affects your ability to perform these tasks.
1595
• If you have epilepsy, tell your doctor if your seizures get worse or if you have any new types
1596
of seizures.
1597
7. How to Take LAMICTAL:
1598
LAMICTAL Tablets should be swallowed whole. Chewing the tablets may leave a bitter taste.
1599
LAMICTAL Chewable Dispersible Tablets may be swallowed whole, chewed, or mixed in
1600
water or diluted fruit juice. If the tablets are chewed, consume a small amount of water or diluted
1601
fruit juice to aid in swallowing.
1602
To disperse LAMICTAL Chewable Dispersible Tablets, add the tablets to a small amount of
1603
liquid (1 teaspoon, or enough to cover the medication) in a glass or spoon. Approximately
1604
1 minute later, when the tablets are completely dispersed, mix the solution and take the entire
1605
amount immediately.
1606
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
54
8. Storing Your Medicine:
1607
Store LAMICTAL at room temperature away from heat and light. Always keep your
1608
medicines out of the reach of children.
1609
This medicine was prescribed for your use only to treat seizures or to treat Bipolar Disorder.
1610
Do not give the drug to others.
1611
If your doctor decides to stop your treatment, do not keep any leftover medicine unless your
1612
doctor tells you to. Throw away your medicine as instructed.
1613
1614
1615
Manufactured for
1616
GlaxoSmithKline
1617
Research Triangle Park, NC 27709
1618
by DSM Pharmaceuticals, Inc.
1619
Greenville, NC 27834 or
1620
GlaxoSmithKline
1621
Research Triangle Park, NC 27709
1622
1623
DEPAKENE and DEPAKOTE are registered trademarks of Abbott Laboratories.
1624
1625
©2005, GlaxoSmithKline. All rights reserved.
1626
1627
(Date of Issue)
RL-
1628
1629
PHARMACIST--DETACH HERE AND GIVE INSTRUCTIONS TO PATIENT
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
1630
1631
Information for the Patient
1632
1633
LAMICTAL® (lamotrigine) Tablets
1634
LAMICTAL® (lamotrigine) Chewable Dispersible Tablets
1635
1636
ALWAYS CHECK THAT YOU RECEIVE LAMICTAL
1637
Patients prescribed LAMICTAL (lah-MICK-tall) have sometimes been given the wrong
1638
medicine in error because many medicines have names similar to LAMICTAL. Taking the
1639
wrong medication can cause serious health problems. When your healthcare provider gives you a
1640
prescription for LAMICTAL
1641
• make sure you can read it clearly.
1642
• talk to your pharmacist to check that you are given the correct medicine.
1643
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
55
• check the tablets you receive against the pictures of the tablets below. The pictures show
1644
actual tablet shape and size and the wording describes the color and printing that is on each
1645
strength of LAMICTAL Tablets and Chewable Dispersible Tablets.
1646
1647
LAMICTAL (lamotrigine) Tablets
1648
1649
25 mg, white
Imprinted with
LAMICTAL 25
100 mg, peach
Imprinted with
LAMICTAL 100
150 mg, cream
Imprinted with
LAMICTAL 150
200 mg, blue
Imprinted with
LAMICTAL 200
1650
LAMICTAL (lamotrigine) Chewable Dispersible Tablets
1651
1652
2 mg, white
Imprinted with
LTG 2
5 mg, white
Imprinted with
GX CL2
25 mg, white
Imprinted with
GX CL5
1653
Please read this leaflet carefully before you take LAMICTAL and read the leaflet provided
1654
with any refill, in case any information has changed. This leaflet provides a summary of the
1655
information about your medicine. Please do not throw away this leaflet until you have finished
1656
your medicine. This leaflet does not contain all the information about LAMICTAL and is not
1657
meant to take the place of talking with your doctor. If you have any questions about
1658
LAMICTAL, ask your doctor or pharmacist.
1659
1660
Information About Your Medicine:
1661
The name of your medicine is LAMICTAL (lamotrigine). The decision to use LAMICTAL is
1662
one that you and your doctor should make together. When taking lamotrigine, it is important to
1663
follow your doctor's instructions.
1664
1665
1. The Purpose of Your Medicine:
1666
For Patients With Epilepsy: LAMICTAL is intended to be used either alone or in
1667
combination with other medicines to treat seizures in people aged 2 years or older.
1668
For Patients With Bipolar Disorder: LAMICTAL is used as maintenance treatment of
1669
Bipolar I Disorder to delay the time to occurrence of mood episodes in people aged 18 years or
1670
older treated for acute mood episodes with standard therapy.
1671
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
56
If you are taking LAMICTAL to help prevent extreme mood swings, you may not experience
1672
the full effect for several weeks. Occasionally, the symptoms of depression or bipolar disorder
1673
may include thoughts of harming yourself or committing suicide. Tell your doctor immediately
1674
or go to the nearest hospital if you have any distressing thoughts or experiences during this initial
1675
period or at any other time. Also contact your doctor if you experience any worsening of your
1676
condition or develop other new symptoms at any time during your treatment.
1677
Some medicines used to treat depression have been associated with suicidal thoughts and
1678
suicidal behavior in children or teenagers. LAMICTAL is not approved for treating children or
1679
teenagers with mood disorders such as bipolar disorder or depression.
1680
2. Who Should Not Take LAMICTAL:
1681
You should not take LAMICTAL if you had an allergic reaction to it in the past.
1682
3. Side Effects to Watch for:
1683
• Most people who take LAMICTAL tolerate it well. Common side effects with
1684
LAMICTAL include dizziness, headache, blurred or double vision, lack of coordination,
1685
sleepiness, nausea, vomiting, insomnia, and rash. LAMICTAL may cause other side effects
1686
not listed in this leaflet. If you develop any side effects or symptoms you are concerned about
1687
or need more information, call your doctor.
1688
• Although most patients who develop rash while receiving LAMICTAL have mild to
1689
moderate symptoms, some individuals may develop a serious skin reaction that requires
1690
hospitalization. Rarely, deaths have been reported. These serious skin reactions are most
1691
likely to happen within the first 8 weeks of treatment with LAMICTAL. Serious skin
1692
reactions occur more often in children than in adults.
1693
• Rashes may be more likely to occur if you: (1) take LAMICTAL in combination with
1694
valproate [DEPAKENE® (valproic acid) or DEPAKOTE® (divalproex sodium)], (2) take a
1695
higher starting dose of LAMICTAL than your doctor prescribed, or (3) increase your dose of
1696
LAMICTAL faster than prescribed.
1697
• It is not possible to predict whether a mild rash will develop into a more serious reaction.
1698
Therefore, if you experience a skin rash, hives, fever, swollen lymph glands, painful
1699
sores in the mouth or around the eyes, or swelling of lips or tongue, tell a doctor
1700
immediately, since these symptoms may be the first signs of a serious reaction. A doctor
1701
should evaluate your condition and decide if you should continue taking LAMICTAL.
1702
4. The Use of LAMICTAL During Pregnancy and Breastfeeding:
1703
The effects of LAMICTAL during pregnancy are not known at this time. If you are pregnant
1704
or are planning to become pregnant, talk to your doctor. Some LAMICTAL passes into breast
1705
milk and the effects of this on infants are unknown. Therefore, if you are breastfeeding, you
1706
should discuss this with your doctor to determine if you should continue to take LAMICTAL.
1707
5. Use of Birth Control Pills or Other Female Hormonal Products:
1708
• Do not start or stop using birth control pills or other female hormonal products until you
1709
have consulted your doctor. Stopping or starting these products may cause side effects
1710
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
57
(such as dizziness, lack of coordination, or double vision) or to decrease the
1711
effectiveness of LAMICTAL.
1712
1713
1714
• Tell your doctor as soon as possible if you experience side effects changes in your menstrual
1715
pattern (e.g., break-through bleeding) while taking LAMICTAL and birth control pills or
1716
other female hormonal products.
1717
6. How to Use LAMICTAL:
1718
• It is important to take LAMICTAL exactly as instructed by your doctor. The dose of
1719
LAMICTAL must be increased slowly. It may take several weeks or months before your
1720
final dosage can be determined by your doctor, based on your response.
1721
• Do not increase your dose of LAMICTAL or take more frequent doses than those indicated
1722
by your doctor. Contact your doctor, if you stop taking LAMICTAL for any reason. Do not
1723
restart without consulting your doctor.
1724
• If you miss a dose of LAMICTAL, do not double your next dose.
1725
• Always tell your doctor and pharmacist if you are taking any other prescription or
1726
over-the-counter medicines. Tell your doctor before you start any other medicines.
1727
• Do NOT stop taking LAMICTAL or any of your other medicines unless instructed by your
1728
doctor.
1729
• Use caution before driving a car or operating complex, hazardous machinery until you know
1730
if LAMICTAL affects your ability to perform these tasks.
1731
• If you have epilepsy, tell your doctor if your seizures get worse or if you have any new types
1732
of seizures.
1733
7. How to Take LAMICTAL:
1734
LAMICTAL Tablets should be swallowed whole. Chewing the tablets may leave a bitter taste.
1735
LAMICTAL Chewable Dispersible Tablets may be swallowed whole, chewed, or mixed in
1736
water or diluted fruit juice. If the tablets are chewed, consume a small amount of water or diluted
1737
fruit juice to aid in swallowing.
1738
To disperse LAMICTAL Chewable Dispersible Tablets, add the tablets to a small amount of
1739
liquid (1 teaspoon, or enough to cover the medication) in a glass or spoon. Approximately
1740
1 minute later, when the tablets are completely dispersed, mix the solution and take the entire
1741
amount immediately.
1742
8. Storing Your Medicine:
1743
Store LAMICTAL at room temperature away from heat and light. Always keep your
1744
medicines out of the reach of children.
1745
This medicine was prescribed for your use only to treat seizures or to treat Bipolar Disorder.
1746
Do not give the drug to others.
1747
If your doctor decides to stop your treatment, do not keep any leftover medicine unless your
1748
doctor tells you to. Throw away your medicine as instructed.
1749
1750
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
58
1751
Manufactured for
1752
GlaxoSmithKline
1753
Research Triangle Park, NC 27709
1754
by DSM Pharmaceuticals, Inc.
1755
Greenville, NC 27834 or
1756
GlaxoSmithKline
1757
Research Triangle Park, NC 27709
1758
1759
DEPAKENE and DEPAKOTE are registered trademarks of Abbott Laboratories.
1760
1761
©2005, GlaxoSmithKline. All rights reserved.
1762
1763
(Date of Issue)
RL-
1764
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:47:11.502139
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/020241s10s21s25s26s27,020764s3s14s18s19s20lbl.pdf', 'application_number': 20241, 'submission_type': 'SUPPL ', 'submission_number': 27}
|
12,364
|
NDA 020241/S-043 and S-044
NDA 020764/S-036 and S-037
NDA 022251/S-005 and S-006
FDA Approved Labeling Text dated 10/12/2010
Page 1
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
LAMICTAL safely and effectively. See full prescribing information for
LAMICTAL.
LAMICTAL (lamotrigine) Tablets
LAMICTAL (lamotrigine) Chewable Dispersible Tablets
LAMICTAL ODT (lamotrigine) Orally Disintegrating Tablets
Initial U.S. Approval: 1994
WARNING: SERIOUS SKIN RASHES
See full prescribing information for complete boxed warning.
Cases of life-threatening serious rashes, including Stevens-Johnson
syndrome, toxic epidermal necrolysis, and/or rash-related death, have
been caused by LAMICTAL. The rate of serious rash is greater in
pediatric patients than in adults. Additional factors that may increase the
risk of rash include (5.1):
• coadministration with valproate
• exceeding recommended initial dose of LAMICTAL
•
exceeding recommended dose escalation of LAMICTAL
Benign rashes are also caused by LAMICTAL; however, it is not possible
to predict which rashes will prove to be serious or life-threatening.
LAMICTAL should be discontinued at the first sign of rash, unless the
rash is clearly not drug-related. (5.1)
---------------------------RECENT MAJOR CHANGES -------------------
Warnings and Precautions, Aseptic Meningitis (5.7)
Month Year
--------------------------- INDICATIONS AND USAGE -------------------
LAMICTAL is an antiepileptic drug (AED) indicated for:
Epilepsy—adjunctive therapy in patients ≥2 years of age: (1.1)
•
partial seizures.
•
primary generalized tonic-clonic seizures.
•
generalized seizures of Lennox-Gastaut syndrome.
Epilepsy—monotherapy in patients ≥16 years of age: conversion to
monotherapy in patients with partial seizures who are receiving treatment with
carbamazepine, phenobarbital, phenytoin, primidone, or valproate as the
single AED. (1.1)
Bipolar Disorder in patients ≥18 years of age: maintenance treatment of
Bipolar I Disorder to delay the time to occurrence of mood episodes in
patients treated for acute mood episodes with standard therapy. (1.2)
----------------------- DOSAGE AND ADMINISTRATION ---------------
• Dosing is based on concomitant medications, indication, and patient age.
(2.2, 2.4)
• To avoid an increased risk of rash, the recommended initial dose and
subsequent dose escalations should not be exceeded. LAMICTAL Starter
Kits and LAMICTAL ODT Patient Titration Kits are available for the
first 5 weeks of treatment. (2.1, 16)
• Do not restart LAMICTAL in patients who discontinued due to rash
unless the potential benefits clearly outweigh the risks. (2.1)
• Adjustments to maintenance doses will in most cases be required in
patients starting or stopping estrogen-containing oral contraceptives. (2.1,
5.9)
• LAMICTAL should be discontinued over a period of at least 2 weeks
(approximately 50% reduction per week). (2.1, 5.10)
Epilepsy
• Adjunctive therapy—See Table 1 for patients >12 years of age and Tables
2 and 3 for patients 2 to 12 years. (2.2)
•
Conversion to monotherapy—See Table 4. (2.3)
Bipolar Disorder: See Tables 5 and 6. (2.4)
---------------------DOSAGE FORMS AND STRENGTHS -------------
Tablets: 25 mg, 100 mg, 150 mg, and 200 mg scored. (3.1, 16)
Chewable Dispersible Tablets: 2 mg, 5 mg, and 25 mg. (3.2, 16)
Orally Disintegrating Tablets: 25 mg, 50 mg, 100 mg, and 200 mg. (3.3, 16)
-------------------------------CONTRAINDICATIONS-----------------------
Hypersensitivity to the drug or its ingredients. (Boxed Warning, 4)
----------------------- WARNINGS AND PRECAUTIONS ---------------
• Life-threatening serious rash and/or rash-related death may result. (Boxed
Warning, 5.1)
• Hypersensitivity reaction may be fatal or life-threatening. Early signs of
hypersensitivity (e.g., fever, lymphadenopathy) may present without rash;
if signs present, patient should be evaluated immediately. LAMICTAL
should be discontinued if alternate etiology for hypersensitivity signs is
not found. (5.2)
• Acute multiorgan failure has resulted (some cases fatal). (5.3)
• Blood dyscrasias (e.g., neutropenia, thrombocytopenia, pancytopenia),
may result either with or without an associated hypersensitivity syndrome.
(5.4)
• Suicidal behavior and ideation. (5.5)
• Clinical worsening, emergence of new symptoms, and suicidal
ideation/behaviors may be associated with treatment of bipolar disorder.
Patients should be closely monitored, particularly early in treatment or
during dosage changes. (5.6)
• Aseptic meningitis reported in pediatric and adult patients. (5.7)
• Medication errors involving LAMICTAL have occurred. In particular the
names LAMICTAL or lamotrigine can be confused with names of other
commonly used medications. Medication errors may also occur between
the different formulations of LAMICTAL. (3.4, 5.8, 16, 17.9)
------------------------------ ADVERSE REACTIONS ----------------------
• Most common adverse reactions (incidence ≥10%) in adult epilepsy
clinical studies were dizziness, headache, diplopia, ataxia, nausea, blurred
vision, somnolence, rhinitis, and rash. Additional adverse reactions
(incidence ≥10%) reported in children in epilepsy clinical studies included
vomiting, infection, fever, accidental injury, pharyngitis, abdominal pain,
and tremor. (6.1)
• Most common adverse reactions (incidence >5%) in adult bipolar clinical
studies were nausea, insomnia, somnolence, back pain, fatigue, rash,
rhinitis, abdominal pain, and xerostomia. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact
GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
-------------------------------DRUG INTERACTIONS-----------------------
• Valproate increases lamotrigine concentrations more than 2-fold. (7, 12.3)
• Carbamazepine, phenytoin, phenobarbital, and primidone decrease
lamotrigine concentrations by approximately 40%. (7, 12.3)
• Oral estrogen-containing contraceptives and rifampin also decrease
lamotrigine concentrations by approximately 50%. (7, 12.3)
----------------------- USE IN SPECIFIC POPULATIONS ---------------
• Hepatic impairment: Dosage adjustments required. (2.1)
• Healthcare professionals can enroll patients in the Lamotrigine Pregnancy
Registry (1-800-336-2176). Patients can enroll themselves in the North
American Antiepileptic Drug Pregnancy Registry (1-888-233-2334). (8.1)
• Efficacy of LAMICTAL, used as adjunctive treatment for partial seizures,
was not demonstrated in a small randomized, double-blind, placebo-
controlled study in very young pediatric patients (1 to 24 months). (8.4)
See 17 for PATIENT COUNSELING INFORMATION and Medication
Guide.
Revised:
2
DOSAGE AND ADMINISTRATION
FULL PRESCRIBING INFORMATION: CONTENTS*
2.1
General Dosing Considerations
WARNING: SERIOUS SKIN RASHES
2.2
Epilepsy – Adjunctive Therapy
1
INDICATIONS AND USAGE
2.3
Epilepsy – Conversion From Adjunctive
1.1
Epilepsy
Therapy to Monotherapy
1.2
Bipolar Disorder
2.4
Bipolar Disorder
1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-043 and S-044
NDA 020764/S-036 and S-037
NDA 022251/S-005 and S-006
FDA Approved Labeling Text dated 10/12/2010
Page 2
2.5
Administration of LAMICTAL Chewable
Dispersible Tablets
2.6
Administration of LAMICTAL ODT Orally
Disintegrating Tablets
3
DOSAGE FORMS AND STRENGTHS
3.1
Tablets
3.2
Chewable Dispersible Tablets
3.3
Orally Disintegrating Tablets
3.4
Potential Medication Errors
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1
Serious Skin Rashes [see Boxed Warning]
5.2
Hypersensitivity Reactions
5.3
Acute Multiorgan Failure
5.4
Blood Dyscrasias
5.5
Suicidal Behavior and Ideation
5.6
Use in Patients With Bipolar Disorder
5.7
Aseptic Meningitis
5.8
Potential Medication Errors
5.9
Concomitant Use With Oral Contraceptives
5.10
Withdrawal Seizures
5.11
Status Epilepticus
5.12
Sudden Unexplained Death in Epilepsy
(SUDEP)
5.13
Addition of LAMICTAL to a Multidrug Regimen
That Includes Valproate
5.14
Binding in the Eye and Other Melanin-
Containing Tissues
5.15
Laboratory Tests
6
ADVERSE REACTIONS
6.1
Clinical Trials
6.2
Other Adverse Reactions Observed in All
Clinical Trials
6.3
Postmarketing Experience
7
DRUG INTERACTIONS
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
8.2
Labor and Delivery
8.3
Nursing Mothers
8.4
Pediatric Use
8.5
Geriatric Use
8.6
Patients With Hepatic Impairment
8.7
Patients With Renal Impairment
10
OVERDOSAGE
10.1
Human Overdose Experience
10.2
Management of Overdose
11
DESCRIPTION
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
12.2
Pharmacodynamics
12.3
Pharmacokinetics
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of
Fertility
14
CLINICAL STUDIES
14.1
Epilepsy
14.2
Bipolar Disorder
16
HOW SUPPLIED/STORAGE AND HANDLING
17
PATIENT COUNSELING INFORMATION
17.1
Rash
17.2
Suicidal Thinking and Behavior
17.3
Worsening of Seizures
17.4
CNS Adverse Effects
17.5
Blood Dyscrasias and/or Acute Multiorgan
Failure
17.6
Pregnancy
17.7
Oral Contraceptive Use
17.8
Discontinuing LAMICTAL
17.9
Aseptic Meningitis
17.10 Potential Medication Errors
*Sections or subsections omitted from the full prescribing information are not listed.
2
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
______________________________________________________________________
NDA 020241/S-043 and S-044
NDA 020764/S-036 and S-037
NDA 022251/S-005 and S-006
FDA Approved Labeling Text dated 10/12/2010
Page 3
1
FULL PRESCRIBING INFORMATION
2
WARNING: SERIOUS SKIN RASHES
3
LAMICTAL® can cause serious rashes requiring hospitalization and
4
discontinuation of treatment. The incidence of these rashes, which have included Stevens
5
Johnson syndrome, is approximately 0.8% (8 per 1,000) in pediatric patients (2 to 16 years
6
of age) receiving LAMICTAL as adjunctive therapy for epilepsy and 0.3% (3 per 1,000) in
7
adults on adjunctive therapy for epilepsy. In clinical trials of bipolar and other mood
8
disorders, the rate of serious rash was 0.08% (0.8 per 1,000) in adult patients receiving
9
LAMICTAL as initial monotherapy and 0.13% (1.3 per 1,000) in adult patients receiving
10
LAMICTAL as adjunctive therapy. In a prospectively followed cohort of 1,983 pediatric
11
patients (2 to 16 years of age) with epilepsy taking adjunctive LAMICTAL, there was 1
12
rash-related death. In worldwide postmarketing experience, rare cases of toxic epidermal
13
necrolysis and/or rash-related death have been reported in adult and pediatric patients, but
14
their numbers are too few to permit a precise estimate of the rate.
15
Other than age, there are as yet no factors identified that are known to predict the
16
risk of occurrence or the severity of rash caused by LAMICTAL. There are suggestions,
17
yet to be proven, that the risk of rash may also be increased by (1) coadministration of
18
LAMICTAL with valproate (includes valproic acid and divalproex sodium), (2) exceeding
19
the recommended initial dose of LAMICTAL, or (3) exceeding the recommended dose
20
escalation for LAMICTAL. However, cases have occurred in the absence of these factors.
21
Nearly all cases of life-threatening rashes caused by LAMICTAL have occurred
22
within 2 to 8 weeks of treatment initiation. However, isolated cases have occurred after
23
prolonged treatment (e.g., 6 months). Accordingly, duration of therapy cannot be relied
24
upon as means to predict the potential risk heralded by the first appearance of a rash.
25
Although benign rashes are also caused by LAMICTAL, it is not possible to predict
26
reliably which rashes will prove to be serious or life-threatening. Accordingly, LAMICTAL
27
should ordinarily be discontinued at the first sign of rash, unless the rash is clearly not
28
drug-related. Discontinuation of treatment may not prevent a rash from becoming life
29
threatening or permanently disabling or disfiguring [see Warnings and Precautions (5.1)].
30
1
INDICATIONS AND USAGE
31
1.1
Epilepsy
32
Adjunctive Therapy: LAMICTAL is indicated as adjunctive therapy for the following
33
seizure types in patients ≥2 years of age:
34
• partial seizures
35
• primary generalized tonic-clonic seizures
36
• generalized seizures of Lennox-Gastaut syndrome
3
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For current labeling information, please visit https://www.fda.gov/drugsatfda
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FDA Approved Labeling Text dated 10/12/2010
Page 4
37
Monotherapy: LAMICTAL is indicated for conversion to monotherapy in adults (≥16
38
years of age) with partial seizures who are receiving treatment with carbamazepine, phenytoin,
39
phenobarbital, primidone, or valproate as the single antiepileptic drug (AED).
40
Safety and effectiveness of LAMICTAL have not been established (1) as initial
41
monotherapy; (2) for conversion to monotherapy from AEDs other than carbamazepine,
42
phenytoin, phenobarbital, primidone, or valproate; or (3) for simultaneous conversion to
43
monotherapy from 2 or more concomitant AEDs.
44
1.2
Bipolar Disorder
45
LAMICTAL is indicated for the maintenance treatment of Bipolar I Disorder to delay the
46
time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in adults
47
(≥18 years of age) treated for acute mood episodes with standard therapy. The effectiveness of
48
LAMICTAL in the acute treatment of mood episodes has not been established.
49
The effectiveness of LAMICTAL as maintenance treatment was established in 2 placebo
50
controlled trials in patients with Bipolar I Disorder as defined by DSM-IV [see Clinical Studies
51
(14.2)]. The physician who elects to prescribe LAMICTAL for periods extending beyond 16
52
weeks should periodically re-evaluate the long-term usefulness of the drug for the individual
53
patient.
54
2
DOSAGE AND ADMINISTRATION
55
2.1
General Dosing Considerations
56
Rash: There are suggestions, yet to be proven, that the risk of severe, potentially life
57
threatening rash may be increased by (1) coadministration of LAMICTAL with valproate, (2)
58
exceeding the recommended initial dose of LAMICTAL, or (3) exceeding the recommended
59
dose escalation for LAMICTAL. However, cases have occurred in the absence of these factors
60
[see Boxed Warning]. Therefore, it is important that the dosing recommendations be followed
61
closely.
62
The risk of nonserious rash may be increased when the recommended initial dose and/or
63
the rate of dose escalation of LAMICTAL is exceeded and in patients with a history of allergy or
64
rash to other AEDs.
65
LAMICTAL Starter Kits and LAMICTAL® ODT™ Patient Titration Kits provide
66
LAMICTAL at doses consistent with the recommended titration schedule for the first 5 weeks of
67
treatment, based upon concomitant medications for patients with epilepsy (>12 years of age) and
68
Bipolar I Disorder (≥18 years of age) and are intended to help reduce the potential for rash. The
69
use of LAMICTAL Starter Kits and LAMICTAL ODT Patient Titration Kits is recommended
70
for appropriate patients who are starting or restarting LAMICTAL [see How Supplied/Storage
71
and Handling (16)].
72
It is recommended that LAMICTAL not be restarted in patients who discontinued due to
73
rash associated with prior treatment with lamotrigine, unless the potential benefits clearly
74
outweigh the risks. If the decision is made to restart a patient who has discontinued lamotrigine,
75
the need to restart with the initial dosing recommendations should be assessed. The greater the
4
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For current labeling information, please visit https://www.fda.gov/drugsatfda
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NDA 020764/S-036 and S-037
NDA 022251/S-005 and S-006
FDA Approved Labeling Text dated 10/12/2010
Page 5
76
interval of time since the previous dose, the greater consideration should be given to restarting
77
with the initial dosing recommendations. If a patient has discontinued lamotrigine for a period of
78
more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be
79
followed. The half-life of lamotrigine is affected by other concomitant medications [see Clinical
80
Pharmacology (12.3)].
81
LAMICTAL Added to Drugs Known to Induce or Inhibit Glucuronidation: Drugs
82
other than those listed in the Clinical Pharmacology section [see Clinical Pharmacology (12.3)]
83
have not been systematically evaluated in combination with lamotrigine. Because lamotrigine is
84
metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or
85
inhibit glucuronidation may affect the apparent clearance of lamotrigine and doses of
86
LAMICTAL may require adjustment based on clinical response.
87
Target Plasma Levels for Patients With Epilepsy or Bipolar Disorder: A therapeutic
88
plasma concentration range has not been established for lamotrigine. Dosing of LAMICTAL
89
should be based on therapeutic response [see Clinical Pharmacology (12.3)].
90
Women Taking Estrogen-Containing Oral Contraceptives: Starting LAMICTAL in
91
Women Taking Estrogen-Containing Oral Contraceptives: Although estrogen-containing
92
oral contraceptives have been shown to increase the clearance of lamotrigine [see Clinical
93
Pharmacology (12.3)], no adjustments to the recommended dose-escalation guidelines for
94
LAMICTAL should be necessary solely based on the use of estrogen-containing oral
95
contraceptives. Therefore, dose escalation should follow the recommended guidelines for
96
initiating adjunctive therapy with LAMICTAL based on the concomitant AED or other
97
concomitant medications (see Table 1 or Table 5). See below for adjustments to maintenance
98
doses of LAMICTAL in women taking estrogen-containing oral contraceptives.
99
Adjustments to the Maintenance Dose of LAMICTAL In Women Taking
100
Estrogen-Containing Oral Contraceptives:
101
(1) Taking Estrogen-Containing Oral Contraceptives: For women not taking
102
carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce
103
lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the
104
maintenance dose of LAMICTAL will in most cases need to be increased, by as much as 2-fold
105
over the recommended target maintenance dose, in order to maintain a consistent lamotrigine
106
plasma level [see Clinical Pharmacology (12.3)].
107
(2) Starting Estrogen-Containing Oral Contraceptives: In women taking a
108
stable dose of LAMICTAL and not taking carbamazepine, phenytoin, phenobarbital, primidone,
109
or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions
110
(7), Clinical Pharmacology (12.3)], the maintenance dose will in most cases need to be increased
111
by as much as 2-fold in order to maintain a consistent lamotrigine plasma level. The dose
112
increases should begin at the same time that the oral contraceptive is introduced and continue,
113
based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases
114
should not exceed the recommended rate (see Table 1 or Table 5) unless lamotrigine plasma
5
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For current labeling information, please visit https://www.fda.gov/drugsatfda
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NDA 020764/S-036 and S-037
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Page 6
115
levels or clinical response support larger increases. Gradual transient increases in lamotrigine
116
plasma levels may occur during the week of inactive hormonal preparation (“pill-free” week),
117
and these increases will be greater if dose increases are made in the days before or during the
118
week of inactive hormonal preparation. Increased lamotrigine plasma levels could result in
119
additional adverse reactions, such as dizziness, ataxia, and diplopia. If adverse reactions
120
attributable to LAMICTAL consistently occur during the “pill-free” week, dose adjustments to
121
the overall maintenance dose may be necessary. Dose adjustments limited to the “pill-free” week
122
are not recommended. For women taking LAMICTAL in addition to carbamazepine, phenytoin,
123
phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine
124
glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the
125
dose of LAMICTAL should be necessary.
126
(3) Stopping Estrogen-Containing Oral Contraceptives: For women not
127
taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that
128
induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)],
129
the maintenance dose of LAMICTAL will in most cases need to be decreased by as much as
130
50% in order to maintain a consistent lamotrigine plasma level. The decrease in dose of
131
LAMICTAL should not exceed 25% of the total daily dose per week over a 2-week period,
132
unless clinical response or lamotrigine plasma levels indicate otherwise [see Clinical
133
Pharmacology (12.3)]. For women taking LAMICTAL in addition to carbamazepine, phenytoin,
134
phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine
135
glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the
136
dose of LAMICTAL should be necessary.
137
Women and Other Hormonal Contraceptive Preparations or Hormone
138
Replacement Therapy: The effect of other hormonal contraceptive preparations or hormone
139
replacement therapy on the pharmacokinetics of lamotrigine has not been systematically
140
evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of
141
lamotrigine up to 2-fold, and the progestin-only pills had no effect on lamotrigine plasma levels.
142
Therefore, adjustments to the dosage of LAMICTAL in the presence of progestogens alone will
143
likely not be needed.
144
Patients With Hepatic Impairment: Experience in patients with hepatic impairment is
145
limited. Based on a clinical pharmacology study in 24 patients with mild, moderate, and severe
146
liver impairment [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)], the
147
following general recommendations can be made. No dosage adjustment is needed in patients
148
with mild liver impairment. Initial, escalation, and maintenance doses should generally be
149
reduced by approximately 25% in patients with moderate and severe liver impairment without
150
ascites and 50% in patients with severe liver impairment with ascites. Escalation and
151
maintenance doses may be adjusted according to clinical response.
152
Patients With Renal Impairment: Initial doses of LAMICTAL should be based on
153
patients' concomitant medications (see Tables 1-3 or Table 5); reduced maintenance doses may
6
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For current labeling information, please visit https://www.fda.gov/drugsatfda
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NDA 020764/S-036 and S-037
NDA 022251/S-005 and S-006
FDA Approved Labeling Text dated 10/12/2010
Page 7
154
be effective for patients with significant renal impairment [see Use in Specific Populations (8.7),
155
Clinical Pharmacology (12.3)]. Few patients with severe renal impairment have been evaluated
156
during chronic treatment with LAMICTAL. Because there is inadequate experience in this
157
population, LAMICTAL should be used with caution in these patients.
158
Discontinuation Strategy: Epilepsy: For patients receiving LAMICTAL in
159
combination with other AEDs, a reevaluation of all AEDs in the regimen should be considered if
160
a change in seizure control or an appearance or worsening of adverse reactions is observed.
161
If a decision is made to discontinue therapy with LAMICTAL, a step-wise reduction of
162
dose over at least 2 weeks (approximately 50% per week) is recommended unless safety
163
concerns require a more rapid withdrawal [see Warnings and Precautions (5.10)].
164
Discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such
165
as rifampin that induce lamotrigine glucuronidation should prolong the half-life of lamotrigine;
166
discontinuing valproate should shorten the half-life of lamotrigine.
167
Bipolar Disorder: In the controlled clinical trials, there was no increase in the
168
incidence, type, or severity of adverse reactions following abrupt termination of LAMICTAL. In
169
clinical trials in patients with Bipolar Disorder, 2 patients experienced seizures shortly after
170
abrupt withdrawal of LAMICTAL. However, there were confounding factors that may have
171
contributed to the occurrence of seizures in these bipolar patients. Discontinuation of
172
LAMICTAL should involve a step-wise reduction of dose over at least 2 weeks (approximately
173
50% per week) unless safety concerns require a more rapid withdrawal [see Warnings and
174
Precautions (5.10)].
175
2.2
Epilepsy – Adjunctive Therapy
176
This section provides specific dosing recommendations for patients greater than 12 years
177
of age and patients 2 to 12 years of age. Within each of these age-groups, specific dosing
178
recommendations are provided depending upon concomitant AED or other concomitant
179
medications (Table 1 for patients greater than 12 years of age and Table 2 for patients 2 to
180
12 years of age). A weight-based dosing guide for patients 2 to 12 years of age on concomitant
181
valproate is provided in Table 3.
182
Patients Over 12 Years of Age: Recommended dosing guidelines are summarized in
183
Table 1.
184
7
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For current labeling information, please visit https://www.fda.gov/drugsatfda
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NDA 020764/S-036 and S-037
NDA 022251/S-005 and S-006
FDA Approved Labeling Text dated 10/12/2010
Page 8
185
Table 1. Escalation Regimen for LAMICTAL in Patients Over 12 Years of Age With
186
Epilepsy
For Patients TAKING
Valproatea
For Patients NOT
TAKING
Carbamazepine,
Phenytoin,
Phenobarbital,
Primidone,b or
Valproatea
For Patients
TAKING
Carbamazepine,
Phenytoin,
Phenobarbital, or
Primidoneb and NOT
TAKING Valproatea
Weeks 1 and 2
25 mg every other day
25 mg every day
50 mg/day
Weeks 3 and 4
25 mg every day
50 mg/day
100 mg/day
(in 2 divided doses)
Week 5 onwards
to maintenance
Increase by 25 to
50 mg/day every 1 to
2 weeks
Increase by 50 mg/day
every 1 to 2 weeks
Increase by
100 mg/day every 1
to 2 weeks.
Usual
Maintenance
Dose
100 to 200 mg/day with
valproate alone
100 to 400 mg/day with
valproate and other
drugs that induce
glucuronidation
(in 1 or 2 divided doses)
225 to 375 mg/day
(in 2 divided doses)
300 to 500 mg/day
(in 2 divided doses)
187
a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of
188
lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].
189
b These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions
190
(7), Clinical Pharmacology (12.3)]. Other drugs which have similar effects include estrogen
191
containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)].
192
Dosing recommendations for oral contraceptives can be found in General Dosing
193
Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs
194
that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing
195
titration/maintenance regimen as that used with anticonvulsants that have this effect.
196
197
Patients 2 to 12 Years of Age: Recommended dosing guidelines are summarized in
198
Table 2.
199
Smaller starting doses and slower dose escalations than those used in clinical trials are
200
recommended because of the suggestion that the risk of rash may be decreased by smaller
201
starting doses and slower dose escalations. Therefore, maintenance doses will take longer to
8
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For current labeling information, please visit https://www.fda.gov/drugsatfda
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NDA 020764/S-036 and S-037
NDA 022251/S-005 and S-006
FDA Approved Labeling Text dated 10/12/2010
Page 9
202
reach in clinical practice than in clinical trials. It may take several weeks to months to achieve an
203
individualized maintenance dose. Maintenance doses in patients weighing less than 30 kg,
204
regardless of age or concomitant AED, may need to be increased as much as 50%, based on
205
clinical response.
206
The smallest available strength of LAMICTAL Chewable Dispersible Tablets is
207
2 mg, and only whole tablets should be administered. If the calculated dose cannot be
208
achieved using whole tablets, the dose should be rounded down to the nearest whole tablet
209
[see How Supplied/Storage and Handling (16) and Medication Guide].
210
211
Table 2. Escalation Regimen for LAMICTAL in Patients 2 to 12 Years of Age With
212
Epilepsy
For Patients TAKING
Valproatea
For Patients NOT
TAKING
Carbamazepine,
Phenytoin,
Phenobarbital,
Primidone,b or Valproatea
For Patients TAKING
Carbamazepine,
Phenytoin,
Phenobarbital, or
Primidoneb and NOT
TAKING Valproate a
Weeks 1 and 2
0.15 mg/kg/day
in 1 or 2 divided doses,
rounded down to the
nearest whole tablet
(see Table 3 for weight
based dosing guide)
0.3 mg/kg/day
in 1 or 2 divided doses,
rounded down to the
nearest whole tablet
0.6 mg/kg/day
in 2 divided doses,
rounded down to the
nearest whole tablet
Weeks 3 and 4
0.3 mg/kg/day
in 1 or 2 divided doses,
rounded down to the
nearest whole tablet
(see Table 3 for weight
based dosing guide)
0.6 mg/kg/day
in 2 divided doses,
rounded down to the
nearest whole tablet
1.2 mg/kg/day
in 2 divided doses,
rounded down to the
nearest whole tablet
Week 5
The dose should be
The dose should be
The dose should be
onwards to
increased every 1 to
increased every 1 to
increased every 1 to
maintenance
2 weeks as follows:
calculate
0.3 mg/kg/day, round
this amount down to
the nearest whole
tablet, and add this
amount to the
previously
2 weeks as follows:
calculate 0.6 mg/kg/day,
round this amount down
to the nearest whole
tablet, and add this
amount to the previously
administered daily dose
2 weeks as follows:
calculate 1.2 mg/kg/day,
round this amount down
to the nearest whole
tablet, and add this
amount to the previously
administered daily dose
9
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For current labeling information, please visit https://www.fda.gov/drugsatfda
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NDA 022251/S-005 and S-006
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Page 10
administered daily
dose
Usual
Maintenance
Dose
1 to 5 mg/kg/day
(maximum
200 mg/day in 1 or
2 divided doses).
1 to 3 mg/kg/day with
valproate alone
4.5 to 7.5 mg/kg/day
(maximum 300 mg/day
in 2 divided doses)
5 to 15 mg/kg/day
(maximum 400 mg/day
in 2 divided doses)
Maintenance
dose in
patients less
than 30 kg
May need to be
increased by as much
as 50%, based on
clinical response
May need to be increased
by as much as 50%,
based on clinical
response
May need to be
increased by as much as
50%, based on clinical
response
213
Note: Only whole tablets should be used for dosing.
214
a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of
215
lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].
216
b These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions
217
(7), Clinical Pharmacology (12.3)]. Other drugs which have similar effects include estrogen
218
containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)].
219
Dosing recommendations for oral contraceptives can be found in General Dosing
220
Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs
221
that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing
222
titration/maintenance regimen as that used with anticonvulsants that have this effect.
223
224
Table 3. The Initial Weight-Based Dosing Guide for Patients 2 to 12 Years Taking
225
Valproate (Weeks 1 to 4) With Epilepsy
If the patient’s weight is
Give this daily dose, using the most appropriate
combination of LAMICTAL 2-mg and 5-mg tablets
Greater than
And less than
Weeks 1 and 2
Weeks 3 and 4
6.7 kg
14 kg
2 mg every other day
2 mg every day
14.1 kg
27 kg
2 mg every day
4 mg every day
27.1 kg
34 kg
4 mg every day
8 mg every day
34.1 kg
40 kg
5 mg every day
10 mg every day
226
227
Usual Adjunctive Maintenance Dose for Epilepsy: The usual maintenance doses
228
identified in Tables 1 and 2 are derived from dosing regimens employed in the placebo
229
controlled adjunctive studies in which the efficacy of LAMICTAL was established. In patients
230
receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidone
231
without valproate, maintenance doses of adjunctive LAMICTAL as high as 700 mg/day have
232
been used. In patients receiving valproate alone, maintenance doses of adjunctive LAMICTAL
10
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Page 11
233
as high as 200 mg/day have been used. The advantage of using doses above those recommended
234
in Tables 1 through 4 has not been established in controlled trials.
235
2.3
Epilepsy – Conversion From Adjunctive Therapy to Monotherapy
236
The goal of the transition regimen is to effect the conversion to monotherapy with
237
LAMICTAL under conditions that ensure adequate seizure control while mitigating the risk of
238
serious rash associated with the rapid titration of LAMICTAL.
239
The recommended maintenance dose of LAMICTAL as monotherapy is 500 mg/day
240
given in 2 divided doses.
241
To avoid an increased risk of rash, the recommended initial dose and subsequent dose
242
escalations of LAMICTAL should not be exceeded [see Boxed Warning].
243
Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin,
244
Phenobarbital, or Primidone to Monotherapy With LAMICTAL: After achieving a dose of
245
500 mg/day of LAMICTAL according to the guidelines in Table 1, the concomitant AED should
246
be withdrawn by 20% decrements each week over a 4-week period. The regimen for the
247
withdrawal of the concomitant AED is based on experience gained in the controlled
248
monotherapy clinical trial.
249
Conversion From Adjunctive Therapy With Valproate to Monotherapy With
250
LAMICTAL: The conversion regimen involves 4 steps outlined in Table 4.
251
252
Table 4. Conversion From Adjunctive Therapy With Valproate to Monotherapy With
253
LAMICTAL in Patients ≥16 Years of Age With Epilepsy
LAMICTAL
Valproate
Step 1
Achieve a dose of 200 mg/day according to
guidelines in Table 1 (if not already on
200 mg/day).
Maintain previous stable dose.
Step 2
Maintain at 200 mg/day.
Decrease to 500 mg/day by
decrements no greater than
500 mg/day/week and then
maintain the dose of
500 mg/day for 1 week.
Step 3
Increase to 300 mg/day and maintain for 1
week.
Simultaneously decrease to
250 mg/day and maintain for
1 week.
Step 4
Increase by 100 mg/day every week to achieve
maintenance dose of 500 mg/day.
Discontinue.
254
255
Conversion From Adjunctive Therapy With AEDs Other Than Carbamazepine,
256
Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy With LAMICTAL: No
11
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NDA 022251/S-005 and S-006
FDA Approved Labeling Text dated 10/12/2010
Page 12
257
specific dosing guidelines can be provided for conversion to monotherapy with LAMICTAL
258
with AEDs other than carbamazepine, phenobarbital, phenytoin, primidone, or valproate.
259
2.4
Bipolar Disorder
260
The goal of maintenance treatment with LAMICTAL is to delay the time to occurrence of
261
mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute
262
mood episodes with standard therapy. The target dose of LAMICTAL is 200 mg/day
263
(100 mg/day in patients taking valproate, which decreases the apparent clearance of lamotrigine,
264
and 400 mg/day in patients not taking valproate and taking either carbamazepine, phenytoin,
265
phenobarbital, primidone, or other drugs such as rifampin that increase the apparent clearance of
266
lamotrigine). In the clinical trials, doses up to 400 mg/day as monotherapy were evaluated;
267
however, no additional benefit was seen at 400 mg/day compared with 200 mg/day [see Clinical
268
Studies (14.2)]. Accordingly, doses above 200 mg/day are not recommended. Treatment with
269
LAMICTAL is introduced, based on concurrent medications, according to the regimen outlined
270
in Table 5. If other psychotropic medications are withdrawn following stabilization, the dose of
271
LAMICTAL should be adjusted. For patients discontinuing valproate, the dose of LAMICTAL
272
should be doubled over a 2-week period in equal weekly increments (see Table 6). For patients
273
discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as
274
rifampin that induce lamotrigine glucuronidation, the dose of LAMICTAL should remain
275
constant for the first week and then should be decreased by half over a 2-week period in equal
276
weekly decrements (see Table 6). The dose of LAMICTAL may then be further adjusted to the
277
target dose (200 mg) as clinically indicated.
278
If other drugs are subsequently introduced, the dose of LAMICTAL may need to be
279
adjusted. In particular, the introduction of valproate requires reduction in the dose of
280
LAMICTAL [see Drug Interactions (7), Clinical Pharmacology (12.3)].
281
To avoid an increased risk of rash, the recommended initial dose and subsequent dose
282
escalations of LAMICTAL should not be exceeded [see Boxed Warning].
283
284
Table 5. Escalation Regimen for LAMICTAL for Patients With Bipolar Disorder
For Patients
TAKING Valproatea
For Patients NOT
TAKING
Carbamazepine,
Phenytoin,
Phenobarbital,
Primidone,b or
Valproatea
For Patients TAKING
Carbamazepine,
Phenytoin,
Phenobarbital, or
Primidoneb and NOT
TAKING Valproatea
Weeks 1 and 2
25 mg every other
day
25 mg daily
50 mg daily
Weeks 3 and 4
25 mg daily
50 mg daily
100 mg daily, in divided
doses
12
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-043 and S-044
NDA 020764/S-036 and S-037
NDA 022251/S-005 and S-006
FDA Approved Labeling Text dated 10/12/2010
Page 13
Week 5
50 mg daily
100 mg daily
200 mg daily, in divided
doses
Week 6
100 mg daily
200 mg daily
300 mg daily, in divided
doses
Week 7
100 mg daily
200 mg daily
up to 400 mg daily, in
divided doses
285
a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of
286
lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].
287
b These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions
288
(7), Clinical Pharmacology (12.3)]. Other drugs which have similar effects include estrogen
289
containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)].
290
Dosing recommendations for oral contraceptives can be found in General Dosing
291
Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs
292
that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing
293
titration/maintenance regimen as that used with anticonvulsants that have this effect.
294
295
Table 6. Dosage Adjustments to LAMICTAL for Patients With Bipolar Disorder Following
296
Discontinuation of Psychotropic Medications
Discontinuation of
Psychotropic Drugs
(excluding
Carbamazepine,
Phenytoin,
After Discontinuation
of Valproatea
After Discontinuation of
Carbamazepine,
Phenytoin,
Phenobarbital, or
Primidoneb
Phenobarbital,
Primidone,b or
Valproatea)
Current dose of
LAMICTAL (mg/day)
100
Current dose of
LAMICTAL (mg/day)
400
Week 1 Maintain current dose of
LAMICTAL
150
400
Week 2 Maintain current dose of
LAMICTAL
200
300
Week 3
onward
Maintain current dose of
LAMICTAL
200
200
297
a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of
298
lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].
299
b These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions
300
(7), Clinical Pharmacology (12.3)]. Other drugs which have similar effects include estrogen
301
containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)].
302
Dosing recommendations for oral contraceptives can be found in General Dosing
303
Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs
13
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-043 and S-044
NDA 020764/S-036 and S-037
NDA 022251/S-005 and S-006
FDA Approved Labeling Text dated 10/12/2010
Page 14
304
that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing
305
titration/maintenance regimen as that used with anticonvulsants that have this effect.
306
307
The benefit of continuing treatment in patients who had been stabilized in an 8- to
308
16-week open-label phase with LAMICTAL was established in 2 randomized, placebo
309
controlled clinical maintenance trials [see Clinical Studies (14.2)]. However, the optimal
310
duration of treatment with LAMICTAL has not been established. Thus, patients should be
311
periodically reassessed to determine the need for maintenance treatment.
312
2.5
Administration of LAMICTAL Chewable Dispersible Tablets
313
LAMICTAL Chewable Dispersible Tablets may be swallowed whole, chewed, or
314
dispersed in water or diluted fruit juice. If the tablets are chewed, consume a small amount of
315
water or diluted fruit juice to aid in swallowing.
316
To disperse LAMICTAL Chewable Dispersible Tablets, add the tablets to a small amount
317
of liquid (1 teaspoon, or enough to cover the medication). Approximately 1 minute later, when
318
the tablets are completely dispersed, swirl the solution and consume the entire quantity
319
immediately. No attempt should be made to administer partial quantities of the dispersed tablets.
320
2.6
Administration of LAMICTAL ODT Orally Disintegrating Tablets
321
LAMICTAL ODT Orally Disintegrating Tablets should be placed onto the tongue and
322
moved around in the mouth. The tablet will disintegrate rapidly, can be swallowed with or
323
without water, and can be taken with or without food.
324
3
DOSAGE FORMS AND STRENGTHS
325
3.1
Tablets
326
25 mg, white, scored, shield-shaped tablets debossed with “LAMICTAL” and “25”
327
100 mg, peach, scored, shield-shaped tablets debossed with "LAMICTAL" and "100"
328
150 mg, cream, scored, shield-shaped tablets debossed with "LAMICTAL" and "150"
329
200 mg, blue, scored, shield-shaped tablets debossed with "LAMICTAL" and "200"
330
3.2
Chewable Dispersible Tablets
331
2 mg, white to off-white, round tablets debossed with “LTG” over “2”
332
5 mg, white to off-white, caplet-shaped tablets debossed with “GX CL2”
333
25 mg, white, super elliptical-shaped tablets debossed with “GX CL5”
334
3.3
Orally Disintegrating Tablets
335
25 mg, white to off-white, round, flat-faced, radius edge, tablets debossed with “LMT”
336
on one side and “25” on the other side.
337
50 mg, white to off-white, round, flat-faced, radius edge, tablets debossed with “LMT”
338
on one side and “50” on the other side.
339
100 mg, white to off-white, round, flat-faced, radius edge, tablets debossed with
340
“LAMICTAL” on one side and “100” on the other side.
341
200 mg, white to off-white, round, flat-faced, radius edge, tablets debossed with
342
“LAMICTAL” on one side and “200” on the other side.
14
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-043 and S-044
NDA 020764/S-036 and S-037
NDA 022251/S-005 and S-006
FDA Approved Labeling Text dated 10/12/2010
Page 15
343
3.4
Potential Medication Errors
344
Patients should be strongly advised to visually inspect their tablets to verify that they are
345
receiving LAMICTAL as well as the correct formulation of LAMICTAL each time they fill their
346
prescription. Depictions of the LAMICTAL Tablets, Chewable Dispersible Tablets, and Orally
347
Disintegrating Tablets can be found in the Medication Guide that accompanies the product.
348
4
CONTRAINDICATIONS
349
LAMICTAL is contraindicated in patients who have demonstrated hypersensitivity to the
350
drug or its ingredients [see Boxed Warning, Warnings and Precautions (5.1), (5.2)].
351
5
WARNINGS AND PRECAUTIONS
352
5.1
Serious Skin Rashes [see Boxed Warning]
353
Pediatric Population: The incidence of serious rash associated with hospitalization and
354
discontinuation of LAMICTAL in a prospectively followed cohort of pediatric patients (2 to
355
16 years of age) with epilepsy receiving adjunctive therapy was approximately 0.8% (16 of
356
1,983). When 14 of these cases were reviewed by 3 expert dermatologists, there was
357
considerable disagreement as to their proper classification. To illustrate, one dermatologist
358
considered none of the cases to be Stevens-Johnson syndrome; another assigned 7 of the 14 to
359
this diagnosis. There was 1 rash-related death in this 1,983-patient cohort. Additionally, there
360
have been rare cases of toxic epidermal necrolysis with and without permanent sequelae and/or
361
death in US and foreign postmarketing experience.
362
There is evidence that the inclusion of valproate in a multidrug regimen increases the risk
363
of serious, potentially life-threatening rash in pediatric patients. In pediatric patients who used
364
valproate concomitantly, 1.2% (6 of 482) experienced a serious rash compared with 0.6% (6 of
365
952) patients not taking valproate.
366
Adult Population: Serious rash associated with hospitalization and discontinuation of
367
LAMICTAL occurred in 0.3% (11 of 3,348) of adult patients who received LAMICTAL in
368
premarketing clinical trials of epilepsy. In the bipolar and other mood disorders clinical trials, the
369
rate of serious rash was 0.08% (1 of 1,233) of adult patients who received LAMICTAL as initial
370
monotherapy and 0.13% (2 of 1,538) of adult patients who received LAMICTAL as adjunctive
371
therapy. No fatalities occurred among these individuals. However, in worldwide postmarketing
372
experience, rare cases of rash-related death have been reported, but their numbers are too few to
373
permit a precise estimate of the rate.
374
Among the rashes leading to hospitalization were Stevens-Johnson syndrome, toxic
375
epidermal necrolysis, angioedema, and a rash associated with a variable number of the following
376
systemic manifestations: fever, lymphadenopathy, facial swelling, and hematologic and
377
hepatologic abnormalities.
378
There is evidence that the inclusion of valproate in a multidrug regimen increases the risk
379
of serious, potentially life-threatening rash in adults. Specifically, of 584 patients administered
380
LAMICTAL with valproate in epilepsy clinical trials, 6 (1%) were hospitalized in association
15
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-043 and S-044
NDA 020764/S-036 and S-037
NDA 022251/S-005 and S-006
FDA Approved Labeling Text dated 10/12/2010
Page 16
381
with rash; in contrast, 4 (0.16%) of 2,398 clinical trial patients and volunteers administered
382
LAMICTAL in the absence of valproate were hospitalized.
383
Patients With History of Allergy or Rash to Other AEDs: The risk of nonserious rash
384
may be increased when the recommended initial dose and/or the rate of dose escalation of
385
LAMICTAL is exceeded and in patients with a history of allergy or rash to other AEDs.
386
5.2
Hypersensitivity Reactions
387
Hypersensitivity reactions, some fatal or life-threatening, have also occurred. Some of
388
these reactions have included clinical features of multiorgan failure/dysfunction, including
389
hepatic abnormalities and evidence of disseminated intravascular coagulation. It is important to
390
note that early manifestations of hypersensitivity (e.g., fever, lymphadenopathy) may be present
391
even though a rash is not evident. If such signs or symptoms are present, the patient should be
392
evaluated immediately. LAMICTAL should be discontinued if an alternative etiology for the
393
signs or symptoms cannot be established.
394
Prior to initiation of treatment with LAMICTAL, the patient should be instructed
395
that a rash or other signs or symptoms of hypersensitivity (e.g., fever, lymphadenopathy)
396
may herald a serious medical event and that the patient should report any such occurrence
397
to a physician immediately.
398
5.3
Acute Multiorgan Failure
399
Multiorgan failure, which in some cases has been fatal or irreversible, has been observed
400
in patients receiving LAMICTAL. Fatalities associated with multiorgan failure and various
401
degrees of hepatic failure have been reported in 2 of 3,796 adult patients and 4 of 2,435 pediatric
402
patients who received LAMICTAL in epilepsy clinical trials. No such fatalities have been
403
reported in bipolar patients in clinical trials. Rare fatalities from multiorgan failure have also
404
been reported in compassionate plea and postmarketing use. The majority of these deaths
405
occurred in association with other serious medical events, including status epilepticus and
406
overwhelming sepsis, and hantavirus, making it difficult to identify the initial cause.
407
Additionally, 3 patients (a 45-year-old woman, a 3.5-year-old boy, and an 11-year-old
408
girl) developed multiorgan dysfunction and disseminated intravascular coagulation 9 to 14 days
409
after LAMICTAL was added to their AED regimens. Rash and elevated transaminases were also
410
present in all patients and rhabdomyolysis was noted in 2 patients. Both pediatric patients were
411
receiving concomitant therapy with valproate, while the adult patient was being treated with
412
carbamazepine and clonazepam. All patients subsequently recovered with supportive care after
413
treatment with LAMICTAL was discontinued.
414
5.4
Blood Dyscrasias
415
There have been reports of blood dyscrasias that may or may not be associated with the
416
hypersensitivity syndrome. These have included neutropenia, leukopenia, anemia,
417
thrombocytopenia, pancytopenia, and, rarely, aplastic anemia and pure red cell aplasia.
418
5.5
Suicidal Behavior and Ideation
16
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-043 and S-044
NDA 020764/S-036 and S-037
NDA 022251/S-005 and S-006
FDA Approved Labeling Text dated 10/12/2010
Page 17
419
Antiepileptic drugs (AEDs), including LAMICTAL, increase the risk of suicidal thoughts
420
or behavior in patients taking these drugs for any indication. Patients treated with any AED for
421
any indication should be monitored for the emergence or worsening of depression, suicidal
422
thoughts or behavior, and/or any unusual changes in mood or behavior.
423
Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive
424
therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had
425
approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or
426
behavior compared to patients randomized to placebo. In these trials, which had a median
427
treatment duration of 12 weeks, the estimated incidence of suicidal behavior or ideation among
428
27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated
429
patients, representing an increase of approximately 1 case of suicidal thinking or behavior for
430
every 530 patients treated. There were 4 suicides in drug-treated patients in the trials and none in
431
placebo-treated patients, but the number of events is too small to allow any conclusion about
432
drug effect on suicide.
433
The increased risk of suicidal thoughts or behavior with AEDs was observed as early
434
as 1 week after starting treatment with AEDs and persisted for the duration of treatment assessed.
435
Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal
436
thoughts or behavior beyond 24 weeks could not be assessed.
437
The risk of suicidal thoughts or behavior was generally consistent among drugs in the
438
data analyzed. The finding of increased risk with AEDs of varying mechanism of action and
439
across a range of indications suggests that the risk applies to all AEDs used for any indication.
440
The risk did not vary substantially by age (5 to 100 years) in the clinical trials analyzed.
441
Table 7 shows absolute and relative risk by indication for all evaluated AEDs.
442
443
Table 7. Risk by Indication for Antiepileptic Drugs in the Pooled Analysis
Indication
Placebo
Patients
With Events
Per 1,000
Patients
Drug Patients
With Events
Per 1,000
Patients
Relative Risk: Incidence
of Events in Drug
Patients/Incidence in
Placebo Patients
Risk Difference:
Additional Drug
Patients With Events
Per 1,000 Patients
Epilepsy
1.0
3.4
3.5
2.4
Psychiatric
5.7
8.5
1.5
2.9
Other
1.0
1.8
1.9
0.9
Total
2.4
4.3
1.8
1.9
444
445
The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy
446
than in clinical trials for psychiatric or other conditions, but the absolute risk differences were
447
similar for the epilepsy and psychiatric indications.
17
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
448
449
450
451
452
453
454
455
456
457
458
459
460
461
462
463
464
465
466
467
468
469
470
471
472
473
474
475
476
477
478
479
480
481
482
483
484
485
486
NDA 020241/S-043 and S-044
NDA 020764/S-036 and S-037
NDA 022251/S-005 and S-006
FDA Approved Labeling Text dated 10/12/2010
Page 18
Anyone considering prescribing LAMICTAL or any other AED must balance the risk of
suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses
for which AEDs are prescribed are themselves associated with morbidity and mortality and an
increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge
during treatment, the prescriber needs to consider whether the emergence of these symptoms in
any given patient may be related to the illness being treated.
Patients, their caregivers, and families should be informed that AEDs increase the risk of
suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or
worsening of the signs and symptoms of depression, any unusual changes in mood or behavior,
or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of
concern should be reported immediately to healthcare providers.
5.6
Use in Patients With Bipolar Disorder
Acute Treatment of Mood Episodes: Safety and effectiveness of LAMICTAL in the
acute treatment of mood episodes have not been established.
Children and Adolescents (less than 18 years of age): Safety and effectiveness of
LAMICTAL in patients below the age of 18 years with mood disorders have not been
established [see Suicidal Behavior and Ideation (5.5)].
Clinical Worsening and Suicide Risk Associated With Bipolar Disorder: Patients
with bipolar disorder may experience worsening of their depressive symptoms and/or the
emergence of suicidal ideation and behaviors (suicidality) whether or not they are taking
medications for bipolar disorder. Patients should be closely monitored for clinical worsening
(including development of new symptoms) and suicidality, especially at the beginning of a
course of treatment or at the time of dose changes.
In addition, patients with a history of suicidal behavior or thoughts, those patients
exhibiting a significant degree of suicidal ideation prior to commencement of treatment, and
young adults are at an increased risk of suicidal thoughts or suicide attempts, and should receive
careful monitoring during treatment [see Suicidal Behavior and Ideation (5.5)].
Consideration should be given to changing the therapeutic regimen, including possibly
discontinuing the medication, in patients who experience clinical worsening (including
development of new symptoms) and/or the emergence of suicidal ideation/behavior especially if
these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting
symptoms.
Prescriptions for LAMICTAL should be written for the smallest quantity of tablets
consistent with good patient management in order to reduce the risk of overdose. Overdoses have
been reported for LAMICTAL, some of which have been fatal [see Overdosage (10.1)].
5.7
Aseptic Meningitis
Therapy with LAMICTAL increases the risk of developing aseptic meningitis. Because
of the potential for serious outcomes of untreated meningitis due to other causes, patients should
also be evaluated for other causes of meningitis and treated as appropriate.
18
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
487
488
489
490
491
492
493
494
495
496
497
498
499
500
501
502
503
504
505
506
507
508
509
510
511
512
513
514
515
516
517
518
519
520
521
522
523
524
525
NDA 020241/S-043 and S-044
NDA 020764/S-036 and S-037
NDA 022251/S-005 and S-006
FDA Approved Labeling Text dated 10/12/2010
Page 19
Postmarketing cases of aseptic meningitis have been reported in pediatric and adult
patients taking LAMICTAL for various indications. Symptoms upon presentation have included
headache, fever, nausea, vomiting, and nuchal rigidity. Rash, photophobia, myalgia, chills,
altered consciousness, and somnolence were also noted in some cases. Symptoms have been
reported to occur within 1 day to one and a half months following the initiation of treatment. In
most cases, symptoms were reported to resolve after discontinuation of LAMICTAL. Re-
exposure resulted in a rapid return of symptoms (from within 30 minutes to 1 day following re
initiation of treatment) that were frequently more severe. Some of the patients treated with
LAMICTAL who developed aseptic meningitis had underlying diagnoses of systemic lupus
erythematosus or other autoimmune diseases.
Cerebrospinal fluid (CSF) analyzed at the time of clinical presentation in reported cases
was characterized by a mild to moderate pleocytosis, normal glucose levels, and mild to
moderate increase in protein. CSF white blood cell count differentials showed a predominance of
neutrophils in a majority of the cases, although a predominance of lymphocytes was reported in
approximately one third of the cases. Some patients also had new onset of signs and symptoms
of involvement of other organs (predominantly hepatic and renal involvement), which may
suggest that in these cases the aseptic meningitis observed was part of a hypersensitivity reaction
[see Warnings and Precautions (5.2)].
5.8
Potential Medication Errors
Medication errors involving LAMICTAL have occurred. In particular, the names
LAMICTAL or lamotrigine can be confused with the names of other commonly used
medications. Medication errors may also occur between the different formulations of
LAMICTAL. To reduce the potential of medication errors, write and say LAMICTAL clearly.
Depictions of the LAMICTAL Tablets, Chewable Dispersible Tablets, and Orally Disintegrating
Tablets can be found in the Medication Guide that accompanies the product to highlight the
distinctive markings, colors, and shapes that serve to identify the different presentations of the
drug and thus may help reduce the risk of medication errors. To avoid the medication error of
using the wrong drug or formulation, patients should be strongly advised to visually inspect their
tablets to verify that they are LAMICTAL, as well as the correct formulation of LAMICTAL,
each time they fill their prescription.
5.9
Concomitant Use With Oral Contraceptives
Some estrogen-containing oral contraceptives have been shown to decrease serum
concentrations of lamotrigine [see Clinical Pharmacology (12.3)]. Dosage adjustments will be
necessary in most patients who start or stop estrogen-containing oral contraceptives while
taking LAMICTAL [see Dosage and Administration (2.1)]. During the week of inactive
hormone preparation (“pill-free” week) of oral contraceptive therapy, plasma lamotrigine levels
are expected to rise, as much as doubling at the end of the week. Adverse reactions consistent
with elevated levels of lamotrigine, such as dizziness, ataxia, and diplopia, could occur.
5.10 Withdrawal Seizures
19
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-043 and S-044
NDA 020764/S-036 and S-037
NDA 022251/S-005 and S-006
FDA Approved Labeling Text dated 10/12/2010
Page 20
526
As with other AEDs, LAMICTAL should not be abruptly discontinued. In patients with
527
epilepsy there is a possibility of increasing seizure frequency. In clinical trials in patients with
528
Bipolar Disorder, 2 patients experienced seizures shortly after abrupt withdrawal of
529
LAMICTAL; however, there were confounding factors that may have contributed to the
530
occurrence of seizures in these bipolar patients. Unless safety concerns require a more rapid
531
withdrawal, the dose of LAMICTAL should be tapered over a period of at least 2 weeks
532
(approximately 50% reduction per week) [see Dosage and Administration (2.1)].
533
5.11 Status Epilepticus
534
Valid estimates of the incidence of treatment-emergent status epilepticus among patients
535
treated with LAMICTAL are difficult to obtain because reporters participating in clinical trials
536
did not all employ identical rules for identifying cases. At a minimum, 7 of 2,343 adult patients
537
had episodes that could unequivocally be described as status epilepticus. In addition, a number of
538
reports of variably defined episodes of seizure exacerbation (e.g., seizure clusters, seizure
539
flurries, etc.) were made.
540
5.12 Sudden Unexplained Death in Epilepsy (SUDEP)
541
During the premarketing development of LAMICTAL, 20 sudden and unexplained
542
deaths were recorded among a cohort of 4,700 patients with epilepsy (5,747 patient-years of
543
exposure).
544
Some of these could represent seizure-related deaths in which the seizure was not
545
observed, e.g., at night. This represents an incidence of 0.0035 deaths per patient-year. Although
546
this rate exceeds that expected in a healthy population matched for age and sex, it is within the
547
range of estimates for the incidence of sudden unexplained deaths in patients with epilepsy not
548
receiving LAMICTAL (ranging from 0.0005 for the general population of patients with epilepsy,
549
to 0.004 for a recently studied clinical trial population similar to that in the clinical development
550
program for LAMICTAL, to 0.005 for patients with refractory epilepsy). Consequently, whether
551
these figures are reassuring or suggest concern depends on the comparability of the populations
552
reported upon to the cohort receiving LAMICTAL and the accuracy of the estimates provided.
553
Probably most reassuring is the similarity of estimated SUDEP rates in patients receiving
554
LAMICTAL and those receiving other AEDs, chemically unrelated to each other, that underwent
555
clinical testing in similar populations. Importantly, that drug is chemically unrelated to
556
LAMICTAL. This evidence suggests, although it certainly does not prove, that the high SUDEP
557
rates reflect population rates, not a drug effect.
558
5.13 Addition of LAMICTAL to a Multidrug Regimen That Includes Valproate
559
Because valproate reduces the clearance of lamotrigine, the dosage of lamotrigine in the
560
presence of valproate is less than half of that required in its absence.
561
5.14 Binding in the Eye and Other Melanin-Containing Tissues
562
Because lamotrigine binds to melanin, it could accumulate in melanin-rich tissues over
563
time. This raises the possibility that lamotrigine may cause toxicity in these tissues after
564
extended use. Although ophthalmological testing was performed in one controlled clinical trial,
20
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-043 and S-044
NDA 020764/S-036 and S-037
NDA 022251/S-005 and S-006
FDA Approved Labeling Text dated 10/12/2010
Page 21
565
the testing was inadequate to exclude subtle effects or injury occurring after long-term exposure.
566
Moreover, the capacity of available tests to detect potentially adverse consequences, if any, of
567
lamotrigine's binding to melanin is unknown [see Clinical Pharmacology (12.2)].
568
Accordingly, although there are no specific recommendations for periodic
569
ophthalmological monitoring, prescribers should be aware of the possibility of long-term
570
ophthalmologic effects.
571
5.15 Laboratory Tests
572
The value of monitoring plasma concentrations of lamotrigine in patients treated with
573
LAMICTAL has not been established. Because of the possible pharmacokinetic interactions
574
between lamotrigine and other drugs including AEDs (see Table 15), monitoring of the plasma
575
levels of lamotrigine and concomitant drugs may be indicated, particularly during dosage
576
adjustments. In general, clinical judgment should be exercised regarding monitoring of plasma
577
levels of lamotrigine and other drugs and whether or not dosage adjustments are necessary.
578
6
ADVERSE REACTIONS
579
The following adverse reactions are described in more detail in the Warnings and
580
Precautions section of the label:
581
• Serious skin rashes [see Warnings and Precautions (5.1)]
582
• Hypersensitivity reactions [see Warnings and Precautions (5.2)]
583
• Acute multiorgan failure [see Warnings and Precautions (5.3)]
584
• Blood dyscrasias [see Warnings and Precautions (5.4)]
585
• Suicidal behavior and ideation [see Warnings and Precautions (5.5)]
586
• Aseptic meningitis [see Warnings and Precautions (5.7)]
587
• Withdrawal seizures [see Warnings and Precautions (5.10)]
588
• Status epilepticus [see Warnings and Precautions (5.11)]
589
• Sudden unexplained death in epilepsy [see Warnings and Precautions (5.12)]
590
6.1
Clinical Trials
591
Because clinical trials are conducted under widely varying conditions, adverse reaction
592
rates observed in the clinical trials of a drug cannot be directly compared with rates in the
593
clinical trials of another drug and may not reflect the rates observed in practice.
594
LAMICTAL has been evaluated for safety in patients with epilepsy and in patients with
595
Bipolar I Disorder. Adverse reactions reported for each of these patient populations are provided
596
below. Excluded are adverse reactions considered too general to be informative and those not
597
reasonably attributable to the use of the drug.
598
Epilepsy: Most Common Adverse Reactions in All Clinical Studies: Adjunctive
599
Therapy in Adults With Epilepsy: The most commonly observed (≥5% for LAMICTAL and
600
more common on drug than placebo) adverse reactions seen in association with LAMICTAL
601
during adjunctive therapy in adults and not seen at an equivalent frequency among placebo
602
treated patients were: dizziness, ataxia, somnolence, headache, diplopia, blurred vision, nausea,
603
vomiting, and rash. Dizziness, diplopia, ataxia, blurred vision, nausea, and vomiting were dose
21
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-043 and S-044
NDA 020764/S-036 and S-037
NDA 022251/S-005 and S-006
FDA Approved Labeling Text dated 10/12/2010
Page 22
604
related. Dizziness, diplopia, ataxia, and blurred vision occurred more commonly in patients
605
receiving carbamazepine with LAMICTAL than in patients receiving other AEDs with
606
LAMICTAL. Clinical data suggest a higher incidence of rash, including serious rash, in patients
607
receiving concomitant valproate than in patients not receiving valproate [see Warnings and
608
Precautions (5.1)].
609
Approximately 11% of the 3,378 adult patients who received LAMICTAL as adjunctive
610
therapy in premarketing clinical trials discontinued treatment because of an adverse reaction. The
611
adverse reactions most commonly associated with discontinuation were rash (3.0%), dizziness
612
(2.8%), and headache (2.5%).
613
In a dose-response study in adults, the rate of discontinuation of LAMICTAL for
614
dizziness, ataxia, diplopia, blurred vision, nausea, and vomiting was dose-related.
615
Monotherapy in Adults With Epilepsy: The most commonly observed (≥5% for
616
LAMICTAL and more common on drug than placebo) adverse reactions seen in association with
617
the use of LAMICTAL during the monotherapy phase of the controlled trial in adults not seen at
618
an equivalent rate in the control group were vomiting, coordination abnormality, dyspepsia,
619
nausea, dizziness, rhinitis, anxiety, insomnia, infection, pain, weight decrease, chest pain, and
620
dysmenorrhea. The most commonly observed (≥5% for LAMICTAL and more common on drug
621
than placebo) adverse reactions associated with the use of LAMICTAL during the conversion to
622
monotherapy (add-on) period, not seen at an equivalent frequency among low-dose valproate
623
treated patients, were dizziness, headache, nausea, asthenia, coordination abnormality, vomiting,
624
rash, somnolence, diplopia, ataxia, accidental injury, tremor, blurred vision, insomnia,
625
nystagmus, diarrhea, lymphadenopathy, pruritus, and sinusitis.
626
Approximately 10% of the 420 adult patients who received LAMICTAL as monotherapy
627
in premarketing clinical trials discontinued treatment because of an adverse reaction. The
628
adverse reactions most commonly associated with discontinuation were rash (4.5%), headache
629
(3.1%), and asthenia (2.4%).
630
Adjunctive Therapy in Pediatric Patients With Epilepsy: The most commonly
631
observed (≥5% for LAMICTAL and more common on drug than placebo) adverse reactions seen
632
in association with the use of LAMICTAL as adjunctive treatment in pediatric patients 2 to
633
16 years of age and not seen at an equivalent rate in the control group were infection, vomiting,
634
rash, fever, somnolence, accidental injury, dizziness, diarrhea, abdominal pain, nausea, ataxia,
635
tremor, asthenia, bronchitis, flu syndrome, and diplopia.
636
In 339 patients 2 to 16 years of age with partial seizures or generalized seizures of
637
Lennox-Gastaut syndrome, 4.2% of patients on LAMICTAL and 2.9% of patients on placebo
638
discontinued due to adverse reactions. The most commonly reported adverse reaction that led to
639
discontinuation of LAMICTAL was rash.
640
Approximately 11.5% of the 1,081 pediatric patients 2 to 16 years of age who received
641
LAMICTAL as adjunctive therapy in premarketing clinical trials discontinued treatment because
22
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-043 and S-044
NDA 020764/S-036 and S-037
NDA 022251/S-005 and S-006
FDA Approved Labeling Text dated 10/12/2010
Page 23
642
of an adverse reaction. The adverse reactions most commonly associated with discontinuation
643
were rash (4.4%), reaction aggravated (1.7%), and ataxia (0.6%).
644
Controlled Adjunctive Clinical Studies in Adults With Epilepsy: Table 8 lists
645
treatment-emergent adverse reactions that occurred in at least 2% of adult patients with epilepsy
646
treated with LAMICTAL in placebo-controlled trials and were numerically more common in the
647
patients treated with LAMICTAL. In these studies, either LAMICTAL or placebo was added to
648
the patient’s current AED therapy. Adverse reactions were usually mild to moderate in intensity.
649
650
Table 8. Treatment-Emergent Adverse Reaction Incidence in Placebo-Controlled
651
Adjunctive Trials in Adult Patients With Epilepsya (Adverse reactions in at least 2% of
652
patients treated with LAMICTAL and numerically more frequent than in the placebo
653
group.)
Body System/
Adverse Reaction
Percent of Patients
Receiving Adjunctive
LAMICTAL
(n = 711)
Percent of Patients
Receiving Adjunctive
Placebo
(n = 419)
Body as a whole
Headache
29
19
Flu syndrome
7
6
Fever
6
4
Abdominal pain
5
4
Neck pain
2
1
Reaction aggravated
(seizure exacerbation)
2
1
Digestive
Nausea
19
10
Vomiting
9
4
Diarrhea
6
4
Dyspepsia
5
2
Constipation
4
3
Anorexia
2
1
Musculoskeletal
Arthralgia
2
0
Nervous
Dizziness
38
13
Ataxia
22
6
Somnolence
14
7
Incoordination
6
2
Insomnia
6
2
23
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-043 and S-044
NDA 020764/S-036 and S-037
NDA 022251/S-005 and S-006
FDA Approved Labeling Text dated 10/12/2010
Page 24
Tremor
4
1
Depression
4
3
Anxiety
4
3
Convulsion
3
1
Irritability
3
2
Speech disorder
3
0
Concentration disturbance
2
1
Respiratory
Rhinitis
14
9
Pharyngitis
10
9
Cough increased
8
6
Skin and appendages
Rash
Pruritus
10
3
5
2
Special senses
Diplopia
28
7
Blurred vision
16
5
Vision abnormality
3
1
Urogenital
Female patients only
(n = 365)
(n = 207)
Dysmenorrhea
7
6
Vaginitis
4
1
Amenorrhea
2
1
654
a Patients in these adjunctive studies were receiving 1 to 3 of the following concomitant
655
AEDs (carbamazepine, phenytoin, phenobarbital, or primidone) in addition to
656
LAMICTAL or placebo. Patients may have reported multiple adverse reactions during
657
the study or at discontinuation; thus, patients may be included in more than one
658
category.
659
660
In a randomized, parallel study comparing placebo and 300 and 500 mg/day of
661
LAMICTAL, some of the more common drug-related adverse reactions were dose-related (see
662
Table 9).
663
24
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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NDA 020764/S-036 and S-037
NDA 022251/S-005 and S-006
FDA Approved Labeling Text dated 10/12/2010
Page 25
664
Table 9. Dose-Related Adverse Reactions From a Randomized, Placebo-Controlled
665
Adjunctive Trial in Adults With Epilepsy
Percent of Patients Experiencing Adverse Reactions
Adverse Reaction
Placebo
(n = 73)
LAMICTAL
300 mg
(n = 71)
LAMICTAL
500 mg
(n = 72)
Ataxia
Blurred vision
Diplopia
Dizziness
Nausea
Vomiting
10
10
8
27
11
4
10
11
24
a
31
18
11
28
ab
25
ab
49
ab
54
ab
25
a
18
a
666
a Significantly greater than placebo group (p<0.05).
b
667
Significantly greater than group receiving LAMICTAL 300 mg (p<0.05).
668
669
The overall adverse reaction profile for LAMICTAL was similar between females and
670
males, and was independent of age. Because the largest non-Caucasian racial subgroup was only
671
6% of patients exposed to LAMICTAL in placebo-controlled trials, there are insufficient data to
672
support a statement regarding the distribution of adverse reaction reports by race. Generally,
673
females receiving either LAMICTAL as adjunctive therapy or placebo were more likely to report
674
adverse reactions than males. The only adverse reaction for which the reports on LAMICTAL
675
were greater than 10% more frequent in females than males (without a corresponding difference
676
by gender on placebo) was dizziness (difference = 16.5%). There was little difference between
677
females and males in the rates of discontinuation of LAMICTAL for individual adverse
678
reactions.
679
Controlled Monotherapy Trial in Adults With Partial Seizures: Table 10 lists
680
treatment-emergent adverse reactions that occurred in at least 5% of patients with epilepsy
681
treated with monotherapy with LAMICTAL in a double-blind trial following discontinuation of
682
either concomitant carbamazepine or phenytoin not seen at an equivalent frequency in the
683
control group.
684
685
Table 10. Treatment-Emergent Adverse Reaction Incidence in Adults With Partial
686
Seizures in a Controlled Monotherapy Triala (Adverse reactions in at least 5% of patients
687
treated with LAMICTAL and numerically more frequent than in the valproate group.)
Body System/
Adverse Reaction
Percent of Patients
Receiving LAMICTAL as
Monotherapyb
(n = 43)
Percent of Patients
Receiving Low-Dose
Valproatec Monotherapy
(n = 44)
Body as a whole
25
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-043 and S-044
NDA 020764/S-036 and S-037
NDA 022251/S-005 and S-006
FDA Approved Labeling Text dated 10/12/2010
Page 26
Pain
Infection
Chest pain
5
5
5
0
2
2
Digestive
Vomiting
Dyspepsia
Nausea
9
7
7
0
2
2
Metabolic and nutritional
Weight decrease
5
2
Nervous
Coordination abnormality
Dizziness
Anxiety
Insomnia
7
7
5
5
0
0
0
2
Respiratory
Rhinitis
7
2
Urogenital (female patients
only)
Dysmenorrhea
(n = 21)
5
(n = 28)
0
688
a Patients in these studies were converted to LAMICTAL or valproate monotherapy from
689
adjunctive therapy with carbamazepine or phenytoin. Patients may have reported multiple
690
adverse reactions during the study; thus, patients may be included in more than one category.
691
b Up to 500 mg/day.
692
c 1,000 mg/day.
693
694
Adverse reactions that occurred with a frequency of less than 5% and greater than 2% of
695
patients receiving LAMICTAL and numerically more frequent than placebo were:
696
Body as a Whole: Asthenia, fever.
697
Digestive: Anorexia, dry mouth, rectal hemorrhage, peptic ulcer.
698
Metabolic and Nutritional: Peripheral edema.
699
Nervous System: Amnesia, ataxia, depression, hypesthesia, libido increase, decreased
700
reflexes, increased reflexes, nystagmus, irritability, suicidal ideation.
701
Respiratory: Epistaxis, bronchitis, dyspnea.
702
Skin and Appendages: Contact dermatitis, dry skin, sweating.
703
Special Senses: Vision abnormality.
704
Incidence in Controlled Adjunctive Trials in Pediatric Patients With
705
Epilepsy: Table 11 lists adverse reactions that occurred in at least 2% of 339 pediatric patients
706
with partial seizures or generalized seizures of Lennox-Gastaut syndrome, who received
26
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-043 and S-044
NDA 020764/S-036 and S-037
NDA 022251/S-005 and S-006
FDA Approved Labeling Text dated 10/12/2010
Page 27
707
LAMICTAL up to 15 mg/kg/day or a maximum of 750 mg/day. Reported adverse reactions were
708
classified using COSTART terminology.
709
710
Table 11. Treatment-Emergent Adverse Reaction Incidence in Placebo-Controlled
711
Adjunctive Trials in Pediatric Patients With Epilepsy (Adverse reactions in at least 2% of
712
patients treated with LAMICTAL and numerically more frequent than in the placebo
713
group.)
Body System/
Adverse Reaction
Percent of Patients
Receiving LAMICTAL
(n = 168)
Percent of Patients Receiving
Placebo
(n = 171)
Body as a whole
Infection
20
17
Fever
15
14
Accidental injury
14
12
Abdominal pain
10
5
Asthenia
8
4
Flu syndrome
7
6
Pain
5
4
Facial edema
2
1
Photosensitivity
2
0
Cardiovascular
Hemorrhage
2
1
Digestive
Vomiting
20
16
Diarrhea
11
9
Nausea
10
2
Constipation
4
2
Dyspepsia
2
1
Hemic and lymphatic
Lymphadenopathy
2
1
Metabolic and nutritional
Edema
2
0
Nervous system
Somnolence
17
15
Dizziness
14
4
Ataxia
11
3
Tremor
10
1
Emotional lability
4
2
Gait abnormality
4
2
27
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-043 and S-044
NDA 020764/S-036 and S-037
NDA 022251/S-005 and S-006
FDA Approved Labeling Text dated 10/12/2010
Page 28
Thinking abnormality
3
2
Convulsions
2
1
Nervousness
2
1
Vertigo
2
1
Respiratory
Pharyngitis
14
11
Bronchitis
7
5
Increased cough
7
6
Sinusitis
2
1
Bronchospasm
2
1
Skin
Rash
14
12
Eczema
2
1
Pruritus
2
1
Special senses
Diplopia
5
1
Blurred vision
4
1
Visual abnormality
2
0
Urogenital
Male and female patients
Urinary tract infection
3
0
714
715
Bipolar Disorder: The most commonly observed (≥5%) treatment-emergent adverse
716
reactions seen in association with the use of LAMICTAL as monotherapy (100 to 400 mg/day)
717
in adult patients (≥18 years of age) with Bipolar Disorder in the 2 double-blind, placebo
718
controlled trials of 18 months’ duration, and numerically more frequent than in placebo-treated
719
patients are included in Table 12. Adverse reactions that occurred in at least 5% of patients and
720
were numerically more common during the dose-escalation phase of LAMICTAL in these trials
721
(when patients may have been receiving concomitant medications) compared with the
722
monotherapy phase were: headache (25%), rash (11%), dizziness (10%), diarrhea (8%), dream
723
abnormality (6%), and pruritus (6%).
724
During the monotherapy phase of the double-blind, placebo-controlled trials of
725
18 months’ duration, 13% of 227 patients who received LAMICTAL (100 to 400 mg/day), 16%
726
of 190 patients who received placebo, and 23% of 166 patients who received lithium
727
discontinued therapy because of an adverse reaction. The adverse reactions which most
728
commonly led to discontinuation of LAMICTAL were rash (3%) and mania/hypomania/mixed
729
mood adverse reactions (2%). Approximately 16% of 2,401 patients who received LAMICTAL
730
(50 to 500 mg/day) for Bipolar Disorder in premarketing trials discontinued therapy because of
28
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-043 and S-044
NDA 020764/S-036 and S-037
NDA 022251/S-005 and S-006
FDA Approved Labeling Text dated 10/12/2010
Page 29
731
an adverse reaction; most commonly due to rash (5%) and mania/hypomania/mixed mood
732
adverse reactions (2%).
733
The overall adverse reaction profile for LAMICTAL was similar between females and
734
males, between elderly and nonelderly patients, and among racial groups.
735
736
Table 12. Treatment-Emergent Adverse Reaction Incidence in 2 Placebo-Controlled Trials
737
in Adults With Bipolar I Disordera (Adverse reactions in at least 5% of patients treated
738
with LAMICTAL as monotherapy and numerically more frequent than in the placebo
739
group.)
Body System/
Adverse Reaction
Percent of Patients
Receiving LAMICTAL
(n = 227)
Percent of Patients
Receiving Placebo
(n = 190)
General
Back pain
Fatigue
Abdominal pain
8
8
6
6
5
3
Digestive
Nausea
Constipation
Vomiting
14
5
5
11
2
2
Nervous System
Insomnia
Somnolence
Xerostomia (dry mouth)
10
9
6
6
7
4
Respiratory
Rhinitis
Exacerbation of cough
Pharyngitis
7
5
5
4
3
4
Skin
Rash (nonserious)b
7
5
740
a Patients in these studies were converted to LAMICTAL (100 to 400 mg/day) or placebo
741
monotherapy from add-on therapy with other psychotropic medications. Patients may have
742
reported multiple adverse reactions during the study; thus, patients may be included in more
743
than one category.
744
b In the overall bipolar and other mood disorders clinical trials, the rate of serious rash was
745
0.08% (1 of 1,233) of adult patients who received LAMICTAL as initial monotherapy and
746
0.13% (2 of 1,538) of adult patients who received LAMICTAL as adjunctive therapy [see
747
Warnings and Precautions (5.1)].
748
29
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-043 and S-044
NDA 020764/S-036 and S-037
NDA 022251/S-005 and S-006
FDA Approved Labeling Text dated 10/12/2010
Page 30
749
These adverse reactions were usually mild to moderate in intensity. Other reactions that
750
occurred in 5% or more patients but equally or more frequently in the placebo group included:
751
dizziness, mania, headache, infection, influenza, pain, accidental injury, diarrhea, and dyspepsia.
752
Adverse reactions that occurred with a frequency of less than 5% and greater than 1% of
753
patients receiving LAMICTAL and numerically more frequent than placebo were:
754
General: Fever, neck pain.
755
Cardiovascular: Migraine.
756
Digestive: Flatulence
757
Metabolic and Nutritional: Weight gain, edema.
758
Musculoskeletal: Arthralgia, myalgia.
759
Nervous System: Amnesia, depression, agitation, emotional lability, dyspraxia,
760
abnormal thoughts, dream abnormality, hypoesthesia.
761
Respiratory: Sinusitis.
762
Urogenital: Urinary frequency.
763
Adverse Reactions Following Abrupt Discontinuation: In the 2 maintenance trials,
764
there was no increase in the incidence, severity or type of adverse reactions in Bipolar Disorder
765
patients after abruptly terminating therapy with LAMICTAL. In clinical trials in patients with
766
Bipolar Disorder, 2 patients experienced seizures shortly after abrupt withdrawal of
767
LAMICTAL. However, there were confounding factors that may have contributed to the
768
occurrence of seizures in these bipolar patients [see Warnings and Precautions (5.10)].
769
Mania/Hypomania/Mixed Episodes: During the double-blind, placebo-controlled
770
clinical trials in Bipolar I Disorder in which patients were converted to monotherapy with
771
LAMICTAL (100 to 400 mg/day) from other psychotropic medications and followed for up to
772
18 months, the rates of manic or hypomanic or mixed mood episodes reported as adverse
773
reactions were 5% for patients treated with LAMICTAL (n = 227), 4% for patients treated with
774
lithium (n = 166), and 7% for patients treated with placebo (n = 190). In all bipolar controlled
775
trials combined, adverse reactions of mania (including hypomania and mixed mood episodes)
776
were reported in 5% of patients treated with LAMICTAL (n = 956), 3% of patients treated with
777
lithium (n = 280), and 4% of patients treated with placebo (n = 803).
778
6.2
Other Adverse Reactions Observed in All Clinical Trials
779
LAMICTAL has been administered to 6,694 individuals for whom complete adverse
780
reaction data was captured during all clinical trials, only some of which were placebo controlled.
781
During these trials, all adverse reactions were recorded by the clinical investigators using
782
terminology of their own choosing. To provide a meaningful estimate of the proportion of
783
individuals having adverse reactions, similar types of adverse reactions were grouped into a
784
smaller number of standardized categories using modified COSTART dictionary terminology.
785
The frequencies presented represent the proportion of the 6,694 individuals exposed to
786
LAMICTAL who experienced an event of the type cited on at least one occasion while receiving
787
LAMICTAL. All reported adverse reactions are included except those already listed in the
30
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-043 and S-044
NDA 020764/S-036 and S-037
NDA 022251/S-005 and S-006
FDA Approved Labeling Text dated 10/12/2010
Page 31
788
previous tables or elsewhere in the labeling, those too general to be informative, and those not
789
reasonably associated with the use of the drug.
790
Adverse reactions are further classified within body system categories and enumerated in
791
order of decreasing frequency using the following definitions: frequent adverse reactions are
792
defined as those occurring in at least 1/100 patients; infrequent adverse reactions are those
793
occurring in 1/100 to 1/1,000 patients; rare adverse reactions are those occurring in fewer than
794
1/1,000 patients.
795
Body as a Whole: Infrequent: Allergic reaction, chills, and malaise.
796
Cardiovascular System: Infrequent: Flushing, hot flashes, hypertension, palpitations,
797
postural hypotension, syncope, tachycardia, and vasodilation.
798
Dermatological: Infrequent: Acne, alopecia, hirsutism, maculopapular rash, skin
799
discoloration, and urticaria. Rare: Angioedema, erythema, exfoliative dermatitis, fungal
800
dermatitis, herpes zoster, leukoderma, multiforme erythema, petechial rash, pustular rash,
801
Stevens-Johnson syndrome, and vesiculobullous rash.
802
Digestive System: Infrequent: Dysphagia, eructation, gastritis, gingivitis, increased
803
appetite, increased salivation, liver function tests abnormal, and mouth ulceration. Rare:
804
Gastrointestinal hemorrhage, glossitis, gum hemorrhage, gum hyperplasia, hematemesis,
805
hemorrhagic colitis, hepatitis, melena, stomach ulcer, stomatitis, and tongue edema.
806
Endocrine System: Rare: Goiter and hypothyroidism.
807
Hematologic and Lymphatic System: Infrequent: Ecchymosis and leukopenia. Rare:
808
Anemia, eosinophilia, fibrin decrease, fibrinogen decrease, iron deficiency anemia, leukocytosis,
809
lymphocytosis, macrocytic anemia, petechia, and thrombocytopenia.
810
Metabolic and Nutritional Disorders: Infrequent: Aspartate transaminase increased.
811
Rare: Alcohol intolerance, alkaline phosphatase increase, alanine transaminase increase,
812
bilirubinemia, general edema, gamma glutamyl transpeptidase increase, and hyperglycemia.
813
Musculoskeletal System: Infrequent: Arthritis, leg cramps, myasthenia, and twitching.
814
Rare: Bursitis, muscle atrophy, pathological fracture, and tendinous contracture.
815
Nervous System: Frequent: Confusion and paresthesia. Infrequent: Akathisia, apathy,
816
aphasia, CNS depression, depersonalization, dysarthria, dyskinesia, euphoria, hallucinations,
817
hostility, hyperkinesia, hypertonia, libido decreased, memory decrease, mind racing, movement
818
disorder, myoclonus, panic attack, paranoid reaction, personality disorder, psychosis, sleep
819
disorder, stupor, and suicidal ideation. Rare: Choreoathetosis, delirium, delusions, dysphoria,
820
dystonia, extrapyramidal syndrome, faintness, grand mal convulsions, hemiplegia, hyperalgesia,
821
hyperesthesia, hypokinesia, hypotonia, manic depression reaction, muscle spasm, neuralgia,
822
neurosis, paralysis, and peripheral neuritis.
823
Respiratory System: Infrequent: Yawn. Rare: Hiccup and hyperventilation.
824
Special Senses: Frequent: Amblyopia. Infrequent: Abnormality of accommodation,
825
conjunctivitis, dry eyes, ear pain, photophobia, taste perversion, and tinnitus. Rare: Deafness,
31
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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NDA 020764/S-036 and S-037
NDA 022251/S-005 and S-006
FDA Approved Labeling Text dated 10/12/2010
Page 32
826
lacrimation disorder, oscillopsia, parosmia, ptosis, strabismus, taste loss, uveitis, and visual field
827
defect.
828
Urogenital System: Infrequent: Abnormal ejaculation, hematuria, impotence,
829
menorrhagia, polyuria, and urinary incontinence. Rare: Acute kidney failure, anorgasmia, breast
830
abscess, breast neoplasm, creatinine increase, cystitis, dysuria, epididymitis, female lactation,
831
kidney failure, kidney pain, nocturia, urinary retention, and urinary urgency.
832
6.3
Postmarketing Experience
833
The following adverse events (not listed above in clinical trials or other sections of the
834
prescribing information) have been identified during postapproval use of LAMICTAL. Because
835
these events are reported voluntarily from a population of uncertain size, it is not always possible
836
to reliably estimate their frequency or establish a causal relationship to drug exposure.
837
Blood and Lymphatic: Agranulocytosis, hemolytic anemia
838
Gastrointestinal: Esophagitis.
839
Hepatobiliary Tract and Pancreas: Pancreatitis.
840
Immunologic: Lupus-like reaction, vasculitis.
841
Lower Respiratory: Apnea.
842
Musculoskeletal: Rhabdomyolysis has been observed in patients experiencing
843
hypersensitivity reactions.
844
Neurology: Exacerbation of Parkinsonian symptoms in patients with pre-existing
845
Parkinson’s disease, tics.
846
Non-site Specific: Progressive immunosuppression.
847
7
DRUG INTERACTIONS
848
Significant drug interactions with lamotrigine are summarized in Table 13. Additional
849
details of these drug interaction studies are provided in the Clinical Pharmacology section [see
850
Clinical Pharmacology (12.3)].
851
852
Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug
Effect on
Concentration of
Lamotrigine or
Concomitant Drug
Clinical Comment
Estrogen-containing oral
contraceptive
preparations containing
30 mcg ethinylestradiol
and 150 mcg
levonorgestrel
↓ lamotrigine
↓ levonorgestrel
Decreased lamotrigine levels
approximately 50%.
Decrease in levonorgestrel component by
19%.
32
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For current labeling information, please visit https://www.fda.gov/drugsatfda
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FDA Approved Labeling Text dated 10/12/2010
Page 33
Carbamazepine (CBZ)
and CBZ epoxide
↓ lamotrigine
? CBZ epoxide
Addition of carbamazepine decreases
lamotrigine concentration approximately
40%.
May increase CBZ epoxide levels
Phenobarbital/Primidone
↓ lamotrigine
Decreased lamotrigine concentration
approximately 40%.
Phenytoin (PHT)
↓ lamotrigine
Decreased lamotrigine concentration
approximately 40%.
Rifampin
↓ lamotrigine
Decreased lamotrigine AUC
approximately 40%.
Valproate
↑ lamotrigine
? valproate
Increased lamotrigine concentrations
slightly more than 2-fold.
Decreased valproate concentrations an
average of 25% over a 3-week period then
stabilized in healthy volunteers; no change
in controlled clinical trials in epilepsy
patients.
853
↓ = Decreased (induces lamotrigine glucuronidation).
854
↑ = Increased (inhibits lamotrigine glucuronidation).
855
? = Conflicting data.
856
8
USE IN SPECIFIC POPULATIONS
857
8.1
Pregnancy
858
Teratogenic Effects: Pregnancy Category C. No evidence of teratogenicity was found in
859
mice, rats, or rabbits when lamotrigine was orally administered to pregnant animals during the
860
period of organogenesis at doses up to 1.2, 0.5, and 1.1 times, respectively, on a mg/m2 basis, the
861
highest usual human maintenance dose (i.e., 500 mg/day). However, maternal toxicity and
862
secondary fetal toxicity producing reduced fetal weight and/or delayed ossification were seen in
863
mice and rats, but not in rabbits at these doses. Teratology studies were also conducted using
864
bolus intravenous administration of the isethionate salt of lamotrigine in rats and rabbits. In rat
865
dams administered an intravenous dose at 0.6 times the highest usual human maintenance dose,
866
the incidence of intrauterine death without signs of teratogenicity was increased.
867
A behavioral teratology study was conducted in rats dosed during the period of
868
organogenesis. At day 21 postpartum, offspring of dams receiving 5 mg/kg/day or higher
869
displayed a significantly longer latent period for open field exploration and a lower frequency of
870
rearing. In a swimming maze test performed on days 39 to 44 postpartum, time to completion
33
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Page 34
871
was increased in offspring of dams receiving 25 mg/kg/day. These doses represent 0.1 and
872
0.5 times the clinical dose on a mg/m2 basis, respectively.
873
Lamotrigine did not affect fertility, teratogenesis, or postnatal development when rats
874
were dosed prior to and during mating, and throughout gestation and lactation at doses
875
equivalent to 0.4 times the highest usual human maintenance dose on a mg/m2 basis.
876
When pregnant rats were orally dosed at 0.1, 0.14, or 0.3 times the highest human
877
maintenance dose (on a mg/m2 basis) during the latter part of gestation (days 15 to 20), maternal
878
toxicity and fetal death were seen. In dams, food consumption and weight gain were reduced,
879
and the gestation period was slightly prolonged (22.6 vs. 22.0 days in the control group).
880
Stillborn pups were found in all 3 drug-treated groups with the highest number in the high-dose
881
group. Postnatal death was also seen, but only in the 2 highest doses, and occurred between days
882
1 and 20. Some of these deaths appear to be drug-related and not secondary to the maternal
883
toxicity. A no-observed-effect level (NOEL) could not be determined for this study.
884
Although lamotrigine was not found to be teratogenic in the above studies, lamotrigine
885
decreases fetal folate concentrations in rats, an effect known to be associated with teratogenesis
886
in animals and humans. There are no adequate and well-controlled studies in pregnant women.
887
Because animal reproduction studies are not always predictive of human response, this drug
888
should be used during pregnancy only if the potential benefit justifies the potential risk to the
889
fetus.
890
Non-Teratogenic Effects: As with other AEDs, physiological changes during
891
pregnancy may affect lamotrigine concentrations and/or therapeutic effect. There have been
892
reports of decreased lamotrigine concentrations during pregnancy and restoration of pre-partum
893
concentrations after delivery. Dosage adjustments may be necessary to maintain clinical
894
response.
895
Pregnancy Exposure Registry: To provide information regarding the effects of in
896
utero exposure to LAMICTAL, physicians are advised to recommend that pregnant patients
897
taking LAMICTAL enroll in the North American Antiepileptic Drug (NAAED) Pregnancy
898
Registry. This can be done by calling the toll-free number 1-888-233-2334, and must be done by
899
patients themselves. Information on the registry can also be found at the website
900
http://www.aedpregnancyregistry.org/.
901
Physicians are also encouraged to register patients in the Lamotrigine Pregnancy
902
Registry; enrollment in this registry must be done prior to any prenatal diagnostic tests and
903
before fetal outcome is known. Physicians can obtain information by calling the Lamotrigine
904
Pregnancy Registry at 1-800-336-2176 (toll-free).
905
8.2
Labor and Delivery
906
The effect of LAMICTAL on labor and delivery in humans is unknown.
907
8.3
Nursing Mothers
34
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For current labeling information, please visit https://www.fda.gov/drugsatfda
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NDA 022251/S-005 and S-006
FDA Approved Labeling Text dated 10/12/2010
Page 35
908
Preliminary data indicate that lamotrigine passes into human milk. Because the effects on
909
the infant exposed to lamotrigine by this route are unknown, breastfeeding while taking
910
LAMICTAL is not recommended.
911
8.4
Pediatric Use
912
LAMICTAL is indicated for adjunctive therapy in patients ≥2 years of age for partial
913
seizures, the generalized seizures of Lennox-Gastaut syndrome, and primary generalized
914
tonic-clonic seizures.
915
Safety and efficacy of LAMICTAL, used as adjunctive treatment for partial seizures,
916
were not demonstrated in a small randomized, double-blind, placebo-controlled, withdrawal
917
study in very young pediatric patients (1 to 24 months). LAMICTAL was associated with an
918
increased risk for infectious adverse reactions (LAMICTAL 37%, Placebo 5%), and respiratory
919
adverse reactions (LAMICTAL 26%, Placebo 5%). Infectious adverse reactions included
920
bronchiolitis, bronchitis, ear infection, eye infection, otitis externa, pharyngitis, urinary tract
921
infection, and viral infection. Respiratory adverse reactions included nasal congestion, cough,
922
and apnea.
923
Safety and effectiveness in patients below the age of 18 years with Bipolar Disorder have
924
not been established.
925
8.5
Geriatric Use
926
Clinical studies of LAMICTAL for epilepsy and in Bipolar Disorder did not include
927
sufficient numbers of subjects 65 years of age and over to determine whether they respond
928
differently from younger subjects or exhibit a different safety profile than that of younger
929
patients. In general, dose selection for an elderly patient should be cautious, usually starting at
930
the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or
931
cardiac function, and of concomitant disease or other drug therapy.
932
8.6
Patients With Hepatic Impairment
933
Experience in patients with hepatic impairment is limited. Based on a clinical
934
pharmacology study in 24 patients with mild, moderate, and severe liver impairment [see
935
Clinical Pharmacology (12.3)], the following general recommendations can be made. No dosage
936
adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance
937
doses should generally be reduced by approximately 25% in patients with moderate and severe
938
liver impairment without ascites and 50% in patients with severe liver impairment with ascites.
939
Escalation and maintenance doses may be adjusted according to clinical response [see Dosage
940
and Administration (2.1)].
941
8.7
Patients With Renal Impairment
942
Lamotrigine is metabolized mainly by glucuronic acid conjugation, with the majority of
943
the metabolites being recovered in the urine. In a small study comparing a single dose of
944
lamotrigine in patients with varying degrees of renal impairment with healthy volunteers, the
945
plasma half-life of lamotrigine was significantly longer in the patients with renal impairment
946
[see Clinical Pharmacology (12.3)].
35
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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NDA 020764/S-036 and S-037
NDA 022251/S-005 and S-006
FDA Approved Labeling Text dated 10/12/2010
Page 36
947
Initial doses of LAMICTAL should be based on patients' AED regimens; reduced
948
maintenance doses may be effective for patients with significant renal impairment. Few patients
949
with severe renal impairment have been evaluated during chronic treatment with LAMICTAL.
950
Because there is inadequate experience in this population, LAMICTAL should be used with
951
caution in these patients [see Dosage and Administration (2.1)].
952
10
OVERDOSAGE
953
10.1 Human Overdose Experience
954
Overdoses involving quantities up to 15 g have been reported for LAMICTAL, some of
955
which have been fatal. Overdose has resulted in ataxia, nystagmus, increased seizures, decreased
956
level of consciousness, coma, and intraventricular conduction delay.
957
10.2 Management of Overdose
958
There are no specific antidotes for lamotrigine. Following a suspected overdose,
959
hospitalization of the patient is advised. General supportive care is indicated, including frequent
960
monitoring of vital signs and close observation of the patient. If indicated, emesis should be
961
induced; usual precautions should be taken to protect the airway. It should be kept in mind that
962
lamotrigine is rapidly absorbed [see Clinical Pharmacology (12.3)]. It is uncertain whether
963
hemodialysis is an effective means of removing lamotrigine from the blood. In 6 renal failure
964
patients, about 20% of the amount of lamotrigine in the body was removed by hemodialysis
965
during a 4-hour session. A Poison Control Center should be contacted for information on the
966
management of overdosage of LAMICTAL.
967
11
DESCRIPTION
968
LAMICTAL (lamotrigine), an AED of the phenyltriazine class, is chemically unrelated to
969
existing AEDs. Its chemical name is 3,5-diamino-6-(2,3-dichlorophenyl)-as-triazine, its
970
molecular formula is C9H7N5Cl2, and its molecular weight is 256.09. Lamotrigine is a white to
971
pale cream-colored powder and has a pKa of 5.7. Lamotrigine is very slightly soluble in water
972
(0.17 mg/mL at 25°C) and slightly soluble in 0.1 M HCl (4.1 mg/mL at 25°C). The structural
973
formula is:
974 structural formula
975
976
977
LAMICTAL Tablets are supplied for oral administration as 25 mg (white), 100 mg
978
(peach), 150 mg (cream), and 200 mg (blue) tablets. Each tablet contains the labeled amount of
979
lamotrigine and the following inactive ingredients: lactose; magnesium stearate; microcrystalline
980
cellulose; povidone; sodium starch glycolate; FD&C Yellow No. 6 Lake (100 mg tablet only);
981
ferric oxide, yellow (150 mg tablet only); and FD&C Blue No. 2 Lake (200 mg tablet only).
36
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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NDA 022251/S-005 and S-006
FDA Approved Labeling Text dated 10/12/2010
Page 37
982
LAMICTAL Chewable Dispersible Tablets are supplied for oral administration. The
983
tablets contain 2 mg (white), 5 mg (white), or 25 mg (white) of lamotrigine and the following
984
inactive ingredients: blackcurrant flavor, calcium carbonate, low-substituted
985
hydroxypropylcellulose, magnesium aluminum silicate, magnesium stearate, povidone, saccharin
986
sodium, and sodium starch glycolate.
987
LAMICTAL ODT Orally Disintegrating Tablets are supplied for oral administration. The
988
tablets contain 25 mg (white to off-white), 50 mg (white to off-white), 100 mg (white to off
989
white), or 200 mg (white to off-white) of lamotrigine and the following inactive ingredients:
990
artificial cherry flavor, crospovidone, ethylcellulose, magnesium stearate, mannitol,
991
polyethylene, and sucralose.
992
LAMICTAL ODT Orally Disintegrating Tablets are formulated using technologies
993
(Microcaps® and AdvaTab®) designed to mask the bitter taste of lamotrigine and achieve a rapid
994
dissolution profile. Tablet characteristics including flavor, mouth-feel, after-taste, and ease of use
995
were rated as favorable in a study of 108 healthy volunteers.
996
12
CLINICAL PHARMACOLOGY
997
12.1 Mechanism of Action
998
The precise mechanism(s) by which lamotrigine exerts its anticonvulsant action are
999
unknown. In animal models designed to detect anticonvulsant activity, lamotrigine was effective
1000
in preventing seizure spread in the maximum electroshock (MES) and pentylenetetrazol (scMet)
1001
tests, and prevented seizures in the visually and electrically evoked after-discharge (EEAD) tests
1002
for antiepileptic activity. Lamotrigine also displayed inhibitory properties in the kindling model
1003
in rats both during kindling development and in the fully kindled state. The relevance of these
1004
models to human epilepsy, however, is not known.
1005
One proposed mechanism of action of lamotrigine, the relevance of which remains to be
1006
established in humans, involves an effect on sodium channels. In vitro pharmacological studies
1007
suggest that lamotrigine inhibits voltage-sensitive sodium channels, thereby stabilizing neuronal
1008
membranes and consequently modulating presynaptic transmitter release of excitatory amino
1009
acids (e.g., glutamate and aspartate).
1010
Although the relevance for human use is unknown, the following data characterize the
1011
performance of lamotrigine in receptor binding assays. Lamotrigine had a weak inhibitory effect
1012
on the serotonin 5-HT3 receptor (IC50 = 18 µM). It does not exhibit high affinity binding
1013
(IC50>100 µM) to the following neurotransmitter receptors: adenosine A1 and A2; adrenergic α1,
1014
α2, and β; dopamine D1 and D2; γ-aminobutyric acid (GABA) A and B; histamine H1; kappa
1015
opioid; muscarinic acetylcholine; and serotonin 5-HT2. Studies have failed to detect an effect of
1016
lamotrigine on dihydropyridine-sensitive calcium channels. It had weak effects at sigma opioid
1017
receptors (IC50 = 145 µM). Lamotrigine did not inhibit the uptake of norepinephrine, dopamine,
1018
or serotonin (IC50>200 µM) when tested in rat synaptosomes and/or human platelets in vitro.
1019
Effect of Lamotrigine on N-Methyl d-Aspartate-Receptor Mediated Activity:
1020
Lamotrigine did not inhibit N-methyl d-aspartate (NMDA)-induced depolarizations in rat cortical
37
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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NDA 020764/S-036 and S-037
NDA 022251/S-005 and S-006
FDA Approved Labeling Text dated 10/12/2010
Page 38
1021
slices or NMDA-induced cyclic GMP formation in immature rat cerebellum, nor did lamotrigine
1022
displace compounds that are either competitive or noncompetitive ligands at this glutamate
1023
receptor complex (CNQX, CGS, TCHP). The IC50 for lamotrigine effects on NMDA-induced
1024
currents (in the presence of 3 µM of glycine) in cultured hippocampal neurons exceeded
1025
100 µM.
1026
The mechanisms by which lamotrigine exerts its therapeutic action in Bipolar Disorder
1027
have not been established.
1028
12.2 Pharmacodynamics
1029
Folate Metabolism: In vitro, lamotrigine inhibited dihydrofolate reductase, the enzyme
1030
that catalyzes the reduction of dihydrofolate to tetrahydrofolate. Inhibition of this enzyme may
1031
interfere with the biosynthesis of nucleic acids and proteins. When oral daily doses of
1032
lamotrigine were given to pregnant rats during organogenesis, fetal, placental, and maternal
1033
folate concentrations were reduced. Significantly reduced concentrations of folate are associated
1034
with teratogenesis [see Use in Specific Populations (8.1)]. Folate concentrations were also
1035
reduced in male rats given repeated oral doses of lamotrigine. Reduced concentrations were
1036
partially returned to normal when supplemented with folinic acid.
1037
Accumulation in Kidneys: Lamotrigine accumulated in the kidney of the male rat,
1038
causing chronic progressive nephrosis, necrosis, and mineralization. These findings are attributed
1039
to α-2 microglobulin, a species- and sex-specific protein that has not been detected in humans or
1040
other animal species.
1041
Melanin Binding: Lamotrigine binds to melanin-containing tissues, e.g., in the eye and
1042
pigmented skin. It has been found in the uveal tract up to 52 weeks after a single dose in rodents.
1043
Cardiovascular: In dogs, lamotrigine is extensively metabolized to a 2-N-methyl
1044
metabolite. This metabolite causes dose-dependent prolongations of the PR interval, widening of
1045
the QRS complex, and, at higher doses, complete AV conduction block. Similar cardiovascular
1046
effects are not anticipated in humans because only trace amounts of the 2-N-methyl metabolite
1047
(<0.6% of lamotrigine dose) have been found in human urine [see Clinical Pharmacology
1048
(12.3)]. However, it is conceivable that plasma concentrations of this metabolite could be
1049
increased in patients with a reduced capacity to glucuronidate lamotrigine (e.g., in patients with
1050
liver disease).
1051
12.3 Pharmacokinetics
1052
The pharmacokinetics of lamotrigine have been studied in patients with epilepsy, healthy
1053
young and elderly volunteers, and volunteers with chronic renal failure. Lamotrigine
1054
pharmacokinetic parameters for adult and pediatric patients and healthy normal volunteers are
1055
summarized in Tables 14 and 16.
1056
38
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For current labeling information, please visit https://www.fda.gov/drugsatfda
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NDA 022251/S-005 and S-006
FDA Approved Labeling Text dated 10/12/2010
Page 39
1057
Table 14. Meana Pharmacokinetic Parameters in Healthy Volunteers and Adult Patients
1058
With Epilepsy
Adult Study Population
Number of
Subjects
Tmax: Time of
Maximum
Plasma
Concentration
(hr)
t½:
Elimination
Half-life
(hr)
Cl/F:
Apparent Plasma
Clearance
(mL/min/kg)
Healthy volunteers taking no
other medications:
Single-dose LAMICTAL
179
2.2
32.8
0.44
(0.25-12.0) (14.0-103.0)
(0.12-1.10)
Multiple-dose LAMICTAL
36
1.7
25.4
0.58
(0.5-4.0)
(11.6-61.6)
(0.24-1.15)
Healthy volunteers taking
valproate:
Single-dose LAMICTAL
6
1.8
48.3
0.30
(1.0-4.0)
(31.5-88.6)
(0.14-0.42)
Multiple-dose LAMICTAL
18
1.9
70.3
0.18
(0.5-3.5)
(41.9-113.5)
(0.12-0.33)
Patients with epilepsy taking
valproate only:
Single-dose LAMICTAL
4
4.8
58.8
0.28
(1.8-8.4)
(30.5-88.8)
(0.16-0.40)
Patients with epilepsy taking
carbamazepine, phenytoin,
phenobarbital, or primidoneb
plus valproate:
Single-dose LAMICTAL
25
3.8
(1.0-10.0)
27.2
(11.2-51.6)
0.53
(0.27-1.04)
Patients with epilepsy taking
carbamazepine, phenytoin,
phenobarbital, or primidone:b
Single-dose LAMICTAL
24
2.3
14.4
1.10
(0.5-5.0)
(6.4-30.4)
(0.51-2.22)
Multiple-dose LAMICTAL
17
2.0
12.6
1.21
(0.75-5.93)
(7.5-23.1)
(0.66-1.82)
1059
a The majority of parameter means determined in each study had coefficients of variation
1060
between 20% and 40% for half-life and Cl/F and between 30% and 70% for Tmax. The overall
1061
mean values were calculated from individual study means that were weighted based on the
39
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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NDA 022251/S-005 and S-006
FDA Approved Labeling Text dated 10/12/2010
Page 40
1062
number of volunteers/patients in each study. The numbers in parentheses below each
1063
parameter mean represent the range of individual volunteer/patient values across studies.
1064
b Carbamazepine, phenobarbital, phenytoin, and primidone have been shown to increase the
1065
apparent clearance of lamotrigine. Estrogen-containing oral contraceptives and other drugs
1066
such as rifampin that induce lamotrigine glucuronidation have also been shown to increase the
1067
apparent clearance of lamotrigine [see Drug Interactions (7)].
1068
1069
Absorption: Lamotrigine is rapidly and completely absorbed after oral administration
1070
with negligible first-pass metabolism (absolute bioavailability is 98%). The bioavailability is not
1071
affected by food. Peak plasma concentrations occur anywhere from 1.4 to 4.8 hours following
1072
drug administration. The lamotrigine chewable/dispersible tablets were found to be equivalent,
1073
whether they were administered as dispersed in water, chewed and swallowed, or swallowed as
1074
whole, to the lamotrigine compressed tablets in terms of rate and extent of absorption. In terms
1075
of rate and extent of absorption, lamotrigine orally disintegrating tablets whether disintegrated in
1076
the mouth or swallowed whole with water were equivalent to the lamotrigine compressed tablets
1077
swallowed with water.
1078
Dose Proportionality: In healthy volunteers not receiving any other medications and
1079
given single doses, the plasma concentrations of lamotrigine increased in direct proportion to the
1080
dose administered over the range of 50 to 400 mg. In 2 small studies (n = 7 and 8) of patients
1081
with epilepsy who were maintained on other AEDs, there also was a linear relationship between
1082
dose and lamotrigine plasma concentrations at steady state following doses of 50 to 350 mg
1083
twice daily.
1084
Distribution: Estimates of the mean apparent volume of distribution (Vd/F) of
1085
lamotrigine following oral administration ranged from 0.9 to 1.3 L/kg. Vd/F is independent of
1086
dose and is similar following single and multiple doses in both patients with epilepsy and in
1087
healthy volunteers.
1088
Protein Binding: Data from in vitro studies indicate that lamotrigine is approximately
1089
55% bound to human plasma proteins at plasma lamotrigine concentrations from 1 to 10 mcg/mL
1090
(10 mcg/mL is 4 to 6 times the trough plasma concentration observed in the controlled efficacy
1091
trials). Because lamotrigine is not highly bound to plasma proteins, clinically significant
1092
interactions with other drugs through competition for protein binding sites are unlikely. The
1093
binding of lamotrigine to plasma proteins did not change in the presence of therapeutic
1094
concentrations of phenytoin, phenobarbital, or valproate. Lamotrigine did not displace other
1095
AEDs (carbamazepine, phenytoin, phenobarbital) from protein-binding sites.
1096
Metabolism: Lamotrigine is metabolized predominantly by glucuronic acid conjugation;
1097
the major metabolite is an inactive 2-N-glucuronide conjugate. After oral administration of
1098
240 mg of 14C-lamotrigine (15 μCi) to 6 healthy volunteers, 94% was recovered in the urine and
1099
2% was recovered in the feces. The radioactivity in the urine consisted of unchanged lamotrigine
40
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For current labeling information, please visit https://www.fda.gov/drugsatfda
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NDA 020764/S-036 and S-037
NDA 022251/S-005 and S-006
FDA Approved Labeling Text dated 10/12/2010
Page 41
1100
(10%), the 2-N-glucuronide (76%), a 5-N-glucuronide (10%), a 2-N-methyl metabolite (0.14%),
1101
and other unidentified minor metabolites (4%).
1102
Enzyme Induction: The effects of lamotrigine on the induction of specific families of
1103
mixed-function oxidase isozymes have not been systematically evaluated.
1104
Following multiple administrations (150 mg twice daily) to normal volunteers taking no
1105
other medications, lamotrigine induced its own metabolism, resulting in a 25% decrease in t½ and
1106
a 37% increase in Cl/F at steady state compared with values obtained in the same volunteers
1107
following a single dose. Evidence gathered from other sources suggests that self-induction by
1108
lamotrigine may not occur when lamotrigine is given as adjunctive therapy in patients receiving
1109
enzyme-inducing drugs such as carbamazepine, phenytoin, phenobarbital, primidone, or drugs
1110
such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7)].
1111
Elimination: The elimination half-life and apparent clearance of lamotrigine following
1112
administration of LAMICTAL to adult patients with epilepsy and healthy volunteers is
1113
summarized in Table 14. Half-life and apparent oral clearance vary depending on concomitant
1114
AEDs.
1115
Drug Interactions: The apparent clearance of lamotrigine is affected by the
1116
coadministration of certain medications [see Warnings and Precautions (5.9, 5.13), Drug
1117
Interactions (7)].
1118
The net effects of drug interactions with LAMICTAL are summarized in Tables 13 and
1119
15, followed by details of the drug interaction studies below.
1120
1121
Table 15. Summary of Drug Interactions With LAMICTAL
Drug
Drug Plasma
Concentration With
Adjunctive LAMICTALa
Lamotrigine Plasma
Concentration With
Adjunctive Drugsb
Oral contraceptives (e.g.,
ethinylestradiol/levonorgestrel)c
Bupropion
Carbamazepine (CBZ)
CBZ epoxidee
Felbamate
Gabapentin
Levetiracetam
Lithium
Olanzapine
Oxcarbazepine
10-monohydroxy oxcarbazepine
metaboliteg
Phenobarbital/primidone
↔d
Not assessed
↔
?
Not assessed
Not assessed
↔
↔
↔
↔
↔
↔
↓
↔
↓
↔
↔
↔
Not assessed
↔f
↔
↓
41
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For current labeling information, please visit https://www.fda.gov/drugsatfda
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FDA Approved Labeling Text dated 10/12/2010
Page 42
Phenytoin (PHT)
Pregabalin
Rifampin
Topiramate
Valproate
Valproate + PHT and/or CBZ
Zonisamide
↔
↔
Not assessed
↔h
↓
Not assessed
Not assessed
↓
↔
↓
↔
↑
↔
↔
1122
a From adjunctive clinical trials and volunteer studies.
1123
b
Net effects were estimated by comparing the mean clearance values obtained in adjunctive
1124
clinical trials and volunteer studies.
1125
c The effect of other hormonal contraceptive preparations or hormone replacement therapy on
1126
the pharmacokinetics of lamotrigine has not been systematically evaluated in clinical trials,
1127
although the effect may be similar to that seen with the ethinylestradiol/levonorgestrel
1128
combinations.
1129
d Modest decrease in levonorgestrel.
1130
e Not administered, but an active metabolite of carbamazepine.
1131
f Slight decrease, not expected to be clinically relevant.
1132
g Not administered, but an active metabolite of oxcarbazepine.
1133
h Slight increase, not expected to be clinically relevant.
1134
↔ = No significant effect.
1135
? = Conflicting data.
1136
1137
Estrogen-Containing Oral Contraceptives: In 16 female volunteers, an oral
1138
contraceptive preparation containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel
1139
increased the apparent clearance of lamotrigine (300 mg/day) by approximately 2-fold with mean
1140
decreases in AUC of 52% and in Cmax of 39%. In this study, trough serum lamotrigine
1141
concentrations gradually increased and were approximately 2-fold higher on average at the end
1142
of the week of the inactive hormone preparation compared with trough lamotrigine
1143
concentrations at the end of the active hormone cycle.
1144
Gradual transient increases in lamotrigine plasma levels (approximate 2-fold increase)
1145
occurred during the week of inactive hormone preparation (“pill-free” week) for women not also
1146
taking a drug that increased the clearance of lamotrigine (carbamazepine, phenytoin,
1147
phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine
1148
glucuronidation [see Drug Interactions (7)]). The increase in lamotrigine plasma levels will be
1149
greater if the dose of LAMICTAL is increased in the few days before or during the “pill-free”
1150
week. Increases in lamotrigine plasma levels could result in dose-dependent adverse reactions.
1151
In the same study, coadministration of LAMICTAL (300 mg/day) in 16 female
1152
volunteers did not affect the pharmacokinetics of the ethinylestradiol component of the oral
1153
contraceptive preparation. There were mean decreases in the AUC and Cmax of the levonorgestrel
42
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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NDA 022251/S-005 and S-006
FDA Approved Labeling Text dated 10/12/2010
Page 43
1154
component of 19% and 12%, respectively. Measurement of serum progesterone indicated that
1155
there was no hormonal evidence of ovulation in any of the 16 volunteers, although measurement
1156
of serum FSH, LH, and estradiol indicated that there was some loss of suppression of the
1157
hypothalamic-pituitary-ovarian axis.
1158
The effects of doses of LAMICTAL other than 300 mg/day have not been systematically
1159
evaluated in controlled clinical trials.
1160
The clinical significance of the observed hormonal changes on ovulatory activity is
1161
unknown. However, the possibility of decreased contraceptive efficacy in some patients cannot
1162
be excluded. Therefore, patients should be instructed to promptly report changes in their
1163
menstrual pattern (e.g., break-through bleeding).
1164
Dosage adjustments may be necessary for women receiving estrogen-containing oral
1165
contraceptive preparations [see Dosage and Administration (2.1)].
1166
Other Hormonal Contraceptives or Hormone Replacement Therapy: The effect of
1167
other hormonal contraceptive preparations or hormone replacement therapy on the
1168
pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that
1169
ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the
1170
progestin-only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the
1171
dosage of LAMICTAL in the presence of progestogens alone will likely not be needed.
1172
Bupropion: The pharmacokinetics of a 100-mg single dose of LAMICTAL in healthy
1173
volunteers (n = 12) were not changed by coadministration of bupropion sustained-release
1174
formulation (150 mg twice daily) starting 11 days before LAMICTAL.
1175
Carbamazepine: LAMICTAL has no appreciable effect on steady-state carbamazepine
1176
plasma concentration. Limited clinical data suggest there is a higher incidence of dizziness,
1177
diplopia, ataxia, and blurred vision in patients receiving carbamazepine with lamotrigine than in
1178
patients receiving other AEDs with lamotrigine [see Adverse Reactions (6.1)]. The mechanism
1179
of this interaction is unclear. The effect of lamotrigine on plasma concentrations of
1180
carbamazepine-epoxide is unclear. In a small subset of patients (n = 7) studied in a
1181
placebo-controlled trial, lamotrigine had no effect on carbamazepine-epoxide plasma
1182
concentrations, but in a small, uncontrolled study (n = 9), carbamazepine-epoxide levels
1183
increased.
1184
The addition of carbamazepine decreases lamotrigine steady-state concentrations by
1185
approximately 40%.
1186
Felbamate: In a study of 21 healthy volunteers, coadministration of felbamate (1,200 mg
1187
twice daily) with lamotrigine (100 mg twice daily for 10 days) appeared to have no clinically
1188
relevant effects on the pharmacokinetics of lamotrigine.
1189
Folate Inhibitors: Lamotrigine is a weak inhibitor of dihydrofolate reductase. Prescribers
1190
should be aware of this action when prescribing other medications that inhibit folate metabolism.
43
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For current labeling information, please visit https://www.fda.gov/drugsatfda
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Page 44
1191
Gabapentin: Based on a retrospective analysis of plasma levels in 34 patients who
1192
received lamotrigine both with and without gabapentin, gabapentin does not appear to change the
1193
apparent clearance of lamotrigine.
1194
Levetiracetam: Potential drug interactions between levetiracetam and lamotrigine were
1195
assessed by evaluating serum concentrations of both agents during placebo-controlled clinical
1196
trials. These data indicate that lamotrigine does not influence the pharmacokinetics of
1197
levetiracetam and that levetiracetam does not influence the pharmacokinetics of lamotrigine.
1198
Lithium: The pharmacokinetics of lithium were not altered in healthy subjects (n = 20) by
1199
coadministration of lamotrigine (100 mg/day) for 6 days.
1200
Olanzapine: The AUC and Cmax of olanzapine were similar following the addition of
1201
olanzapine (15 mg once daily) to lamotrigine (200 mg once daily) in healthy male volunteers
1202
(n = 16) compared with the AUC and Cmax in healthy male volunteers receiving olanzapine alone
1203
(n = 16).
1204
In the same study, the AUC and Cmax of lamotrigine were reduced on average by 24%
1205
and 20%, respectively, following the addition of olanzapine to lamotrigine in healthy male
1206
volunteers compared with those receiving lamotrigine alone. This reduction in lamotrigine
1207
plasma concentrations is not expected to be clinically relevant.
1208
Oxcarbazepine: The AUC and Cmax of oxcarbazepine and its active 10-monohydroxy
1209
oxcarbazepine metabolite were not significantly different following the addition of
1210
oxcarbazepine (600 mg twice daily) to lamotrigine (200 mg once daily) in healthy male
1211
volunteers (n = 13) compared with healthy male volunteers receiving oxcarbazepine alone
1212
(n = 13).
1213
In the same study, the AUC and Cmax of lamotrigine were similar following the addition
1214
of oxcarbazepine (600 mg twice daily) to LAMICTAL in healthy male volunteers compared with
1215
those receiving LAMICTAL alone. Limited clinical data suggest a higher incidence of headache,
1216
dizziness, nausea, and somnolence with coadministration of lamotrigine and oxcarbazepine
1217
compared with lamotrigine alone or oxcarbazepine alone.
1218
Phenobarbital, Primidone: The addition of phenobarbital or primidone decreases
1219
lamotrigine steady-state concentrations by approximately 40%.
1220
Phenytoin: Lamotrigine has no appreciable effect on steady-state phenytoin plasma
1221
concentrations in patients with epilepsy. The addition of phenytoin decreases lamotrigine steady
1222
state concentrations by approximately 40%.
1223
Pregabalin: Steady-state trough plasma concentrations of lamotrigine were not affected
1224
by concomitant pregabalin (200 mg 3 times daily) administration. There are no pharmacokinetic
1225
interactions between lamotrigine and pregabalin.
1226
Rifampin: In 10 male volunteers, rifampin (600 mg/day for 5 days) significantly
1227
increased the apparent clearance of a single 25-mg dose of lamotrigine by approximately 2-fold
1228
(AUC decreased by approximately 40%).
44
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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NDA 022251/S-005 and S-006
FDA Approved Labeling Text dated 10/12/2010
Page 45
1229
Topiramate: Topiramate resulted in no change in plasma concentrations of lamotrigine.
1230
Administration of lamotrigine resulted in a 15% increase in topiramate concentrations.
1231
Valproate: When lamotrigine was administered to healthy volunteers (n = 18) receiving
1232
valproate, the trough steady-state valproate plasma concentrations decreased by an average of
1233
25% over a 3-week period, and then stabilized. However, adding lamotrigine to the existing
1234
therapy did not cause a change in valproate plasma concentrations in either adult or pediatric
1235
patients in controlled clinical trials.
1236
The addition of valproate increased lamotrigine steady-state concentrations in normal
1237
volunteers by slightly more than 2-fold. In one study, maximal inhibition of lamotrigine
1238
clearance was reached at valproate doses between 250 and 500 mg/day and did not increase as
1239
the valproate dose was further increased.
1240
Zonisamide: In a study of 18 patients with epilepsy, coadministration of zonisamide
1241
(200 to 400 mg/day) with lamotrigine (150 to 500 mg/day for 35 days) had no significant effect
1242
on the pharmacokinetics of lamotrigine.
1243
Known Inducers or Inhibitors of Glucuronidation: Drugs other than those listed above
1244
have not been systematically evaluated in combination with lamotrigine. Since lamotrigine is
1245
metabolized predominately by glucuronic acid conjugation, drugs that are known to induce or
1246
inhibit glucuronidation may affect the apparent clearance of lamotrigine and doses of lamotrigine
1247
may require adjustment based on clinical response.
1248
Other: Results of in vitro experiments suggest that clearance of lamotrigine is unlikely to
1249
be reduced by concomitant administration of amitriptyline, clonazepam, clozapine, fluoxetine,
1250
haloperidol, lorazepam, phenelzine, risperidone, sertraline, or trazodone.
1251
Results of in vitro experiments suggest that lamotrigine does not reduce the clearance of
1252
drugs eliminated predominantly by CYP2D6.
1253
Special Populations: Patients With Renal Impairment: Twelve volunteers with
1254
chronic renal failure (mean creatinine clearance: 13 mL/min; range: 6 to 23) and another
1255
6 individuals undergoing hemodialysis were each given a single 100-mg dose of lamotrigine.
1256
The mean plasma half-lives determined in the study were 42.9 hours (chronic renal failure),
1257
13.0 hours (during hemodialysis), and 57.4 hours (between hemodialysis) compared with
1258
26.2 hours in healthy volunteers. On average, approximately 20% (range: 5.6 to 35.1) of the
1259
amount of lamotrigine present in the body was eliminated by hemodialysis during a 4-hour
1260
session [see Dosage and Administration (2.1)].
1261
Hepatic Disease: The pharmacokinetics of lamotrigine following a single 100-mg
1262
dose of lamotrigine were evaluated in 24 subjects with mild, moderate, and severe hepatic
1263
impairment (Child-Pugh Classification system) and compared with 12 subjects without hepatic
1264
impairment. The patients with severe hepatic impairment were without ascites (n = 2) or with
1265
ascites (n = 5). The mean apparent clearances of lamotrigine in patients with mild (n = 12),
1266
moderate (n = 5), severe without ascites (n = 2), and severe with ascites (n = 5) liver impairment
1267
were 0.30 ± 0.09, 0.24 ± 0.1, 0.21 ± 0.04, and 0.15 ± 0.09 mL/min/kg, respectively, as compared
45
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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NDA 020764/S-036 and S-037
NDA 022251/S-005 and S-006
FDA Approved Labeling Text dated 10/12/2010
Page 46
1268
with 0.37 ± 0.1 mL/min/kg in the healthy controls. Mean half-lives of lamotrigine in patients
1269
with mild, moderate, severe without ascites, and severe with ascites hepatic impairment were
1270
46 ± 20, 72 ± 44, 67 ± 11, and 100 ± 48 hours, respectively, as compared with 33 ± 7 hours in
1271
healthy controls [see Dosage and Administration (2.1)].
1272
Age: Pediatric Patients: The pharmacokinetics of lamotrigine following a single
1273
2-mg/kg dose were evaluated in 2 studies of pediatric patients (n = 29 for patients 10 months to
1274
5.9 years of age and n = 26 for patients 5 to 11 years of age). Forty-three patients received
1275
concomitant therapy with other AEDs and 12 patients received lamotrigine as monotherapy.
1276
Lamotrigine pharmacokinetic parameters for pediatric patients are summarized in Table 16.
1277
Population pharmacokinetic analyses involving patients 2 to 18 years of age
1278
demonstrated that lamotrigine clearance was influenced predominantly by total body weight and
1279
concurrent AED therapy. The oral clearance of lamotrigine was higher, on a body weight basis,
1280
in pediatric patients than in adults. Weight-normalized lamotrigine clearance was higher in those
1281
subjects weighing less than 30 kg, compared with those weighing greater than 30 kg.
1282
Accordingly, patients weighing less than 30 kg may need an increase of as much as 50% in
1283
maintenance doses, based on clinical response, as compared with subjects weighing more than
1284
30 kg being administered the same AEDs [see Dosage and Administration (2.2)]. These analyses
1285
also revealed that, after accounting for body weight, lamotrigine clearance was not significantly
1286
influenced by age. Thus, the same weight-adjusted doses should be administered to children
1287
irrespective of differences in age. Concomitant AEDs which influence lamotrigine clearance in
1288
adults were found to have similar effects in children.
1289
1290
Table 16. Mean Pharmacokinetic Parameters in Pediatric Patients With Epilepsy
Pediatric Study Population
Number
of
Subjects
Tmax
(hr)
t½
(hr)
Cl/F
(mL/min/kg)
Ages 10 months-5.3 years
Patients taking carbamazepine,
10
3.0
7.7
3.62
phenytoin, phenobarbital, or
primidonea
(1.0-5.9)
(5.7-11.4)
(2.44-5.28)
Patients taking AEDs with no known
7
5.2
19.0
1.2
effect on the apparent clearance of
lamotrigine
(2.9-6.1)
(12.9-27.1)
(0.75-2.42)
Patients taking valproate only
8
2.9
44.9
0.47
(1.0-6.0)
(29.5-52.5)
(0.23-0.77)
Ages 5-11 years
Patients taking carbamazepine,
7
1.6
7.0
2.54
phenytoin, phenobarbital, or
primidonea
(1.0-3.0)
(3.8-9.8)
(1.35-5.58)
46
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For current labeling information, please visit https://www.fda.gov/drugsatfda
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FDA Approved Labeling Text dated 10/12/2010
Page 47
Patients taking carbamazepine,
phenytoin, phenobarbital, or
primidonea plus valproate
Patients taking valproate only
b
8
3
3.3
(1.0-6.4)
4.5
(3.0-6.0)
19.1
(7.0-31.2)
65.8
(50.7-73.7)
0.89
(0.39-1.93)
0.24
(0.21-0.26)
Ages 13-18 years
Patients taking carbamazepine,
phenytoin, phenobarbital, or
primidonea
Patients taking carbamazepine,
phenytoin, phenobarbital, or
primidonea plus valproate
Patients taking valproate only
11
8
4
c
c
c
c
c
c
1.3
0.5
0.3
1291
a Carbamazepine, phenobarbital, phenytoin, and primidone have been shown to increase the
1292
apparent clearance of lamotrigine. Estrogen-containing oral contraceptives and rifampin have
1293
also been shown to increase the apparent clearance of lamotrigine [see Drug Interactions (7)].
b
1294
Two subjects were included in the calculation for mean Tmax
1295
c Parameter not estimated.
1296
1297
Elderly: The pharmacokinetics of lamotrigine following a single 150-mg dose of
1298
LAMICTAL were evaluated in 12 elderly volunteers between the ages of 65 and 76 years (mean
1299
creatinine clearance = 61 mL/min, range: 33 to 108 mL/min). The mean half-life of lamotrigine
1300
in these subjects was 31.2 hours (range: 24.5 to 43.4 hours), and the mean clearance was
1301
0.40 mL/min/kg (range: 0.26 to 0.48 mL/min/kg).
1302
Gender: The clearance of lamotrigine is not affected by gender. However, during
1303
dose escalation of LAMICTAL in one clinical trial in patients with epilepsy on a stable dose of
1304
valproate (n = 77), mean trough lamotrigine concentrations, unadjusted for weight, were 24% to
1305
45% higher (0.3 to 1.7 mcg/mL) in females than in males.
1306
Race: The apparent oral clearance of lamotrigine was 25% lower in non-Caucasians
1307
than Caucasians.
1308
13
NONCLINICAL TOXICOLOGY
1309
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
1310
No evidence of carcinogenicity was seen in 1 mouse study or 2 rat studies following oral
1311
administration of lamotrigine for up to 2 years at maximum tolerated doses (30 mg/kg/day for
1312
mice and 10 to 15 mg/kg/day for rats, doses that are equivalent to 90 mg/m2 and 60 to 90 mg/m2,
1313
respectively). Steady-state plasma concentrations ranged from 1 to 4 mcg/mL in the mouse study
1314
and 1 to 10 mcg/mL in the rat study. Plasma concentrations associated with the recommended
47
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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NDA 020764/S-036 and S-037
NDA 022251/S-005 and S-006
FDA Approved Labeling Text dated 10/12/2010
Page 48
1315
human doses of 300 to 500 mg/day are generally in the range of 2 to 5 mcg/mL, but
1316
concentrations as high as 19 mcg/mL have been recorded.
1317
Lamotrigine was not mutagenic in the presence or absence of metabolic activation when
1318
tested in 2 gene mutation assays (the Ames test and the in vitro mammalian mouse lymphoma
1319
assay). In 2 cytogenetic assays (the in vitro human lymphocyte assay and the in vivo rat bone
1320
marrow assay), lamotrigine did not increase the incidence of structural or numerical
1321
chromosomal abnormalities.
1322
No evidence of impairment of fertility was detected in rats given oral doses of
1323
lamotrigine up to 2.4 times the highest usual human maintenance dose of 8.33 mg/kg/day or
1324
0.4 times the human dose on a mg/m2 basis. The effect of lamotrigine on human fertility is
1325
unknown.
1326
14
CLINICAL STUDIES
1327
14.1 Epilepsy
1328
Monotherapy With LAMICTAL in Adults With Partial Seizures Already Receiving
1329
Treatment With Carbamazepine, Phenytoin, Phenobarbital, or Primidone as the Single
1330
AED: The effectiveness of monotherapy with LAMICTAL was established in a multicenter,
1331
double-blind clinical trial enrolling 156 adult outpatients with partial seizures. The patients
1332
experienced at least 4 simple partial, complex partial, and/or secondarily generalized seizures
1333
during each of 2 consecutive 4-week periods while receiving carbamazepine or phenytoin
1334
monotherapy during baseline. LAMICTAL (target dose of 500 mg/day) or valproate
1335
(1,000 mg/day) was added to either carbamazepine or phenytoin monotherapy over a 4-week
1336
period. Patients were then converted to monotherapy with LAMICTAL or valproate during the
1337
next 4 weeks, then continued on monotherapy for an additional 12-week period.
1338
Study endpoints were completion of all weeks of study treatment or meeting an escape
1339
criterion. Criteria for escape relative to baseline were: (1) doubling of average monthly seizure
1340
count, (2) doubling of highest consecutive 2-day seizure frequency, (3) emergence of a new
1341
seizure type (defined as a seizure that did not occur during the 8-week baseline) that is more
1342
severe than seizure types that occur during study treatment, or (4) clinically significant
1343
prolongation of generalized tonic-clonic (GTC) seizures. The primary efficacy variable was the
1344
proportion of patients in each treatment group who met escape criteria.
1345
The percentages of patients who met escape criteria were 42% (32/76) in the group
1346
receiving LAMICTAL and 69% (55/80) in the valproate group. The difference in the percentage
1347
of patients meeting escape criteria was statistically significant (p= 0.0012) in favor of
1348
LAMICTAL. No differences in efficacy based on age, sex, or race were detected.
1349
Patients in the control group were intentionally treated with a relatively low dose of
1350
valproate; as such, the sole objective of this study was to demonstrate the effectiveness and
1351
safety of monotherapy with LAMICTAL, and cannot be interpreted to imply the superiority of
1352
LAMICTAL to an adequate dose of valproate.
48
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-043 and S-044
NDA 020764/S-036 and S-037
NDA 022251/S-005 and S-006
FDA Approved Labeling Text dated 10/12/2010
Page 49
1353
Adjunctive Therapy With LAMICTAL in Adults With Partial Seizures: The
1354
effectiveness of LAMICTAL as adjunctive therapy (added to other AEDs) was established in
1355
3 multicenter, placebo-controlled, double-blind clinical trials in 355 adults with refractory partial
1356
seizures. The patients had a history of at least 4 partial seizures per month in spite of receiving
1357
one or more AEDs at therapeutic concentrations and, in 2 of the studies, were observed on their
1358
established AED regimen during baselines that varied between 8 to 12 weeks. In the third,
1359
patients were not observed in a prospective baseline. In patients continuing to have at least
1360
4 seizures per month during the baseline, LAMICTAL or placebo was then added to the existing
1361
therapy. In all 3 studies, change from baseline in seizure frequency was the primary measure of
1362
effectiveness. The results given below are for all partial seizures in the intent-to-treat population
1363
(all patients who received at least one dose of treatment) in each study, unless otherwise
1364
indicated. The median seizure frequency at baseline was 3 per week while the mean at baseline
1365
was 6.6 per week for all patients enrolled in efficacy studies.
1366
One study (n = 216) was a double-blind, placebo-controlled, parallel trial consisting of a
1367
24-week treatment period. Patients could not be on more than 2 other anticonvulsants and
1368
valproate was not allowed. Patients were randomized to receive placebo, a target dose of
1369
300 mg/day of LAMICTAL, or a target dose of 500 mg/day of LAMICTAL. The median
1370
reductions in the frequency of all partial seizures relative to baseline were 8% in patients
1371
receiving placebo, 20% in patients receiving 300 mg/day of LAMICTAL, and 36% in patients
1372
receiving 500 mg/day of LAMICTAL. The seizure frequency reduction was statistically
1373
significant in the 500-mg/day group compared with the placebo group, but not in the 300-mg/day
1374
group.
1375
A second study (n = 98) was a double-blind, placebo-controlled, randomized, crossover
1376
trial consisting of two 14-week treatment periods (the last 2 weeks of which consisted of dose
1377
tapering) separated by a 4-week washout period. Patients could not be on more than 2 other
1378
anticonvulsants and valproate was not allowed. The target dose of LAMICTAL was 400 mg/day.
1379
When the first 12 weeks of the treatment periods were analyzed, the median change in seizure
1380
frequency was a 25% reduction on LAMICTAL compared with placebo (p<0.001).
1381
The third study (n = 41) was a double-blind, placebo-controlled, crossover trial consisting
1382
of two 12-week treatment periods separated by a 4-week washout period. Patients could not be
1383
on more than 2 other anticonvulsants. Thirteen patients were on concomitant valproate; these
1384
patients received 150 mg/day of LAMICTAL. The 28 other patients had a target dose of
1385
300 mg/day of LAMICTAL. The median change in seizure frequency was a 26% reduction on
1386
LAMICTAL compared with placebo (p<0.01).
1387
No differences in efficacy based on age, sex, or race, as measured by change in seizure
1388
frequency, were detected.
1389
Adjunctive Therapy With LAMICTAL in Pediatric Patients With Partial Seizures:
1390
The effectiveness of LAMICTAL as adjunctive therapy in pediatric patients with partial seizures
1391
was established in a multicenter, double-blind, placebo-controlled trial in 199 patients 2 to 16
49
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-043 and S-044
NDA 020764/S-036 and S-037
NDA 022251/S-005 and S-006
FDA Approved Labeling Text dated 10/12/2010
Page 50
1392
years of age (n = 98 on LAMICTAL, n = 101 on placebo). Following an 8-week baseline phase,
1393
patients were randomized to 18 weeks of treatment with LAMICTAL or placebo added to their
1394
current AED regimen of up to 2 drugs. Patients were dosed based on body weight and valproate
1395
use. Target doses were designed to approximate 5 mg/kg/day for patients taking valproate
1396
(maximum dose: 250 mg/day) and 15 mg/kg/day for the patients not taking valproate (maximum
1397
dose: 750 mg/day). The primary efficacy endpoint was percentage change from baseline in all
1398
partial seizures. For the intent-to-treat population, the median reduction of all partial seizures
1399
was 36% in patients treated with LAMICTAL and 7% on placebo, a difference that was
1400
statistically significant (p<0.01).
1401
Adjunctive Therapy With LAMICTAL in Pediatric and Adult Patients With
1402
Lennox-Gastaut Syndrome: The effectiveness of LAMICTAL as adjunctive therapy in
1403
patients with Lennox-Gastaut syndrome was established in a multicenter, double-blind,
1404
placebo-controlled trial in 169 patients 3 to 25 years of age (n = 79 on LAMICTAL, n = 90 on
1405
placebo). Following a 4-week single-blind, placebo phase, patients were randomized to 16 weeks
1406
of treatment with LAMICTAL or placebo added to their current AED regimen of up to 3 drugs.
1407
Patients were dosed on a fixed-dose regimen based on body weight and valproate use. Target
1408
doses were designed to approximate 5 mg/kg/day for patients taking valproate (maximum dose:
1409
200 mg/day) and 15 mg/kg/day for patients not taking valproate (maximum dose: 400 mg/day).
1410
The primary efficacy endpoint was percentage change from baseline in major motor seizures
1411
(atonic, tonic, major myoclonic, and tonic-clonic seizures). For the intent-to-treat population, the
1412
median reduction of major motor seizures was 32% in patients treated with LAMICTAL and 9%
1413
on placebo, a difference that was statistically significant (p<0.05). Drop attacks were
1414
significantly reduced by LAMICTAL (34%) compared with placebo (9%), as were tonic-clonic
1415
seizures (36% reduction versus 10% increase for LAMICTAL and placebo, respectively).
1416
Adjunctive Therapy With LAMICTAL in Pediatric and Adult Patients With Primary
1417
Generalized Tonic-Clonic Seizures: The effectiveness of LAMICTAL as adjunctive therapy
1418
in patients with primary generalized tonic-clonic seizures was established in a multicenter,
1419
double-blind, placebo-controlled trial in 117 pediatric and adult patients ≥2 years (n = 58 on
1420
LAMICTAL, n = 59 on placebo). Patients with at least 3 primary generalized tonic-clonic
1421
seizures during an 8-week baseline phase were randomized to 19 to 24 weeks of treatment with
1422
LAMICTAL or placebo added to their current AED regimen of up to 2 drugs. Patients were
1423
dosed on a fixed-dose regimen, with target doses ranging from 3 mg/kg/day to 12 mg/kg/day for
1424
pediatric patients and from 200 mg/day to 400 mg/day for adult patients based on concomitant
1425
AED.
1426
The primary efficacy endpoint was percentage change from baseline in primary
1427
generalized tonic-clonic seizures. For the intent-to-treat population, the median percent reduction
1428
of primary generalized tonic-clonic seizures was 66% in patients treated with LAMICTAL and
1429
34% on placebo, a difference that was statistically significant (p = 0.006).
1430
14.2 Bipolar Disorder
50
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-043 and S-044
NDA 020764/S-036 and S-037
NDA 022251/S-005 and S-006
FDA Approved Labeling Text dated 10/12/2010
Page 51
1431
The effectiveness of LAMICTAL in the maintenance treatment of Bipolar I Disorder was
1432
established in 2 multicenter, double-blind, placebo-controlled studies in adult patients who met
1433
DSM-IV criteria for Bipolar I Disorder. Study 1 enrolled patients with a current or recent (within
1434
60 days) depressive episode as defined by DSM-IV and Study 2 included patients with a current
1435
or recent (within 60 days) episode of mania or hypomania as defined by DSM-IV. Both studies
1436
included a cohort of patients (30% of 404 patients in Study 1 and 28% of 171 patients in Study
1437
2) with rapid cycling Bipolar Disorder (4 to 6 episodes per year).
1438
In both studies, patients were titrated to a target dose of 200 mg of LAMICTAL, as add
1439
on therapy or as monotherapy, with gradual withdrawal of any psychotropic medications during
1440
an 8- to 16-week open-label period. Overall 81% of 1,305 patients participating in the open-label
1441
period were receiving 1 or more other psychotropic medications, including benzodiazepines,
1442
selective serotonin reuptake inhibitors (SSRIs), atypical antipsychotics (including olanzapine),
1443
valproate, or lithium, during titration of LAMICTAL. Patients with a CGI-severity score of 3 or
1444
less maintained for at least 4 continuous weeks, including at least the final week on monotherapy
1445
with LAMICTAL, were randomized to a placebo-controlled, double-blind treatment period for
1446
up to 18 months. The primary endpoint was TIME (time to intervention for a mood episode or
1447
one that was emerging, time to discontinuation for either an adverse event that was judged to be
1448
related to Bipolar Disorder, or for lack of efficacy). The mood episode could be depression,
1449
mania, hypomania, or a mixed episode.
1450
In Study 1, patients received double-blind monotherapy with LAMICTAL 50 mg/day
1451
(n = 50), LAMICTAL 200 mg/day (n = 124), LAMICTAL 400 mg/day (n = 47), or placebo
1452
(n = 121). LAMICTAL (200- and 400-mg/day treatment groups combined) was superior to
1453
placebo in delaying the time to occurrence of a mood episode. Separate analyses of the 200- and
1454
400-mg/day dose groups revealed no added benefit from the higher dose.
1455
In Study 2, patients received double-blind monotherapy with LAMICTAL (100 to
1456
400 mg/day, n = 59), or placebo (n = 70). LAMICTAL was superior to placebo in delaying time
1457
to occurrence of a mood episode. The mean dose of LAMICTAL was about 211 mg/day.
1458
Although these studies were not designed to separately evaluate time to the occurrence of
1459
depression or mania, a combined analysis for the 2 studies revealed a statistically significant
1460
benefit for LAMICTAL over placebo in delaying the time to occurrence of both depression and
1461
mania, although the finding was more robust for depression.
1462
16
HOW SUPPLIED/STORAGE AND HANDLING
1463
LAMICTAL (lamotrigine) Tablets
1464
25 mg, white, scored, shield-shaped tablets debossed with “LAMICTAL” and “25”,
1465
bottles of 100 (NDC 0173-0633-02).
1466
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled
1467
Room Temperature] in a dry place.
1468
100 mg, peach, scored, shield-shaped tablets debossed with “LAMICTAL” and “100”,
1469
bottles of 100 (NDC 0173-0642-55).
51
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-043 and S-044
NDA 020764/S-036 and S-037
NDA 022251/S-005 and S-006
FDA Approved Labeling Text dated 10/12/2010
Page 52
1470
150 mg, cream, scored, shield-shaped tablets debossed with “LAMICTAL” and “150”,
1471
bottles of 60 (NDC 0173-0643-60).
1472
200 mg, blue, scored, shield-shaped tablets debossed with “LAMICTAL” and “200”,
1473
bottles of 60 (NDC 0173-0644-60).
1474
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled
1475
Room Temperature] in a dry place and protect from light.
1476
1477
LAMICTAL (lamotrigine) Starter Kit for Patients Taking Valproate (Blue Kit)
1478
25 mg, white, scored, shield-shaped tablets debossed with “LAMICTAL” and “25”,
1479
blisterpack of 35 tablets (NDC 0173-0633-10).
1480
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled
1481
Room Temperature] in a dry place.
1482
LAMICTAL (lamotrigine) Starter Kit for Patients Taking Carbamazepine,
1483
Phenytoin, Phenobarbital, or Primidone and Not Taking Valproate (Green Kit)
1484
25 mg, white, scored, shield-shaped tablets debossed with “LAMICTAL” and “25” and
1485
100 mg, peach, scored, shield-shaped tablets debossed with “LAMICTAL” and “100”,
1486
blisterpack of 98 tablets (84/25-mg tablets and 14/100-mg tablets) (NDC 0173-0817-28).
1487
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled
1488
Room Temperature] in a dry place and protect from light.
1489
LAMICTAL (lamotrigine) Starter Kit for Patients Not Taking Carbamazepine,
1490
Phenytoin, Phenobarbital, Primidone, or Valproate (Orange Kit)
1491
25 mg, white, scored, shield-shaped tablets debossed with “LAMICTAL” and “25” and
1492
100 mg, peach, scored, shield-shaped tablets debossed with “LAMICTAL” and “100”,
1493
blisterpack of 49 tablets (42/25-mg tablets and 7/100-mg tablets) (NDC 0173-0594-02).
1494
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled
1495
Room Temperature] in a dry place and protect from light.
1496
1497
LAMICTAL (lamotrigine) Chewable Dispersible Tablets
1498
2 mg, white to off-white, round tablets debossed with “LTG” over “2”, bottles of 30
1499
(NDC 0173-0699-00). ORDER DIRECTLY FROM GlaxoSmithKline 1-800-334-4153.
1500
5 mg, white to off-white, caplet-shaped tablets debossed with “GX CL2”, bottles of 100
1501
(NDC 0173-0526-00).
1502
25 mg, white, super elliptical-shaped tablets debossed with “GX CL5”, bottles of 100
1503
(NDC 0173-0527-00).
1504
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled
1505
Room Temperature] in a dry place.
1506
1507
LAMICTAL ODT (lamotrigine) Orally Disintegrating Tablets
52
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-043 and S-044
NDA 020764/S-036 and S-037
NDA 022251/S-005 and S-006
FDA Approved Labeling Text dated 10/12/2010
Page 53
1508
25 mg, white to off-white, round, flat-faced, radius edge, tablets debossed with “LMT”
1509
on one side and “25” on the other, Maintenance Packs of 30 (NDC 0173-0772-02).
1510
50 mg, white to off-white, round, flat-faced, radius edge, tablets debossed with “LMT”
1511
on one side and “50” on the other, Maintenance Packs of 30 (NDC 0173-0774-02).
1512
100 mg, white to off-white, round, flat-faced, radius edge, tablets debossed with
1513
“LAMICTAL” on one side and “100” on the other, Maintenance Packs of 30 (NDC 0173-0776
1514
02).
1515
200 mg, white to off-white, round, flat-faced, radius edge, tablets debossed with
1516
“LAMICTAL” on one side and “200” on the other, Maintenance Packs of 30 (NDC 0173-0777
1517
02).
1518
Store between 20°C to 25°C (68°F to 77°F); with excursions permitted between 15°C and
1519
30°C (59°F and 86°F).
1520
LAMICTAL ODT (lamotrigine) Patient Titration Kit for Patients Taking Valproate
1521
(Blue ODT Kit)
1522
25 mg, white to off-white, round, flat-faced, radius edge, tablets debossed with “LMT”
1523
on one side and “25” on the other, and 50 mg, white to off-white, round, flat-faced, radius edge,
1524
tablets debossed with “LMT” on one side and “50” on the other, blisterpack of 28 tablets
1525
(21/25-mg tablets and 7/50-mg tablets) (NDC 0173-0779-00).
1526
LAMICTAL ODT (lamotrigine) Patient Titration Kit for Patients Taking
1527
Carbamazepine, Phenytoin, Phenobarbital, or Primidone and Not Taking Valproate
1528
(Green ODT Kit)
1529
50 mg, white to off-white, round, flat-faced, radius edge, tablets debossed with “LMT”
1530
on one side and “50” on the other, and 100 mg, white to off-white, round, flat-faced, radius edge,
1531
tablets debossed with “LAMICTAL” on one side and “100” on the other, blisterpack of 56
1532
tablets (42/50-mg tablets and 14/100-mg tablets) (NDC 0173-0780-00).
1533
LAMICTAL ODT (lamotrigine) Patient Titration Kit for Patients Not Taking
1534
Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate (Orange ODT Kit)
1535
25 mg, white to off-white, round, flat-faced, radius edge, tablets debossed with “LMT”
1536
on one side and “25” on the other, 50 mg, white to off-white, round, flat-faced, radius edge,
1537
tablets debossed with “LMT” on one side and “50” on the other, and 100 mg, white to off-white,
1538
round, flat-faced, radius edge, tablets debossed with “LAMICTAL” on one side and “100” on the
1539
other, blisterpack of 35 (14/25-mg tablets, 14/50-mg tablets, and 7/100-mg tablets) (NDC 0173
1540
0778-00).
1541
Store between 20°C to 25°C (68°F to 77°F); with excursions permitted between 15°C and
1542
30°C (59°F and 86°F).
1543
Blisterpacks: If the product is dispensed in a blisterpack, the patient should be advised to
1544
examine the blisterpack before use and not use if blisters are torn, broken, or missing.
1545
17
PATIENT COUNSELING INFORMATION
1546
See Medication Guide that accompanies the product.
53
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-043 and S-044
NDA 020764/S-036 and S-037
NDA 022251/S-005 and S-006
FDA Approved Labeling Text dated 10/12/2010
Page 54
1547
17.1 Rash
1548
Prior to initiation of treatment with LAMICTAL, the patient should be instructed that a
1549
rash or other signs or symptoms of hypersensitivity (e.g., fever, lymphadenopathy) may herald a
1550
serious medical event and that the patient should report any such occurrence to a physician
1551
immediately.
1552
17.2 Suicidal Thinking and Behavior
1553
Patients, their caregivers, and families should be counseled that AEDs, including
1554
LAMICTAL, may increase the risk of suicidal thoughts and behavior and should be advised of
1555
the need to be alert for the emergence or worsening of symptoms of depression, any unusual
1556
changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about
1557
self-harm. Behaviors of concern should be reported immediately to healthcare providers.
1558
17.3 Worsening of Seizures
1559
Patients should be advised to notify their physician if worsening of seizure control
1560
occurs.
1561
17.4 CNS Adverse Effects
1562
Patients should be advised that LAMICTAL may cause dizziness, somnolence, and other
1563
symptoms and signs of central nervous system (CNS) depression. Accordingly, they should be
1564
advised neither to drive a car nor to operate other complex machinery until they have gained
1565
sufficient experience on LAMICTAL to gauge whether or not it adversely affects their mental
1566
and/or motor performance.
1567
17.5 Blood Dyscrasias and/or Acute Multiorgan Failure
1568
Patients should be advised of the possibility of blood dyscrasias and/or acute multiorgan
1569
failure and to contact their physician immediately if they experience any signs or symptoms of
1570
these conditions [see Warnings and Precautions (5.3, 5.4)].
1571
17.6 Pregnancy
1572
Patients should be advised to notify their physicians if they become pregnant or intend to
1573
become pregnant during therapy. Patients should be advised to notify their physicians if they
1574
intend to breastfeed or are breastfeeding an infant.
1575
Patients should also be encouraged to enroll in the NAAED Pregnancy Registry if they
1576
become pregnant. This registry is collecting information about the safety of antiepileptic drugs
1577
during pregnancy. To enroll, patients can call the toll-free number 1-888-233-2334 [see Use in
1578
Specific Populations (8.1)].
1579
17.7 Oral Contraceptive Use
1580
Women should be advised to notify their physician if they plan to start or stop use of oral
1581
contraceptives or other female hormonal preparations. Starting estrogen-containing oral
1582
contraceptives may significantly decrease lamotrigine plasma levels and stopping estrogen
1583
containing oral contraceptives (including the “pill-free” week) may significantly increase
1584
lamotrigine plasma levels [see Warnings and Precautions (5.9), Clinical Pharmacology (12.3)].
1585
Women should also be advised to promptly notify their physician if they experience adverse
54
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-043 and S-044
NDA 020764/S-036 and S-037
NDA 022251/S-005 and S-006
FDA Approved Labeling Text dated 10/12/2010
Page 55
1586
reactions or changes in menstrual pattern (e.g., break-through bleeding) while receiving
1587
LAMICTAL in combination with these medications.
1588
17.8 Discontinuing LAMICTAL
1589
Patients should be advised to notify their physician if they stop taking LAMICTAL for
1590
any reason and not to resume LAMICTAL without consulting their physician.
1591
17.9 Aseptic Meningitis
1592
Patients should be advised that LAMICTAL may cause aseptic meningitis. Patients
1593
should be advised to notify their physician immediately if they develop signs and symptoms of
1594
meningitis such as headache, fever, nausea, vomiting, stiff neck, rash, abnormal sensitivity to
1595
light, myalgia, chills, confusion, or drowsiness while taking LAMICTAL.
1596
17.10 Potential Medication Errors
1597
Medication errors involving LAMICTAL have occurred. In particular the names
1598
LAMICTAL or lamotrigine can be confused with the names of other commonly used
1599
medications. Medication errors may also occur between the different formulations of
1600
LAMICTAL. To reduce the potential of medication errors, write and say LAMICTAL clearly.
1601
Depictions of the LAMICTAL Tablets, Chewable Dispersible Tablets, and Orally Disintegrating
1602
Tablets can be found in the Medication Guide that accompanies the product to highlight the
1603
distinctive markings, colors, and shapes that serve to identify the different presentations of the
1604
drug and thus may help reduce the risk of medication errors. To avoid a medication error of
1605
using the wrong drug or formulation, patients should be strongly advised to visually
1606
inspect their tablets to verify that they are LAMICTAL, as well as the correct formulation
1607
of LAMICTAL, each time they fill their prescription [see Dosage Forms and Strengths (3.1,
1608
3.2, 3.3), How Supplied/Storage and Handling (16)].
1609
compa
ny logo
1612
GlaxoSmithKline
1613
Research Triangle Park, NC 27709
1614
1615
LAMICTAL Tablets and Chewable Dispersible Tablets are manufactured by
1616
DSM Pharmaceuticals, Inc., Greenville, NC 27834 or
1617
GlaxoSmithKline, Research Triangle Park, NC 27709
1618
LAMICTAL Orally Disintegrating Tablets are manufactured by
1619
Eurand, Inc., Vandalia, OH 45377
1620
1621
LAMICTAL is a registered trademark of GlaxoSmithKline.
1622
1623
Microcaps and AdvaTab are registered trademarks of Eurand, Inc.
55
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-043 and S-044
NDA 020764/S-036 and S-037
NDA 022251/S-005 and S-006
FDA Approved Labeling Text dated 10/12/2010
Page 56
1624
1625
©2010, GlaxoSmithKline. All rights reserved.
1626
LMT:xPI
1627
56
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:47:12.271228
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020241s043s044,020764s036s037,022251s005s006lbl.pdf', 'application_number': 20241, 'submission_type': 'SUPPL ', 'submission_number': 43}
|
12,362
|
NDA 020241/S-035 & S-040
NDA 020764/S-028 & S-033
NDA 022251/S-009 & S-002
FDA Approved Labeling Text dated 12/23/2014
Page 1
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
LAMICTAL safely and effectively. See full prescribing information for
LAMICTAL.
LAMICTAL (lamotrigine) Tablets
LAMICTAL (lamotrigine) Chewable Dispersible Tablets
LAMICTAL ODT (lamotrigine) Orally Disintegrating Tablets
Initial U.S. Approval: 1994
WARNING: SERIOUS SKIN RASHES
See full prescribing information for complete boxed warning.
• Cases of life-threatening serious rashes, including Stevens-Johnson
syndrome and toxic epidermal necrolysis, and/or rash-related death
have been caused by lamotrigine. The rate of serious rash is greater
in pediatric patients than in adults. Additional factors that may
increase the risk of rash include:
• coadministration with valproate.
• exceeding recommended initial dose of LAMICTAL.
• exceeding recommended dose escalation for LAMICTAL. (5.1)
• Benign rashes are also caused by lamotrigine; however, it is not
possible to predict which rashes will prove to be serious or life
threatening. LAMICTAL should be discontinued at the first sign of
rash, unless the rash is clearly not drug related. (5.1)
---------------------------RECENT MAJOR CHANGES --------------------------
Dosage and Administration (2.1, 2.2, 2.4)
12/2014
----------------------------INDICATIONS AND USAGE ---------------------------
LAMICTAL is an antiepileptic drug (AED) indicated for:
Epilepsy—adjunctive therapy in patients aged 2 years and older:
• partial-onset seizures.
• primary generalized tonic-clonic seizures.
•
generalized seizures of Lennox-Gastaut syndrome. (1.1)
Epilepsy—monotherapy in patients aged 16 years and older: Conversion
to monotherapy in patients with partial-onset seizures who are receiving
treatment with carbamazepine, phenytoin, phenobarbital, primidone, or
valproate as the single AED. (1.1)
Bipolar disorder in patients aged 18 years and older: Maintenance
treatment of bipolar I disorder to delay the time to occurrence of mood
episodes in patients treated for acute mood episodes with standard therapy.
(1.2)
----------------------- DOSAGE AND ADMINISTRATION ----------------------
• Dosing is based on concomitant medications, indication, and patient age.
(2.1, 2.2, 2.3, 2.4)
• To avoid an increased risk of rash, the recommended initial dose and
subsequent dose escalations should not be exceeded. LAMICTAL Starter
Kits and LAMICTAL ODT Patient Titration Kits are available for the
first 5 weeks of treatment. (2.1, 16)
• Do not restart LAMICTAL in patients who discontinued due to rash
unless the potential benefits clearly outweigh the risks. (2.1, 5.1)
• Adjustments to maintenance doses will be necessary in most patients
starting or stopping estrogen-containing oral contraceptives. (2.1, 5.8)
• Discontinuation: Taper over a period of at least 2 weeks (approximately
50% dose reduction per week). (2.1, 5.9)
Epilepsy:
• Adjunctive therapy—See Table 1 for patients older than 12 years and
Tables 2 and 3 for patients aged 2 to 12 years. (2.2)
•
Conversion to monotherapy—See Table 4. (2.3)
Bipolar disorder: See Tables 5 and 6. (2.4)
--------------------- DOSAGE FORMS AND STRENGTHS --------------------
Tablets: 25 mg, 100 mg, 150 mg, and 200 mg; scored. (3.1, 16)
Chewable Dispersible Tablets: 2 mg, 5 mg, and 25 mg. (3.2, 16)
Orally Disintegrating Tablets: 25 mg, 50 mg, 100 mg, and 200 mg. (3.3, 16)
-------------------------------CONTRAINDICATIONS ------------------------------
Hypersensitivity to the drug or its ingredients. (Boxed Warning, 4)
----------------------- WARNINGS AND PRECAUTIONS ----------------------
• Life-threatening serious rash and/or rash-related death: Discontinue at the
first sign of rash, unless the rash is clearly not drug related. (Boxed
Warning, 5.1)
• Fatal or life-threatening hypersensitivity reaction: Multiorgan
hypersensitivity reactions, also known as drug reaction with eosinophilia
and systemic symptoms (DRESS), may be fatal or life threatening. Early
signs may include rash, fever, and lymphadenopathy. These reactions may
be associated with other organ involvement, such as hepatitis, hepatic
failure, blood dyscrasias, or acute multiorgan failure. LAMICTAL should
be discontinued if alternate etiology for this reaction is not found. (5.2)
• Blood dyscrasias (e.g., neutropenia, thrombocytopenia, pancytopenia):
May occur, either with or without an associated hypersensitivity
syndrome. Monitor for signs of anemia, unexpected infection, or bleeding.
(5.3)
• Suicidal behavior and ideation: Monitor for suicidal thoughts or
behaviors. (5.4)
• Clinical worsening, emergence of new symptoms, and suicidal
ideation/behaviors may be associated with treatment of bipolar disorder.
Patients should be closely monitored, particularly early in treatment or
during dosage changes. (5.5)
• Aseptic meningitis: Monitor for signs of meningitis. (5.6)
• Medication errors due to product name confusion: Strongly advise
patients to visually inspect tablets to verify the received drug is correct.
(3.4, 5.7, 16, 17)
------------------------------ ADVERSE REACTIONS -----------------------------
• Most common adverse reactions (incidence ≥10%) in adult epilepsy
clinical trials were dizziness, headache, diplopia, ataxia, nausea, blurred
vision, somnolence, rhinitis, pharyngitis, and rash. Additional adverse
reactions (incidence ≥10%) reported in children in epilepsy clinical trials
included vomiting, diarrhea, infection, fever, accidental injury, abdominal
pain, and tremor. (6.1)
• Most common adverse reactions (incidence >5%) in adult bipolar clinical
trials were nausea, insomnia, somnolence, back pain, fatigue, rash,
rhinitis, abdominal pain, and xerostomia. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact
GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
-------------------------------DRUG INTERACTIONS ------------------------------
• Valproate increases lamotrigine concentrations more than 2-fold. (7, 12.3)
• Carbamazepine, phenytoin, phenobarbital, primidone, and rifampin
decrease lamotrigine concentrations by approximately 40%. (7, 12.3)
• Estrogen-containing oral contraceptives decrease lamotrigine
concentrations by approximately 50%. (7, 12.3)
• Protease inhibitors lopinavir/ritonavir and atazanavir/lopinavir decrease
lamotrigine exposure by approximately 50% and 32%, respectively. (7,
12.3)
----------------------- USE IN SPECIFIC POPULATIONS ----------------------
• Pregnancy: Based on animal data may cause fetal harm. (8.1)
• Efficacy of LAMICTAL, used as adjunctive treatment for partial-onset
seizures, was not demonstrated in a small, randomized, double-blind,
placebo-controlled trial in very young pediatric patients (1 to 24 months).
(8.4)
• Hepatic impairment: Dosage adjustments required in patients with
moderate and severe liver impairment. (2.1, 8.6)
• Renal impairment: Reduced maintenance doses may be effective for
patients with significant renal impairment. (2.1, 8.7)
See 17 for PATIENT COUNSELING INFORMATION and Medication
Guide.
Revised: 12/2014
1
Reference ID: 3677876
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-035 & S-040
NDA 020764/S-028 & S-033
NDA 022251/S-009 & S-002
FDA Approved Labeling Text dated 12/23/2014
Page 2
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: SERIOUS SKIN RASHES
1
INDICATIONS AND USAGE
1.1
Epilepsy
1.2
Bipolar Disorder
2
DOSAGE AND ADMINISTRATION
2.1
General Dosing Considerations
2.2
Epilepsy—Adjunctive Therapy
2.3
Epilepsy—Conversion From Adjunctive
Therapy to Monotherapy
2.4
Bipolar Disorder
2.5
Administration of LAMICTAL Chewable
Dispersible Tablets
2.6
Administration of LAMICTAL ODT Orally
Disintegrating Tablets
3
DOSAGE FORMS AND STRENGTHS
3.1
Tablets
3.2
Chewable Dispersible Tablets
3.3
Orally Disintegrating Tablets
3.4
Potential Medication Errors
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1
Serious Skin Rashes [see Boxed Warning]
5.2
Multiorgan Hypersensitivity Reactions and
Organ Failure
5.3
Blood Dyscrasias
5.4
Suicidal Behavior and Ideation
5.5
Use in Patients With Bipolar Disorder
5.6
Aseptic Meningitis
5.7
Potential Medication Errors
5.8
Concomitant Use With Oral Contraceptives
5.9
Withdrawal Seizures
5.10
Status Epilepticus
5.11
Sudden Unexplained Death in Epilepsy
(SUDEP)
5.12
Addition of LAMICTAL to a Multidrug Regimen
That Includes Valproate
5.13
Binding in the Eye and Other Melanin-
Containing Tissues
5.14
Laboratory Tests
6
ADVERSE REACTIONS
6.1
Clinical Trial Experience
6.2
Other Adverse Reactions Observed in All
Clinical Trials
6.3
Postmarketing Experience
7
DRUG INTERACTIONS
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
8.2
Labor and Delivery
8.3
Nursing Mothers
8.4
Pediatric Use
8.5
Geriatric Use
8.6
Patients With Hepatic Impairment
8.7
Patients With Renal Impairment
10
OVERDOSAGE
10.1
Human Overdose Experience
10.2
Management of Overdose
11
DESCRIPTION
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
12.2
Pharmacodynamics
12.3
Pharmacokinetics
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of
Fertility
14
CLINICAL STUDIES
14.1
Epilepsy
14.2
Bipolar Disorder
16
HOW SUPPLIED/STORAGE AND HANDLING
17
PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information are not
listed.
______________________________________________________________________
1
FULL PRESCRIBING INFORMATION
2
WARNING: SERIOUS SKIN RASHES
3
LAMICTAL® can cause serious rashes requiring hospitalization and
4
discontinuation of treatment. The incidence of these rashes, which have included Stevens
5
Johnson syndrome, is approximately 0.8% (8 per 1,000) in pediatric patients (aged 2 to 16
6
years) receiving LAMICTAL as adjunctive therapy for epilepsy and 0.3% (3 per 1,000) in
7
adults on adjunctive therapy for epilepsy. In clinical trials of bipolar and other mood
8
disorders, the rate of serious rash was 0.08% (0.8 per 1,000) in adult patients receiving
9
LAMICTAL as initial monotherapy and 0.13% (1.3 per 1,000) in adult patients receiving
10
LAMICTAL as adjunctive therapy. In a prospectively followed cohort of 1,983 pediatric
11
patients (aged 2 to 16 years) with epilepsy taking adjunctive LAMICTAL, there was 1
12
rash-related death. In worldwide postmarketing experience, rare cases of toxic epidermal
13
necrolysis and/or rash-related death have been reported in adult and pediatric patients, but
14
their numbers are too few to permit a precise estimate of the rate.
2
Reference ID: 3677876
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-035 & S-040
NDA 020764/S-028 & S-033
NDA 022251/S-009 & S-002
FDA Approved Labeling Text dated 12/23/2014
Page 3
15
Other than age, there are as yet no factors identified that are known to predict the
16
risk of occurrence or the severity of rash caused by LAMICTAL. There are suggestions,
17
yet to be proven, that the risk of rash may also be increased by (1) coadministration of
18
LAMICTAL with valproate (includes valproic acid and divalproex sodium), (2) exceeding
19
the recommended initial dose of LAMICTAL, or (3) exceeding the recommended dose
20
escalation for LAMICTAL. However, cases have occurred in the absence of these factors.
21
Nearly all cases of life-threatening rashes caused by LAMICTAL have occurred
22
within 2 to 8 weeks of treatment initiation. However, isolated cases have occurred after
23
prolonged treatment (e.g., 6 months). Accordingly, duration of therapy cannot be relied
24
upon as means to predict the potential risk heralded by the first appearance of a rash.
25
Although benign rashes are also caused by LAMICTAL, it is not possible to predict
26
reliably which rashes will prove to be serious or life threatening. Accordingly, LAMICTAL
27
should ordinarily be discontinued at the first sign of rash, unless the rash is clearly not
28
drug related. Discontinuation of treatment may not prevent a rash from becoming life
29
threatening or permanently disabling or disfiguring [se Warnings and Precautions (5.1)].
30
1
INDICATIONS AND USAGE
31
1.1
Epilepsy
32
Adjunctive Therapy: LAMICTAL is indicated as adjunctive therapy for the following
33
seizure types in patients aged 2 years and older:
34
• partial-onset seizures.
35
• primary generalized tonic-clonic (PGTC) seizures.
36
• generalized seizures of Lennox-Gastaut syndrome.
37
Monotherapy: LAMICTAL is indicated for conversion to monotherapy in adults (aged
38
16 years and older) with partial-onset seizures who are receiving treatment with carbamazepine,
39
phenytoin, phenobarbital, primidone, or valproate as the single antiepileptic drug (AED).
40
Safety and effectiveness of LAMICTAL have not been established (1) as initial
41
monotherapy; (2) for conversion to monotherapy from AEDs other than carbamazepine,
42
phenytoin, phenobarbital, primidone, or valproate; or (3) for simultaneous conversion to
43
monotherapy from 2 or more concomitant AEDs.
44
1.2
Bipolar Disorder
45
LAMICTAL is indicated for the maintenance treatment of bipolar I disorder to delay the
46
time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in adults
47
(aged 18 years and older) treated for acute mood episodes with standard therapy. The
48
effectiveness of LAMICTAL in the acute treatment of mood episodes has not been established.
49
The effectiveness of LAMICTAL as maintenance treatment was established in 2 placebo
50
controlled trials in patients with bipolar I disorder as defined by DSM-IV [see Clinical Studies
51
(14.2)]. The physician who elects to prescribe LAMICTAL for periods extending beyond 16
52
weeks should periodically re-evaluate the long-term usefulness of the drug for the individual
53
patient.
3
Reference ID: 3677876
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
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79
80
81
82
83
84
85
86
87
88
89
90
91
92
NDA 020241/S-035 & S-040
NDA 020764/S-028 & S-033
NDA 022251/S-009 & S-002
FDA Approved Labeling Text dated 12/23/2014
Page 4
2
DOSAGE AND ADMINISTRATION
2.1
General Dosing Considerations
Rash: There are suggestions, yet to be proven, that the risk of severe, potentially life-
threatening rash may be increased by (1) coadministration of LAMICTAL with valproate, (2)
exceeding the recommended initial dose of LAMICTAL, or (3) exceeding the recommended
dose escalation for LAMICTAL. However, cases have occurred in the absence of these factors
[see Boxed Warning]. Therefore, it is important that the dosing recommendations be followed
closely.
The risk of nonserious rash may be increased when the recommended initial dose and/or
the rate of dose escalation for LAMICTAL is exceeded and in patients with a history of allergy
or rash to other AEDs.
LAMICTAL Starter Kits and LAMICTAL ODT® Patient Titration Kits provide
LAMICTAL at doses consistent with the recommended titration schedule for the first 5 weeks of
treatment, based upon concomitant medications, for patients with epilepsy (older than 12 years)
and bipolar I disorder (aged 18 years and older) and are intended to help reduce the potential for
rash. The use of LAMICTAL Starter Kits and LAMICTAL ODT Patient Titration Kits is
recommended for appropriate patients who are starting or restarting LAMICTAL [see How
Supplied/Storage and Handling (16)].
It is recommended that LAMICTAL not be restarted in patients who discontinued due to
rash associated with prior treatment with lamotrigine unless the potential benefits clearly
outweigh the risks. If the decision is made to restart a patient who has discontinued LAMICTAL,
the need to restart with the initial dosing recommendations should be assessed. The greater the
interval of time since the previous dose, the greater consideration should be given to restarting
with the initial dosing recommendations. If a patient has discontinued lamotrigine for a period of
more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be
followed. The half-life of lamotrigine is affected by other concomitant medications [see Clinical
Pharmacology (12.3)].
LAMICTAL Added to Drugs Known to Induce or Inhibit Glucuronidation: Because
lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known
to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine. Drugs that
induce glucuronidation include carbamazepine, phenytoin, phenobarbital, primidone, rifampin,
estrogen-containing oral contraceptives, and the protease inhibitors lopinavir/ritonavir and
atazanavir/ritonavir. Valproate inhibits glucuronidation. For dosing considerations for
LAMICTAL in patients on estrogen-containing contraceptives and atazanavir/ritonavir, see
below and Table 13. For dosing considerations for LAMICTAL in patients on other drugs known
to induce or inhibit glucuronidation, see Table 1, Table 2, Table 5, Table 6, and Table 13.
Target Plasma Levels for Patients With Epilepsy or Bipolar Disorder: A therapeutic
plasma concentration range has not been established for lamotrigine. Dosing of LAMICTAL
should be based on therapeutic response [see Clinical Pharmacology (12.3)].
4
Reference ID: 3677876
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-035 & S-040
NDA 020764/S-028 & S-033
NDA 022251/S-009 & S-002
FDA Approved Labeling Text dated 12/23/2014
Page 5
93
Women Taking Estrogen-Containing Oral Contraceptives: Starting LAMICTAL in
94
Women Taking Estrogen-Containing Oral Contraceptives: Although estrogen-containing
95
oral contraceptives have been shown to increase the clearance of lamotrigine [see Clinical
96
Pharmacology (12.3)], no adjustments to the recommended dose-escalation guidelines for
97
LAMICTAL should be necessary solely based on the use of estrogen-containing oral
98
contraceptives. Therefore, dose escalation should follow the recommended guidelines for
99
initiating adjunctive therapy with LAMICTAL based on the concomitant AED or other
100
concomitant medications (see Table 1 or Table 5). See below for adjustments to maintenance
101
doses of LAMICTAL in women taking estrogen-containing oral contraceptives.
102
Adjustments to the Maintenance Dose of LAMICTAL in Women Taking
103
Estrogen-Containing Oral Contraceptives:
104
(1) Taking Estrogen-Containing Oral Contraceptives: In women not taking
105
carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the
106
protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine
107
glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance
108
dose of LAMICTAL will in most cases need to be increased by as much as 2-fold over the
109
recommended target maintenance dose to maintain a consistent lamotrigine plasma level.
110
(2) Starting Estrogen-Containing Oral Contraceptives: In women taking a
111
stable dose of LAMICTAL and not taking carbamazepine, phenytoin, phenobarbital, primidone,
112
or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and
113
atazanavir/ritonavir that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical
114
Pharmacology (12.3)], the maintenance dose will in most cases need to be increased by as much
115
as 2-fold to maintain a consistent lamotrigine plasma level. The dose increases should begin at
116
the same time that the oral contraceptive is introduced and continue, based on clinical response,
117
no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the
118
recommended rate (see Table 1 or Table 5) unless lamotrigine plasma levels or clinical response
119
support larger increases. Gradual transient increases in lamotrigine plasma levels may occur
120
during the week of inactive hormonal preparation (pill-free week), and these increases will be
121
greater if dose increases are made in the days before or during the week of inactive hormonal
122
preparation. Increased lamotrigine plasma levels could result in additional adverse reactions,
123
such as dizziness, ataxia, and diplopia. If adverse reactions attributable to LAMICTAL
124
consistently occur during the pill-free week, dose adjustments to the overall maintenance dose
125
may be necessary. Dose adjustments limited to the pill-free week are not recommended. For
126
women taking LAMICTAL in addition to carbamazepine, phenytoin, phenobarbital, primidone,
127
or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and
128
atazanavir/ritonavir that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical
129
Pharmacology (12.3)], no adjustment to the dose of LAMICTAL should be necessary.
130
(3) Stopping Estrogen-Containing Oral Contraceptives: In women not taking
131
carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the
5
Reference ID: 3677876
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
132
133
134
135
136
137
138
139
140
141
142
143
144
145
146
147
148
149
150
151
152
153
154
155
156
157
158
159
160
161
162
163
164
165
166
167
168
169
170
NDA 020241/S-035 & S-040
NDA 020764/S-028 & S-033
NDA 022251/S-009 & S-002
FDA Approved Labeling Text dated 12/23/2014
Page 6
protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine
glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance
dose of LAMICTAL will in most cases need to be decreased by as much as 50% in order to
maintain a consistent lamotrigine plasma level. The decrease in dose of LAMICTAL should not
exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or
lamotrigine plasma levels indicate otherwise [see Clinical Pharmacology (12.3)]. In women
taking LAMICTAL in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other
drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir
that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology
(12.3)], no adjustment to the dose of LAMICTAL should be necessary.
Women and Other Hormonal Contraceptive Preparations or Hormone
Replacement Therapy: The effect of other hormonal contraceptive preparations or hormone
replacement therapy on the pharmacokinetics of lamotrigine has not been systematically
evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of
lamotrigine up to 2-fold, and the progestin-only pills had no effect on lamotrigine plasma levels.
Therefore, adjustments to the dosage of LAMICTAL in the presence of progestogens alone will
likely not be needed.
Patients Taking Atazanavir/Ritonavir: While atazanavir/ritonavir does reduce the
lamotrigine plasma concentration, no adjustments to the recommended dose-escalation
guidelines for LAMICTAL should be necessary solely based on the use of atazanavir/ritonavir.
Dose escalation should follow the recommended guidelines for initiating adjunctive therapy with
LAMICTAL based on concomitant AED or other concomitant medications (see Tables 1, 2, and
5). In patients already taking maintenance doses of LAMICTAL and not taking glucuronidation
inducers, the dose of LAMICTAL may need to be increased if atazanavir/ritonavir is added, or
decreased if atazanavir/ritonavir is discontinued [see Clinical Pharmacology (12.3)].
Patients With Hepatic Impairment: Experience in patients with hepatic impairment is
limited. Based on a clinical pharmacology study in 24 subjects with mild, moderate, and severe
liver impairment [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)], the
following general recommendations can be made. No dosage adjustment is needed in patients
with mild liver impairment. Initial, escalation, and maintenance doses should generally be
reduced by approximately 25% in patients with moderate and severe liver impairment without
ascites and 50% in patients with severe liver impairment with ascites. Escalation and
maintenance doses may be adjusted according to clinical response.
Patients With Renal Impairment: Initial doses of LAMICTAL should be based on
patients’ concomitant medications (see Tables 1-3 or Table 5); reduced maintenance doses may
be effective for patients with significant renal impairment [see Use in Specific Populations (8.7),
Clinical Pharmacology (12.3)]. Few patients with severe renal impairment have been evaluated
during chronic treatment with LAMICTAL. Because there is inadequate experience in this
population, LAMICTAL should be used with caution in these patients.
6
Reference ID: 3677876
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-035 & S-040
NDA 020764/S-028 & S-033
NDA 022251/S-009 & S-002
FDA Approved Labeling Text dated 12/23/2014
Page 7
171
Discontinuation Strategy: Epilepsy: For patients receiving LAMICTAL in
172
combination with other AEDs, a re-evaluation of all AEDs in the regimen should be considered
173
if a change in seizure control or an appearance or worsening of adverse reactions is observed.
174
If a decision is made to discontinue therapy with LAMICTAL, a step-wise reduction of
175
dose over at least 2 weeks (approximately 50% per week) is recommended unless safety
176
concerns require a more rapid withdrawal [see Warnings and Precautions (5.9)].
177
Discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such
178
as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce
179
lamotrigine glucuronidation should prolong the half-life of lamotrigine; discontinuing valproate
180
should shorten the half-life of lamotrigine.
181
Bipolar Disorder: In the controlled clinical trials, there was no increase in the
182
incidence, type, or severity of adverse reactions following abrupt termination of LAMICTAL. In
183
clinical trials in patients with bipolar disorder, 2 patients experienced seizures shortly after
184
abrupt withdrawal of LAMICTAL. However, there were confounding factors that may have
185
contributed to the occurrence of seizures in these patients with bipolar disorder. Discontinuation
186
of LAMICTAL should involve a step-wise reduction of dose over at least 2 weeks
187
(approximately 50% per week) unless safety concerns require a more rapid withdrawal [see
188
Warnings and Precautions (5.9)].
189
2.2
Epilepsy—Adjunctive Therapy
190
This section provides specific dosing recommendations for patients older than 12 years
191
and patients aged 2 to 12 years. Within each of these age-groups, specific dosing
192
recommendations are provided depending upon concomitant AEDs or other concomitant
193
medications (see Table 1 for patients older than 12 years and Table 2 for patients aged 2 to
194
12 years). A weight-based dosing guide for patients aged 2 to 12 years on concomitant valproate
195
is provided in Table 3.
196
Patients Older Than 12 Years: Recommended dosing guidelines are summarized in
197
Table 1.
198
7
Reference ID: 3677876
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-035 & S-040
NDA 020764/S-028 & S-033
NDA 022251/S-009 & S-002
FDA Approved Labeling Text dated 12/23/2014
Page 8
199
Table 1. Escalation Regimen for LAMICTAL in Patients Older Than 12 Years With
200
Epilepsy
In Patients
TAKING Valproatea
In Patients
NOT TAKING
Carbamazepine,
Phenytoin,
Phenobarbital,
Primidone,b or
Valproatea
In Patients TAKING
Carbamazepine,
Phenytoin,
Phenobarbital, or
Primidoneb and NOT
TAKING Valproatea
Weeks 1 and 2
25 mg every other day
25 mg every day
50 mg/day
Weeks 3 and 4
25 mg every day
50 mg/day
100 mg/day
(in 2 divided doses)
Week 5 onward
to maintenance
Increase by
25 to 50 mg/day
every 1 to 2 weeks.
Increase by
50 mg/day
every 1 to 2 weeks.
Increase by
100 mg/day
every 1 to 2 weeks.
Usual
maintenance dose
100 to 200 mg/day
with valproate alone
100 to 400 mg/day
with valproate and
other drugs that
induce glucuronidation
(in 1 or 2 divided doses)
225 to 375 mg/day
(in 2 divided doses)
300 to 500 mg/day
(in 2 divided doses)
201
202
203
204
205
206
207
208
209
210
211
212
213
214
215
216
a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of
lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].
b Drugs that induce lamotrigine glucuronidation and increase clearance, other than the specified
antiepileptic drugs, include estrogen-containing oral contraceptives, rifampin, and the protease
inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Dosing recommendations for oral
contraceptives and the protease inhibitor atazanavir/ritonavir can be found in General Dosing
Considerations [see Dosage and Administration (2.1)]. Patients on rifampin and the protease
inhibitor lopinavir/ritonavir should follow the same dosing titration/maintenance regimen used
with antiepileptic drugs that induce glucuronidation and increase clearance [see Dosage and
Administration (2.1), Drug Interactions (7), and Clinical Pharmacology (12.3)].
Patients Aged 2 to 12 Years: Recommended dosing guidelines are summarized in
Table 2.
Smaller starting doses and slower dose escalations than those used in clinical trials are
recommended because of the suggestion that the risk of rash may be decreased by smaller
starting doses and slower dose escalations. Therefore, maintenance doses will take longer to
8
Reference ID: 3677876
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For current labeling information, please visit https://www.fda.gov/drugsatfda
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NDA 020764/S-028 & S-033
NDA 022251/S-009 & S-002
FDA Approved Labeling Text dated 12/23/2014
Page 9
217
reach in clinical practice than in clinical trials. It may take several weeks to months to achieve an
218
individualized maintenance dose. Maintenance doses in patients weighing less than 30 kg,
219
regardless of age or concomitant AED, may need to be increased as much as 50%, based on
220
clinical response.
221
The smallest available strength of LAMICTAL Chewable Dispersible Tablets is
222
2 mg, and only whole tablets should be administered. If the calculated dose cannot be
223
achieved using whole tablets, the dose should be rounded down to the nearest whole tablet
224
[see How Supplied/Storage and Handling (16) and Medication Guide].
225
226
Table 2. Escalation Regimen for LAMICTAL in Patients Aged 2 to 12 Years With Epilepsy
In Patients TAKING
Valproatea
In Patients
NOT TAKING
Carbamazepine,
Phenytoin,
Phenobarbital,
Primidone,b or
Valproatea
In Patients TAKING
Carbamazepine,
Phenytoin,
Phenobarbital, or
Primidoneb and NOT
TAKING Valproatea
Weeks 1 and 2
0.15 mg/kg/day
in 1 or 2 divided doses,
rounded down to the
nearest whole tablet
(see Table 3 for
weight-based dosing
guide)
0.3 mg/kg/day
in 1 or 2 divided doses,
rounded down to the
nearest whole tablet
0.6 mg/kg/day
in 2 divided doses,
rounded down to the
nearest whole tablet
Weeks 3 and 4
0.3 mg/kg/day
in 1 or 2 divided doses,
rounded down to the
nearest whole tablet
(see Table 3 for
weight-based dosing
guide)
0.6 mg/kg/day
in 2 divided doses,
rounded down to the
nearest whole tablet
1.2 mg/kg/day
in 2 divided doses,
rounded down to the
nearest whole tablet
9
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For current labeling information, please visit https://www.fda.gov/drugsatfda
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NDA 022251/S-009 & S-002
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Page 10
Week 5 onward to
maintenance
The dose should be
increased every 1 to 2
weeks as follows:
calculate
0.3 mg/kg/day,
round this amount
down to the nearest
whole tablet, and add
this amount to the
previously
administered daily
dose.
The dose should be
increased every 1 to 2
weeks as follows:
calculate
0.6 mg/kg/day,
round this amount
down to the nearest
whole tablet, and add
this amount to the
previously
administered daily
dose.
The dose should be
increased every 1 to 2
weeks as follows:
calculate
1.2 mg/kg/day,
round this amount
down to the nearest
whole tablet, and add
this amount to the
previously
administered daily
dose.
Usual
maintenance dose
1 to 5 mg/kg/day
(maximum
200 mg/day in 1 or 2
divided doses)
1 to 3 mg/kg/day
with valproate alone
4.5 to 7.5 mg/kg/day
(maximum
300 mg/day in 2
divided doses)
5 to 15 mg/kg/day
(maximum
400 mg/day in 2
divided doses)
Maintenance dose
May need to be
May need to be
May need to be
in patients less
increased by as much
increased by as much
increased by as much
than 30 kg
as 50%, based on
clinical response.
as 50%, based on
clinical response.
as 50%, based on
clinical response.
227
228
229
230
231
232
233
234
235
236
237
238
Note: Only whole tablets should be used for dosing.
a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of
lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].
b Drugs that induce lamotrigine glucuronidation and increase clearance, other than the specified
antiepileptic drugs, include estrogen-containing oral contraceptives, rifampin, and the protease
inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Dosing recommendations for oral
contraceptives and the protease inhibitor atazanavir/ritonavir can be found in General Dosing
Considerations [see Dosage and Administration (2.1)]. Patients on rifampin and the protease
inhibitor lopinavir/ritonavir should follow the same dosing titration/maintenance regimen used
with antiepileptic drugs that induce glucuronidation and increase clearance [see Dosage and
Administration (2.1), Drug Interactions (7), and Clinical Pharmacology (12.3)].
10
Reference ID: 3677876
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-035 & S-040
NDA 020764/S-028 & S-033
NDA 022251/S-009 & S-002
FDA Approved Labeling Text dated 12/23/2014
Page 11
239
Table 3. The Initial Weight-Based Dosing Guide for Patients Aged 2 to 12 Years Taking
240
Valproate (Weeks 1 to 4) With Epilepsy
If the patient’s weight is
Give this daily dose, using the most appropriate
combination of LAMICTAL 2- and 5-mg tablets
Greater than
And less than
Weeks 1 and 2
Weeks 3 and 4
6.7 kg
14 kg
2 mg every other day
2 mg every day
14.1 kg
27 kg
2 mg every day
4 mg every day
27.1 kg
34 kg
4 mg every day
8 mg every day
34.1 kg
40 kg
5 mg every day
10 mg every day
241
242
Usual Adjunctive Maintenance Dose for Epilepsy: The usual maintenance doses
243
identified in Tables 1 and 2 are derived from dosing regimens employed in the
244
placebo-controlled adjunctive trials in which the efficacy of LAMICTAL was established. In
245
patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or
246
primidone without valproate, maintenance doses of adjunctive LAMICTAL as high as
247
700 mg/day have been used. In patients receiving valproate alone, maintenance doses of
248
adjunctive LAMICTAL as high as 200 mg/day have been used. The advantage of using doses
249
above those recommended in Tables 1-4 has not been established in controlled trials.
250
2.3
Epilepsy—Conversion From Adjunctive Therapy to Monotherapy
251
The goal of the transition regimen is to attempt to maintain seizure control while
252
mitigating the risk of serious rash associated with the rapid titration of LAMICTAL.
253
The recommended maintenance dose of LAMICTAL as monotherapy is 500 mg/day
254
given in 2 divided doses.
255
To avoid an increased risk of rash, the recommended initial dose and subsequent dose
256
escalations for LAMICTAL should not be exceeded [see Boxed Warning].
257
Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin,
258
Phenobarbital, or Primidone to Monotherapy With LAMICTAL: After achieving a dose of
259
500 mg/day of LAMICTAL using the guidelines in Table 1, the concomitant enzyme-inducing
260
AED should be withdrawn by 20% decrements each week over a 4-week period. The regimen for
261
the withdrawal of the concomitant AED is based on experience gained in the controlled
262
monotherapy clinical trial.
263
Conversion From Adjunctive Therapy With Valproate to Monotherapy With
264
LAMICTAL: The conversion regimen involves the 4 steps outlined in Table 4.
265
11
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Page 12
266
Table 4. Conversion From Adjunctive Therapy With Valproate to Monotherapy With
267
LAMICTAL in Patients Aged 16 Years and Older With Epilepsy
LAMICTAL
Valproate
Step 1
Achieve a dose of 200 mg/day according
to guidelines in Table 1.
Maintain established stable dose.
Step 2
Maintain at 200 mg/day.
Decrease dose by decrements no
greater than 500 mg/day/week to
500 mg/day and then maintain for 1
week.
Step 3
Increase to 300 mg/day and maintain for 1
week.
Simultaneously decrease to
250 mg/day and maintain for 1 week.
Step 4
Increase by 100 mg/day every week to
achieve maintenance dose of 500 mg/day.
Discontinue.
268
269
Conversion From Adjunctive Therapy With Antiepileptic Drugs Other Than
270
Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy
271
With LAMICTAL: No specific dosing guidelines can be provided for conversion to monotherapy
272
with LAMICTAL with AEDs other than carbamazepine, phenytoin, phenobarbital, primidone, or
273
valproate.
274
2.4
Bipolar Disorder
275
The goal of maintenance treatment with LAMICTAL is to delay the time to occurrence of
276
mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute
277
mood episodes with standard therapy. The target dose of LAMICTAL is 200 mg/day
278
(100 mg/day in patients taking valproate, which decreases the apparent clearance of lamotrigine,
279
and 400 mg/day in patients not taking valproate and taking either carbamazepine, phenytoin,
280
phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitor
281
lopinavir/ritonavir that increase the apparent clearance of lamotrigine). In the clinical trials,
282
doses up to 400 mg/day as monotherapy were evaluated; however, no additional benefit was seen
283
at 400 mg/day compared with 200 mg/day [see Clinical Studies (14.2)]. Accordingly, doses
284
above 200 mg/day are not recommended. Treatment with LAMICTAL is introduced, based on
285
concurrent medications, according to the regimen outlined in Table 5. If other psychotropic
286
medications are withdrawn following stabilization, the dose of LAMICTAL should be adjusted.
287
For patients discontinuing valproate, the dose of LAMICTAL should be doubled over a 2-week
288
period in equal weekly increments (see Table 6). For patients discontinuing carbamazepine,
289
phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors
290
lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation, the dose of
291
LAMICTAL should remain constant for the first week and then should be decreased by half over
292
a 2-week period in equal weekly decrements (see Table 6). The dose of LAMICTAL may then
293
be further adjusted to the target dose (200 mg) as clinically indicated.
12
Reference ID: 3677876
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For current labeling information, please visit https://www.fda.gov/drugsatfda
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NDA 022251/S-009 & S-002
FDA Approved Labeling Text dated 12/23/2014
Page 13
294
If other drugs are subsequently introduced, the dose of LAMICTAL may need to be
295
adjusted. In particular, the introduction of valproate requires reduction in the dose of
296
LAMICTAL [see Drug Interactions (7), Clinical Pharmacology (12.3)].
297
To avoid an increased risk of rash, the recommended initial dose and subsequent dose
298
escalations of LAMICTAL should not be exceeded [see Boxed Warning].
299
300
Table 5. Escalation Regimen for LAMICTAL in Patients With Bipolar Disorder
In Patients TAKING
Valproatea
In Patients
NOT TAKING
Carbamazepine,
Phenytoin,
Phenobarbital,
Primidone,b or
Valproatea
In Patients TAKING
Carbamazepine,
Phenytoin,
Phenobarbital, or
Primidoneb and NOT
TAKING Valproatea
Weeks 1 and 2
25 mg every other day
25 mg daily
50 mg daily
Weeks 3 and 4
25 mg daily
50 mg daily
100 mg daily,
in divided doses
Week 5
50 mg daily
100 mg daily
200 mg daily,
in divided doses
Week 6
100 mg daily
200 mg daily
300 mg daily,
in divided doses
Week 7
100 mg daily
200 mg daily
up to 400 mg daily,
in divided doses
301
a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of
302
lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].
303
b Drugs that induce lamotrigine glucuronidation and increase clearance, other than the
304
specified antiepileptic drugs, include estrogen-containing oral contraceptives, rifampin, and
305
the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Dosing
306
recommendations for oral contraceptives and the protease inhibitor atazanavir/ritonavir can
307
be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients
308
on rifampin and the protease inhibitor lopinavir/ritonavir should follow the same dosing
309
titration/maintenance regimen used with antiepileptic drugs that induce glucuronidation and
310
increase clearance [see Dosage and Administration (2.1), Drug Interactions (7), and
311
Clinical Pharmacology (12.3)].
312
13
Reference ID: 3677876
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-035 & S-040
NDA 020764/S-028 & S-033
NDA 022251/S-009 & S-002
FDA Approved Labeling Text dated 12/23/2014
Page 14
313
Table 6. Dosage Adjustments to LAMICTAL in Patients With Bipolar Disorder Following
314
Discontinuation of Psychotropic Medications
Discontinuation
of Psychotropic Drugs
(excluding Valproate,a
After Discontinuation
of Valproatea
After Discontinuation of
Carbamazepine,
Phenytoin, Phenobarbital,
or Primidoneb
Carbamazepine,
Phenytoin, Phenobarbital,
or Primidoneb)
Current dose of
LAMICTAL (mg/day)
100
Current dose of
LAMICTAL (mg/day)
400
Week 1
Maintain current dose
of LAMICTAL
150
400
Week 2
Maintain current dose
of LAMICTAL
200
300
Week 3
onward
Maintain current dose
of LAMICTAL
200
200
315
316
317
318
319
320
321
322
323
324
325
326
327
328
329
330
331
332
333
334
335
336
337
338
a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of
lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].
b Drugs that induce lamotrigine glucuronidation and increase clearance, other than the specified
antiepileptic drugs, include estrogen-containing oral contraceptives, rifampin, and the protease
inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Dosing recommendations for oral
contraceptives and the protease inhibitor atazanavir/ritonavir can be found in General Dosing
Considerations [see Dosage and Administration (2.1)]. Patients on rifampin and the protease
inhibitor lopinavir/ritonavir should follow the same dosing titration/maintenance regimen used
with antiepileptic drugs that induce glucuronidation and increase clearance [see Dosage and
Administration (2.1), Drug Interactions (7), and Clinical Pharmacology (12.3)].
The benefit of continuing treatment in patients who had been stabilized in an 8- to 16
week open-label phase with LAMICTAL was established in 2 randomized, placebo-controlled
clinical maintenance trials [see Clinical Studies (14.2)]. However, the optimal duration of
treatment with LAMICTAL has not been established. Thus, patients should be periodically
reassessed to determine the need for maintenance treatment.
2.5
Administration of LAMICTAL Chewable Dispersible Tablets
LAMICTAL Chewable Dispersible Tablets may be swallowed whole, chewed, or
dispersed in water or diluted fruit juice. If the tablets are chewed, consume a small amount of
water or diluted fruit juice to aid in swallowing.
To disperse LAMICTAL Chewable Dispersible Tablets, add the tablets to a small amount
of liquid (1 teaspoon, or enough to cover the medication). Approximately 1 minute later, when
the tablets are completely dispersed, swirl the solution and consume the entire quantity
immediately. No attempt should be made to administer partial quantities of the dispersed tablets.
14
Reference ID: 3677876
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-035 & S-040
NDA 020764/S-028 & S-033
NDA 022251/S-009 & S-002
FDA Approved Labeling Text dated 12/23/2014
Page 15
339
2.6
Administration of LAMICTAL ODT Orally Disintegrating Tablets
340
LAMICTAL ODT Orally Disintegrating Tablets should be placed onto the tongue and
341
moved around in the mouth. The tablet will disintegrate rapidly, can be swallowed with or
342
without water, and can be taken with or without food.
343
3
DOSAGE FORMS AND STRENGTHS
344
3.1
Tablets
345
25 mg, white, scored, shield-shaped tablets debossed with “LAMICTAL” and “25.”
346
100 mg, peach, scored, shield-shaped tablets debossed with “LAMICTAL” and “100.”
347
150 mg, cream, scored, shield-shaped tablets debossed with “LAMICTAL” and “150.”
348
200 mg, blue, scored, shield-shaped tablets debossed with “LAMICTAL” and “200.”
349
3.2
Chewable Dispersible Tablets
350
2 mg, white to off-white, round tablets debossed with “LTG” over “2.”
351
5 mg, white to off-white, caplet-shaped tablets debossed with “GX CL2.”
352
25 mg, white, super elliptical-shaped tablets debossed with “GX CL5.”
353
3.3
Orally Disintegrating Tablets
354
25 mg, white to off-white, round, flat-faced, radius-edged tablets debossed with “LMT”
355
on one side and “25” on the other side.
356
50 mg, white to off-white, round, flat-faced, radius-edged tablets debossed with “LMT”
357
on one side and “50” on the other side.
358
100 mg, white to off-white, round, flat-faced, radius-edged tablets debossed with
359
“LAMICTAL” on one side and “100” on the other side.
360
200 mg, white to off-white, round, flat-faced, radius-edged tablets debossed with
361
“LAMICTAL” on one side and “200” on the other side.
362
3.4
Potential Medication Errors
363
Patients should be strongly advised to visually inspect their tablets to verify that they are
364
receiving LAMICTAL, as opposed to other medications, and that they are receiving the correct
365
formulation of lamotrigine each time they fill their prescription. Depictions of the LAMICTAL
366
Tablets, Chewable Dispersible Tablets, and Orally Disintegrating Tablets can be found in the
367
Medication Guide.
368
4
CONTRAINDICATIONS
369
LAMICTAL is contraindicated in patients who have demonstrated hypersensitivity (e.g.,
370
rash, angioedema, acute urticaria, extensive pruritus, mucosal ulceration) to the drug or its
371
ingredients [see Boxed Warning, Warnings and Precautions (5.1, 5.2)].
372
5
WARNINGS AND PRECAUTIONS
373
5.1
Serious Skin Rashes [see Boxed Warning]
374
Pediatric Population: The incidence of serious rash associated with hospitalization and
375
discontinuation of LAMICTAL in a prospectively followed cohort of pediatric patients (aged 2
15
Reference ID: 3677876
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For current labeling information, please visit https://www.fda.gov/drugsatfda
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NDA 020764/S-028 & S-033
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Page 16
376
to 16 years) with epilepsy receiving adjunctive therapy was approximately 0.8% (16 of 1,983).
377
When 14 of these cases were reviewed by 3 expert dermatologists, there was considerable
378
disagreement as to their proper classification. To illustrate, one dermatologist considered none of
379
the cases to be Stevens-Johnson syndrome; another assigned 7 of the 14 to this diagnosis. There
380
was 1 rash-related death in this 1,983-patient cohort. Additionally, there have been rare cases of
381
toxic epidermal necrolysis with and without permanent sequelae and/or death in US and foreign
382
postmarketing experience.
383
There is evidence that the inclusion of valproate in a multidrug regimen increases the risk
384
of serious, potentially life-threatening rash in pediatric patients. In pediatric patients who used
385
valproate concomitantly, 1.2% (6 of 482) experienced a serious rash compared with 0.6% (6 of
386
952) patients not taking valproate.
387
Adult Population: Serious rash associated with hospitalization and discontinuation of
388
LAMICTAL occurred in 0.3% (11 of 3,348) of adult patients who received LAMICTAL in
389
premarketing clinical trials of epilepsy. In the bipolar and other mood disorders clinical trials, the
390
rate of serious rash was 0.08% (1 of 1,233) of adult patients who received LAMICTAL as initial
391
monotherapy and 0.13% (2 of 1,538) of adult patients who received LAMICTAL as adjunctive
392
therapy. No fatalities occurred among these individuals. However, in worldwide postmarketing
393
experience, rare cases of rash-related death have been reported, but their numbers are too few to
394
permit a precise estimate of the rate.
395
Among the rashes leading to hospitalization were Stevens-Johnson syndrome, toxic
396
epidermal necrolysis, angioedema, and those associated with multiorgan hypersensitivity [see
397
Warnings and Precautions (5.2)].
398
There is evidence that the inclusion of valproate in a multidrug regimen increases the risk
399
of serious, potentially life-threatening rash in adults. Specifically, of 584 patients administered
400
LAMICTAL with valproate in epilepsy clinical trials, 6 (1%) were hospitalized in association
401
with rash; in contrast, 4 (0.16%) of 2,398 clinical trial patients and volunteers administered
402
LAMICTAL in the absence of valproate were hospitalized.
403
Patients With History of Allergy or Rash to Other Antiepileptic Drugs: The risk of
404
nonserious rash may be increased when the recommended initial dose and/or the rate of dose
405
escalation for LAMICTAL is exceeded and in patients with a history of allergy or rash to other
406
AEDs.
407
5.2
Multiorgan Hypersensitivity Reactions and Organ Failure
408
Multiorgan hypersensitivity reactions, also known as drug reaction with eosinophilia and
409
systemic symptoms (DRESS), have occurred with lamotrigine. Some have been fatal or life
410
threatening. DRESS typically, although not exclusively, presents with fever, rash, and/or
411
lymphadenopathy in association with other organ system involvement, such as hepatitis,
412
nephritis, hematologic abnormalities, myocarditis, or myositis, sometimes resembling an acute
413
viral infection. Eosinophilia is often present. This disorder is variable in its expression, and other
414
organ systems not noted here may be involved.
16
Reference ID: 3677876
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-035 & S-040
NDA 020764/S-028 & S-033
NDA 022251/S-009 & S-002
FDA Approved Labeling Text dated 12/23/2014
Page 17
415
Fatalities associated with acute multiorgan failure and various degrees of hepatic failure
416
have been reported in 2 of 3,796 adult patients and 4 of 2,435 pediatric patients who received
417
lamotrigine in epilepsy clinical trials. Rare fatalities from multiorgan failure have also been
418
reported in postmarketing use.
419
Isolated liver failure without rash or involvement of other organs has also been reported
420
with lamotrigine.
421
It is important to note that early manifestations of hypersensitivity (e.g., fever,
422
lymphadenopathy) may be present even though a rash is not evident. If such signs or symptoms
423
are present, the patient should be evaluated immediately. LAMICTAL should be discontinued if
424
an alternative etiology for the signs or symptoms cannot be established.
425
Prior to initiation of treatment with LAMICTAL, the patient should be instructed
426
that a rash or other signs or symptoms of hypersensitivity (e.g., fever, lymphadenopathy)
427
may herald a serious medical event and that the patient should report any such occurrence
428
to a physician immediately.
429
5.3
Blood Dyscrasias
430
There have been reports of blood dyscrasias that may or may not be associated with
431
multiorgan hypersensitivity (also known as DRESS) [see Warnings and Precautions (5.2)].
432
These have included neutropenia, leukopenia, anemia, thrombocytopenia, pancytopenia, and,
433
rarely, aplastic anemia and pure red cell aplasia.
434
5.4
Suicidal Behavior and Ideation
435
AEDs, including LAMICTAL, increase the risk of suicidal thoughts or behavior in
436
patients taking these drugs for any indication. Patients treated with any AED for any indication
437
should be monitored for the emergence or worsening of depression, suicidal thoughts or
438
behavior, and/or any unusual changes in mood or behavior.
439
Pooled analyses of 199 placebo-controlled clinical trials (monotherapy and adjunctive
440
therapy) of 11 different AEDs showed that patients randomized to 1 of the AEDs had
441
approximately twice the risk (adjusted Relative Risk 1.8, 95% CI: 1.2, 2.7) of suicidal thinking
442
or behavior compared with patients randomized to placebo. In these trials, which had a median
443
treatment duration of 12 weeks, the estimated incidence of suicidal behavior or ideation among
444
27,863 AED-treated patients was 0.43%, compared with 0.24% among 16,029 placebo-treated
445
patients, representing an increase of approximately 1 case of suicidal thinking or behavior for
446
every 530 patients treated. There were 4 suicides in drug-treated patients in the trials and none in
447
placebo-treated patients, but the number of events is too small to allow any conclusion about
448
drug effect on suicide.
449
The increased risk of suicidal thoughts or behavior with AEDs was observed as early as 1
450
week after starting treatment with AEDs and persisted for the duration of treatment assessed.
451
Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal
452
thoughts or behavior beyond 24 weeks could not be assessed.
17
Reference ID: 3677876
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-035 & S-040
NDA 020764/S-028 & S-033
NDA 022251/S-009 & S-002
FDA Approved Labeling Text dated 12/23/2014
Page 18
453
The risk of suicidal thoughts or behavior was generally consistent among drugs in the
454
data analyzed. The finding of increased risk with AEDs of varying mechanism of action and
455
across a range of indications suggests that the risk applies to all AEDs used for any indication.
456
The risk did not vary substantially by age (5 to 100 years) in the clinical trials analyzed.
457
Table 7 shows absolute and relative risk by indication for all evaluated AEDs.
458
459
Table 7. Risk by Indication for Antiepileptic Drugs in the Pooled Analysis
Indication
Placebo
Patients With
Events per
1,000 Patients
Drug Patients
With Events
per 1,000
Patients
Relative Risk:
Incidence of
Events in Drug
Patients/
Incidence in
Placebo Patients
Risk Difference:
Additional Drug
Patients With
Events per
1,000 Patients
Epilepsy
1.0
3.4
3.5
2.4
Psychiatric
5.7
8.5
1.5
2.9
Other
1.0
1.8
1.9
0.9
Total
2.4
4.3
1.8
1.9
460
461
The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy
462
than in clinical trials for psychiatric or other conditions, but the absolute risk differences were
463
similar for the epilepsy and psychiatric indications.
464
Anyone considering prescribing LAMICTAL or any other AED must balance the risk of
465
suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses
466
for which AEDs are prescribed are themselves associated with morbidity and mortality and an
467
increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge
468
during treatment, the prescriber needs to consider whether the emergence of these symptoms in
469
any given patient may be related to the illness being treated.
470
Patients, their caregivers, and families should be informed that AEDs increase the risk of
471
suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or
472
worsening of the signs and symptoms of depression, any unusual changes in mood or behavior,
473
the emergence of suicidal thoughts or suicidal behavior, or thoughts about self-harm. Behaviors
474
of concern should be reported immediately to healthcare providers.
475
5.5
Use in Patients With Bipolar Disorder
476
Acute Treatment of Mood Episodes: Safety and effectiveness of LAMICTAL in the
477
acute treatment of mood episodes have not been established.
478
Children and Adolescents (younger than 18 years): Safety and effectiveness of
479
LAMICTAL in patients younger than 18 years with mood disorders have not been established
480
[see Warnings and Precautions (5.4)].
18
Reference ID: 3677876
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-035 & S-040
NDA 020764/S-028 & S-033
NDA 022251/S-009 & S-002
FDA Approved Labeling Text dated 12/23/2014
Page 19
481
Clinical Worsening and Suicide Risk Associated With Bipolar Disorder: Patients
482
with bipolar disorder may experience worsening of their depressive symptoms and/or the
483
emergence of suicidal ideation and behaviors (suicidality) whether or not they are taking
484
medications for bipolar disorder. Patients should be closely monitored for clinical worsening
485
(including development of new symptoms) and suicidality, especially at the beginning of a
486
course of treatment or at the time of dose changes.
487
In addition, patients with a history of suicidal behavior or thoughts, those patients
488
exhibiting a significant degree of suicidal ideation prior to commencement of treatment, and
489
young adults are at an increased risk of suicidal thoughts or suicide attempts and should receive
490
careful monitoring during treatment [see Warnings and Precautions (5.4)].
491
Consideration should be given to changing the therapeutic regimen, including possibly
492
discontinuing the medication, in patients who experience clinical worsening (including
493
development of new symptoms) and/or the emergence of suicidal ideation/behavior, especially if
494
these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting
495
symptoms.
496
Prescriptions for LAMICTAL should be written for the smallest quantity of tablets
497
consistent with good patient management in order to reduce the risk of overdose. Overdoses have
498
been reported for LAMICTAL, some of which have been fatal [see Overdosage (10.1)].
499
5.6
Aseptic Meningitis
500
Therapy with lamotrigine increases the risk of developing aseptic meningitis. Because of
501
the potential for serious outcomes of untreated meningitis due to other causes, patients should
502
also be evaluated for other causes of meningitis and treated as appropriate.
503
Postmarketing cases of aseptic meningitis have been reported in pediatric and adult
504
patients taking lamotrigine for various indications. Symptoms upon presentation have included
505
headache, fever, nausea, vomiting, and nuchal rigidity. Rash, photophobia, myalgia, chills,
506
altered consciousness, and somnolence were also noted in some cases. Symptoms have been
507
reported to occur within 1 day to one and a half months following the initiation of treatment. In
508
most cases, symptoms were reported to resolve after discontinuation of lamotrigine. Re-exposure
509
resulted in a rapid return of symptoms (from within 30 minutes to 1 day following re-initiation of
510
treatment) that were frequently more severe. Some of the patients treated with lamotrigine who
511
developed aseptic meningitis had underlying diagnoses of systemic lupus erythematosus or other
512
autoimmune diseases.
513
Cerebrospinal fluid (CSF) analyzed at the time of clinical presentation in reported cases
514
was characterized by a mild to moderate pleocytosis, normal glucose levels, and mild to
515
moderate increase in protein. CSF white blood cell count differentials showed a predominance of
516
neutrophils in a majority of the cases, although a predominance of lymphocytes was reported in
517
approximately one third of the cases. Some patients also had new onset of signs and symptoms
518
of involvement of other organs (predominantly hepatic and renal involvement), which may
19
Reference ID: 3677876
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-035 & S-040
NDA 020764/S-028 & S-033
NDA 022251/S-009 & S-002
FDA Approved Labeling Text dated 12/23/2014
Page 20
519
suggest that in these cases the aseptic meningitis observed was part of a hypersensitivity reaction
520
[see Warnings and Precautions (5.2)].
521
5.7
Potential Medication Errors
522
Medication errors involving LAMICTAL have occurred. In particular, the names
523
LAMICTAL or lamotrigine can be confused with the names of other commonly used
524
medications. Medication errors may also occur between the different formulations of
525
LAMICTAL. To reduce the potential of medication errors, write and say LAMICTAL clearly.
526
Depictions of the LAMICTAL Tablets, Chewable Dispersible Tablets, and Orally Disintegrating
527
Tablets can be found in the Medication Guide that accompanies the product to highlight the
528
distinctive markings, colors, and shapes that serve to identify the different presentations of the
529
drug and thus may help reduce the risk of medication errors. To avoid the medication error of
530
using the wrong drug or formulation, patients should be strongly advised to visually inspect their
531
tablets to verify that they are LAMICTAL, as well as the correct formulation of LAMICTAL,
532
each time they fill their prescription.
533
5.8
Concomitant Use With Oral Contraceptives
534
Some estrogen-containing oral contraceptives have been shown to decrease serum
535
concentrations of lamotrigine [see Clinical Pharmacology (12.3)]. Dosage adjustments will be
536
necessary in most patients who start or stop estrogen-containing oral contraceptives while
537
taking LAMICTAL [see Dosage and Administration (2.1)]. During the week of inactive
538
hormone preparation (pill-free week) of oral contraceptive therapy, plasma lamotrigine levels are
539
expected to rise, as much as doubling at the end of the week. Adverse reactions consistent with
540
elevated levels of lamotrigine, such as dizziness, ataxia, and diplopia, could occur.
541
5.9
Withdrawal Seizures
542
As with other AEDs, LAMICTAL should not be abruptly discontinued. In patients with
543
epilepsy there is a possibility of increasing seizure frequency. In clinical trials in patients with
544
bipolar disorder, 2 patients experienced seizures shortly after abrupt withdrawal of LAMICTAL;
545
however, there were confounding factors that may have contributed to the occurrence of seizures
546
in these patients with bipolar disorder. Unless safety concerns require a more rapid withdrawal,
547
the dose of LAMICTAL should be tapered over a period of at least 2 weeks (approximately 50%
548
reduction per week) [see Dosage and Administration (2.1)].
549
5.10 Status Epilepticus
550
Valid estimates of the incidence of treatment-emergent status epilepticus among patients
551
treated with LAMICTAL are difficult to obtain because reporters participating in clinical trials
552
did not all employ identical rules for identifying cases. At a minimum, 7 of 2,343 adult patients
553
had episodes that could unequivocally be described as status epilepticus. In addition, a number of
554
reports of variably defined episodes of seizure exacerbation (e.g., seizure clusters, seizure
555
flurries) were made.
556
5.11 Sudden Unexplained Death in Epilepsy (SUDEP)
20
Reference ID: 3677876
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For current labeling information, please visit https://www.fda.gov/drugsatfda
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NDA 022251/S-009 & S-002
FDA Approved Labeling Text dated 12/23/2014
Page 21
557
During the premarketing development of LAMICTAL, 20 sudden and unexplained
558
deaths were recorded among a cohort of 4,700 patients with epilepsy (5,747 patient-years of
559
exposure).
560
Some of these could represent seizure-related deaths in which the seizure was not
561
observed, e.g., at night. This represents an incidence of 0.0035 deaths per patient-year. Although
562
this rate exceeds that expected in a healthy population matched for age and sex, it is within the
563
range of estimates for the incidence of sudden unexplained death in epilepsy (SUDEP) in
564
patients not receiving LAMICTAL (ranging from 0.0005 for the general population of patients
565
with epilepsy, to 0.004 for a recently studied clinical trial population similar to that in the clinical
566
development program for LAMICTAL, to 0.005 for patients with refractory epilepsy).
567
Consequently, whether these figures are reassuring or suggest concern depends on the
568
comparability of the populations reported upon with the cohort receiving LAMICTAL and the
569
accuracy of the estimates provided. Probably most reassuring is the similarity of estimated
570
SUDEP rates in patients receiving LAMICTAL and those receiving other AEDs, chemically
571
unrelated to each other, that underwent clinical testing in similar populations. Importantly, that
572
drug is chemically unrelated to LAMICTAL. This evidence suggests, although it certainly does
573
not prove, that the high SUDEP rates reflect population rates, not a drug effect.
574
5.12 Addition of LAMICTAL to a Multidrug Regimen That Includes Valproate
575
Because valproate reduces the clearance of lamotrigine, the dosage of lamotrigine in the
576
presence of valproate is less than half of that required in its absence [see Dosage and
577
Administration (2.2, 2.3, 2.4), Drug Interactions (7)].
578
5.13 Binding in the Eye and Other Melanin-Containing Tissues
579
Because lamotrigine binds to melanin, it could accumulate in melanin-rich tissues over
580
time. This raises the possibility that lamotrigine may cause toxicity in these tissues after
581
extended use. Although ophthalmological testing was performed in 1 controlled clinical trial, the
582
testing was inadequate to exclude subtle effects or injury occurring after long-term exposure.
583
Moreover, the capacity of available tests to detect potentially adverse consequences, if any, of
584
lamotrigine’s binding to melanin is unknown [see Clinical Pharmacology (12.2)].
585
Accordingly, although there are no specific recommendations for periodic
586
ophthalmological monitoring, prescribers should be aware of the possibility of long-term
587
ophthalmologic effects.
588
5.14 Laboratory Tests
589
The value of monitoring plasma concentrations of lamotrigine in patients treated with
590
LAMICTAL has not been established. Because of the possible pharmacokinetic interactions
591
between lamotrigine and other drugs, including AEDs (see Table 15), monitoring of the plasma
592
levels of lamotrigine and concomitant drugs may be indicated, particularly during dosage
593
adjustments. In general, clinical judgment should be exercised regarding monitoring of plasma
594
levels of lamotrigine and other drugs and whether or not dosage adjustments are necessary.
21
Reference ID: 3677876
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-035 & S-040
NDA 020764/S-028 & S-033
NDA 022251/S-009 & S-002
FDA Approved Labeling Text dated 12/23/2014
Page 22
595
6
ADVERSE REACTIONS
596
The following adverse reactions are described in more detail in the Warnings and
597
Precautions section of the label:
598
• Serious skin rashes [see Warnings and Precautions (5.1)]
599
• Multiorgan hypersensitivity reactions and organ failure [see Warnings and Precautions (5.2)]
600
• Blood dyscrasias [see Warnings and Precautions (5.3)]
601
• Suicidal behavior and ideation [see Warnings and Precautions (5.4)]
602
• Aseptic meningitis [see Warnings and Precautions (5.6)]
603
• Withdrawal seizures [see Warnings and Precautions (5.9)]
604
• Status epilepticus [see Warnings and Precautions (5.10)]
605
• Sudden unexplained death in epilepsy [see Warnings and Precautions (5.11)]
606
6.1
Clinical Trial Experience
607
Because clinical trials are conducted under widely varying conditions, adverse reaction
608
rates observed in the clinical trials of a drug cannot be directly compared with rates in the
609
clinical trials of another drug and may not reflect the rates observed in practice.
610
LAMICTAL has been evaluated for safety in patients with epilepsy and in patients with
611
bipolar I disorder. Adverse reactions reported for each of these patient populations are provided
612
below. Excluded are adverse reactions considered too general to be informative and those not
613
reasonably attributable to the use of the drug.
614
Epilepsy: Most Common Adverse Reactions in All Clinical Trials: Adjunctive
615
Therapy in Adults With Epilepsy: The most commonly observed (≥5% for LAMICTAL and
616
more common on drug than placebo) adverse reactions seen in association with LAMICTAL
617
during adjunctive therapy in adults and not seen at an equivalent frequency among placebo
618
treated patients were: dizziness, ataxia, somnolence, headache, diplopia, blurred vision, nausea,
619
vomiting, and rash. Dizziness, diplopia, ataxia, blurred vision, nausea, and vomiting were dose
620
related. Dizziness, diplopia, ataxia, and blurred vision occurred more commonly in patients
621
receiving carbamazepine with LAMICTAL than in patients receiving other AEDs with
622
LAMICTAL. Clinical data suggest a higher incidence of rash, including serious rash, in patients
623
receiving concomitant valproate than in patients not receiving valproate [see Warnings and
624
Precautions (5.1)].
625
Approximately 11% of the 3,378 adult patients who received LAMICTAL as adjunctive
626
therapy in premarketing clinical trials discontinued treatment because of an adverse reaction. The
627
adverse reactions most commonly associated with discontinuation were rash (3.0%), dizziness
628
(2.8%), and headache (2.5%).
629
In a dose-response trial in adults, the rate of discontinuation of LAMICTAL for
630
dizziness, ataxia, diplopia, blurred vision, nausea, and vomiting was dose related.
631
Monotherapy in Adults With Epilepsy: The most commonly observed (≥5% for
632
LAMICTAL and more common on drug than placebo) adverse reactions seen in association with
633
the use of LAMICTAL during the monotherapy phase of the controlled trial in adults not seen at
22
Reference ID: 3677876
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-035 & S-040
NDA 020764/S-028 & S-033
NDA 022251/S-009 & S-002
FDA Approved Labeling Text dated 12/23/2014
Page 23
634
an equivalent rate in the control group were vomiting, coordination abnormality, dyspepsia,
635
nausea, dizziness, rhinitis, anxiety, insomnia, infection, pain, weight decrease, chest pain, and
636
dysmenorrhea. The most commonly observed (≥5% for LAMICTAL and more common on drug
637
than placebo) adverse reactions associated with the use of LAMICTAL during the conversion to
638
monotherapy (add-on) period, not seen at an equivalent frequency among low-dose valproate
639
treated patients, were dizziness, headache, nausea, asthenia, coordination abnormality, vomiting,
640
rash, somnolence, diplopia, ataxia, accidental injury, tremor, blurred vision, insomnia,
641
nystagmus, diarrhea, lymphadenopathy, pruritus, and sinusitis.
642
Approximately 10% of the 420 adult patients who received LAMICTAL as monotherapy
643
in premarketing clinical trials discontinued treatment because of an adverse reaction. The
644
adverse reactions most commonly associated with discontinuation were rash (4.5%), headache
645
(3.1%), and asthenia (2.4%).
646
Adjunctive Therapy in Pediatric Patients With Epilepsy: The most commonly
647
observed (≥5% for LAMICTAL and more common on drug than placebo) adverse reactions seen
648
in association with the use of LAMICTAL as adjunctive treatment in pediatric patients aged 2 to
649
16 years and not seen at an equivalent rate in the control group were infection, vomiting, rash,
650
fever, somnolence, accidental injury, dizziness, diarrhea, abdominal pain, nausea, ataxia, tremor,
651
asthenia, bronchitis, flu syndrome, and diplopia.
652
In 339 patients aged 2 to 16 years with partial-onset seizures or generalized seizures of
653
Lennox-Gastaut syndrome, 4.2% of patients on LAMICTAL and 2.9% of patients on placebo
654
discontinued due to adverse reactions. The most commonly reported adverse reaction that led to
655
discontinuation of LAMICTAL was rash.
656
Approximately 11.5% of the 1,081 pediatric patients aged 2 to 16 years who received
657
LAMICTAL as adjunctive therapy in premarketing clinical trials discontinued treatment because
658
of an adverse reaction. The adverse reactions most commonly associated with discontinuation
659
were rash (4.4%), reaction aggravated (1.7%), and ataxia (0.6%).
660
Controlled Adjunctive Clinical Trials in Adults With Epilepsy: Table 8 lists
661
treatment-emergent adverse reactions that occurred in at least 2% of adult patients with epilepsy
662
treated with LAMICTAL in placebo-controlled trials and were numerically more frequent in the
663
patients treated with LAMICTAL. In these trials, either LAMICTAL or placebo was added to the
664
patient’s current AED therapy. Adverse reactions were usually mild to moderate in intensity.
665
23
Reference ID: 3677876
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-035 & S-040
NDA 020764/S-028 & S-033
NDA 022251/S-009 & S-002
FDA Approved Labeling Text dated 12/23/2014
Page 24
666
Table 8. Treatment-Emergent Adverse Reaction Incidence in Placebo-Controlled
667
Adjunctive Trials in Adult Patients With Epilepsya (Adverse reactions in at least 2% of
668
patients treated with LAMICTAL and numerically more frequent than in the placebo
669
group.)
Body System/
Adverse Reaction
Percent of Patients
Receiving Adjunctive
LAMICTAL
(n = 711)
Percent of Patients
Receiving Adjunctive
Placebo
(n = 419)
Body as a whole
Headache
29
19
Flu syndrome
7
6
Fever
6
4
Abdominal pain
5
4
Neck pain
2
1
Reaction aggravated
(seizure exacerbation)
2
1
Digestive
Nausea
19
10
Vomiting
9
4
Diarrhea
6
4
Dyspepsia
5
2
Constipation
4
3
Anorexia
2
1
Musculoskeletal
Arthralgia
2
0
Nervous
Dizziness
38
13
Ataxia
22
6
Somnolence
14
7
Incoordination
6
2
Insomnia
6
2
Tremor
4
1
Depression
4
3
Anxiety
4
3
Convulsion
3
1
Irritability
3
2
Speech disorder
3
0
Concentration disturbance
2
1
24
Reference ID: 3677876
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-035 & S-040
NDA 020764/S-028 & S-033
NDA 022251/S-009 & S-002
FDA Approved Labeling Text dated 12/23/2014
Page 25
Respiratory
Rhinitis
14
9
Pharyngitis
10
9
Cough increased
8
6
Skin and appendages
Rash
Pruritus
10
3
5
2
Special senses
Diplopia
28
7
Blurred vision
16
5
Vision abnormality
3
1
Urogenital
Female patients only
Dysmenorrhea
Vaginitis
Amenorrhea
(n = 365)
7
4
2
(n = 207)
6
1
1
670
a Patients in these adjunctive trials were receiving 1 to 3 of the concomitant antiepileptic drugs
671
carbamazepine, phenytoin, phenobarbital, or primidone in addition to LAMICTAL or
672
placebo. Patients may have reported multiple adverse reactions during the trial or at
673
discontinuation; thus, patients may be included in more than 1 category.
674
675
In a randomized, parallel trial comparing placebo with 300 and 500 mg/day of
676
LAMICTAL, some of the more common drug-related adverse reactions were dose related (see
677
Table 9).
678
679
Table 9. Dose-Related Adverse Reactions From a Randomized, Placebo-Controlled,
680
Adjunctive Trial in Adults With Epilepsy
Adverse Reaction
Percent of Patients Experiencing Adverse Reactions
Placebo
(n = 73)
LAMICTAL
300 mg
(n = 71)
LAMICTAL
500 mg
(n = 72)
Ataxia
Blurred vision
Diplopia
Dizziness
Nausea
Vomiting
10
10
8
27
11
4
10
11
24
a
31
18
11
28
a,b
25
a,b
49
a,b
54
a,b
25
a
18
a
681
a Significantly greater than placebo group (P<0.05).
682
b Significantly greater than group receiving LAMICTAL 300 mg (P<0.05).
25
Reference ID: 3677876
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-035 & S-040
NDA 020764/S-028 & S-033
NDA 022251/S-009 & S-002
FDA Approved Labeling Text dated 12/23/2014
Page 26
683
684
The overall adverse reaction profile for LAMICTAL was similar between females and
685
males and was independent of age. Because the largest non-Caucasian racial subgroup was only
686
6% of patients exposed to LAMICTAL in placebo-controlled trials, there are insufficient data to
687
support a statement regarding the distribution of adverse reaction reports by race. Generally,
688
females receiving either LAMICTAL as adjunctive therapy or placebo were more likely to report
689
adverse reactions than males. The only adverse reaction for which the reports on LAMICTAL
690
were greater than 10% more frequent in females than males (without a corresponding difference
691
by gender on placebo) was dizziness (difference = 16.5%). There was little difference between
692
females and males in the rates of discontinuation of LAMICTAL for individual adverse
693
reactions.
694
Controlled Monotherapy Trial in Adults With Partial-Onset Seizures: Table
695
10 lists treatment-emergent adverse reactions that occurred in at least 5% of patients with
696
epilepsy treated with monotherapy with LAMICTAL in a double-blind trial following
697
discontinuation of either concomitant carbamazepine or phenytoin not seen at an equivalent
698
frequency in the control group.
699
700
Table 10. Treatment-Emergent Adverse Reaction Incidence in a Controlled
701
Monotherapy Trial in Adult Patients With Partial-Onset Seizuresa (Adverse reactions in
702
at least 5% of patients treated with LAMICTAL and numerically more frequent than in
703
the valproate group.)
Body System/
Adverse Reaction
Percent of Patients
Receiving LAMICTALb as
Monotherapy
(n = 43)
Percent of Patients
Receiving Low-Dose
Valproatec Monotherapy
(n = 44)
Body as a whole
Pain
5
0
Infection
5
2
Chest pain
5
2
Digestive
Vomiting
9
0
Dyspepsia
7
2
Nausea
7
2
Metabolic and nutritional
Weight decrease
5
2
Nervous
Coordination abnormality
7
0
Dizziness
7
0
Anxiety
5
0
26
Reference ID: 3677876
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-035 & S-040
NDA 020764/S-028 & S-033
NDA 022251/S-009 & S-002
FDA Approved Labeling Text dated 12/23/2014
Page 27
Insomnia
5
2
Respiratory
Rhinitis
7
2
Urogenital (female patients
only)
Dysmenorrhea
(n = 21)
5
(n = 28)
0
704
a Patients in this trial were converted to LAMICTAL or valproate monotherapy from
705
adjunctive therapy with carbamazepine or phenytoin. Patients may have reported multiple
706
adverse reactions during the trial; thus, patients may be included in more than 1 category.
707
b Up to 500 mg/day.
708
c 1,000 mg/day.
709
710
Adverse reactions that occurred with a frequency of less than 5% and greater than 2% of
711
patients receiving LAMICTAL and numerically more frequent than placebo were:
712
Body as a Whole: Asthenia, fever.
713
Digestive: Anorexia, dry mouth, rectal hemorrhage, peptic ulcer.
714
Metabolic and Nutritional: Peripheral edema.
715
Nervous System: Amnesia, ataxia, depression, hypesthesia, libido increase, decreased
716
reflexes, increased reflexes, nystagmus, irritability, suicidal ideation.
717
Respiratory: Epistaxis, bronchitis, dyspnea.
718
Skin and Appendages: Contact dermatitis, dry skin, sweating.
719
Special Senses: Vision abnormality.
720
Incidence in Controlled Adjunctive Trials in Pediatric Patients With
721
Epilepsy: Table 11 lists adverse reactions that occurred in at least 2% of 339 pediatric patients
722
with partial-onset seizures or generalized seizures of Lennox-Gastaut syndrome who received
723
LAMICTAL up to 15 mg/kg/day or a maximum of 750 mg/day. Reported adverse reactions were
724
classified using COSTART terminology.
725
726
Table 11. Treatment-Emergent Adverse Reaction Incidence in Placebo-Controlled
727
Adjunctive Trials in Pediatric Patients With Epilepsy (Adverse reactions in at least
728
2% of patients treated with LAMICTAL and numerically more frequent than in the
729
placebo group.)
Body System/Adverse Reaction
Percent of Patients
Receiving LAMICTAL
(n = 168)
Percent of Patients
Receiving Placebo
(n = 171)
Body as a whole
Infection
Fever
Accidental injury
20
15
14
17
14
12
27
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FDA Approved Labeling Text dated 12/23/2014
Page 28
Abdominal pain
10
5
Asthenia
8
4
Flu syndrome
7
6
Pain
5
4
Facial edema
2
1
Photosensitivity
2
0
Cardiovascular
Hemorrhage
2
1
Digestive
Vomiting
20
16
Diarrhea
11
9
Nausea
10
2
Constipation
4
2
Dyspepsia
2
1
Hemic and lymphatic
Lymphadenopathy
2
1
Metabolic and nutritional
Edema
2
0
Nervous system
Somnolence
17
15
Dizziness
14
4
Ataxia
11
3
Tremor
10
1
Emotional lability
4
2
Gait abnormality
4
2
Thinking abnormality
3
2
Convulsions
2
1
Nervousness
2
1
Vertigo
2
1
Respiratory
Pharyngitis
14
11
Bronchitis
7
5
Increased cough
7
6
Sinusitis
2
1
Bronchospasm
2
1
Skin
Rash
14
12
Eczema
2
1
Pruritus
2
1
28
Reference ID: 3677876
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For current labeling information, please visit https://www.fda.gov/drugsatfda
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FDA Approved Labeling Text dated 12/23/2014
Page 29
Special senses
Diplopia
Blurred vision
Visual abnormality
5
4
2
1
1
0
Urogenital
Male and female patients
Urinary tract infection
3
0
730
731
Bipolar Disorder: The most commonly observed (≥5%) treatment-emergent adverse
732
reactions seen in association with the use of LAMICTAL as monotherapy (100 to 400 mg/day)
733
in adult patients (aged 18 years and older) with bipolar disorder in the 2 double-blind, placebo
734
controlled trials of 18 months’ duration, and numerically more frequent than in placebo-treated
735
patients are included in Table 12. Adverse reactions that occurred in at least 5% of patients and
736
were numerically more frequent during the dose-escalation phase of LAMICTAL in these trials
737
(when patients may have been receiving concomitant medications) compared with the
738
monotherapy phase were: headache (25%), rash (11%), dizziness (10%), diarrhea (8%), dream
739
abnormality (6%), and pruritus (6%).
740
During the monotherapy phase of the double-blind, placebo-controlled trials of 18
741
months’ duration, 13% of 227 patients who received LAMICTAL (100 to 400 mg/day), 16% of
742
190 patients who received placebo, and 23% of 166 patients who received lithium discontinued
743
therapy because of an adverse reaction. The adverse reactions which most commonly led to
744
discontinuation of LAMICTAL were rash (3%) and mania/hypomania/mixed mood adverse
745
reactions (2%). Approximately 16% of 2,401 patients who received LAMICTAL (50 to
746
500 mg/day) for bipolar disorder in premarketing trials discontinued therapy because of an
747
adverse reaction, most commonly due to rash (5%) and mania/hypomania/mixed mood adverse
748
reactions (2%).
749
The overall adverse reaction profile for LAMICTAL was similar between females and
750
males, between elderly and nonelderly patients, and among racial groups.
751
29
Reference ID: 3677876
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NDA 022251/S-009 & S-002
FDA Approved Labeling Text dated 12/23/2014
Page 30
752
Table 12. Treatment-Emergent Adverse Reaction Incidence in 2 Placebo-Controlled Trials
753
in Adult Patients With Bipolar I Disordera (Adverse reactions in at least 5% of patients
754
treated with LAMICTAL as monotherapy and numerically more frequent than in the
755
placebo group.)
Body System/
Adverse Reaction
Percent of Patients
Receiving LAMICTAL
(n = 227)
Percent of Patients
Receiving Placebo
(n = 190)
General
Back pain
Fatigue
Abdominal pain
8
8
6
6
5
3
Digestive
Nausea
Constipation
Vomiting
14
5
5
11
2
2
Nervous System
Insomnia
Somnolence
Xerostomia (dry mouth)
10
9
6
6
7
4
Respiratory
Rhinitis
Exacerbation of cough
Pharyngitis
7
5
5
4
3
4
Skin
Rash (nonserious)b
7
5
756
a Patients in these trials were converted to LAMICTAL (100 to 400 mg/day) or placebo
757
monotherapy from add-on therapy with other psychotropic medications. Patients may have
758
reported multiple adverse reactions during the trial; thus, patients may be included in more
759
than 1 category.
760
b In the overall bipolar and other mood disorders clinical trials, the rate of serious rash was
761
0.08% (1 of 1,233) of adult patients who received LAMICTAL as initial monotherapy and
762
0.13% (2 of 1,538) of adult patients who received LAMICTAL as adjunctive therapy [see
763
Warnings and Precautions (5.1)].
764
765
These adverse reactions were usually mild to moderate in intensity. Other reactions that
766
occurred in 5% or more patients but equally or more frequently in the placebo group included:
767
dizziness, mania, headache, infection, influenza, pain, accidental injury, diarrhea, and dyspepsia.
768
Adverse reactions that occurred with a frequency of less than 5% and greater than 1% of
769
patients receiving LAMICTAL and numerically more frequent than placebo were:
30
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FDA Approved Labeling Text dated 12/23/2014
Page 31
770
General: Fever, neck pain.
771
Cardiovascular: Migraine.
772
Digestive: Flatulence.
773
Metabolic and Nutritional: Weight gain, edema.
774
Musculoskeletal: Arthralgia, myalgia.
775
Nervous System: Amnesia, depression, agitation, emotional lability, dyspraxia, abnormal
776
thoughts, dream abnormality, hypoesthesia.
777
Respiratory: Sinusitis.
778
Urogenital: Urinary frequency.
779
Adverse Reactions Following Abrupt Discontinuation: In the 2 maintenance trials,
780
there was no increase in the incidence, severity, or type of adverse reactions in patients with
781
bipolar disorder after abruptly terminating therapy with LAMICTAL. In clinical trials in patients
782
with bipolar disorder, 2 patients experienced seizures shortly after abrupt withdrawal of
783
LAMICTAL. However, there were confounding factors that may have contributed to the
784
occurrence of seizures in these patients with bipolar disorder [see Warnings and Precautions
785
(5.9)].
786
Mania/Hypomania/Mixed Episodes: During the double-blind, placebo-controlled
787
clinical trials in bipolar I disorder in which patients were converted to monotherapy with
788
LAMICTAL (100 to 400 mg/day) from other psychotropic medications and followed for up to
789
18 months, the rates of manic or hypomanic or mixed mood episodes reported as adverse
790
reactions were 5% for patients treated with LAMICTAL (n = 227), 4% for patients treated with
791
lithium (n = 166), and 7% for patients treated with placebo (n = 190). In all bipolar controlled
792
trials combined, adverse reactions of mania (including hypomania and mixed mood episodes)
793
were reported in 5% of patients treated with LAMICTAL (n = 956), 3% of patients treated with
794
lithium (n = 280), and 4% of patients treated with placebo (n = 803).
795
6.2
Other Adverse Reactions Observed in All Clinical Trials
796
LAMICTAL has been administered to 6,694 individuals for whom complete adverse
797
reaction data was captured during all clinical trials, only some of which were placebo controlled.
798
During these trials, all adverse reactions were recorded by the clinical investigators using
799
terminology of their own choosing. To provide a meaningful estimate of the proportion of
800
individuals having adverse reactions, similar types of adverse reactions were grouped into a
801
smaller number of standardized categories using modified COSTART dictionary terminology.
802
The frequencies presented represent the proportion of the 6,694 individuals exposed to
803
LAMICTAL who experienced an event of the type cited on at least 1 occasion while receiving
804
LAMICTAL. All reported adverse reactions are included except those already listed in the
805
previous tables or elsewhere in the labeling, those too general to be informative, and those not
806
reasonably associated with the use of the drug.
807
Adverse reactions are further classified within body system categories and enumerated in
808
order of decreasing frequency using the following definitions: frequent adverse reactions are
31
Reference ID: 3677876
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Page 32
809
defined as those occurring in at least 1/100 patients; infrequent adverse reactions are those
810
occurring in 1/100 to 1/1,000 patients; rare adverse reactions are those occurring in fewer than
811
1/1,000 patients.
812
Body as a Whole: Infrequent: Allergic reaction, chills, malaise.
813
Cardiovascular System: Infrequent: Flushing, hot flashes, hypertension, palpitations,
814
postural hypotension, syncope, tachycardia, vasodilation.
815
Dermatological: Infrequent: Acne, alopecia, hirsutism, maculopapular rash, skin
816
discoloration, urticaria. Rare: Angioedema, erythema, exfoliative dermatitis, fungal dermatitis,
817
herpes zoster, leukoderma, multiforme erythema, petechial rash, pustular rash, Stevens-Johnson
818
syndrome, vesiculobullous rash.
819
Digestive System: Infrequent: Dysphagia, eructation, gastritis, gingivitis, increased
820
appetite, increased salivation, liver function tests abnormal, mouth ulceration. Rare:
821
Gastrointestinal hemorrhage, glossitis, gum hemorrhage, gum hyperplasia, hematemesis,
822
hemorrhagic colitis, hepatitis, melena, stomach ulcer, stomatitis, tongue edema.
823
Endocrine System: Rare: Goiter, hypothyroidism.
824
Hematologic and Lymphatic System: Infrequent: Ecchymosis, leukopenia. Rare:
825
Anemia, eosinophilia, fibrin decrease, fibrinogen decrease, iron deficiency anemia, leukocytosis,
826
lymphocytosis, macrocytic anemia, petechia, thrombocytopenia.
827
Metabolic and Nutritional Disorders: Infrequent: Aspartate transaminase increased.
828
Rare: Alcohol intolerance, alkaline phosphatase increase, alanine transaminase increase,
829
bilirubinemia, general edema, gamma glutamyl transpeptidase increase, hyperglycemia.
830
Musculoskeletal System: Infrequent: Arthritis, leg cramps, myasthenia, twitching.
831
Rare: Bursitis, muscle atrophy, pathological fracture, tendinous contracture.
832
Nervous System: Frequent: Confusion, paresthesia. Infrequent: Akathisia, apathy,
833
aphasia, central nervous system depression, depersonalization, dysarthria, dyskinesia, euphoria,
834
hallucinations, hostility, hyperkinesia, hypertonia, libido decreased, memory decrease, mind
835
racing, movement disorder, myoclonus, panic attack, paranoid reaction, personality disorder,
836
psychosis, sleep disorder, stupor, suicidal ideation. Rare: Choreoathetosis, delirium, delusions,
837
dysphoria, dystonia, extrapyramidal syndrome, faintness, grand mal convulsions, hemiplegia,
838
hyperalgesia, hyperesthesia, hypokinesia, hypotonia, manic depression reaction, muscle spasm,
839
neuralgia, neurosis, paralysis, peripheral neuritis.
840
Respiratory System: Infrequent: Yawn. Rare: Hiccup, hyperventilation.
841
Special Senses: Frequent: Amblyopia. Infrequent: Abnormality of accommodation,
842
conjunctivitis, dry eyes, ear pain, photophobia, taste perversion, tinnitus. Rare: Deafness,
843
lacrimation disorder, oscillopsia, parosmia, ptosis, strabismus, taste loss, uveitis, visual field
844
defect.
845
Urogenital System: Infrequent: Abnormal ejaculation, hematuria, impotence,
846
menorrhagia, polyuria, urinary incontinence. Rare: Acute kidney failure, anorgasmia, breast
32
Reference ID: 3677876
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NDA 022251/S-009 & S-002
FDA Approved Labeling Text dated 12/23/2014
Page 33
847
abscess, breast neoplasm, creatinine increase, cystitis, dysuria, epididymitis, female lactation,
848
kidney failure, kidney pain, nocturia, urinary retention, urinary urgency.
849
6.3
Postmarketing Experience
850
The following adverse events (not listed above in clinical trials or other sections of the
851
prescribing information) have been identified during postapproval use of LAMICTAL. Because
852
these events are reported voluntarily from a population of uncertain size, it is not always possible
853
to reliably estimate their frequency or establish a causal relationship to drug exposure.
854
Blood and Lymphatic: Agranulocytosis, hemolytic anemia, lymphadenopathy not
855
associated with hypersensitivity disorder.
856
Gastrointestinal: Esophagitis.
857
Hepatobiliary Tract and Pancreas: Pancreatitis.
858
Immunologic: Lupus-like reaction, vasculitis.
859
Lower Respiratory: Apnea.
860
Musculoskeletal: Rhabdomyolysis has been observed in patients experiencing
861
hypersensitivity reactions.
862
Neurology: Exacerbation of Parkinsonian symptoms in patients with pre-existing
863
Parkinson’s disease, tics.
864
Non-site Specific: Progressive immunosuppression.
865
7
DRUG INTERACTIONS
866
Significant drug interactions with lamotrigine are summarized in Table 13. Additional
867
details of these drug interaction studies are provided in the Clinical Pharmacology section [see
868
Clinical Pharmacology (12.3)].
869
870
Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug
Effect on
Concentration of
Lamotrigine or
Concomitant Drug
Clinical Comment
Estrogen-containing oral
contraceptive
preparations containing
30 mcg ethinylestradiol
and 150 mcg
levonorgestrel
↓ lamotrigine
↓ levonorgestrel
Decreased lamotrigine concentrations
approximately 50%.
Decrease in levonorgestrel component by
19%.
Carbamazepine and
↓ lamotrigine
Addition of carbamazepine decreases
carbamazepine epoxide
? carbamazepine
epoxide
lamotrigine concentration approximately
40%.
May increase carbamazepine epoxide
levels.
33
Reference ID: 3677876
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Page 34
Lopinavir/ritonavir
↓ lamotrigine
Decreased lamotrigine concentration
approximately 50%.
Atazanavir/ritonavir
↓ lamotrigine
Decreased lamotrigine AUC
approximately 32%.
Phenobarbital/primidone
↓ lamotrigine
Decreased lamotrigine concentration
approximately 40%.
Phenytoin
↓ lamotrigine
Decreased lamotrigine concentration
approximately 40%.
Rifampin
↓ lamotrigine
Decreased lamotrigine AUC
approximately 40%.
Valproate
↑ lamotrigine
? valproate
Increased lamotrigine concentrations
slightly more than 2-fold.
There are conflicting study results
regarding effect of lamotrigine on
valproate concentrations: 1) a mean 25%
decrease in valproate concentrations in
healthy volunteers, 2) no change in
valproate concentrations in controlled
clinical trials in patients with epilepsy.
871
↓ = Decreased (induces lamotrigine glucuronidation).
872
↑ = Increased (inhibits lamotrigine glucuronidation).
873
? = Conflicting data.
874
8
USE IN SPECIFIC POPULATIONS
875
8.1
Pregnancy
876
Teratogenic Effects: Pregnancy Category C. No evidence of teratogenicity was found in
877
mice, rats, or rabbits when lamotrigine was orally administered to pregnant animals during the
878
period of organogenesis at doses up to 1.2, 0.5, and 1.1 times, respectively, on a mg/m2 basis, the
879
highest usual human maintenance dose (i.e., 500 mg/day). However, maternal toxicity and
880
secondary fetal toxicity producing reduced fetal weight and/or delayed ossification were seen in
881
mice and rats, but not in rabbits at these doses. Teratology studies were also conducted using
882
bolus intravenous administration of the isethionate salt of lamotrigine in rats and rabbits. In rat
883
dams administered an intravenous dose at 0.6 times the highest usual human maintenance dose,
884
the incidence of intrauterine death without signs of teratogenicity was increased.
885
A behavioral teratology study was conducted in rats dosed during the period of
886
organogenesis. At day 21 postpartum, offspring of dams receiving 5 mg/kg/day or higher
887
displayed a significantly longer latent period for open field exploration and a lower frequency of
888
rearing. In a swimming maze test performed on days 39 to 44 postpartum, time to completion
34
Reference ID: 3677876
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Page 35
889
was increased in offspring of dams receiving 25 mg/kg/day. These doses represent 0.1 and 0.5
890
times the clinical dose on a mg/m2 basis, respectively.
891
Lamotrigine did not affect fertility, teratogenesis, or postnatal development when rats
892
were dosed prior to and during mating, and throughout gestation and lactation at doses
893
equivalent to 0.4 times the highest usual human maintenance dose on a mg/m2 basis.
894
When pregnant rats were orally dosed at 0.1, 0.14, or 0.3 times the highest human
895
maintenance dose (on a mg/m2 basis) during the latter part of gestation (days 15 to 20), maternal
896
toxicity and fetal death were seen. In dams, food consumption and weight gain were reduced,
897
and the gestation period was slightly prolonged (22.6 vs. 22.0 days in the control group).
898
Stillborn pups were found in all 3 drug-treated groups, with the highest number in the high-dose
899
group. Postnatal death was also seen, but only in the 2 highest doses, and occurred between days
900
1 and 20. Some of these deaths appear to be drug related and not secondary to the maternal
901
toxicity. A no-observed-effect level (NOEL) could not be determined for this study.
902
Although lamotrigine was not found to be teratogenic in the above studies, lamotrigine
903
decreases fetal folate concentrations in rats, an effect known to be associated with teratogenesis
904
in animals and humans. There are no adequate and well-controlled trials in pregnant women.
905
Because animal reproduction studies are not always predictive of human response, this drug
906
should be used during pregnancy only if the potential benefit justifies the potential risk to the
907
fetus.
908
Nonteratogenic Effects: As with other AEDs, physiological changes during pregnancy
909
may affect lamotrigine concentrations and/or therapeutic effect. There have been reports of
910
decreased lamotrigine concentrations during pregnancy and restoration of pre-partum
911
concentrations after delivery. Dosage adjustments may be necessary to maintain clinical
912
response.
913
Pregnancy Registry: To provide information regarding the effects of in utero exposure
914
to LAMICTAL, physicians are advised to recommend that pregnant patients taking LAMICTAL
915
enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be
916
done by calling the toll-free number 1-888-233-2334 and must be done by patients themselves.
917
Information on the registry can also be found at the website
918
http://www.aedpregnancyregistry.org.
919
8.2
Labor and Delivery
920
The effect of LAMICTAL on labor and delivery in humans is unknown.
921
8.3
Nursing Mothers
922
Lamotrigine is present in milk from lactating women taking LAMICTAL. Data from
923
multiple small studies indicate that lamotrigine plasma levels in human milk-fed infants have
924
been reported to be as high as 50% of the maternal serum levels. Neonates and young infants are
925
at risk for high serum levels because maternal serum and milk levels can rise to high levels
926
postpartum if lamotrigine dosage has been increased during pregnancy but not later reduced to
927
the pre-pregnancy dosage. Lamotrigine exposure is further increased due to the immaturity of the
35
Reference ID: 3677876
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-035 & S-040
NDA 020764/S-028 & S-033
NDA 022251/S-009 & S-002
FDA Approved Labeling Text dated 12/23/2014
Page 36
928
infant glucuronidation capacity needed for drug clearance. Events including apnea, drowsiness,
929
and poor sucking have been reported in infants who have been human milk-fed by mothers using
930
lamotrigine; whether or not these events were caused by lamotrigine is unknown. Human milk
931
fed infants should be closely monitored for adverse events resulting from lamotrigine.
932
Measurement of infant serum levels should be performed to rule out toxicity if concerns arise.
933
Human milk-feeding should be discontinued in infants with lamotrigine toxicity. Caution should
934
be exercised when LAMICTAL is administered to a nursing woman.
935
8.4
Pediatric Use
936
LAMICTAL is indicated for adjunctive therapy in patients aged 2 years and older for
937
partial-onset seizures, the generalized seizures of Lennox-Gastaut syndrome, and PGTC seizures.
938
Safety and efficacy of LAMICTAL used as adjunctive treatment for partial-onset seizures
939
were not demonstrated in a small, randomized, double-blind, placebo-controlled withdrawal trial
940
in very young pediatric patients (aged 1 to 24 months). LAMICTAL was associated with an
941
increased risk for infectious adverse reactions (LAMICTAL 37%, placebo 5%), and respiratory
942
adverse reactions (LAMICTAL 26%, placebo 5%). Infectious adverse reactions included
943
bronchiolitis, bronchitis, ear infection, eye infection, otitis externa, pharyngitis, urinary tract
944
infection, and viral infection. Respiratory adverse reactions included nasal congestion, cough,
945
and apnea.
946
Safety and effectiveness in patients younger than 18 years with bipolar disorder have not
947
been established.
948
8.5
Geriatric Use
949
Clinical trials of LAMICTAL for epilepsy and bipolar disorder did not include sufficient
950
numbers of patients aged 65 years and older to determine whether they respond differently from
951
younger patients or exhibit a different safety profile than that of younger patients. In general,
952
dose selection for an elderly patient should be cautious, usually starting at the low end of the
953
dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and
954
of concomitant disease or other drug therapy.
955
8.6
Patients With Hepatic Impairment
956
Experience in patients with hepatic impairment is limited. Based on a clinical
957
pharmacology study in 24 subjects with mild, moderate, and severe liver impairment [see
958
Clinical Pharmacology (12.3)], the following general recommendations can be made. No dosage
959
adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance
960
doses should generally be reduced by approximately 25% in patients with moderate and severe
961
liver impairment without ascites and 50% in patients with severe liver impairment with ascites.
962
Escalation and maintenance doses may be adjusted according to clinical response [see Dosage
963
and Administration (2.1)].
964
8.7
Patients With Renal Impairment
965
Lamotrigine is metabolized mainly by glucuronic acid conjugation, with the majority of
966
the metabolites being recovered in the urine. In a small study comparing a single dose of
36
Reference ID: 3677876
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
s
t
r
u
ctur
al formula
NDA 020241/S-035 & S-040
NDA 020764/S-028 & S-033
NDA 022251/S-009 & S-002
FDA Approved Labeling Text dated 12/23/2014
Page 37
967
lamotrigine in subjects with varying degrees of renal impairment with healthy volunteers, the
968
plasma half-life of lamotrigine was approximately twice as long in the subjects with chronic
969
renal failure [see Clinical Pharmacology (12.3)].
970
Initial doses of LAMICTAL should be based on patients’ AED regimens; reduced
971
maintenance doses may be effective for patients with significant renal impairment. Few patients
972
with severe renal impairment have been evaluated during chronic treatment with lamotrigine.
973
Because there is inadequate experience in this population, LAMICTAL should be used with
974
caution in these patients [see Dosage and Administration (2.1)].
975
10
OVERDOSAGE
976
10.1 Human Overdose Experience
977
Overdoses involving quantities up to 15 g have been reported for LAMICTAL, some of
978
which have been fatal. Overdose has resulted in ataxia, nystagmus, seizures (including tonic
979
clonic seizures), decreased level of consciousness, coma, and intraventricular conduction delay.
980
10.2 Management of Overdose
981
There are no specific antidotes for lamotrigine. Following a suspected overdose,
982
hospitalization of the patient is advised. General supportive care is indicated, including frequent
983
monitoring of vital signs and close observation of the patient. If indicated, emesis should be
984
induced; usual precautions should be taken to protect the airway. It should be kept in mind that
985
immediate-release lamotrigine is rapidly absorbed [see Clinical Pharmacology (12.3)]. It is
986
uncertain whether hemodialysis is an effective means of removing lamotrigine from the blood. In
987
6 renal failure patients, about 20% of the amount of lamotrigine in the body was removed by
988
hemodialysis during a 4-hour session. A Poison Control Center should be contacted for
989
information on the management of overdosage of LAMICTAL.
990
11
DESCRIPTION
991
LAMICTAL (lamotrigine), an AED of the phenyltriazine class, is chemically unrelated to
992
existing AEDs. Lamotrigine’s chemical name is 3,5-diamino-6-(2,3-dichlorophenyl)-as-triazine,
993
its molecular formula is C9H7N5Cl2, and its molecular weight is 256.09. Lamotrigine is a white to
994
pale cream-colored powder and has a pKa of 5.7. Lamotrigine is very slightly soluble in water
995
(0.17 mg/mL at 25°C) and slightly soluble in 0.1 M HCl (4.1 mg/mL at 25°C). The structural
996
formula is:
997
1000
LAMICTAL Tablets are supplied for oral administration as 25-mg (white), 100-mg
1001
(peach), 150-mg (cream), and 200-mg (blue) tablets. Each tablet contains the labeled amount of
37
Reference ID: 3677876
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Page 38
1002
lamotrigine and the following inactive ingredients: lactose; magnesium stearate; microcrystalline
1003
cellulose; povidone; sodium starch glycolate; FD&C Yellow No. 6 Lake (100-mg tablet only);
1004
ferric oxide, yellow (150-mg tablet only); and FD&C Blue No. 2 Lake (200-mg tablet only).
1005
LAMICTAL Chewable Dispersible Tablets are supplied for oral administration. The
1006
tablets contain 2 mg (white), 5 mg (white), or 25 mg (white) of lamotrigine and the following
1007
inactive ingredients: blackcurrant flavor, calcium carbonate, low-substituted
1008
hydroxypropylcellulose, magnesium aluminum silicate, magnesium stearate, povidone, saccharin
1009
sodium, and sodium starch glycolate.
1010
LAMICTAL ODT Orally Disintegrating Tablets are supplied for oral administration. The
1011
tablets contain 25 mg (white to off-white), 50 mg (white to off-white), 100 mg (white to
1012
off-white), or 200 mg (white to off-white) of lamotrigine and the following inactive ingredients:
1013
artificial cherry flavor, crospovidone, ethylcellulose, magnesium stearate, mannitol,
1014
polyethylene, and sucralose.
1015
LAMICTAL ODT Orally Disintegrating Tablets are formulated using technologies
1016
(Microcaps® and AdvaTab®) designed to mask the bitter taste of lamotrigine and achieve a rapid
1017
dissolution profile. Tablet characteristics including flavor, mouth-feel, after-taste, and ease of use
1018
were rated as favorable in a study in 108 healthy volunteers.
1019
12
CLINICAL PHARMACOLOGY
1020
12.1 Mechanism of Action
1021
The precise mechanism(s) by which lamotrigine exerts its anticonvulsant action are
1022
unknown. In animal models designed to detect anticonvulsant activity, lamotrigine was effective
1023
in preventing seizure spread in the maximum electroshock (MES) and pentylenetetrazol (scMet)
1024
tests, and prevented seizures in the visually and electrically evoked after-discharge (EEAD) tests
1025
for antiepileptic activity. Lamotrigine also displayed inhibitory properties in the kindling model
1026
in rats both during kindling development and in the fully kindled state. The relevance of these
1027
models to human epilepsy, however, is not known.
1028
One proposed mechanism of action of lamotrigine, the relevance of which remains to be
1029
established in humans, involves an effect on sodium channels. In vitro pharmacological studies
1030
suggest that lamotrigine inhibits voltage-sensitive sodium channels, thereby stabilizing neuronal
1031
membranes and consequently modulating presynaptic transmitter release of excitatory amino
1032
acids (e.g., glutamate and aspartate).
1033
Although the relevance for human use is unknown, the following data characterize the
1034
performance of lamotrigine in receptor binding assays. Lamotrigine had a weak inhibitory effect
1035
on the serotonin 5-HT3 receptor (IC50 = 18 µM). It does not exhibit high affinity binding
1036
(IC50>100 µM) to the following neurotransmitter receptors: adenosine A1 and A2; adrenergic α1,
1037
α2, and β; dopamine D1 and D2; γ-aminobutyric acid (GABA) A and B; histamine H1; kappa
1038
opioid; muscarinic acetylcholine; and serotonin 5-HT2. Studies have failed to detect an effect of
1039
lamotrigine on dihydropyridine-sensitive calcium channels. It had weak effects at sigma opioid
38
Reference ID: 3677876
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For current labeling information, please visit https://www.fda.gov/drugsatfda
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Page 39
1040
receptors (IC50 = 145 µM). Lamotrigine did not inhibit the uptake of norepinephrine, dopamine,
1041
or serotonin (IC50>200 µM) when tested in rat synaptosomes and/or human platelets in vitro.
1042
Effect of Lamotrigine on N-Methyl d-Aspartate-Receptor Mediated Activity:
1043
Lamotrigine did not inhibit N-methyl d-aspartate (NMDA)-induced depolarizations in rat cortical
1044
slices or NMDA-induced cyclic GMP formation in immature rat cerebellum, nor did lamotrigine
1045
displace compounds that are either competitive or noncompetitive ligands at this glutamate
1046
receptor complex (CNQX, CGS, TCHP). The IC50 for lamotrigine effects on NMDA-induced
1047
currents (in the presence of 3 µM of glycine) in cultured hippocampal neurons exceeded 100
1048
µM.
1049
The mechanisms by which lamotrigine exerts its therapeutic action in bipolar disorder
1050
have not been established.
1051
12.2 Pharmacodynamics
1052
Folate Metabolism: In vitro, lamotrigine inhibited dihydrofolate reductase, the enzyme
1053
that catalyzes the reduction of dihydrofolate to tetrahydrofolate. Inhibition of this enzyme may
1054
interfere with the biosynthesis of nucleic acids and proteins. When oral daily doses of
1055
lamotrigine were given to pregnant rats during organogenesis, fetal, placental, and maternal
1056
folate concentrations were reduced. Significantly reduced concentrations of folate are associated
1057
with teratogenesis [see Use in Specific Populations (8.1)]. Folate concentrations were also
1058
reduced in male rats given repeated oral doses of lamotrigine. Reduced concentrations were
1059
partially returned to normal when supplemented with folinic acid.
1060
Accumulation in Kidneys: Lamotrigine accumulated in the kidney of the male rat,
1061
causing chronic progressive nephrosis, necrosis, and mineralization. These findings are attributed
1062
to α-2 microglobulin, a species- and sex-specific protein that has not been detected in humans or
1063
other animal species.
1064
Melanin Binding: Lamotrigine binds to melanin-containing tissues, e.g., in the eye and
1065
pigmented skin. It has been found in the uveal tract up to 52 weeks after a single dose in rodents.
1066
Cardiovascular: In dogs, lamotrigine is extensively metabolized to a 2-N-methyl
1067
metabolite. This metabolite causes dose-dependent prolongation of the PR interval, widening of
1068
the QRS complex, and, at higher doses, complete AV conduction block. Similar cardiovascular
1069
effects are not anticipated in humans because only trace amounts of the 2-N-methyl metabolite
1070
(<0.6% of lamotrigine dose) have been found in human urine [see Clinical Pharmacology
1071
(12.3)]. However, it is conceivable that plasma concentrations of this metabolite could be
1072
increased in patients with a reduced capacity to glucuronidate lamotrigine (e.g., in patients with
1073
liver disease, patients taking concomitant medications that inhibit glucuronidation).
1074
12.3 Pharmacokinetics
1075
The pharmacokinetics of lamotrigine have been studied in subjects with epilepsy, healthy
1076
young and elderly volunteers, and volunteers with chronic renal failure. Lamotrigine
1077
pharmacokinetic parameters for adult and pediatric subjects and healthy normal volunteers are
1078
summarized in Tables 14 and 16.
39
Reference ID: 3677876
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Page 40
1079
1080
Table 14. Mean Pharmacokinetic Parametersa in Healthy Volunteers and Adult Subjects
1081
With Epilepsy
Adult Study Population
Number
of
Subjects
Tmax: Time of
Maximum
Plasma
Concentration
(h)
t½:
Elimination
Half-life
(h)
CL/F:
Apparent
Plasma
Clearance
(mL/min/kg)
Healthy volunteers taking no
other medications:
Single-dose LAMICTAL
179
2.2
32.8
0.44
(0.25-12.0)
(14.0-103.0)
(0.12-1.10)
Multiple-dose LAMICTAL
36
1.7
25.4
0.58
(0.5-4.0)
(11.6-61.6)
(0.24-1.15)
Healthy volunteers taking
valproate:
Single-dose LAMICTAL
6
1.8
48.3
0.30
(1.0-4.0)
(31.5-88.6)
(0.14-0.42)
Multiple-dose LAMICTAL
18
1.9
70.3
0.18
(0.5-3.5)
(41.9-113.5)
(0.12-0.33)
Subjects with epilepsy taking
valproate only:
Single-dose LAMICTAL
4
4.8
58.8
0.28
(1.8-8.4)
(30.5-88.8)
(0.16-0.40)
Subjects with epilepsy taking
carbamazepine, phenytoin,
phenobarbital, or primidoneb
plus valproate:
Single-dose LAMICTAL
25
3.8
(1.0-10.0)
27.2
(11.2-51.6)
0.53
(0.27-1.04)
Subjects with epilepsy taking
carbamazepine, phenytoin,
phenobarbital, or primidone:b
Single-dose LAMICTAL
24
2.3
14.4
1.10
(0.5-5.0)
(6.4-30.4)
(0.51-2.22)
Multiple-dose LAMICTAL
17
2.0
12.6
1.21
(0.75-5.93)
(7.5-23.1)
(0.66-1.82)
1082
a The majority of parameter means determined in each study had coefficients of variation
1083
between 20% and 40% for half-life and CL/F and between 30% and 70% for Tmax. The overall
40
Reference ID: 3677876
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Page 41
1084
mean values were calculated from individual study means that were weighted based on the
1085
number of volunteers/subjects in each study. The numbers in parentheses below each
1086
parameter mean represent the range of individual volunteer/subject values across studies.
1087
b Carbamazepine, phenytoin, phenobarbital, and primidone have been shown to increase the
1088
apparent clearance of lamotrigine. Estrogen-containing oral contraceptives and other drugs,
1089
such as rifampin and protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir, that
1090
induce lamotrigine glucuronidation have also been shown to increase the apparent clearance
1091
of lamotrigine [see Drug Interactions (7)].
1092
1093
Absorption: Lamotrigine is rapidly and completely absorbed after oral administration
1094
with negligible first-pass metabolism (absolute bioavailability is 98%). The bioavailability is not
1095
affected by food. Peak plasma concentrations occur anywhere from 1.4 to 4.8 hours following
1096
drug administration. The lamotrigine chewable/dispersible tablets were found to be equivalent
1097
whether administered as dispersed in water, chewed and swallowed, or swallowed as whole, to
1098
the lamotrigine compressed tablets in terms of rate and extent of absorption. In terms of rate and
1099
extent of absorption, lamotrigine orally disintegrating tablets whether disintegrated in the mouth
1100
or swallowed whole with water were equivalent to the lamotrigine compressed tablets swallowed
1101
with water.
1102
Dose Proportionality: In healthy volunteers not receiving any other medications and
1103
given single doses, the plasma concentrations of lamotrigine increased in direct proportion to the
1104
dose administered over the range of 50 to 400 mg. In 2 small studies (n = 7 and 8) of patients
1105
with epilepsy who were maintained on other AEDs, there also was a linear relationship between
1106
dose and lamotrigine plasma concentrations at steady state following doses of 50 to 350 mg
1107
twice daily.
1108
Distribution: Estimates of the mean apparent volume of distribution (Vd/F) of
1109
lamotrigine following oral administration ranged from 0.9 to 1.3 L/kg. Vd/F is independent of
1110
dose and is similar following single and multiple doses in both patients with epilepsy and in
1111
healthy volunteers.
1112
Protein Binding: Data from in vitro studies indicate that lamotrigine is approximately
1113
55% bound to human plasma proteins at plasma lamotrigine concentrations from 1 to 10 mcg/mL
1114
(10 mcg/mL is 4 to 6 times the trough plasma concentration observed in the controlled efficacy
1115
trials). Because lamotrigine is not highly bound to plasma proteins, clinically significant
1116
interactions with other drugs through competition for protein binding sites are unlikely. The
1117
binding of lamotrigine to plasma proteins did not change in the presence of therapeutic
1118
concentrations of phenytoin, phenobarbital, or valproate. Lamotrigine did not displace other
1119
AEDs (carbamazepine, phenytoin, phenobarbital) from protein-binding sites.
1120
Metabolism: Lamotrigine is metabolized predominantly by glucuronic acid conjugation;
1121
the major metabolite is an inactive 2-N-glucuronide conjugate. After oral administration of
1122
240 mg of 14C-lamotrigine (15 µCi) to 6 healthy volunteers, 94% was recovered in the urine and
41
Reference ID: 3677876
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1123
2% was recovered in the feces. The radioactivity in the urine consisted of unchanged lamotrigine
1124
(10%), the 2-N-glucuronide (76%), a 5-N-glucuronide (10%), a 2-N-methyl metabolite (0.14%),
1125
and other unidentified minor metabolites (4%).
1126
Enzyme Induction: The effects of lamotrigine on the induction of specific families of
1127
mixed-function oxidase isozymes have not been systematically evaluated.
1128
Following multiple administrations (150 mg twice daily) to normal volunteers taking no
1129
other medications, lamotrigine induced its own metabolism, resulting in a 25% decrease in t½ and
1130
a 37% increase in CL/F at steady state compared with values obtained in the same volunteers
1131
following a single dose. Evidence gathered from other sources suggests that self-induction by
1132
lamotrigine may not occur when lamotrigine is given as adjunctive therapy in patients receiving
1133
enzyme-inducing drugs such as carbamazepine, phenytoin, phenobarbital, primidone, or other
1134
drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir
1135
that induce lamotrigine glucuronidation [see Drug Interactions (7)].
1136
Elimination: The elimination half-life and apparent clearance of lamotrigine following
1137
oral administration of LAMICTAL to adult subjects with epilepsy and healthy volunteers is
1138
summarized in Table 14. Half-life and apparent oral clearance vary depending on concomitant
1139
AEDs.
1140
Drug Interactions: The apparent clearance of lamotrigine is affected by the
1141
coadministration of certain medications [see Warnings and Precautions (5.8, 5.12), Drug
1142
Interactions (7)].
1143
The net effects of drug interactions with lamotrigine are summarized in Tables 13 and 15,
1144
followed by details of the drug interaction studies below.
1145
1146
Table 15. Summary of Drug Interactions With Lamotrigine
Drug
Drug Plasma
Concentration With
Adjunctive Lamotriginea
Lamotrigine Plasma
Concentration With
Adjunctive Drugsb
Oral contraceptives (e.g.,
ethinylestradiol/levonorgestrel)c
Atazanavir/ritonavir
Bupropion
Carbamazepine
Carbamazepine epoxidef
Felbamate
Gabapentin
Levetiracetam
Lithium
Lopinavir/ritonavir
Olanzapine
↔d
↔e
Not assessed
↔
?
Not assessed
Not assessed
↔
↔
↔e
↔
↓
↓
↔
↓
↔
↔
↔
Not assessed
↓
↔g
42
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Page 43
Oxcarbazepine
10-Monohydroxy oxcarbazepine
metaboliteh
Phenobarbital/primidone
Phenytoin
Pregabalin
Rifampin
Risperidone
9-hydroxyrisperidonei
Topiramate
Valproate
Valproate + phenytoin and/or
carbamazepine
Zonisamide
↔
↔
↔
↔
↔
Not assessed
↔
↔
↔j
↓
Not assessed
Not assessed
↔
↓
↓
↔
↓
Not assessed
↔
↑
↔
↔
1147
a From adjunctive clinical trials and volunteer trials.
1148
b Net effects were estimated by comparing the mean clearance values obtained in adjunctive
1149
clinical trials and volunteer trials.
1150
c The effect of other hormonal contraceptive preparations or hormone replacement therapy on
1151
the pharmacokinetics of lamotrigine has not been systematically evaluated in clinical trials,
1152
although the effect may be similar to that seen with the ethinylestradiol/levonorgestrel
1153
combinations.
1154
d Modest decrease in levonorgestrel.
1155
e Compared to historical controls.
1156
f Not administered, but an active metabolite of carbamazepine.
1157
g Slight decrease, not expected to be clinically relevant.
1158
h Not administered, but an active metabolite of oxcarbazepine.
1159
i Not administered, but an active metabolite of risperidone.
1160
j Slight increase, not expected to be clinically relevant.
1161
↔ = No significant effect.
1162
? = Conflicting data.
1163
1164
Estrogen-Containing Oral Contraceptives: In 16 female volunteers, an oral
1165
contraceptive preparation containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel
1166
increased the apparent clearance of lamotrigine (300 mg/day) by approximately 2-fold with mean
1167
decreases in AUC of 52% and in Cmax of 39%. In this study, trough serum lamotrigine
1168
concentrations gradually increased and were approximately 2-fold higher on average at the end
1169
of the week of the inactive hormone preparation compared with trough lamotrigine
1170
concentrations at the end of the active hormone cycle.
43
Reference ID: 3677876
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Page 44
1171
Gradual transient increases in lamotrigine plasma levels (approximate 2-fold increase)
1172
occurred during the week of inactive hormone preparation (pill-free week) for women not also
1173
taking a drug that increased the clearance of lamotrigine (carbamazepine, phenytoin,
1174
phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors
1175
lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation) [see Drug
1176
Interactions (7)]. The increase in lamotrigine plasma levels will be greater if the dose of
1177
LAMICTAL is increased in the few days before or during the pill-free week. Increases in
1178
lamotrigine plasma levels could result in dose-dependent adverse reactions.
1179
In the same study, coadministration of lamotrigine (300 mg/day) in 16 female volunteers
1180
did not affect the pharmacokinetics of the ethinylestradiol component of the oral contraceptive
1181
preparation. There were mean decreases in the AUC and Cmax of the levonorgestrel component of
1182
19% and 12%, respectively. Measurement of serum progesterone indicated that there was no
1183
hormonal evidence of ovulation in any of the 16 volunteers, although measurement of serum
1184
FSH, LH, and estradiol indicated that there was some loss of suppression of the hypothalamic
1185
pituitary-ovarian axis.
1186
The effects of doses of lamotrigine other than 300 mg/day have not been systematically
1187
evaluated in controlled clinical trials.
1188
The clinical significance of the observed hormonal changes on ovulatory activity is
1189
unknown. However, the possibility of decreased contraceptive efficacy in some patients cannot
1190
be excluded. Therefore, patients should be instructed to promptly report changes in their
1191
menstrual pattern (e.g., break-through bleeding).
1192
Dosage adjustments may be necessary for women receiving estrogen-containing oral
1193
contraceptive preparations [see Dosage and Administration (2.1)].
1194
Other Hormonal Contraceptives or Hormone Replacement Therapy: The effect of
1195
other hormonal contraceptive preparations or hormone replacement therapy on the
1196
pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that
1197
ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the
1198
progestin-only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the
1199
dosage of LAMICTAL in the presence of progestogens alone will likely not be needed.
1200
Atazanavir/Ritonavir: In a study in healthy volunteers, daily doses of
1201
atazanavir/ritonavir (300 mg/100 mg) reduced the plasma AUC and Cmax of lamotrigine (single
1202
100-mg dose) by an average of 32% and 6%, respectively, and shortened the elimination half
1203
lives by 27%. In the presence of atazanavir/ritonavir (300 mg/100 mg), the metabolite-to
1204
lamotrigine ratio was increased from 0.45 to 0.71 consistent with induction of glucuronidation.
1205
The pharmacokinetics of atazanavir/ritonavir were similar in the presence of concomitant
1206
lamotrigine to the historical data of the pharmacokinetics in the absence of lamotrigine.
1207
Bupropion: The pharmacokinetics of a 100-mg single dose of lamotrigine in healthy
1208
volunteers (n = 12) were not changed by coadministration of bupropion sustained-release
1209
formulation (150 mg twice daily) starting 11 days before lamotrigine.
44
Reference ID: 3677876
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For current labeling information, please visit https://www.fda.gov/drugsatfda
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Page 45
1210
Carbamazepine: Lamotrigine has no appreciable effect on steady-state carbamazepine
1211
plasma concentration. Limited clinical data suggest there is a higher incidence of dizziness,
1212
diplopia, ataxia, and blurred vision in patients receiving carbamazepine with lamotrigine than in
1213
patients receiving other AEDs with lamotrigine [see Adverse Reactions (6.1)]. The mechanism
1214
of this interaction is unclear. The effect of lamotrigine on plasma concentrations of
1215
carbamazepine-epoxide is unclear. In a small subset of patients (n = 7) studied in a placebo
1216
controlled trial, lamotrigine had no effect on carbamazepine-epoxide plasma concentrations, but
1217
in a small, uncontrolled study (n = 9), carbamazepine-epoxide levels increased.
1218
The addition of carbamazepine decreases lamotrigine steady-state concentrations by
1219
approximately 40%.
1220
Felbamate: In a trial in 21 healthy volunteers, coadministration of felbamate (1,200 mg
1221
twice daily) with lamotrigine (100 mg twice daily for 10 days) appeared to have no clinically
1222
relevant effects on the pharmacokinetics of lamotrigine.
1223
Folate Inhibitors: Lamotrigine is a weak inhibitor of dihydrofolate reductase. Prescribers
1224
should be aware of this action when prescribing other medications that inhibit folate metabolism.
1225
Gabapentin: Based on a retrospective analysis of plasma levels in 34 subjects who
1226
received lamotrigine both with and without gabapentin, gabapentin does not appear to change the
1227
apparent clearance of lamotrigine.
1228
Levetiracetam: Potential drug interactions between levetiracetam and lamotrigine were
1229
assessed by evaluating serum concentrations of both agents during placebo-controlled clinical
1230
trials. These data indicate that lamotrigine does not influence the pharmacokinetics of
1231
levetiracetam and that levetiracetam does not influence the pharmacokinetics of lamotrigine.
1232
Lithium: The pharmacokinetics of lithium were not altered in healthy subjects (n = 20) by
1233
coadministration of lamotrigine (100 mg/day) for 6 days.
1234
Lopinavir/Ritonavir: The addition of lopinavir (400 mg twice daily)/ritonavir (100 mg
1235
twice daily) decreased the AUC, Cmax, and elimination half-life of lamotrigine by approximately
1236
50% to 55.4% in 18 healthy subjects. The pharmacokinetics of lopinavir/ritonavir were similar
1237
with concomitant lamotrigine, compared to that in historical controls.
1238
Olanzapine: The AUC and Cmax of olanzapine were similar following the addition of
1239
olanzapine (15 mg once daily) to lamotrigine (200 mg once daily) in healthy male volunteers
1240
(n = 16) compared with the AUC and Cmax in healthy male volunteers receiving olanzapine alone
1241
(n = 16).
1242
In the same trial, the AUC and Cmax of lamotrigine were reduced on average by 24% and
1243
20%, respectively, following the addition of olanzapine to lamotrigine in healthy male volunteers
1244
compared with those receiving lamotrigine alone. This reduction in lamotrigine plasma
1245
concentrations is not expected to be clinically relevant.
1246
Oxcarbazepine: The AUC and Cmax of oxcarbazepine and its active 10-monohydroxy
1247
oxcarbazepine metabolite were not significantly different following the addition of
1248
oxcarbazepine (600 mg twice daily) to lamotrigine (200 mg once daily) in healthy male
45
Reference ID: 3677876
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Page 46
1249
volunteers (n = 13) compared with healthy male volunteers receiving oxcarbazepine alone
1250
(n = 13).
1251
In the same trial, the AUC and Cmax of lamotrigine were similar following the addition of
1252
oxcarbazepine (600 mg twice daily) to lamotrigine in healthy male volunteers compared with
1253
those receiving lamotrigine alone. Limited clinical data suggest a higher incidence of headache,
1254
dizziness, nausea, and somnolence with coadministration of lamotrigine and oxcarbazepine
1255
compared with lamotrigine alone or oxcarbazepine alone.
1256
Phenobarbital, Primidone: The addition of phenobarbital or primidone decreases
1257
lamotrigine steady-state concentrations by approximately 40%.
1258
Phenytoin: Lamotrigine has no appreciable effect on steady-state phenytoin plasma
1259
concentrations in patients with epilepsy. The addition of phenytoin decreases lamotrigine steady
1260
state concentrations by approximately 40%.
1261
Pregabalin: Steady-state trough plasma concentrations of lamotrigine were not affected
1262
by concomitant pregabalin (200 mg 3 times daily) administration. There are no pharmacokinetic
1263
interactions between lamotrigine and pregabalin.
1264
Rifampin: In 10 male volunteers, rifampin (600 mg/day for 5 days) significantly
1265
increased the apparent clearance of a single 25-mg dose of lamotrigine by approximately 2-fold
1266
(AUC decreased by approximately 40%).
1267
Risperidone: In a 14 healthy volunteers study, multiple oral doses of lamotrigine 400 mg
1268
daily had no clinically significant effect on the single-dose pharmacokinetics of risperidone 2 mg
1269
and its active metabolite 9-OH risperidone. Following the coadministration of risperidone 2 mg
1270
with lamotrigine, 12 of the 14 volunteers reported somnolence compared with 1 out of 20 when
1271
risperidone was given alone, and none when lamotrigine was administered alone.
1272
Topiramate: Topiramate resulted in no change in plasma concentrations of lamotrigine.
1273
Administration of lamotrigine resulted in a 15% increase in topiramate concentrations.
1274
Valproate: When lamotrigine was administered to healthy volunteers (n = 18) receiving
1275
valproate, the trough steady-state valproate plasma concentrations decreased by an average of
1276
25% over a 3-week period, and then stabilized. However, adding lamotrigine to the existing
1277
therapy did not cause a change in valproate plasma concentrations in either adult or pediatric
1278
patients in controlled clinical trials.
1279
The addition of valproate increased lamotrigine steady-state concentrations in normal
1280
volunteers by slightly more than 2-fold. In 1 trial, maximal inhibition of lamotrigine clearance
1281
was reached at valproate doses between 250 and 500 mg/day and did not increase as the
1282
valproate dose was further increased.
1283
Zonisamide: In a study in 18 patients with epilepsy, coadministration of zonisamide
1284
(200 to 400 mg/day) with lamotrigine (150 to 500 mg/day for 35 days) had no significant effect
1285
on the pharmacokinetics of lamotrigine.
1286
Known Inducers or Inhibitors of Glucuronidation: Drugs other than those listed above
1287
have not been systematically evaluated in combination with lamotrigine. Since lamotrigine is
46
Reference ID: 3677876
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-035 & S-040
NDA 020764/S-028 & S-033
NDA 022251/S-009 & S-002
FDA Approved Labeling Text dated 12/23/2014
Page 47
1288
metabolized predominately by glucuronic acid conjugation, drugs that are known to induce or
1289
inhibit glucuronidation may affect the apparent clearance of lamotrigine and doses of lamotrigine
1290
may require adjustment based on clinical response.
1291
Other: Results of in vitro experiments suggest that clearance of lamotrigine is unlikely to
1292
be reduced by concomitant administration of amitriptyline, clonazepam, clozapine, fluoxetine,
1293
haloperidol, lorazepam, phenelzine, sertraline, or trazodone.
1294
Results of in vitro experiments suggest that lamotrigine does not reduce the clearance of
1295
drugs eliminated predominantly by CYP2D6.
1296
Specific Populations: Subjects With Renal Impairment: Twelve volunteers with
1297
chronic renal failure (mean creatinine clearance: 13 mL/min, range: 6 to 23) and another 6
1298
individuals undergoing hemodialysis were each given a single 100-mg dose of lamotrigine. The
1299
mean plasma half-lives determined in the study were 42.9 hours (chronic renal failure),
1300
13.0 hours (during hemodialysis), and 57.4 hours (between hemodialysis) compared with
1301
26.2 hours in healthy volunteers. On average, approximately 20% (range: 5.6 to 35.1) of the
1302
amount of lamotrigine present in the body was eliminated by hemodialysis during a 4-hour
1303
session [see Dosage and Administration (2.1)].
1304
Hepatic Disease: The pharmacokinetics of lamotrigine following a single 100-mg
1305
dose of lamotrigine were evaluated in 24 subjects with mild, moderate, and severe hepatic
1306
impairment (Child-Pugh Classification system) and compared with 12 subjects without hepatic
1307
impairment. The subjects with severe hepatic impairment were without ascites (n = 2) or with
1308
ascites (n = 5). The mean apparent clearances of lamotrigine in subjects with mild (n = 12),
1309
moderate (n = 5), severe without ascites (n = 2), and severe with ascites (n = 5) liver impairment
1310
were 0.30 ± 0.09, 0.24 ± 0.1, 0.21 ± 0.04, and 0.15 ± 0.09 mL/min/kg, respectively, as compared
1311
with 0.37 ± 0.1 mL/min/kg in the healthy controls. Mean half-lives of lamotrigine in subjects
1312
with mild, moderate, severe without ascites, and severe with ascites hepatic impairment were
1313
46 ± 20, 72 ± 44, 67 ± 11, and 100 ± 48 hours, respectively, as compared with 33 ± 7 hours in
1314
healthy controls [see Dosage and Administration (2.1)].
1315
Age: Pediatric Subjects: The pharmacokinetics of lamotrigine following a single
1316
2-mg/kg dose were evaluated in 2 studies in pediatric subjects (n = 29 for subjects aged 10
1317
months to 5.9 years and n = 26 for subjects aged 5 to 11 years). Forty-three subjects received
1318
concomitant therapy with other AEDs and 12 subjects received lamotrigine as monotherapy.
1319
Lamotrigine pharmacokinetic parameters for pediatric patients are summarized in Table 16.
1320
Population pharmacokinetic analyses involving subjects aged 2 to 18 years demonstrated
1321
that lamotrigine clearance was influenced predominantly by total body weight and concurrent
1322
AED therapy. The oral clearance of lamotrigine was higher, on a body weight basis, in pediatric
1323
patients than in adults. Weight-normalized lamotrigine clearance was higher in those subjects
1324
weighing less than 30 kg compared with those weighing greater than 30 kg. Accordingly,
1325
patients weighing less than 30 kg may need an increase of as much as 50% in maintenance doses,
1326
based on clinical response, as compared with subjects weighing more than 30 kg being
47
Reference ID: 3677876
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-035 & S-040
NDA 020764/S-028 & S-033
NDA 022251/S-009 & S-002
FDA Approved Labeling Text dated 12/23/2014
Page 48
1327
administered the same AEDs [see Dosage and Administration (2.2)]. These analyses also
1328
revealed that, after accounting for body weight, lamotrigine clearance was not significantly
1329
influenced by age. Thus, the same weight-adjusted doses should be administered to children
1330
irrespective of differences in age. Concomitant AEDs which influence lamotrigine clearance in
1331
adults were found to have similar effects in children.
1332
1333
Table 16. Mean Pharmacokinetic Parameters in Pediatric Subjects With Epilepsy
Pediatric Study Population
Number of
Subjects
Tmax
(h)
t½
(h)
CL/F
(mL/min/kg)
Ages 10 months-5.3 years
Subjects taking carbamazepine,
10
3.0
7.7
3.62
phenytoin, phenobarbital, or
primidonea
(1.0-5.9)
(5.7-11.4)
(2.44-5.28)
Subjects taking AEDs with no
7
5.2
19.0
1.2
known effect on the apparent
clearance of lamotrigine
(2.9-6.1)
(12.9-27.1)
(0.75-2.42)
Subjects taking valproate only
8
2.9
44.9
0.47
(1.0-6.0)
(29.5-52.5)
(0.23-0.77)
Ages 5-11 years
Subjects taking carbamazepine,
7
1.6
7.0
2.54
phenytoin, phenobarbital, or
primidonea
(1.0-3.0)
(3.8-9.8)
(1.35-5.58)
Subjects taking carbamazepine,
8
3.3
19.1
0.89
phenytoin, phenobarbital, or
primidonea plus valproate
(1.0-6.4)
(7.0-31.2)
(0.39-1.93)
Subjects taking valproate only
b
3
4.5
65.8
0.24
(3.0-6.0)
(50.7-73.7)
(0.21-0.26)
Ages 13-18 years
Subjects taking carbamazepine,
phenytoin, phenobarbital, or
primidonea
11
___ c
___ c
1.3
Subjects taking carbamazepine,
phenytoin, phenobarbital, or
primidonea plus valproate
8
___ c
___ c
0.5
Subjects taking valproate only
4
___ c
___ c
0.3
1334
a Carbamazepine, phenytoin, phenobarbital, and primidone have been shown to increase the
1335
apparent clearance of lamotrigine. Estrogen-containing oral contraceptives, rifampin, and the
1336
protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir have also been shown to
1337
increase the apparent clearance of lamotrigine [see Drug Interactions (7)].
48
Reference ID: 3677876
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-035 & S-040
NDA 020764/S-028 & S-033
NDA 022251/S-009 & S-002
FDA Approved Labeling Text dated 12/23/2014
Page 49
1338
b Two subjects were included in the calculation for mean Tmax.
1339
c Parameter not estimated.
1340
1341
Elderly: The pharmacokinetics of lamotrigine following a single 150-mg dose of
1342
lamotrigine were evaluated in 12 elderly volunteers between the ages of 65 and 76 years (mean
1343
creatinine clearance = 61 mL/min, range: 33 to 108 mL/min). The mean half-life of lamotrigine
1344
in these subjects was 31.2 hours (range: 24.5 to 43.4 hours), and the mean clearance was
1345
0.40 mL/min/kg (range: 0.26 to 0.48 mL/min/kg).
1346
Gender: The clearance of lamotrigine is not affected by gender. However, during
1347
dose escalation of lamotrigine in 1 clinical trial in patients with epilepsy on a stable dose of
1348
valproate (n = 77), mean trough lamotrigine concentrations unadjusted for weight were 24% to
1349
45% higher (0.3 to 1.7 mcg/mL) in females than in males.
1350
Race: The apparent oral clearance of lamotrigine was 25% lower in non-Caucasians
1351
than Caucasians.
1352
13
NONCLINICAL TOXICOLOGY
1353
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
1354
No evidence of carcinogenicity was seen in 1 mouse study or 2 rat studies following oral
1355
administration of lamotrigine for up to 2 years at maximum tolerated doses (30 mg/kg/day for
1356
mice and 10 to 15 mg/kg/day for rats, doses that are equivalent to 90 mg/m2 and 60 to 90 mg/m2 ,
1357
respectively). Steady-state plasma concentrations ranged from 1 to 4 mcg/mL in the mouse study
1358
and 1 to 10 mcg/mL in the rat study. Plasma concentrations associated with the recommended
1359
human doses of 300 to 500 mg/day are generally in the range of 2 to 5 mcg/mL, but
1360
concentrations as high as 19 mcg/mL have been recorded.
1361
Lamotrigine was not mutagenic in the presence or absence of metabolic activation when
1362
tested in 2 gene mutation assays (the Ames test and the in vitro mammalian mouse lymphoma
1363
assay). In 2 cytogenetic assays (the in vitro human lymphocyte assay and the in vivo rat bone
1364
marrow assay), lamotrigine did not increase the incidence of structural or numerical
1365
chromosomal abnormalities.
1366
No evidence of impairment of fertility was detected in rats given oral doses of
1367
lamotrigine up to 2.4 times the highest usual human maintenance dose of 8.33 mg/kg/day or
1368
0.4 times the human dose on a mg/m2 basis. The effect of lamotrigine on human fertility is
1369
unknown.
1370
14
CLINICAL STUDIES
1371
14.1 Epilepsy
1372
Monotherapy With LAMICTAL in Adults With Partial-Onset Seizures Already
1373
Receiving Treatment With Carbamazepine, Phenytoin, Phenobarbital, or Primidone as
1374
the Single Antiepileptic Drug: The effectiveness of monotherapy with LAMICTAL was
1375
established in a multicenter, double-blind clinical trial enrolling 156 adult outpatients with
49
Reference ID: 3677876
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-035 & S-040
NDA 020764/S-028 & S-033
NDA 022251/S-009 & S-002
FDA Approved Labeling Text dated 12/23/2014
Page 50
1376
partial-onset seizures. The patients experienced at least 4 simple partial-onset, complex partial
1377
onset, and/or secondarily generalized seizures during each of 2 consecutive 4-week periods while
1378
receiving carbamazepine or phenytoin monotherapy during baseline. LAMICTAL (target dose of
1379
500 mg/day) or valproate (1,000 mg/day) was added to either carbamazepine or phenytoin
1380
monotherapy over a 4-week period. Patients were then converted to monotherapy with
1381
LAMICTAL or valproate during the next 4 weeks, then continued on monotherapy for an
1382
additional 12-week period.
1383
Trial endpoints were completion of all weeks of trial treatment or meeting an escape
1384
criterion. Criteria for escape relative to baseline were: (1) doubling of average monthly seizure
1385
count, (2) doubling of highest consecutive 2-day seizure frequency, (3) emergence of a new
1386
seizure type (defined as a seizure that did not occur during the 8-week baseline) that is more
1387
severe than seizure types that occur during study treatment, or (4) clinically significant
1388
prolongation of generalized tonic-clonic seizures. The primary efficacy variable was the
1389
proportion of patients in each treatment group who met escape criteria.
1390
The percentages of patients who met escape criteria were 42% (32/76) in the group
1391
receiving LAMICTAL and 69% (55/80) in the valproate group. The difference in the percentage
1392
of patients meeting escape criteria was statistically significant (P = 0.0012) in favor of
1393
LAMICTAL. No differences in efficacy based on age, sex, or race were detected.
1394
Patients in the control group were intentionally treated with a relatively low dose of
1395
valproate; as such, the sole objective of this trial was to demonstrate the effectiveness and safety
1396
of monotherapy with LAMICTAL, and cannot be interpreted to imply the superiority of
1397
LAMICTAL to an adequate dose of valproate.
1398
Adjunctive Therapy With LAMICTAL in Adults With Partial-Onset Seizures: The
1399
effectiveness of LAMICTAL as adjunctive therapy (added to other AEDs) was initially
1400
established in 3 pivotal, multicenter, placebo-controlled, double-blind clinical trials in 355 adults
1401
with refractory partial-onset seizures. The patients had a history of at least 4 partial-onset
1402
seizures per month in spite of receiving 1 or more AEDs at therapeutic concentrations and in 2 of
1403
the trials were observed on their established AED regimen during baselines that varied between 8
1404
to 12 weeks. In the third trial, patients were not observed in a prospective baseline. In patients
1405
continuing to have at least 4 seizures per month during the baseline, LAMICTAL or placebo was
1406
then added to the existing therapy. In all 3 trials, change from baseline in seizure frequency was
1407
the primary measure of effectiveness. The results given below are for all partial-onset seizures in
1408
the intent-to-treat population (all patients who received at least 1 dose of treatment) in each trial,
1409
unless otherwise indicated. The median seizure frequency at baseline was 3 per week while the
1410
mean at baseline was 6.6 per week for all patients enrolled in efficacy trials.
1411
One trial (n = 216) was a double-blind, placebo-controlled, parallel trial consisting of a
1412
24-week treatment period. Patients could not be on more than 2 other anticonvulsants and
1413
valproate was not allowed. Patients were randomized to receive placebo, a target dose of
1414
300 mg/day of LAMICTAL, or a target dose of 500 mg/day of LAMICTAL. The median
50
Reference ID: 3677876
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-035 & S-040
NDA 020764/S-028 & S-033
NDA 022251/S-009 & S-002
FDA Approved Labeling Text dated 12/23/2014
Page 51
1415
reductions in the frequency of all partial-onset seizures relative to baseline were 8% in patients
1416
receiving placebo, 20% in patients receiving 300 mg/day of LAMICTAL, and 36% in patients
1417
receiving 500 mg/day of LAMICTAL. The seizure frequency reduction was statistically
1418
significant in the 500-mg/day group compared with the placebo group, but not in the 300-mg/day
1419
group.
1420
A second trial (n = 98) was a double-blind, placebo-controlled, randomized, crossover
1421
trial consisting of two 14-week treatment periods (the last 2 weeks of which consisted of dose
1422
tapering) separated by a 4-week washout period. Patients could not be on more than 2 other
1423
anticonvulsants and valproate was not allowed. The target dose of LAMICTAL was 400 mg/day.
1424
When the first 12 weeks of the treatment periods were analyzed, the median change in seizure
1425
frequency was a 25% reduction on LAMICTAL compared with placebo (P<0.001).
1426
The third trial (n = 41) was a double-blind, placebo-controlled, crossover trial consisting
1427
of two 12-week treatment periods separated by a 4-week washout period. Patients could not be
1428
on more than 2 other anticonvulsants. Thirteen patients were on concomitant valproate; these
1429
patients received 150 mg/day of LAMICTAL. The 28 other patients had a target dose of
1430
300 mg/day of LAMICTAL. The median change in seizure frequency was a 26% reduction on
1431
LAMICTAL compared with placebo (P<0.01).
1432
No differences in efficacy based on age, sex, or race, as measured by change in seizure
1433
frequency, were detected.
1434
Adjunctive Therapy With LAMICTAL in Pediatric Patients With Partial-Onset
1435
Seizures: The effectiveness of LAMICTAL as adjunctive therapy in pediatric patients with
1436
partial-onset seizures was established in a multicenter, double-blind, placebo-controlled trial in
1437
199 patients aged 2 to 16 years (n = 98 on LAMICTAL, n = 101 on placebo). Following an 8
1438
week baseline phase, patients were randomized to 18 weeks of treatment with LAMICTAL or
1439
placebo added to their current AED regimen of up to 2 drugs. Patients were dosed based on body
1440
weight and valproate use. Target doses were designed to approximate 5 mg/kg/day for patients
1441
taking valproate (maximum dose: 250 mg/day) and 15 mg/kg/day for the patients not taking
1442
valproate (maximum dose: 750 mg/day). The primary efficacy endpoint was percentage change
1443
from baseline in all partial-onset seizures. For the intent-to-treat population, the median
1444
reduction of all partial-onset seizures was 36% in patients treated with LAMICTAL and 7% on
1445
placebo, a difference that was statistically significant (P<0.01).
1446
Adjunctive Therapy With LAMICTAL in Pediatric and Adult Patients With Lennox
1447
Gastaut Syndrome: The effectiveness of LAMICTAL as adjunctive therapy in patients with
1448
Lennox-Gastaut syndrome was established in a multicenter, double-blind, placebo-controlled
1449
trial in 169 patients aged 3 to 25 years (n = 79 on LAMICTAL, n = 90 on placebo). Following a
1450
4-week, single-blind, placebo phase, patients were randomized to 16 weeks of treatment with
1451
LAMICTAL or placebo added to their current AED regimen of up to 3 drugs. Patients were
1452
dosed on a fixed-dose regimen based on body weight and valproate use. Target doses were
1453
designed to approximate 5 mg/kg/day for patients taking valproate (maximum dose: 200 mg/day)
51
Reference ID: 3677876
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-035 & S-040
NDA 020764/S-028 & S-033
NDA 022251/S-009 & S-002
FDA Approved Labeling Text dated 12/23/2014
Page 52
1454
and 15 mg/kg/day for patients not taking valproate (maximum dose: 400 mg/day). The primary
1455
efficacy endpoint was percentage change from baseline in major motor seizures (atonic, tonic,
1456
major myoclonic, and tonic-clonic seizures). For the intent-to-treat population, the median
1457
reduction of major motor seizures was 32% in patients treated with LAMICTAL and 9% on
1458
placebo, a difference that was statistically significant (P<0.05). Drop attacks were significantly
1459
reduced by LAMICTAL (34%) compared with placebo (9%), as were tonic-clonic seizures (36%
1460
reduction versus 10% increase for LAMICTAL and placebo, respectively).
1461
Adjunctive Therapy With LAMICTAL in Pediatric and Adult Patients With Primary
1462
Generalized Tonic-Clonic Seizures: The effectiveness of LAMICTAL as adjunctive therapy
1463
in patients with PGTC seizures was established in a multicenter, double-blind, placebo
1464
controlled trial in 117 pediatric and adult patients aged 2 years and older (n = 58 on
1465
LAMICTAL, n = 59 on placebo). Patients with at least 3 PGTC seizures during an 8-week
1466
baseline phase were randomized to 19 to 24 weeks of treatment with LAMICTAL or placebo
1467
added to their current AED regimen of up to 2 drugs. Patients were dosed on a fixed-dose
1468
regimen, with target doses ranging from 3 to 12 mg/kg/day for pediatric patients and from 200 to
1469
400 mg/day for adult patients based on concomitant AEDs.
1470
The primary efficacy endpoint was percentage change from baseline in PGTC seizures.
1471
For the intent-to-treat population, the median percent reduction in PGTC seizures was 66% in
1472
patients treated with LAMICTAL and 34% on placebo, a difference that was statistically
1473
significant (P = 0.006).
1474
14.2 Bipolar Disorder
1475
The effectiveness of LAMICTAL in the maintenance treatment of bipolar I disorder was
1476
established in 2 multicenter, double-blind, placebo-controlled trials in adult patients who met
1477
DSM-IV criteria for bipolar I disorder. Trial 1 enrolled patients with a current or recent (within
1478
60 days) depressive episode as defined by DSM-IV and Trial 2 included patients with a current
1479
or recent (within 60 days) episode of mania or hypomania as defined by DSM-IV. Both trials
1480
included a cohort of patients (30% of 404 subjects in Trial 1 and 28% of 171 patients in Trial 2)
1481
with rapid cycling bipolar disorder (4 to 6 episodes per year).
1482
In both trials, patients were titrated to a target dose of 200 mg of LAMICTAL as add-on
1483
therapy or as monotherapy with gradual withdrawal of any psychotropic medications during an
1484
8- to 16-week open-label period. Overall 81% of 1,305 patients participating in the open-label
1485
period were receiving 1 or more other psychotropic medications, including benzodiazepines,
1486
selective serotonin reuptake inhibitors (SSRIs), atypical antipsychotics (including olanzapine),
1487
valproate, or lithium, during titration of LAMICTAL. Patients with a CGI-severity score of 3 or
1488
less maintained for at least 4 continuous weeks, including at least the final week on monotherapy
1489
with LAMICTAL, were randomized to a placebo-controlled, double-blind treatment period for
1490
up to 18 months. The primary endpoint was TIME (time to intervention for a mood episode or
1491
one that was emerging, time to discontinuation for either an adverse event that was judged to be
52
Reference ID: 3677876
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-035 & S-040
NDA 020764/S-028 & S-033
NDA 022251/S-009 & S-002
FDA Approved Labeling Text dated 12/23/2014
Page 53
1492
related to bipolar disorder, or for lack of efficacy). The mood episode could be depression,
1493
mania, hypomania, or a mixed episode.
1494
In Trial 1, patients received double-blind monotherapy with LAMICTAL 50 mg/day (n =
1495
50), LAMICTAL 200 mg/day (n = 124), LAMICTAL 400 mg/day (n = 47), or placebo
1496
(n = 121). LAMICTAL (200- and 400-mg/day treatment groups combined) was superior to
1497
placebo in delaying the time to occurrence of a mood episode. Separate analyses of the 200- and
1498
400-mg/day dose groups revealed no added benefit from the higher dose.
1499
In Trial 2, patients received double-blind monotherapy with LAMICTAL (100 to
1500
400 mg/day, n = 59), or placebo (n = 70). LAMICTAL was superior to placebo in delaying time
1501
to occurrence of a mood episode. The mean dose of LAMICTAL was about 211 mg/day.
1502
Although these trials were not designed to separately evaluate time to the occurrence of
1503
depression or mania, a combined analysis for the 2 trials revealed a statistically significant
1504
benefit for LAMICTAL over placebo in delaying the time to occurrence of both depression and
1505
mania, although the finding was more robust for depression.
1506
16
HOW SUPPLIED/STORAGE AND HANDLING
1507
LAMICTAL (lamotrigine) Tablets
1508
25 mg, white, scored, shield-shaped tablets debossed with “LAMICTAL” and “25”,
1509
bottles of 100 (NDC 0173-0633-02).
1510
Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP
1511
Controlled Room Temperature] in a dry place.
1512
100 mg, peach, scored, shield-shaped tablets debossed with “LAMICTAL” and “100”,
1513
bottles of 100 (NDC 0173-0642-55).
1514
150 mg, cream, scored, shield-shaped tablets debossed with “LAMICTAL” and “150”,
1515
bottles of 60 (NDC 0173-0643-60).
1516
200 mg, blue, scored, shield-shaped tablets debossed with “LAMICTAL” and “200”,
1517
bottles of 60 (NDC 0173-0644-60).
1518
Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP
1519
Controlled Room Temperature] in a dry place and protect from light.
1520
1521
LAMICTAL (lamotrigine) Starter Kit for Patients Taking Valproate (Blue Kit)
1522
25 mg, white, scored, shield-shaped tablets debossed with “LAMICTAL” and “25”,
1523
blisterpack of 35 tablets (NDC 0173-0633-10).
1524
Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP
1525
Controlled Room Temperature] in a dry place.
1526
LAMICTAL (lamotrigine) Starter Kit for Patients Taking Carbamazepine,
1527
Phenytoin, Phenobarbital, or Primidone and Not Taking Valproate (Green Kit)
1528
25 mg, white, scored, shield-shaped tablets debossed with “LAMICTAL” and “25” and
1529
100 mg, peach, scored, shield-shaped tablets debossed with “LAMICTAL” and “100”,
1530
blisterpack of 98 tablets (84/25-mg tablets and 14/100-mg tablets) (NDC 0173-0817-28).
53
Reference ID: 3677876
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-035 & S-040
NDA 020764/S-028 & S-033
NDA 022251/S-009 & S-002
FDA Approved Labeling Text dated 12/23/2014
Page 54
1531
Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP
1532
Controlled Room Temperature] in a dry place and protect from light.
1533
LAMICTAL (lamotrigine) Starter Kit for Patients Not Taking Carbamazepine,
1534
Phenytoin, Phenobarbital, Primidone, or Valproate (Orange Kit)
1535
25 mg, white, scored, shield-shaped tablets debossed with “LAMICTAL” and “25” and
1536
100 mg, peach, scored, shield-shaped tablets debossed with “LAMICTAL” and “100”,
1537
blisterpack of 49 tablets (42/25-mg tablets and 7/100-mg tablets) (NDC 0173-0594-02).
1538
Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP
1539
Controlled Room Temperature] in a dry place and protect from light.
1540
1541
LAMICTAL (lamotrigine) Chewable Dispersible Tablets
1542
2 mg, white to off-white, round tablets debossed with “LTG” over “2”, bottles of 30
1543
(NDC 0173-0699-00). ORDER DIRECTLY FROM GlaxoSmithKline 1-800-334-4153.
1544
5 mg, white to off-white, caplet-shaped tablets debossed with “GX CL2”, bottles of 100
1545
(NDC 0173-0526-00).
1546
25 mg, white, super elliptical-shaped tablets debossed with “GX CL5”, bottles of 100
1547
(NDC 0173-0527-00).
1548
Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP
1549
Controlled Room Temperature] in a dry place.
1550
1551
LAMICTAL ODT (lamotrigine) Orally Disintegrating Tablets
1552
25 mg, white to off-white, round, flat-faced, radius-edged tablets debossed with “LMT”
1553
on one side and “25” on the other, Maintenance Packs of 30 (NDC 0173-0772-02).
1554
50 mg, white to off-white, round, flat-faced, radius-edged tablets debossed with “LMT”
1555
on one side and “50” on the other, Maintenance Packs of 30 (NDC 0173-0774-02).
1556
100 mg, white to off-white, round, flat-faced, radius-edged tablets debossed with
1557
“LAMICTAL” on one side and “100” on the other, Maintenance Packs of 30 (NDC 0173-0776
1558
02).
1559
200 mg, white to off-white, round, flat-faced, radius-edged tablets debossed with
1560
“LAMICTAL” on one side and “200” on the other, Maintenance Packs of 30 (NDC 0173-0777
1561
02).
1562
Store between 20°C and 25°C (68°F and 77°F); with excursions permitted between 15°C
1563
and 30°C (59°F and 86°F).
1564
LAMICTAL ODT (lamotrigine) Patient Titration Kit for Patients Taking Valproate
1565
(Blue ODT Kit)
1566
25 mg, white to off-white, round, flat-faced, radius-edged tablets debossed with “LMT”
1567
on one side and “25” on the other, and 50 mg, white to off-white, round, flat-faced, radius-edged
1568
tablets debossed with “LMT” on one side and “50” on the other, blisterpack of 28 tablets
1569
(21/25-mg tablets and 7/50-mg tablets) (NDC 0173-0779-00).
54
Reference ID: 3677876
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-035 & S-040
NDA 020764/S-028 & S-033
NDA 022251/S-009 & S-002
FDA Approved Labeling Text dated 12/23/2014
Page 55
1570
LAMICTAL ODT (lamotrigine) Patient Titration Kit for Patients Taking
1571
Carbamazepine, Phenytoin, Phenobarbital, or Primidone and Not Taking Valproate
1572
(Green ODT Kit)
1573
50 mg, white to off-white, round, flat-faced, radius-edged tablets debossed with “LMT”
1574
on one side and “50” on the other, and 100 mg, white to off-white, round, flat-faced, radius
1575
edged tablets debossed with “LAMICTAL” on one side and “100” on the other, blisterpack of 56
1576
tablets (42/50-mg tablets and 14/100-mg tablets) (NDC 0173-0780-00).
1577
LAMICTAL ODT (lamotrigine) Patient Titration Kit for Patients Not Taking
1578
Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate (Orange ODT Kit)
1579
25 mg, white to off-white, round, flat-faced, radius-edged tablets debossed with “LMT”
1580
on one side and “25” on the other, 50 mg, white to off-white, round, flat-faced, radius-edged
1581
tablets debossed with “LMT” on one side and “50” on the other, and 100 mg, white to off-white,
1582
round, flat-faced, radius-edged tablets debossed with “LAMICTAL” on one side and “100” on
1583
the other, blisterpack of 35 (14/25-mg tablets, 14/50-mg tablets, and 7/100-mg tablets) (NDC
1584
0173-0778-00).
1585
Store between 20°C and 25°C (68°F and 77°F); with excursions permitted between 15°C
1586
and 30°C (59°F and 86°F).
1587
Blisterpacks: If the product is dispensed in a blisterpack, the patient should be advised to
1588
examine the blisterpack before use and not use if blisters are torn, broken, or missing.
1589
17
PATIENT COUNSELING INFORMATION
1590
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
1591
Rash: Prior to initiation of treatment with LAMICTAL, inform patients that a rash or
1592
other signs or symptoms of hypersensitivity (e.g., fever, lymphadenopathy) may herald a serious
1593
medical event and instruct them to report any such occurrence to their physician immediately.
1594
Multiorgan Hypersensitivity Reactions, Blood Dyscrasias, and Organ Failure:
1595
Inform patients that multiorgan hypersensitivity reactions and acute multiorgan failure may
1596
occur with LAMICTAL. Isolated organ failure or isolated blood dyscrasias without evidence of
1597
multiorgan hypersensitivity may also occur. Instruct patients to contact their physician
1598
immediately if they experience any signs or symptoms of these conditions [see Warnings and
1599
Precautions (5.2, 5.3)].
1600
Suicidal Thinking and Behavior: Inform patients, their caregivers, and families that
1601
AEDs, including LAMICTAL, may increase the risk of suicidal thoughts and behavior. Instruct
1602
them to be alert for the emergence or worsening of symptoms of depression, any unusual
1603
changes in mood or behavior, or the emergence of suicidal thoughts or behavior or thoughts
1604
about self-harm. They should immediately report behaviors of concern to their physician.
1605
Worsening of Seizures: Advise patients to notify their physician if worsening of
1606
seizure control occurs.
1607
Central Nervous System Adverse Effects: Inform patients that LAMICTAL may
1608
cause dizziness, somnolence, and other symptoms and signs of central nervous system
55
Reference ID: 3677876
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-035 & S-040
NDA 020764/S-028 & S-033
NDA 022251/S-009 & S-002
FDA Approved Labeling Text dated 12/23/2014
Page 56
1609
depression. Accordingly, instruct them neither to drive a car nor to operate other complex
1610
machinery until they have gained sufficient experience on LAMICTAL to gauge whether or not
1611
it adversely affects their mental and/or motor performance.
1612
Pregnancy and Nursing: Instruct patients to notify their physician if they become
1613
pregnant or intend to become pregnant during therapy and if they intend to breastfeed or are
1614
breastfeeding an infant.
1615
Encourage patients to enroll in the NAAED Pregnancy Registry if they become pregnant.
1616
This registry is collecting information about the safety of antiepileptic drugs during pregnancy.
1617
To enroll, patients can call the toll-free number 1-888-233-2334 [see Use in Specific Populations
1618
(8.1)].
1619
Inform patients who intend to breastfeed that LAMICTAL is present in breast milk and
1620
advise them to monitor their child for potential adverse effects of this drug. Discuss the benefits
1621
and risks of continuing breastfeeding.
1622
Oral Contraceptive Use: Instruct women to notify their physician if they plan to start or
1623
stop use of oral contraceptives or other female hormonal preparations. Starting estrogen
1624
containing oral contraceptives may significantly decrease lamotrigine plasma levels and stopping
1625
estrogen-containing oral contraceptives (including the pill-free week) may significantly increase
1626
lamotrigine plasma levels [see Warnings and Precautions (5.8), Clinical Pharmacology (12.3)].
1627
Also instruct women to promptly notify their physician if they experience adverse reactions or
1628
changes in menstrual pattern (e.g., break-through bleeding) while receiving LAMICTAL in
1629
combination with these medications.
1630
Discontinuing LAMICTAL: Instruct patients to notify their physician if they stop taking
1631
LAMICTAL for any reason and not to resume LAMICTAL without consulting their physician.
1632
Aseptic Meningitis: Inform patients that LAMICTAL may cause aseptic meningitis.
1633
Instruct them to notify their physician immediately if they develop signs and symptoms of
1634
meningitis such as headache, fever, nausea, vomiting, stiff neck, rash, abnormal sensitivity to
1635
light, myalgia, chills, confusion, or drowsiness while taking LAMICTAL.
1636
Potential Medication Errors: Medication errors involving LAMICTAL have occurred.
1637
In particular the names LAMICTAL or lamotrigine can be confused with the names of other
1638
commonly used medications. Medication errors may also occur between the different
1639
formulations of LAMICTAL. To reduce the potential of medication errors, write and say
1640
LAMICTAL clearly. Depictions of the LAMICTAL Tablets, Chewable Dispersible Tablets, and
1641
Orally Disintegrating Tablets can be found in the Medication Guide that accompanies the
1642
product to highlight the distinctive markings, colors, and shapes that serve to identify the
1643
different presentations of the drug and thus may help reduce the risk of medication errors. To
1644
avoid a medication error of using the wrong drug or formulation, strongly advise patients
1645
to visually inspect their tablets to verify that they are LAMICTAL, as well as the correct
1646
formulation of LAMICTAL, each time they fill their prescription [see Dosage Forms and
1647
Strengths (3.1, 3.2, 3.3), How Supplied/Storage and Handling (16)].
56
Reference ID: 3677876
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-035 & S-040
NDA 020764/S-028 & S-033
NDA 022251/S-009 & S-002
FDA Approved Labeling Text dated 12/23/2014
Page 57
1648
1649
LAMICTAL and LAMICTAL ODT are registered trademarks of the GSK group of companies.
1650
The other brands listed are trademarks of their respective owners and are not trademarks of the
1651
GSK group of companies. The makers of these brands are not affiliated with and do not endorse
1652
the GSK group of companies or its products.
1653
1654
1655
Distributed by company logo
1656
1657
GlaxoSmithKline
1658
Research Triangle Park, NC 27709
1659
1660
2014, the GSK group of companies. All rights reserved.
1661
1662
LMT:xPI
1663
1664
MEDICATION GUIDE
1665
1666
LAMICTAL® (la-MIK-tal) (lamotrigine) Tablets and Chewable Dispersible
1667
Tablets
1668
LAMICTAL ODT® (lamotrigine) Orally Disintegrating Tablets
1669
1670
Read this Medication Guide before you start taking LAMICTAL and each time you
1671
get a refill. There may be new information. This information does not take the place
1672
of talking with your healthcare provider about your medical condition or treatment.
1673
If you have questions about LAMICTAL, ask your healthcare provider or pharmacist.
1674
1675
What is the most important information I should know about LAMICTAL?
1676
1. LAMICTAL may cause a serious skin rash that may cause you to be
1677
hospitalized or even cause death.
1678
There is no way to tell if a mild rash will become more serious. A serious skin
1679
rash can happen at any time during your treatment with LAMICTAL, but is more
1680
likely to happen within the first 2 to 8 weeks of treatment. Children aged
1681
between 2 and 16 years have a higher chance of getting this serious skin rash
1682
while taking LAMICTAL.
1683
The risk of getting a serious skin rash is higher if you:
57
Reference ID: 3677876
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-035 & S-040
NDA 020764/S-028 & S-033
NDA 022251/S-009 & S-002
FDA Approved Labeling Text dated 12/23/2014
Page 58
1684
•
take LAMICTAL while taking valproate [DEPAKENE® (valproic acid) or
1685
DEPAKOTE® (divalproex sodium)].
1686
•
take a higher starting dose of LAMICTAL than your healthcare provider
1687
prescribed.
1688
•
increase your dose of LAMICTAL faster than prescribed.
1689
Call your healthcare provider right away if you have any of the
1690
following:
1691
•
a skin rash
1692
•
blistering or peeling of your skin
1693
•
hives
1694
•
painful sores in your mouth or around your eyes
1695
These symptoms may be the first signs of a serious skin reaction. A healthcare
1696
provider should examine you to decide if you should continue taking LAMICTAL.
1697
2. Other serious reactions, including serious blood problems or liver
1698
problems. LAMICTAL can also cause other types of allergic reactions or serious
1699
problems that may affect organs and other parts of your body like your liver or
1700
blood cells. You may or may not have a rash with these types of reactions. Call
1701
your healthcare provider right away if you have any of these symptoms:
1702
•
fever
1703
•
frequent infections
1704
•
severe muscle pain
1705
•
swelling of your face, eyes, lips, or tongue
1706
•
swollen lymph glands
1707
•
unusual bruising or bleeding
1708
•
weakness, fatigue
1709
•
yellowing of your skin or the white part of your eyes
1710
3. Like other antiepileptic drugs, LAMICTAL may cause suicidal thoughts or
1711
actions in a very small number of people, about 1 in 500.
1712
Call a healthcare provider right away if you have any of these
1713
symptoms, especially if they are new, worse, or worry you:
1714
•
thoughts about suicide or dying
1715
•
attempt to commit suicide
1716
•
new or worse depression
1717
•
new or worse anxiety
1718
•
feeling agitated or restless
1719
•
panic attacks
1720
•
trouble sleeping (insomnia)
58
Reference ID: 3677876
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-035 & S-040
NDA 020764/S-028 & S-033
NDA 022251/S-009 & S-002
FDA Approved Labeling Text dated 12/23/2014
Page 59
1721
•
new or worse irritability
1722
•
acting aggressive, being angry, or violent
1723
•
acting on dangerous impulses
1724
•
an extreme increase in activity and talking (mania)
1725
•
other unusual changes in behavior or mood
1726
Do not stop LAMICTAL without first talking to a healthcare provider.
1727
•
Stopping LAMICTAL suddenly can cause serious problems.
1728
•
Suicidal thoughts or actions can be caused by things other than medicines. If
1729
you have suicidal thoughts or actions, your healthcare provider may check
1730
for other causes.
1731
How can I watch for early symptoms of suicidal thoughts and actions?
1732
•
Pay attention to any changes, especially sudden changes, in mood,
1733
behaviors, thoughts, or feelings.
1734
•
Keep all follow-up visits with your healthcare provider as scheduled.
1735
•
Call your healthcare provider between visits as needed, especially if you are
1736
worried about symptoms.
1737
4. LAMICTAL may rarely cause aseptic meningitis, a serious inflammation
1738
of the protective membrane that covers the brain and spinal cord.
1739
Call your healthcare provider right away if you have any of the following
1740
symptoms:
1741
•
headache
1742
•
fever
1743
•
nausea
1744
•
vomiting
1745
•
stiff neck
1746
•
rash
1747
•
unusual sensitivity to light
1748
•
muscle pains
1749
•
chills
1750
•
confusion
1751
•
drowsiness
1752
Meningitis has many causes other than LAMICTAL, which your doctor would
1753
check for if you developed meningitis while taking LAMICTAL.
1754
LAMICTAL can have other serious side effects. For more information ask
1755
your healthcare provider or pharmacist. Tell your healthcare provider if you have
1756
any side effect that bothers you. Be sure to read the section below entitled
1757
“What are the possible side effects of LAMICTAL?”
59
Reference ID: 3677876
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-035 & S-040
NDA 020764/S-028 & S-033
NDA 022251/S-009 & S-002
FDA Approved Labeling Text dated 12/23/2014
Page 60
1758
5. Patients prescribed LAMICTAL have sometimes been given the wrong
1759
medicine because many medicines have names similar to LAMICTAL, so
1760
always check that you receive LAMICTAL.
1761
Taking the wrong medication can cause serious health problems. When your
1762
healthcare provider gives you a prescription for LAMICTAL:
1763
•
Make sure you can read it clearly.
1764
•
Talk to your pharmacist to check that you are given the correct medicine.
1765
•
Each time you fill your prescription, check the tablets you receive against the
1766
pictures of the tablets below.
1767
These pictures show the distinct wording, colors, and shapes of the tablets
1768
that help to identify the right strength of LAMICTAL Tablets, Chewable
1769
Dispersible Tablets, and Orally Disintegrating Tablets. Immediately call your
1770
pharmacist if you receive a LAMICTAL tablet that does not look like one of the
1771
tablets shown below, as you may have received the wrong medication.
1772
LAMICTAL (lamotrigine) Tablets
25 mg, white
100 mg, peach
150 mg, cream
200 mg, blue
Imprinted with
Imprinted with
Imprinted with
Imprinted with
LAMICTAL 25
LAMICTAL 100
LAMICTAL 150
LAMICTAL 200
1773
LAMICTAL (lamotrigine) Chewable Dispersible
1774
Tablets
2 mg, white
5 mg, white
25 mg, white
Imprinted with
Imprinted with
Imprinted with
LTG 2
GX CL2
GX CL5
60
Reference ID: 3677876
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-035 & S-040
NDA 020764/S-028 & S-033
NDA 022251/S-009 & S-002
FDA Approved Labeling Text dated 12/23/2014
Page 61
1775
LAMICTAL ODT (lamotrigine) Orally Disintegrating Tablets
25 mg, white
50 mg, white
100 mg, white
200 mg, white
to off-white
to off-white
to off-white
to off-white
Imprinted with
Imprinted with
Imprinted with
Imprinted with
LMT on one
LMT on one
LAMICTAL on
LAMICTAL on
side
side
one side
one side
25 on the other 50 on the other
100 on the
200 on the
other
other
1776
1777
What is LAMICTAL?
1778
LAMICTAL is a prescription medicine used:
1779
1. together with other medicines to treat certain types of seizures (partial-onset
1780
seizures, primary generalized tonic-clonic seizures, generalized seizures of
1781
Lennox-Gastaut syndrome) in people aged 2 years and older.
1782
2. alone when changing from 1 other medicine used to treat partial-onset seizures
1783
in people aged 16 years and older.
1784
3. for the long-term treatment of bipolar I disorder to lengthen the time between
1785
mood episodes in people aged 18 years and older who have been treated for
1786
mood episodes with other medicine.
1787
It is not known if LAMICTAL is safe or effective in children or teenagers younger
1788
than 18 years with mood disorders such as bipolar disorder or depression.
1789
It is not known if LAMICTAL is safe or effective when used alone as the first
1790
treatment of seizures.
1791
1792
Who should not take LAMICTAL?
1793
You should not take LAMICTAL if you have had an allergic reaction to lamotrigine or
1794
to any of the inactive ingredients in LAMICTAL. See the end of this leaflet for a
1795
complete list of ingredients in LAMICTAL.
1796
1797
What should I tell my healthcare provider before taking LAMICTAL?
1798
Before taking LAMICTAL, tell your healthcare provider about all of your medical
1799
conditions, including if you:
61
Reference ID: 3677876
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-035 & S-040
NDA 020764/S-028 & S-033
NDA 022251/S-009 & S-002
FDA Approved Labeling Text dated 12/23/2014
Page 62
1800
•
have had a rash or allergic reaction to another antiseizure medicine.
1801
•
have or have had depression, mood problems, or suicidal thoughts or behavior.
1802
•
have had aseptic meningitis after taking LAMICTAL or LAMICTAL XR
1803
(lamotrigine).
1804
•
are taking oral contraceptives (birth control pills) or other female hormonal
1805
medicines. Do not start or stop taking birth control pills or other female
1806
hormonal medicine until you have talked with your healthcare provider. Tell your
1807
healthcare provider if you have any changes in your menstrual pattern such as
1808
breakthrough bleeding. Stopping these medicines may cause side effects (such
1809
as dizziness, lack of coordination, or double vision). Starting these medicines
1810
may lessen how well LAMICTAL works.
1811
•
are pregnant or plan to become pregnant. It is not known if LAMICTAL will harm
1812
your unborn baby. If you become pregnant while taking LAMICTAL, talk to your
1813
healthcare provider about registering with the North American Antiepileptic Drug
1814
Pregnancy Registry. You can enroll in this registry by calling 1-888-233-2334.
1815
The purpose of this registry is to collect information about the safety of
1816
antiepileptic drugs during pregnancy.
1817
•
are breastfeeding. LAMICTAL passes into breast milk and may cause side effects
1818
in a breastfed baby. If you breastfeed while taking LAMICTAL, watch your baby
1819
closely for trouble breathing, episodes of temporarily stopping breathing,
1820
sleepiness, or poor sucking. Call your baby’s healthcare provider right away if
1821
you see any of these problems. Talk to your healthcare provider about the best
1822
way to feed your baby if you take LAMICTAL.
1823
Tell your healthcare provider about all the medicines you take or if you are planning
1824
to take a new medicine, including prescription and non-prescription medicines,
1825
vitamins, and herbal supplements. If you use LAMICTAL with certain other
1826
medicines, they can affect each other, causing side effects.
1827
1828
How should I take LAMICTAL?
1829
•
Take LAMICTAL exactly as prescribed.
1830
•
Your healthcare provider may change your dose. Do not change your dose
1831
without talking to your healthcare provider.
1832
•
Do not stop taking LAMICTAL without talking to your healthcare provider.
1833
Stopping LAMICTAL suddenly may cause serious problems. For example, if you
1834
have epilepsy and you stop taking LAMICTAL suddenly, you may have seizures
1835
that do not stop. Talk with your healthcare provider about how to stop
1836
LAMICTAL slowly.
1837
•
If you miss a dose of LAMICTAL, take it as soon as you remember. If it is almost
1838
time for your next dose, just skip the missed dose. Take the next dose at your
62
Reference ID: 3677876
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-035 & S-040
NDA 020764/S-028 & S-033
NDA 022251/S-009 & S-002
FDA Approved Labeling Text dated 12/23/2014
Page 63
1839
regular time. Do not take 2 doses at the same time.
1840
•
If you take too much LAMICTAL, call your healthcare provider or your local
1841
Poison Control Center or go to the nearest hospital emergency room right away.
1842
•
If you take too much LAMICTAL, call your healthcare provider or your local
1843
Poison Control Center or go to the nearest hospital emergency room right away.
1844
•
You may not feel the full effect of LAMICTAL for several weeks.
1845
•
If you have epilepsy, tell your healthcare provider if your seizures get worse or if
1846
you have any new types of seizures.
1847
•
Swallow LAMICTAL Tablets whole.
1848
•
If you have trouble swallowing LAMICTAL Tablets, tell your healthcare provider
1849
because there may be another form of LAMICTAL you can take.
1850
•
LAMICTAL ODT should be placed on the tongue and moved around the mouth.
1851
The tablet will rapidly disintegrate, can be swallowed with or without water, and
1852
can be taken with or without food.
1853
•
LAMICTAL Chewable Dispersible tablets may be swallowed whole, chewed, or
1854
mixed in water or diluted fruit juice. If the tablets are chewed, drink a small
1855
amount of water or diluted fruit juice to help in swallowing. To break up
1856
LAMICTAL Chewable Dispersible tablets, add the tablets to a small amount of
1857
liquid (1 teaspoon, or enough to cover the medicine) in a glass or spoon. Wait at
1858
least 1 minute or until the tablets are completely broken up, mix the solution
1859
together, and take the whole amount right away.
1860
•
If you receive LAMICTAL in a blisterpack, examine the blisterpack before use. Do
1861
not use if blisters are torn, broken, or missing.
1862
1863
What should I avoid while taking LAMICTAL?
1864
Do not drive a car or operate complex, hazardous machinery until you know how
1865
LAMICTAL affects you.
1866
1867
What are the possible side effects of LAMICTAL?
1868
See “What is the most important information I should know about LAMICTAL?”
1869
Common side effects of LAMICTAL include:
1870
•
dizziness
1871
•
tremor
1872
•
headache
1873
•
rash
1874
•
blurred or double vision
1875
•
fever
1876
•
lack of coordination
63
Reference ID: 3677876
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-035 & S-040
NDA 020764/S-028 & S-033
NDA 022251/S-009 & S-002
FDA Approved Labeling Text dated 12/23/2014
Page 64
1877
•
abdominal pain
1878
•
sleepiness
1879
•
back pain
1880
•
nausea, vomiting
1881
•
tiredness
1882
•
insomnia
1883
•
dry mouth
1884
Tell your healthcare provider about any side effect that bothers you or that does
1885
not go away.
1886
These are not all the possible side effects of LAMICTAL. For more information, ask
1887
your healthcare provider or pharmacist.
1888
Call your doctor for medical advice about side effects. You may report side effects
1889
to FDA at 1-800-FDA-1088.
1890
1891
How should I store LAMICTAL?
1892
•
Store LAMICTAL at room temperature between 68oF and 77oF (20oC and 25oC).
1893
•
Keep LAMICTAL and all medicines out of the reach of children.
1894
1895
General information about LAMICTAL
1896
Medicines are sometimes prescribed for purposes other than those listed in a
1897
Medication Guide. Do not use LAMICTAL for a condition for which it was not
1898
prescribed. Do not give LAMICTAL to other people, even if they have the same
1899
symptoms you have. It may harm them.
1900
This Medication Guide summarizes the most important information about
1901
LAMICTAL. If you would like more information, talk with your healthcare provider.
1902
You can ask your healthcare provider or pharmacist for information about
1903
LAMICTAL that is written for healthcare professionals.
1904
For more information, go to www.lamictal.com or call 1-888-825-5249.
1905
1906
What are the ingredients in LAMICTAL?
1907
LAMICTAL Tablets
1908
Active ingredient: lamotrigine.
1909
Inactive ingredients: lactose; magnesium stearate, microcrystalline cellulose,
1910
povidone, sodium starch glycolate, FD&C Yellow No. 6 Lake (100-mg tablet only),
1911
ferric oxide, yellow (150-mg tablet only), and FD&C Blue No. 2 Lake (200-mg tablet
1912
only).
64
Reference ID: 3677876
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-035 & S-040
NDA 020764/S-028 & S-033
NDA 022251/S-009 & S-002
FDA Approved Labeling Text dated 12/23/2014
Page 65
1913
LAMICTAL Chewable Dispersible Tablets
1914
Active ingredient: lamotrigine.
1915
Inactive ingredients: blackcurrant flavor, calcium carbonate, low-substituted
1916
hydroxypropylcellulose, magnesium aluminum silicate, magnesium stearate,
1917
povidone, saccharin sodium, and sodium starch glycolate.
1918
LAMICTAL ODT Orally Disintegrating Tablets
1919
Active ingredient: lamotrigine.
1920
Inactive ingredients: artificial cherry flavor, crospovidone, ethylcellulose,
1921
magnesium stearate, mannitol, polyethylene, and sucralose.
1922
1923
This Medication Guide has been approved by the U.S. Food and Drug
1924
Administration.
1925
1926
LAMICTAL and LAMICTAL ODT are registered trademarks of the GSK group of
1927
companies. The other brands listed are trademarks of their respective owners and
1928
are not trademarks of the GSK group of companies. The makers of these brands
1929
are not affiliated with and do not endorse the GSK group of companies or its
1930
products.
1931
1932
1933
Distributed by
65
Reference ID: 3677876
1934
1935
GlaxoSmithKline
1936
Research Triangle Park, NC 27709
1937
1938
2014, the GSK group of companies. All rights reserved.
1939
1940
December 2014
1941
LMT:xMG
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 022115/S-004 & S-014
FDA Proposed Labeling Text dated 12/23/2014
Page 1
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
LAMICTAL XR safely and effectively. See full prescribing information
for LAMICTAL XR.
LAMICTAL XR (lamotrigine) Extended-Release Tablets
Initial U.S. Approval: 1994
WARNING: SERIOUS SKIN RASHES
See full prescribing information for complete boxed warning.
• Cases of life-threatening serious rashes, including Stevens-Johnson
syndrome and toxic epidermal necrolysis, and/or rash-related death
have been caused by lamotrigine. The rate of serious rash is greater
in pediatric patients than in adults. Additional factors that may
increase the risk of rash include:
• coadministration with valproate.
• exceeding recommended initial dose of LAMICTAL XR.
• exceeding recommended dose escalation for LAMICTAL XR.
(5.1)
• Benign rashes are also caused by lamotrigine; however, it is not
possible to predict which rashes will prove to be serious or life
threatening. LAMICTAL should be discontinued at the first sign of
rash, unless the rash is clearly not drug related. (5.1)
---------------------------RECENT MAJOR CHANGES --------------------------
Dosage and Administration (2.1, 2.2)
12/2014
----------------------------INDICATIONS AND USAGE ---------------------------
LAMICTAL XR is an antiepileptic drug (AED) indicated for:
• adjunctive therapy for primary generalized tonic-clonic seizures and
partial-onset seizures with or without secondary generalization in patients
aged 13 years and older. (1.1)
• conversion to monotherapy in patients aged 13 years and older with
partial-onset seizures who are receiving treatment with a single AED.
(1.2)
Limitation of use: Safety and effectiveness in patients younger than 13 years
have not been established. (1.3)
----------------------- DOSAGE AND ADMINISTRATION ----------------------
• Do not exceed the recommended initial dosage and subsequent dose
escalation. (2.1)
• Initiation of adjunctive therapy and conversion to monotherapy requires
slow titration dependent on concomitant AEDs; the prescriber must refer
to the appropriate algorithm in Dosage and Administration. (2.2, 2.3)
• Adjunct therapy target therapeutic dose range is 200 to 600 mg daily
and is dependent on concomitant AEDs. (2.2)
• Conversion to monotherapy: Target therapeutic dosage range is 250
to 300 mg daily. (2.3)
• Conversion from immediate-release lamotrigine to LAMICTAL XR: The
initial dose of LAMICTAL XR should match the total daily dose of the
immediate-release lamotrigine. Patients should be closely monitored for
seizure control after conversion. (2.4)
• Do not restart LAMICTAL XR in patients who discontinued due to rash
unless the potential benefits clearly outweigh the risks. (2.1, 5.1)
• Adjustments to maintenance doses will be necessary in most patients
starting or stopping estrogen-containing oral contraceptives. (2.1, 5.7)
• Discontinuation: Taper over a period of at least 2 weeks (approximately
50% dose reduction per week). (2.1, 5.8)
--------------------- DOSAGE FORMS AND STRENGTHS --------------------
Extended-Release Tablets: 25 mg, 50 mg, 100 mg, 200 mg, 250 mg, and
300 mg. (3.1, 16)
-------------------------------CONTRAINDICATIONS ------------------------------
Hypersensitivity to the drug or its ingredients. (Boxed Warning, 4)
----------------------- WARNINGS AND PRECAUTIONS ----------------------
• Life-threatening serious rash and/or rash-related death: Discontinue at the
first sign of rash, unless the rash is clearly not drug related. (Boxed
Warning, 5.1)
• Fatal or life-threatening hypersensitivity reaction: Multiorgan
hypersensitivity reactions, also known as drug reaction with eosinophilia
and systemic symptoms (DRESS), may be fatal or life threatening. Early
signs may include rash, fever, and lymphadenopathy. These reactions may
be associated with other organ involvement, such as hepatitis, hepatic
failure, blood dyscrasias, or acute multiorgan failure. LAMICTAL XR
should be discontinued if alternate etiology for this reaction is not found.
(5.2)
• Blood dyscrasias (e.g., neutropenia, thrombocytopenia, pancytopenia):
May occur, either with or without an associated hypersensitivity
syndrome. Monitor for signs of anemia, unexpected infection, or bleeding.
(5.3)
• Suicidal behavior and ideation: Monitor for suicidal thoughts or
behaviors. (5.4)
• Aseptic meningitis: Monitor for signs of meningitis. (5.5)
• Medication errors due to product name confusion: Strongly advise
patients to visually inspect tablets to verify the received drug is correct.
(3.2, 5.6, 16, 17)
------------------------------ ADVERSE REACTIONS -----------------------------
• Most common adverse reactions with use as adjunctive therapy (treatment
difference between LAMICTAL XR and placebo ≥4%) are dizziness,
tremor/intention tremor, vomiting, and diplopia. (6.1)
• Most common adverse reactions with use as monotherapy were similar to
those seen with previous trials conducted with immediate-release
lamotrigine and LAMICTAL XR. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact
GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
-------------------------------DRUG INTERACTIONS ------------------------------
• Valproate increases lamotrigine concentrations more than 2-fold. (7, 12.3)
• Carbamazepine, phenytoin, phenobarbital, primidone, and rifampin
decrease lamotrigine concentrations by approximately 40%. (7, 12.3)
• Estrogen-containing oral contraceptives decrease lamotrigine
concentrations by approximately 50%. (7, 12.3)
• Protease inhibitors lopinavir/ritonavir and atazanavir/lopinavir decrease
lamotrigine exposure by approximately 50% and 32%, respectively. (7,
12.3)
----------------------- USE IN SPECIFIC POPULATIONS ----------------------
• Pregnancy: Based on animal data may cause fetal harm. (8.1)
• Hepatic impairment: Dosage adjustments required in patients with
moderate and severe liver impairment. (2.1, 8.6)
• Renal impairment: Reduced maintenance doses may be effective for
patients with significant renal impairment. (2.1, 8.7)
See 17 for PATIENT COUNSELING INFORMATION and Medication
Guide.
Revised: 12/2014
1
Reference ID: 3677876
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 022115/S-004 & S-014
FDA Proposed Labeling Text dated 12/23/2014
Page 2
FULL PRESCRIBING INFORMATION: CONTENTS*
6
ADVERSE REACTIONS
WARNING: SERIOUS SKIN RASHES
6.1
Clinical Trial Experience With LAMICTAL XR
1
INDICATIONS AND USAGE
for Treatment of Primary Generalized Tonic
1.1
Adjunctive Therapy
Clonic and Partial-Onset Seizures
1.2
Monotherapy
6.2
Other Adverse Reactions Observed During the
1.3
Limitation of Use
Clinical Development of Immediate-Release
2
DOSAGE AND ADMINISTRATION
Lamotrigine
2.1
General Dosing Considerations
6.3
Postmarketing Experience With Immediate
2.2
Adjunctive Therapy for Primary Generalized
Release Lamotrigine
Tonic-Clonic and Partial-Onset Seizures
7
DRUG INTERACTIONS
2.3
Conversion From Adjunctive Therapy to
8
USE IN SPECIFIC POPULATIONS
Monotherapy
8.1
Pregnancy
2.4
Conversion From Immediate-Release
8.2
Labor and Delivery
Lamotrigine Tablets to LAMICTAL XR
8.3
Nursing Mothers
3
DOSAGE FORMS AND STRENGTHS
8.4
Pediatric Use
3.1
Extended-Release Tablets
8.5
Geriatric Use
3.2
Potential Medication Errors
8.6
Patients With Hepatic Impairment
4
CONTRAINDICATIONS
8.7
Patients With Renal Impairment
5
WARNINGS AND PRECAUTIONS
10
OVERDOSAGE
5.1
Serious Skin Rashes [see Boxed Warning]
10.1
Human Overdose Experience
5.2
Multiorgan Hypersensitivity Reactions and
10.2
Management of Overdose
Organ Failure
11
DESCRIPTION
5.3
Blood Dyscrasias
12
CLINICAL PHARMACOLOGY
5.4
Suicidal Behavior and Ideation
12.1
Mechanism of Action
5.5
Aseptic Meningitis
12.2
Pharmacodynamics
5.6
Potential Medication Errors
12.3
Pharmacokinetics
5.7
Concomitant Use With Oral Contraceptives
13
NONCLINICAL TOXICOLOGY
5.8
Withdrawal Seizures
13.1
Carcinogenesis, Mutagenesis, Impairment of
5.9
Status Epilepticus
Fertility
5.10
Sudden Unexplained Death in Epilepsy
14
CLINICAL STUDIES
(SUDEP)
14.1
Adjunctive Therapy for Primary Generalized
5.11
Addition of LAMICTAL XR to a Multidrug
Tonic-Clonic Seizures
Regimen That Includes Valproate
14.2
Adjunctive Therapy for Partial-Onset Seizures
5.12
Binding in the Eye and Other Melanin-
14.3
Conversion to Monotherapy for Partial-Onset
Containing Tissues
Seizures
5.13
Laboratory Tests
15
REFERENCES
16
HOW SUPPLIED/STORAGE AND HANDLING
17
PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information
are not listed.
1
FULL PRESCRIBING INFORMATION
2
WARNING: SERIOUS SKIN RASHES
3
LAMICTAL® XR™ can cause serious rashes requiring hospitalization and
4
discontinuation of treatment. The incidence of these rashes, which have included Stevens
5
Johnson syndrome, is approximately 0.8% (8 per 1,000) in pediatric patients (aged 2 to 16
6
years) receiving immediate-release lamotrigine as adjunctive therapy for epilepsy and
7
0.3% (3 per 1,000) in adults on adjunctive therapy for epilepsy. In a prospectively followed
8
cohort of 1,983 pediatric patients (aged 2 to 16 years) with epilepsy taking adjunctive
9
immediate-release lamotrigine, there was 1 rash-related death. LAMICTAL XR is not
10
approved for patients younger than 13 years. In worldwide postmarketing experience, rare
11
cases of toxic epidermal necrolysis and/or rash-related death have been reported in adult
12
and pediatric patients, but their numbers are too few to permit a precise estimate of the
13
rate.
2
Reference ID: 3677876
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 022115/S-004 & S-014
FDA Proposed Labeling Text dated 12/23/2014
Page 3
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The risk of serious rash caused by treatment with LAMICTAL XR is not expected
to differ from that with immediate-release lamotrigine. However, the relatively limited
treatment experience with LAMICTAL XR makes it difficult to characterize the frequency
and risk of serious rashes caused by treatment with LAMICTAL XR.
Other than age, there are as yet no factors identified that are known to predict the
risk of occurrence or the severity of rash caused by LAMICTAL XR. There are
suggestions, yet to be proven, that the risk of rash may also be increased by (1)
coadministration of LAMICTAL XR with valproate (includes valproic acid and divalproex
sodium), (2) exceeding the recommended initial dose of LAMICTAL XR, or (3) exceeding
the recommended dose escalation for LAMICTAL XR. However, cases have occurred in
the absence of these factors.
Nearly all cases of life-threatening rashes caused by immediate-release lamotrigine
have occurred within 2 to 8 weeks of treatment initiation. However, isolated cases have
occurred after prolonged treatment (e.g., 6 months). Accordingly, duration of therapy
cannot be relied upon as means to predict the potential risk heralded by the first
appearance of a rash.
Although benign rashes are also caused by LAMICTAL XR, it is not possible to
predict reliably which rashes will prove to be serious or life threatening. Accordingly,
LAMICTAL XR should ordinarily be discontinued at the first sign of rash, unless the rash
is clearly not drug related. Discontinuation of treatment may not prevent a rash from
becoming life threatening or permanently disabling or disfiguring [se Warnings and
Precautions (5.1)].
36
1
INDICATIONS AND USAGE
37
1.1
Adjunctive Therapy
38
LAMICTAL XR is indicated as adjunctive therapy for primary generalized tonic-clonic
39
(PGTC) seizures and partial-onset seizures with or without secondary generalization in patients
40
aged 13 years and older.
41
1.2
Monotherapy
42
LAMICTAL XR is indicated for conversion to monotherapy in patients aged 13 years
43
and older with partial-onset seizures who are receiving treatment with a single antiepileptic drug
44
(AED).
45
Safety and effectiveness of LAMICTAL XR have not been established (1) as initial
46
monotherapy or (2) for simultaneous conversion to monotherapy from 2 or more concomitant
47
AEDs.
48
1.3
Limitation of Use
49
Safety and effectiveness of LAMICTAL XR for use in patients younger than 13 years
50
have not been established.
3
Reference ID: 3677876
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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Page 4
2
DOSAGE AND ADMINISTRATION
LAMICTAL XR Extended-Release Tablets are taken once daily, with or without food.
Tablets must be swallowed whole and must not be chewed, crushed, or divided.
2.1
General Dosing Considerations
Rash: There are suggestions, yet to be proven, that the risk of severe, potentially life-
threatening rash may be increased by (1) coadministration of LAMICTAL XR with valproate,
(2) exceeding the recommended initial dose of LAMICTAL XR, or (3) exceeding the
recommended dose escalation for LAMICTAL XR. However, cases have occurred in the
absence of these factors [see Boxed Warning]. Therefore, it is important that the dosing
recommendations be followed closely.
The risk of nonserious rash may be increased when the recommended initial dose and/or
the rate of dose escalation for LAMICTAL XR is exceeded and in patients with a history of
allergy or rash to other AEDs.
LAMICTAL XR Patient Titration Kits provide LAMICTAL XR at doses consistent with
the recommended titration schedule for the first 5 weeks of treatment, based upon concomitant
medications, for patients with partial-onset seizures and are intended to help reduce the potential
for rash. The use of LAMICTAL XR Patient Titration Kits is recommended for appropriate
patients who are starting or restarting LAMICTAL XR [see How Supplied/Storage and Handling
(16)].
It is recommended that LAMICTAL XR not be restarted in patients who discontinued
due to rash associated with prior treatment with lamotrigine unless the potential benefits clearly
outweigh the risks. If the decision is made to restart a patient who has discontinued LAMICTAL
XR, the need to restart with the initial dosing recommendations should be assessed. The greater
the interval of time since the previous dose, the greater consideration should be given to
restarting with the initial dosing recommendations. If a patient has discontinued lamotrigine for a
period of more than 5 half-lives, it is recommended that initial dosing recommendations and
guidelines be followed. The half-life of lamotrigine is affected by other concomitant medications
[see Clinical Pharmacology (12.3)].
LAMICTAL XR Added to Drugs Known to Induce or Inhibit Glucuronidation:
Because lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are
known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine.
Drugs that induce glucuronidation include carbamazepine, phenytoin, phenobarbital, primidone,
rifampin, estrogen-containing oral contraceptives, and the protease inhibitors lopinavir/ritonavir
and atazanavir/ritonavir. Valproate inhibits glucuronidation. For dosing considerations for
LAMICTAL XR in patients on estrogen-containing contraceptives and atazanavir/ritonavir, see
below and Table 5. For dosing considerations for LAMICTAL XR in patients on other drugs
known to induce or inhibit glucuronidation, see Table 1 and Table 5.
Target Plasma Levels: A therapeutic plasma concentration range has not been
established for lamotrigine. Dosing of LAMICTAL XR should be based on therapeutic response
[see Clinical Pharmacology (12.3)].
4
Reference ID: 3677876
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 022115/S-004 & S-014
FDA Proposed Labeling Text dated 12/23/2014
Page 5
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Women Taking Estrogen-Containing Oral Contraceptives: Starting LAMICTAL
XR in Women Taking Estrogen-Containing Oral Contraceptives: Although estrogen-
containing oral contraceptives have been shown to increase the clearance of lamotrigine [see
Clinical Pharmacology (12.3)], no adjustments to the recommended dose-escalation guidelines
for LAMICTAL XR should be necessary solely based on the use of estrogen-containing oral
contraceptives. Therefore, dose escalation should follow the recommended guidelines for
initiating adjunctive therapy with LAMICTAL XR based on the concomitant AED or other
concomitant medications (see Table 1). See below for adjustments to maintenance doses of
LAMICTAL XR in women taking estrogen-containing oral contraceptives.
Adjustments to the Maintenance Dose of LAMICTAL XR in Women Taking
Estrogen-Containing Oral Contraceptives:
(1) Taking Estrogen-Containing Oral Contraceptives: In women not taking
carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the
protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine
glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance
dose of LAMICTAL XR will in most cases need to be increased by as much as 2-fold over the
recommended target maintenance dose to maintain a consistent lamotrigine plasma level.
(2) Starting Estrogen-Containing Oral Contraceptives: In women taking a
stable dose of LAMICTAL XR and not taking carbamazepine, phenytoin, phenobarbital,
primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and
atazanavir/ritonavir that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical
Pharmacology (12.3)], the maintenance dose will in most cases need to be increased by as much
as 2-fold to maintain a consistent lamotrigine plasma level. The dose increases should begin at
the same time that the oral contraceptive is introduced and continue, based on clinical response,
no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the
recommended rate (see Table 1) unless lamotrigine plasma levels or clinical response support
larger increases. Gradual transient increases in lamotrigine plasma levels may occur during the
week of inactive hormonal preparation (pill-free week), and these increases will be greater if
dose increases are made in the days before or during the week of inactive hormonal preparation.
Increased lamotrigine plasma levels could result in additional adverse reactions, such as
dizziness, ataxia, and diplopia. If adverse reactions attributable to LAMICTAL XR consistently
occur during the pill-free week, dose adjustments to the overall maintenance dose may be
necessary. Dose adjustments limited to the pill-free week are not recommended. For women
taking LAMICTAL XR in addition to carbamazepine, phenytoin, phenobarbital, primidone, or
other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and
atazanavir/ritonavir that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical
Pharmacology (12.3)], no adjustment to the dose of LAMICTAL XR should be necessary.
(3) Stopping Estrogen-Containing Oral Contraceptives: In women not taking
carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the
protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine
5
Reference ID: 3677876
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance
dose of LAMICTAL XR will in most cases need to be decreased by as much as 50% in order to
maintain a consistent lamotrigine plasma level. The decrease in dose of LAMICTAL XR should
not exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or
lamotrigine plasma levels indicate otherwise [see Clinical Pharmacology (12.3)]. In women
taking LAMICTAL XR in addition to carbamazepine, phenytoin, phenobarbital, primidone, or
other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and
atazanavir/ritonavir that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical
Pharmacology (12.3)], no adjustment to the dose of LAMICTAL XR should be necessary.
Women and Other Hormonal Contraceptive Preparations or Hormone
Replacement Therapy: The effect of other hormonal contraceptive preparations or hormone
replacement therapy on the pharmacokinetics of lamotrigine has not been systematically
evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of
lamotrigine up to 2-fold, and the progestin-only pills had no effect on lamotrigine plasma levels.
Therefore, adjustments to the dosage of LAMICTAL XR in the presence of progestogens alone
will likely not be needed.
Patients Taking Atazanavir/Ritonavir: While atazanavir/ritonavir does reduce the
lamotrigine plasma concentration, no adjustments to the recommended dose-escalation
guidelines for LAMICTAL XR should be necessary solely based on the use of
atazanavir/ritonavir. Dose escalation should follow the recommended guidelines for initiating
adjunctive therapy with LAMICTAL XR based on concomitant AED or other concomitant
medications (see Tables 1 and 5). In patients already taking maintenance doses of LAMICTAL
XR and not taking glucuronidation inducers, the dose of LAMICTAL XR may need to be
increased if atazanavir/ritonavir is added, or decreased if atazanavir/ritonavir is discontinued [see
Clinical Pharmacology (12.3)].
Patients With Hepatic Impairment: Experience in patients with hepatic impairment is
limited. Based on a clinical pharmacology study in 24 subjects with mild, moderate, and severe
liver impairment [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)], the
following general recommendations can be made. No dosage adjustment is needed in patients
with mild liver impairment. Initial, escalation, and maintenance doses should generally be
reduced by approximately 25% in patients with moderate and severe liver impairment without
ascites and 50% in patients with severe liver impairment with ascites. Escalation and
maintenance doses may be adjusted according to clinical response.
Patients With Renal Impairment: Initial doses of LAMICTAL XR should be based on
patients’ concomitant medications (see Table 1); reduced maintenance doses may be effective for
patients with significant renal impairment [see Use in Specific Populations (8.7), Clinical
Pharmacology (12.3)]. Few patients with severe renal impairment have been evaluated during
chronic treatment with immediate-release lamotrigine. Because there is inadequate experience in
this population, LAMICTAL XR should be used with caution in these patients.
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Reference ID: 3677876
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Discontinuation Strategy: For patients receiving LAMICTAL XR in combination with
171
other AEDs, a re-evaluation of all AEDs in the regimen should be considered if a change in
172
seizure control or an appearance or worsening of adverse reactions is observed.
173
If a decision is made to discontinue therapy with LAMICTAL XR, a step-wise reduction
174
of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety
175
concerns require a more rapid withdrawal [see Warnings and Precautions (5.8)].
176
Discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such
177
as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce
178
lamotrigine glucuronidation should prolong the half-life of lamotrigine; discontinuing valproate
179
should shorten the half-life of lamotrigine.
180
2.2
Adjunctive Therapy for Primary Generalized Tonic-Clonic and Partial-Onset
181
Seizures
182
This section provides specific dosing recommendations for patients aged 13 years and
183
older. Specific dosing recommendations are provided depending upon concomitant AEDs or
184
other concomitant medications.
185
186
Table 1. Escalation Regimen for LAMICTAL XR in Patients Aged 13 Years and Older
In Patients TAKING
Valproatea
In Patients NOT
TAKING
Carbamazepine,
Phenytoin,
Phenobarbital,
Primidone,b or
Valproatea
In Patients TAKING
Carbamazepine,
Phenytoin,
Phenobarbital, or
Primidoneb and NOT
TAKING Valproatea
Weeks 1 and 2
25 mg every other day
25 mg every day
50 mg every day
Weeks 3 and 4
25 mg every day
50 mg every day
100 mg every day
Week 5
50 mg every day
100 mg every day
200 mg every day
Week 6
100 mg every day
150 mg every day
300 mg every day
Week 7
150 mg every day
200 mg every day
400 mg every day
Maintenance range
(week 8 and
onward)
200 to 250 mg
every dayc
300 to 400 mg
every dayc
400 to 600 mg
every dayc
187
a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of
188
lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].
189
b Drugs that induce lamotrigine glucuronidation and increase clearance, other than the specified
190
antiepileptic drugs, include estrogen-containing oral contraceptives, rifampin, and the protease
191
inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Dosing recommendations for oral
192
contraceptives and the protease inhibitor atazanavir/ritonavir can be found in General Dosing
193
Considerations [see Dosage and Administration (2.1)]. Patients on rifampin and the protease
194
inhibitor lopinavir/ritonavir should follow the same dosing titration/maintenance regimen used
7
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with antiepileptic drugs that induce glucuronidation and increase clearance [see Dosage and
196
Administration (2.1), Drug Interactions (7), and Clinical Pharmacology (12.3)].
197
c Dose increases at week 8 or later should not exceed 100 mg daily at weekly intervals.
198
199
2.3
Conversion From Adjunctive Therapy to Monotherapy
200
The goal of the transition regimen is to attempt to maintain seizure control while
201
mitigating the risk of serious rash associated with the rapid titration of LAMICTAL XR.
202
To avoid an increased risk of rash, the recommended maintenance dosage range of
203
LAMICTAL XR as monotherapy is 250 to 300 mg given once daily.
204
The recommended initial dose and subsequent dose escalations for LAMICTAL XR
205
should not be exceeded [see Boxed Warning].
206
Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin,
207
Phenobarbital, or Primidone to Monotherapy With LAMICTAL XR: After achieving a dose
208
of 500 mg/day of LAMICTAL XR using the guidelines in Table 1, the concomitant enzyme
209
inducing AED should be withdrawn by 20% decrements each week over a 4-week period. Two
210
weeks after completion of withdrawal of the enzyme-inducing AED, the dosage of
211
LAMICTAL XR may be decreased no faster than 100 mg/day each week to achieve the
212
monotherapy maintenance dosage range of 250 to 300 mg/day.
213
The regimen for the withdrawal of the concomitant AED is based on experience gained in
214
the controlled monotherapy clinical trial using immediate-release lamotrigine.
215
Conversion From Adjunctive Therapy With Valproate to Monotherapy With
216
LAMICTAL XR: The conversion regimen involves the 4 steps outlined in Table 2.
217
218
Table 2. Conversion From Adjunctive Therapy With Valproate to Monotherapy With
219
LAMICTAL XR in Patients Aged 13 Years and Older With Epilepsy
LAMICTAL XR
Valproate
Step 1
Achieve a dose of 150 mg/day according
to guidelines in Table 1.
Maintain established stable dose.
Step 2
Maintain at 150 mg/day.
Decrease dose by decrements no
greater than 500 mg/day/week to
500 mg/day and then maintain for
1 week.
Step 3
Increase to 200 mg/day.
Simultaneously decrease to
250 mg/day and maintain for 1 week.
Step 4
Increase to 250 or 300 mg/day.
Discontinue.
220
221
Conversion From Adjunctive Therapy With Antiepileptic Drugs Other Than
222
Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy
223
With LAMICTAL XR: After achieving a dosage of 250 to 300 mg/day of LAMICTAL XR using
224
the guidelines in Table 1, the concomitant AED should be withdrawn by 20% decrements each
8
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225
week over a 4-week period. No adjustment to the monotherapy dose of LAMICTAL XR is
226
needed.
227
2.4
Conversion From Immediate-Release Lamotrigine Tablets to LAMICTAL XR
228
Patients may be converted directly from immediate-release lamotrigine to LAMICTAL
229
XR Extended-Release Tablets. The initial dose of LAMICTAL XR should match the total daily
230
dose of immediate-release lamotrigine. However, some subjects on concomitant enzyme
231
inducing agents may have lower plasma levels of lamotrigine on conversion and should be
232
monitored [see Clinical Pharmacology (12.3)].
233
Following conversion to LAMICTAL XR, all patients (but especially those on drugs that
234
induce lamotrigine glucuronidation) should be closely monitored for seizure control [see Drug
235
Interactions (7)]. Depending on the therapeutic response after conversion, the total daily dose
236
may need to be adjusted within the recommended dosing instructions (Table 1).
237
3
DOSAGE FORMS AND STRENGTHS
238
3.1
Extended-Release Tablets
239
25 mg, yellow with white center, round, biconvex, film-coated tablets printed with
240
“LAMICTAL” and “XR 25.”
241
50 mg, green with white center, round, biconvex, film-coated tablets printed with
242
“LAMICTAL” and “XR 50.”
243
100 mg, orange with white center, round, biconvex, film-coated tablets printed with
244
“LAMICTAL” and “XR 100.”
245
200 mg, blue with white center, round, biconvex, film-coated tablets printed with
246
“LAMICTAL” and “XR 200.”
247
250 mg, purple with white center, caplet-shaped, film-coated tablets printed with
248
“LAMICTAL” and “XR 250.”
249
300 mg, gray with white center, caplet-shaped, film-coated tablets printed with
250
“LAMICTAL” and “XR 300.”
251
3.2
Potential Medication Errors
252
Patients should be strongly advised to visually inspect their tablets to verify that they are
253
receiving LAMICTAL XR, as opposed to other medications, and that they are receiving the
254
correct formulation of lamotrigine each time they fill their prescription. Depictions of the
255
LAMICTAL XR tablets can be found in the Medication Guide.
256
4
CONTRAINDICATIONS
257
LAMICTAL XR is contraindicated in patients who have demonstrated hypersensitivity
258
(e.g., rash, angioedema, acute urticaria, extensive pruritus, mucosal ulceration) to the drug or its
259
ingredients [see Boxed Warning, Warnings and Precautions (5.1, 5.2)].
260
5
WARNINGS AND PRECAUTIONS
261
5.1
Serious Skin Rashes [see Boxed Warning]
9
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The risk of serious rash caused by treatment with LAMICTAL XR is not expected to
263
differ from that with immediate-release lamotrigine [see Boxed Warning]. However, the
264
relatively limited treatment experience with LAMICTAL XR makes it difficult to characterize
265
the frequency and risk of serious rashes caused by treatment with LAMICTAL XR.
266
Pediatric Population: The incidence of serious rash associated with hospitalization and
267
discontinuation of immediate-release lamotrigine in a prospectively followed cohort of pediatric
268
patients (aged 2 to 16 years) with epilepsy receiving adjunctive therapy with immediate-release
269
lamotrigine was approximately 0.8% (16 of 1,983). When 14 of these cases were reviewed by 3
270
expert dermatologists, there was considerable disagreement as to their proper classification. To
271
illustrate, one dermatologist considered none of the cases to be Stevens-Johnson syndrome;
272
another assigned 7 of the 14 to this diagnosis. There was 1 rash-related death in this
273
1,983-patient cohort. Additionally, there have been rare cases of toxic epidermal necrolysis with
274
and without permanent sequelae and/or death in US and foreign postmarketing experience.
275
There is evidence that the inclusion of valproate in a multidrug regimen increases the risk
276
of serious, potentially life-threatening rash in pediatric patients. In pediatric patients who used
277
valproate concomitantly, 1.2% (6 of 482) experienced a serious rash compared with 0.6% (6 of
278
952) patients not taking valproate.
279
LAMICTAL XR is not approved in patients younger than 13 years.
280
Adult Population: Serious rash associated with hospitalization and discontinuation of
281
immediate-release lamotrigine occurred in 0.3% (11 of 3,348) of adult patients who received
282
immediate-release lamotrigine in premarketing clinical trials of epilepsy. In worldwide
283
postmarketing experience, rare cases of rash-related death have been reported, but their numbers
284
are too few to permit a precise estimate of the rate.
285
Among the rashes leading to hospitalization were Stevens-Johnson syndrome, toxic
286
epidermal necrolysis, angioedema, and those associated with multiorgan hypersensitivity [see
287
Warnings and Precautions (5.2)].
288
There is evidence that the inclusion of valproate in a multidrug regimen increases the risk
289
of serious, potentially life-threatening rash in adults. Specifically, of 584 patients administered
290
immediate-release lamotrigine with valproate in epilepsy clinical trials, 6 (1%) were hospitalized
291
in association with rash; in contrast, 4 (0.16%) of 2,398 clinical trial patients and volunteers
292
administered immediate-release lamotrigine in the absence of valproate were hospitalized.
293
Patients With History of Allergy or Rash to Other Antiepileptic Drugs: The risk of
294
nonserious rash may be increased when the recommended initial dose and/or the rate of dose
295
escalation for LAMICTAL XR is exceeded and in patients with a history of allergy or rash to
296
other AEDs.
297
5.2
Multiorgan Hypersensitivity Reactions and Organ Failure
298
Multiorgan hypersensitivity reactions, also known as drug reaction with eosinophilia and
299
systemic symptoms (DRESS), have occurred with lamotrigine. Some have been fatal or life
300
threatening. DRESS typically, although not exclusively, presents with fever, rash, and/or
301
lymphadenopathy in association with other organ system involvement, such as hepatitis,
10
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nephritis, hematologic abnormalities, myocarditis, or myositis, sometimes resembling an acute
303
viral infection. Eosinophilia is often present. This disorder is variable in its expression and other
304
organ systems not noted here may be involved.
305
Fatalities associated with acute multiorgan failure and various degrees of hepatic failure
306
have been reported in 2 of 3,796 adult patients and 4 of 2,435 pediatric patients who received
307
lamotrigine in epilepsy clinical trials. Rare fatalities from multiorgan failure have also been
308
reported in postmarketing use.
309
Isolated liver failure without rash or involvement of other organs has also been reported
310
with lamotrigine.
311
It is important to note that early manifestations of hypersensitivity (e.g., fever,
312
lymphadenopathy) may be present even though a rash is not evident. If such signs or symptoms
313
are present, the patient should be evaluated immediately. LAMICTAL XR should be
314
discontinued if an alternative etiology for the signs or symptoms cannot be established.
315
Prior to initiation of treatment with LAMICTAL XR, the patient should be
316
instructed that a rash or other signs or symptoms of hypersensitivity (e.g., fever,
317
lymphadenopathy) may herald a serious medical event and that the patient should report
318
any such occurrence to a physician immediately.
319
5.3
Blood Dyscrasias
320
There have been reports of blood dyscrasias with immediate-release lamotrigine that may
321
or may not be associated with multiorgan hypersensitivity (also known as DRESS) [see
322
Warnings and Precautions (5.2)]. These have included neutropenia, leukopenia, anemia,
323
thrombocytopenia, pancytopenia, and, rarely, aplastic anemia and pure red cell aplasia.
324
5.4
Suicidal Behavior and Ideation
325
AEDs, including LAMICTAL XR, increase the risk of suicidal thoughts or behavior in
326
patients taking these drugs for any indication. Patients treated with any AED for any indication
327
should be monitored for the emergence or worsening of depression, suicidal thoughts or
328
behavior, and/or any unusual changes in mood or behavior.
329
Pooled analyses of 199 placebo-controlled clinical trials (monotherapy and adjunctive
330
therapy) of 11 different AEDs showed that patients randomized to 1 of the AEDs had
331
approximately twice the risk (adjusted Relative Risk 1.8, 95% CI: 1.2, 2.7) of suicidal thinking
332
or behavior compared with patients randomized to placebo. In these trials, which had a median
333
treatment duration of 12 weeks, the estimated incidence of suicidal behavior or ideation among
334
27,863 AED-treated patients was 0.43%, compared with 0.24% among 16,029 placebo-treated
335
patients, representing an increase of approximately 1 case of suicidal thinking or behavior for
336
every 530 patients treated. There were 4 suicides in drug-treated patients in the trials and none in
337
placebo-treated patients, but the number of events is too small to allow any conclusion about
338
drug effect on suicide.
339
The increased risk of suicidal thoughts or behavior with AEDs was observed as early as
340
1 week after starting treatment with AEDs and persisted for the duration of treatment assessed.
11
Reference ID: 3677876
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Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal
342
thoughts or behavior beyond 24 weeks could not be assessed.
343
The risk of suicidal thoughts or behavior was generally consistent among drugs in the
344
data analyzed. The finding of increased risk with AEDs of varying mechanism of action and
345
across a range of indications suggests that the risk applies to all AEDs used for any indication.
346
The risk did not vary substantially by age (5 to 100 years) in the clinical trials analyzed.
347
Table 3 shows absolute and relative risk by indication for all evaluated AEDs.
348
349
Table 3. Risk by Indication for Antiepileptic Drugs in the Pooled Analysis
Indication
Placebo
Patients With
Events per
1,000 Patients
Drug Patients
With Events
per 1,000
Patients
Relative Risk:
Incidence of Events
in Drug Patients/
Incidence in
Placebo Patients
Risk Difference:
Additional Drug
Patients With
Events per
1,000 Patients
Epilepsy
1.0
3.4
3.5
2.4
Psychiatric
5.7
8.5
1.5
2.9
Other
1.0
1.8
1.9
0.9
Total
2.4
4.3
1.8
1.9
350
351
The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy
352
than in clinical trials for psychiatric or other conditions, but the absolute risk differences were
353
similar for the epilepsy and psychiatric indications.
354
Anyone considering prescribing LAMICTAL XR or any other AED must balance the risk
355
of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other
356
illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality
357
and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior
358
emerge during treatment, the prescriber needs to consider whether the emergence of these
359
symptoms in any given patient may be related to the illness being treated.
360
Patients, their caregivers, and families should be informed that AEDs increase the risk of
361
suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or
362
worsening of the signs and symptoms of depression, any unusual changes in mood or behavior,
363
the emergence of suicidal thoughts or suicidal behavior, or thoughts about self-harm. Behaviors
364
of concern should be reported immediately to healthcare providers.
365
5.5
Aseptic Meningitis
366
Therapy with lamotrigine increases the risk of developing aseptic meningitis. Because of
367
the potential for serious outcomes of untreated meningitis due to other causes, patients should
368
also be evaluated for other causes of meningitis and treated as appropriate.
369
Postmarketing cases of aseptic meningitis have been reported in pediatric and adult
370
patients taking lamotrigine for various indications. Symptoms upon presentation have included
371
headache, fever, nausea, vomiting, and nuchal rigidity. Rash, photophobia, myalgia, chills,
12
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372
altered consciousness, and somnolence were also noted in some cases. Symptoms have been
373
reported to occur within 1 day to one and a half months following the initiation of treatment. In
374
most cases, symptoms were reported to resolve after discontinuation of lamotrigine. Re-exposure
375
resulted in a rapid return of symptoms (from within 30 minutes to 1 day following re-initiation of
376
treatment) that were frequently more severe. Some of the patients treated with lamotrigine who
377
developed aseptic meningitis had underlying diagnoses of systemic lupus erythematosus or other
378
autoimmune diseases.
379
Cerebrospinal fluid (CSF) analyzed at the time of clinical presentation in reported cases
380
was characterized by a mild to moderate pleocytosis, normal glucose levels, and mild to
381
moderate increase in protein. CSF white blood cell count differentials showed a predominance of
382
neutrophils in a majority of the cases, although a predominance of lymphocytes was reported in
383
approximately one third of the cases. Some patients also had new onset of signs and symptoms
384
of involvement of other organs (predominantly hepatic and renal involvement), which may
385
suggest that in these cases the aseptic meningitis observed was part of a hypersensitivity reaction
386
[see Warnings and Precautions (5.2)].
387
5.6
Potential Medication Errors
388
Medication errors involving LAMICTAL have occurred. In particular, the names
389
LAMICTAL or lamotrigine can be confused with the names of other commonly used
390
medications. Medication errors may also occur between the different formulations of
391
LAMICTAL. To reduce the potential of medication errors, write and say LAMICTAL XR
392
clearly. Depictions of the LAMICTAL XR Extended-Release Tablets can be found in the
393
Medication Guide. Each LAMICTAL XR tablet has a distinct color and white center, and is
394
printed with “LAMICTAL XR” and the tablet strength. These distinctive features serve to
395
identify the different presentations of the drug and thus may help reduce the risk of medication
396
errors. LAMICTAL XR is supplied in round, unit-of-use bottles with orange caps containing
397
30 tablets. The label on the bottle includes a depiction of the tablets that further communicates to
398
patients and pharmacists that the medication is LAMICTAL XR and the specific tablet strength
399
included in the bottle. The unit-of-use bottle with a distinctive orange cap and distinctive bottle
400
label features serves to identify the different presentations of the drug and thus may help to
401
reduce the risk of medication errors. To avoid the medication error of using the wrong drug or
402
formulation, patients should be strongly advised to visually inspect their tablets to verify that
403
they are LAMICTAL XR each time they fill their prescription.
404
5.7
Concomitant Use With Oral Contraceptives
405
Some estrogen-containing oral contraceptives have been shown to decrease serum
406
concentrations of lamotrigine [see Clinical Pharmacology (12.3)]. Dosage adjustments will be
407
necessary in most patients who start or stop estrogen-containing oral contraceptives while
408
taking LAMICTAL XR [see Dosage and Administration (2.1)]. During the week of inactive
409
hormone preparation (pill-free week) of oral contraceptive therapy, plasma lamotrigine levels are
410
expected to rise, as much as doubling at the end of the week. Adverse reactions consistent with
411
elevated levels of lamotrigine, such as dizziness, ataxia, and diplopia, could occur.
13
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412
5.8
Withdrawal Seizures
413
As with other AEDs, LAMICTAL XR should not be abruptly discontinued. In patients
414
with epilepsy there is a possibility of increasing seizure frequency. Unless safety concerns
415
require a more rapid withdrawal, the dose of LAMICTAL XR should be tapered over a period of
416
at least 2 weeks (approximately 50% reduction per week) [see Dosage and Administration
417
(2.1)].
418
5.9
Status Epilepticus
419
Valid estimates of the incidence of treatment-emergent status epilepticus among patients
420
treated with immediate-release lamotrigine are difficult to obtain because reporters participating
421
in clinical trials did not all employ identical rules for identifying cases. At a minimum, 7 of 2,343
422
adult patients had episodes that could unequivocally be described as status epilepticus. In
423
addition, a number of reports of variably defined episodes of seizure exacerbation (e.g., seizure
424
clusters, seizure flurries) were made.
425
5.10 Sudden Unexplained Death in Epilepsy (SUDEP)
426
During the premarketing development of immediate-release lamotrigine, 20 sudden and
427
unexplained deaths were recorded among a cohort of 4,700 patients with epilepsy (5,747 patient
428
years of exposure).
429
Some of these could represent seizure-related deaths in which the seizure was not
430
observed, e.g., at night. This represents an incidence of 0.0035 deaths per patient-year. Although
431
this rate exceeds that expected in a healthy population matched for age and sex, it is within the
432
range of estimates for the incidence of sudden unexplained death in epilepsy (SUDEP) in
433
patients not receiving lamotrigine (ranging from 0.0005 for the general population of patients
434
with epilepsy, to 0.004 for a recently studied clinical trial population similar to that in the clinical
435
development program for immediate-release lamotrigine, to 0.005 for patients with refractory
436
epilepsy). Consequently, whether these figures are reassuring or suggest concern depends on the
437
comparability of the populations reported upon with the cohort receiving immediate-release
438
lamotrigine and the accuracy of the estimates provided. Probably most reassuring is the
439
similarity of estimated SUDEP rates in patients receiving immediate-release lamotrigine and
440
those receiving other AEDs, chemically unrelated to each other, that underwent clinical testing in
441
similar populations. Importantly, that drug is chemically unrelated to lamotrigine. This evidence
442
suggests, although it certainly does not prove, that the high SUDEP rates reflect population rates,
443
not a drug effect.
444
5.11 Addition of LAMICTAL XR to a Multidrug Regimen That Includes Valproate
445
Because valproate reduces the clearance of lamotrigine, the dosage of lamotrigine in the
446
presence of valproate is less than half of that required in its absence [see Dosage and
447
Administration (2.1, 2.2), Drug Interactions (7)].
448
5.12 Binding in the Eye and Other Melanin-Containing Tissues
449
Because lamotrigine binds to melanin, it could accumulate in melanin-rich tissues over
450
time. This raises the possibility that lamotrigine may cause toxicity in these tissues after
451
extended use. Although ophthalmological testing was performed in 1 controlled clinical trial, the
14
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452
testing was inadequate to exclude subtle effects or injury occurring after long-term exposure.
453
Moreover, the capacity of available tests to detect potentially adverse consequences, if any, of
454
lamotrigine’s binding to melanin is unknown.
455
Accordingly, although there are no specific recommendations for periodic
456
ophthalmological monitoring, prescribers should be aware of the possibility of long-term
457
ophthalmologic effects.
458
5.13 Laboratory Tests
459
Plasma Concentrations of Lamotrigine: The value of monitoring plasma
460
concentrations of lamotrigine in patients treated with LAMICTAL XR has not been established.
461
Because of the possible pharmacokinetic interactions between lamotrigine and other drugs,
462
including AEDs (see Table 6), monitoring of the plasma levels of lamotrigine and concomitant
463
drugs may be indicated, particularly during dosage adjustments. In general, clinical judgment
464
should be exercised regarding monitoring of plasma levels of lamotrigine and other drugs and
465
whether or not dosage adjustments are necessary.
466
Effect on Leukocytes: Treatment with LAMICTAL XR caused an increased incidence
467
of subnormal (below the reference range) values in some hematology analytes (e.g., total white
468
blood cells, monocytes). The treatment effect (LAMICTAL XR % - Placebo %) incidence of
469
subnormal counts was 3% for total white blood cells and 4% for monocytes.
470
6
ADVERSE REACTIONS
471
The following adverse reactions are described in more detail in the Warnings and
472
Precautions section of the label:
473
• Serious skin rashes [see Warnings and Precautions (5.1)]
474
• Multiorgan hypersensitivity reactions and organ failure [see Warnings and Precautions (5.2)]
475
• Blood dyscrasias [see Warnings and Precautions (5.3)]
476
• Suicidal behavior and ideation [see Warnings and Precautions (5.4)]
477
• Aseptic meningitis [see Warnings and Precautions (5.5)]
478
• Withdrawal seizures [see Warnings and Precautions (5.8)]
479
• Status epilepticus [see Warnings and Precautions (5.9)]
480
• Sudden unexplained death in epilepsy [see Warnings and Precautions (5.10)]
481
6.1
Clinical Trial Experience With LAMICTAL XR for Treatment of Primary
482
Generalized Tonic-Clonic and Partial-Onset Seizures
483
Most Common Adverse Reactions in Clinical Trials: Adjunctive Therapy in
484
Patients With Epilepsy: Because clinical trials are conducted under widely varying conditions,
485
adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with
486
rates in the clinical trials of another drug and may not reflect the rates observed in practice.
487
LAMICTAL XR has been evaluated for safety in patients aged 13 years and older with
488
PGTC and partial-onset seizures. The most commonly observed adverse reactions in these 2
489
double-blind, placebo-controlled trials of adjunctive therapy with LAMICTAL XR were, in
15
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490
order of decreasing incidence (treatment difference between LAMICTAL XR and placebo ≥4%):
491
dizziness, tremor/intention tremor, vomiting, and diplopia.
492
In these 2 trials, adverse reactions led to withdrawal of 4 (2%) patients in the group
493
receiving placebo and 10 (5%) patients in the group receiving LAMICTAL XR. Dizziness was
494
the most common reason for withdrawal in the group receiving LAMICTAL XR (5 patients
495
[3%]). The next most common adverse reactions leading to withdrawal in 2 patients each (1%)
496
were rash, headache, nausea, and nystagmus.
497
Table 4 displays the incidence of adverse reactions in these two 19-week, double-blind,
498
placebo-controlled trials of patients with PGTC and partial onset seizures.
499
500
Table 4. Adverse Reaction Incidence in Double-Blind, Placebo-Controlled Adjunctive
501
Trials in Patients With Epilepsy (Adverse reactions ≥2% of patients treated with
502
LAMICTAL XR and numerically more frequent than in the placebo group.)
Body System/
Adverse Reaction
Percent of Patients
Receiving Adjunctive
LAMICTAL XR
(n = 190)
Percent of Patients
Receiving Adjunctive
Placebo
(n = 195)
Ear and labyrinth disorders
Vertigo
3
<1
Eye disorders
Diplopia
Vision blurred
5
3
<1
2
Gastrointestinal disorders
Nausea
Vomiting
Diarrhea
Constipation
Dry mouth
7
6
5
2
2
4
3
3
<1
1
General disorders and
administration site
conditions
Asthenia and fatigue
6
4
Infections and infestations
Sinusitis
2
1
Metabolic and nutritional
disorders
Anorexia
3
2
Musculoskeletal and
connective tissue disorder
Myalgia
2
0
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Page 17
Nervous system
Dizziness
Tremor and intention
tremor
Somnolence
Cerebellar coordination
and balance disorder
Nystagmus
14
6
5
3
2
6
1
3
0
<1
Psychiatric disorders
Depression
Anxiety
3
3
<1
0
Respiratory, thoracic, and
mediastinal disorders
Pharyngolaryngeal pain
3
2
Vascular disorder
Hot flush
2
0
503
Note: In these trials the incidence of nonserious rash was 2% for LAMICTAL XR and 3% for
504
placebo. In clinical trials evaluating immediate-release lamotrigine, the rate of serious rash was
505
0.3% in adults on adjunctive therapy for epilepsy [see Boxed Warning].
506
507
Adverse reactions were also analyzed to assess the incidence of the onset of an event in
508
the titration period, and in the maintenance period, and if adverse reactions occurring in the
509
titration phase persisted in the maintenance phase.
510
The incidence for many adverse reactions caused by treatment with LAMICTAL XR was
511
increased relative to placebo (i.e., treatment difference between LAMICTAL XR and placebo
512
≥2%) in either the titration or maintenance phases of the trial. During the titration phase, an
513
increased incidence (shown in descending order of % treatment difference) was observed for
514
diarrhea, nausea, vomiting, somnolence, vertigo, myalgia, hot flush, and anxiety. During the
515
maintenance phase, an increased incidence was observed for dizziness, tremor, and diplopia.
516
Some adverse reactions developing in the titration phase were notable for persisting (>7 days)
517
into the maintenance phase. These persistent adverse reactions included somnolence and
518
dizziness.
519
There were inadequate data to evaluate the effect of dose and/or concentration on the
520
incidence of adverse reactions because, although patients were randomized to different target
521
doses based upon concomitant AEDs, the plasma exposure was expected to be generally similar
522
among all patients receiving different doses. However, in a randomized, parallel trial comparing
523
placebo with 300 and 500 mg/day of immediate-release lamotrigine, the incidence of the most
524
common adverse reactions (>5%) such as ataxia, blurred vision, diplopia, and dizziness were
525
dose related. Less common adverse reactions (<5%) were not assessed for dose-response
526
relationships.
17
Reference ID: 3677876
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Page 18
527
Monotherapy in Patients With Epilepsy: Adverse reactions observed in this trial
528
were generally similar to those observed and attributed to drug in adjunctive and monotherapy
529
immediate-release lamotrigine and adjunctive LAMICTAL XR placebo-controlled trials. Only 2
530
adverse events, nasopharyngitis and upper respiratory tract infection, were observed at a rate of
531
>3% and not reported at a similar rate in previous trials. Because this trial did not include a
532
placebo control group, causality could not be established [see Clinical Studies (14.3)].
533
6.2
Other Adverse Reactions Observed During the Clinical Development of
534
Immediate-Release Lamotrigine
535
All reported reactions are included except those already listed in the previous tables or
536
elsewhere in the labeling, those too general to be informative, and those not reasonably
537
associated with the use of the drug.
538
Adjunctive Therapy in Adults With Epilepsy: In addition to the adverse reactions
539
reported above from the development of LAMICTAL XR, the following adverse reactions with
540
an uncertain relationship to lamotrigine were reported during the clinical development of
541
immediate-release lamotrigine for treatment of epilepsy in adults. These reactions occurred in
542
≥2% of patients receiving immediate-release lamotrigine and more frequently than in the placebo
543
group.
544
Body as a Whole: Headache, flu syndrome, fever, neck pain.
545
Musculoskeletal: Arthralgia.
546
Nervous: Insomnia, convulsion, irritability, speech disorder, concentration
547
disturbance.
548
Respiratory: Pharyngitis, cough increased.
549
Skin and Appendages: Rash, pruritus.
550
Urogenital (female patients only): Vaginitis, amenorrhea, dysmenorrhea.
551
Monotherapy in Adults With Epilepsy: In addition to the adverse reactions reported
552
above from the development of LAMICTAL XR, the following adverse reactions with an
553
uncertain relationship to lamotrigine were reported during the clinical development of
554
immediate-release lamotrigine for treatment of epilepsy in adults. These reactions occurred in
555
>2% of patients receiving immediate-release lamotrigine and more frequently than in the placebo
556
group.
557
Body as a Whole: Chest pain.
558
Digestive: Rectal hemorrhage, peptic ulcer.
559
Metabolic and Nutritional: Weight decrease, peripheral edema.
560
Nervous: Hypesthesia, libido increase, decreased reflexes.
561
Respiratory: Epistaxis, dyspnea.
562
Skin and Appendages: Contact dermatitis, dry skin, sweating.
563
Special Senses: Vision abnormality.
564
Urogenital (female patients only): Dysmenorrhea.
18
Reference ID: 3677876
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Page 19
565
Other Clinical Trial Experience: Immediate-release lamotrigine has been administered
566
to 6,694 individuals for whom complete adverse reaction data was captured during all clinical
567
trials, only some of which were placebo controlled.
568
Adverse reactions are further classified within body system categories and enumerated in
569
order of decreasing frequency using the following definitions: frequent adverse reactions are
570
defined as those occurring in at least 1/100 patients; infrequent adverse reactions are those
571
occurring in 1/100 to 1/1,000 patients; rare adverse reactions are those occurring in fewer than
572
1/1,000 patients.
573
Cardiovascular System: Infrequent: Hypertension, palpitations, postural
574
hypotension, syncope, tachycardia, vasodilation.
575
Dermatological: Infrequent: Acne, alopecia, hirsutism, maculopapular rash, urticaria.
576
Rare: Leukoderma, multiforme erythema, petechial rash, pustular rash.
577
Digestive System: Infrequent: Dysphagia, liver function tests abnormal, mouth
578
ulceration. Rare: Gastrointestinal hemorrhage, hemorrhagic colitis, hepatitis, melena and
579
stomach ulcer.
580
Endocrine System: Rare: Goiter, hypothyroidism.
581
Hematologic and Lymphatic System: Infrequent: Ecchymosis, leukopenia. Rare:
582
Anemia, eosinophilia, fibrin decrease, fibrinogen decrease, iron deficiency anemia, leukocytosis,
583
lymphocytosis, macrocytic anemia, petechia, thrombocytopenia.
584
Metabolic and Nutritional Disorders: Infrequent: Aspartate transaminase increased.
585
Rare: Alcohol intolerance, alkaline phosphatase increase, alanine transaminase increase,
586
bilirubinemia, gamma glutamyl transpeptidase increase, hyperglycemia.
587
Musculoskeletal System: Rare: Muscle atrophy, pathological fracture, tendinous
588
contracture.
589
Nervous System: Frequent: Confusion. Infrequent: Akathisia, apathy, aphasia,
590
depersonalization, dysarthria, dyskinesia, euphoria, hallucinations, hostility, hyperkinesia,
591
hypertonia, libido decreased, memory decrease, mind racing, movement disorder, myoclonus,
592
panic attack, paranoid reaction, personality disorder, psychosis, stupor. Rare: Choreoathetosis,
593
delirium, delusions, dysphoria, dystonia, extrapyramidal syndrome, hemiplegia, hyperalgesia,
594
hyperesthesia, hypokinesia, hypotonia, manic depression reaction, neuralgia, paralysis,
595
peripheral neuritis.
596
Respiratory System: Rare: Hiccup, hyperventilation.
597
Special Senses: Frequent: Amblyopia. Infrequent: Abnormality of
598
accommodation, conjunctivitis, dry eyes, ear pain, photophobia, taste perversion, tinnitus. Rare:
599
Deafness, lacrimation disorder, oscillopsia, parosmia, ptosis, strabismus, taste loss, uveitis, visual
600
field defect.
601
Urogenital System: Infrequent: Abnormal ejaculation, hematuria, impotence,
602
menorrhagia, polyuria, urinary incontinence. Rare: Acute kidney failure, breast neoplasm,
603
creatinine increase, female lactation, kidney failure, kidney pain, nocturia, urinary retention,
604
urinary urgency.
19
Reference ID: 3677876
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 022115/S-004 & S-014
FDA Proposed Labeling Text dated 12/23/2014
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605
6.3
Postmarketing Experience With Immediate-Release Lamotrigine
606
The following adverse events (not listed above in clinical trials or other sections of the
607
prescribing information) have been identified during postapproval use of immediate-release
608
lamotrigine. Because these events are reported voluntarily from a population of uncertain size, it
609
is not always possible to reliably estimate their frequency or establish a causal relationship to
610
drug exposure.
611
Blood and Lymphatic: Agranulocytosis, hemolytic anemia, lymphadenopathy not
612
associated with hypersensitivity disorder.
613
Gastrointestinal: Esophagitis.
614
Hepatobiliary Tract and Pancreas: Pancreatitis.
615
Immunologic: Lupus-like reaction, vasculitis.
616
Lower Respiratory: Apnea.
617
Musculoskeletal: Rhabdomyolysis has been observed in patients experiencing
618
hypersensitivity reactions.
619
Neurology: Exacerbation of Parkinsonian symptoms in patients with pre-existing
620
Parkinson’s disease, tics.
621
Non-site Specific: Progressive immunosuppression.
622
7
DRUG INTERACTIONS
623
Significant drug interactions with lamotrigine are summarized in Table 5. Additional
624
details of these drug interaction studies, which were conducted using immediate-release
625
lamotrigine, are provided in the Clinical Pharmacology section [see Clinical Pharmacology
626
(12.3)].
627
20
Reference ID: 3677876
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Page 21
628
Table 5. Established and Other Potentially Significant Drug Interactions
Concomitant Drug
Effect on
Concentration of
Lamotrigine or
Concomitant Drug
Clinical Comment
Estrogen-containing oral
contraceptive
preparations containing
30 mcg ethinylestradiol
and 150 mcg
levonorgestrel
↓ lamotrigine
↓ levonorgestrel
Decreased lamotrigine concentrations
approximately 50%.
Decrease in levonorgestrel component by
19%.
Carbamazepine and
carbamazepine epoxide
↓ lamotrigine
? carbamazepine
epoxide
Addition of carbamazepine decreases
lamotrigine concentration approximately
40%.
May increase carbamazepine epoxide
levels.
Lopinavir/ritonavir
↓ lamotrigine
Decreased lamotrigine concentration
approximately 50%.
Atazanavir/ritonavir
↓ lamotrigine
Decreased lamotrigine AUC
approximately 32%.
Phenobarbital/primidone
↓ lamotrigine
Decreased lamotrigine concentration
approximately 40%.
Phenytoin
↓ lamotrigine
Decreased lamotrigine concentration
approximately 40%.
Rifampin
↓ lamotrigine
Decreased lamotrigine AUC
approximately 40%.
Valproate
↑ lamotrigine
? valproate
Increased lamotrigine concentrations
slightly more than 2-fold.
There are conflicting study results
regarding effect of lamotrigine on
valproate concentrations: 1) a mean 25%
decrease in valproate concentrations in
healthy volunteers, 2) no change in
valproate concentrations in controlled
clinical trials in patients with epilepsy.
629
↓ = Decreased (induces lamotrigine glucuronidation).
630
↑ = Increased (inhibits lamotrigine glucuronidation).
631
? = Conflicting data.
21
Reference ID: 3677876
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Page 22
632
8
USE IN SPECIFIC POPULATIONS
633
8.1
Pregnancy
634
Teratogenic Effects: Pregnancy Category C. There are no adequate and well-controlled
635
trials in pregnant women. In animal studies, lamotrigine was developmentally toxic at doses
636
lower than those administered clinically. LAMICTAL XR should be used during pregnancy only
637
if the potential benefit justifies the potential risk to the fetus.
638
When lamotrigine was administered to pregnant mice, rats, or rabbits during the period of
639
organogenesis (oral doses of up to 125, 25, and 30 mg/kg, respectively), reduced fetal body
640
weight and increased incidences of fetal skeletal variations were seen in mice and rats at doses
641
that were also maternally toxic. The no-effect doses for embryo-fetal developmental toxicity in
642
mice, rats, and rabbits (75, 6.25, and 30 mg/kg, respectively) are similar to (mice and rabbits) or
643
less than the human dose of 400 mg/day on a body surface area (mg/m2) basis.
644
In a study in which pregnant rats were administered lamotrigine (oral doses of 5 or
645
25 mg/kg) during the period of organogenesis and offspring were evaluated postnatally,
646
behavioral abnormalities were observed in exposed offspring at both doses. The lowest effect
647
dose for developmental neurotoxicity in rats is less than the human dose of 400 mg/day on a
648
mg/m2 basis. Maternal toxicity was observed at the higher dose tested.
649
When pregnant rats were administered lamotrigine (oral doses of 5, 10, or 20 mg/kg)
650
during the latter part of gestation, increased offspring mortality (including stillbirths) was seen at
651
all doses. The lowest effect dose for peri/postnatal developmental toxicity in rats is less than the
652
human dose of 400 mg/day on a mg/m2 basis. Maternal toxicity was observed at the 2 highest
653
doses tested.
654
Lamotrigine decreases fetal folate concentrations in rat, an effect known to be associated
655
with adverse pregnancy outcomes in animals and humans.
656
Nonteratogenic Effects: As with other AEDs, physiological changes during pregnancy
657
may affect lamotrigine concentrations and/or therapeutic effect. There have been reports of
658
decreased lamotrigine concentrations during pregnancy and restoration of pre-partum
659
concentrations after delivery. Dosage adjustments may be necessary to maintain clinical
660
response.
661
Pregnancy Registry: To provide information regarding the effects of in utero exposure
662
to LAMICTAL XR, physicians are advised to recommend that pregnant patients taking
663
LAMICTAL XR enroll in the North American Antiepileptic Drug (NAAED) Pregnancy
664
Registry. This can be done by calling the toll-free number 1-888-233-2334 and must be done by
665
patients themselves. Information on the registry can also be found at the website
666
http://www.aedpregnancyregistry.org.
667
8.2
Labor and Delivery
668
The effect of LAMICTAL XR on labor and delivery in humans is unknown.
669
8.3
Nursing Mothers
670
Lamotrigine is present in milk from lactating women taking LAMICTAL XR. Data from
671
multiple small studies indicate that lamotrigine plasma levels in human milk-fed infants have
22
Reference ID: 3677876
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Reference ID: 3677876
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Page 24
712
8.6
Patients With Hepatic Impairment
713
Experience in patients with hepatic impairment is limited. Based on a clinical
714
pharmacology study with immediate-release lamotrigine in 24 subjects with mild, moderate, and
715
severe liver impairment [see Clinical Pharmacology (12.3)], the following general
716
recommendations can be made. No dosage adjustment is needed in patients with mild liver
717
impairment. Initial, escalation, and maintenance doses should generally be reduced by
718
approximately 25% in patients with moderate and severe liver impairment without ascites and
719
50% in patients with severe liver impairment with ascites. Escalation and maintenance doses
720
may be adjusted according to clinical response [see Dosage and Administration (2.1)].
721
8.7
Patients With Renal Impairment
722
Lamotrigine is metabolized mainly by glucuronic acid conjugation, with the majority of
723
the metabolites being recovered in the urine. In a small study comparing a single dose of
724
immediate-release lamotrigine in subjects with varying degrees of renal impairment with healthy
725
volunteers, the plasma half-life of lamotrigine was approximately twice as long in the subjects
726
with chronic renal failure [see Clinical Pharmacology (12.3)].
727
Initial doses of LAMICTAL XR should be based on patients’ AED regimens; reduced
728
maintenance doses may be effective for patients with significant renal impairment. Few patients
729
with severe renal impairment have been evaluated during chronic treatment with lamotrigine.
730
Because there is inadequate experience in this population, LAMICTAL XR should be used with
731
caution in these patients [see Dosage and Administration (2.1)].
732
10
OVERDOSAGE
733
10.1 Human Overdose Experience
734
Overdoses involving quantities up to 15 g have been reported for immediate-release
735
lamotrigine, some of which have been fatal. Overdose has resulted in ataxia, nystagmus, seizures
736
(including tonic-clonic seizures), decreased level of consciousness, coma, and intraventricular
737
conduction delay.
738
10.2 Management of Overdose
739
There are no specific antidotes for lamotrigine. Following a suspected overdose,
740
hospitalization of the patient is advised. General supportive care is indicated, including frequent
741
monitoring of vital signs and close observation of the patient. If indicated, emesis should be
742
induced; usual precautions should be taken to protect the airway. It is uncertain whether
743
hemodialysis is an effective means of removing lamotrigine from the blood. In 6 renal failure
744
patients, about 20% of the amount of lamotrigine in the body was removed by hemodialysis
745
during a 4-hour session. A Poison Control Center should be contacted for information on the
746
management of overdosage of LAMICTAL XR.
747
11
DESCRIPTION
748
LAMICTAL XR (lamotrigine), an AED of the phenyltriazine class, is chemically
749
unrelated to existing AEDs. Lamotrigine’s chemical name is 3,5-diamino-6-(2,3
750
dichlorophenyl)-as-triazine, its molecular formula is C9H7N5Cl2, and its molecular weight is
24
Reference ID: 3677876
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
s
t
r
u
ctur
al formula
NDA 022115/S-004 & S-014
FDA Proposed Labeling Text dated 12/23/2014
Page 25
751
256.09. Lamotrigine is a white to pale cream-colored powder and has a pKa of 5.7. Lamotrigine
752
is very slightly soluble in water (0.17 mg/mL at 25°C) and slightly soluble in 0.1 M HCl
753
(4.1 mg/mL at 25°C). The structural formula is:
754
757
LAMICTAL XR Extended-Release Tablets are supplied for oral administration as 25-mg
758
(yellow with white center), 50-mg (green with white center), 100-mg (orange with white center),
759
200-mg (blue with white center), 250-mg (purple with white center), and 300-mg (gray with
760
white center) tablets. Each tablet contains the labeled amount of lamotrigine and the following
761
inactive ingredients: glycerol monostearate, hypromellose, lactose monohydrate; magnesium
762
stearate; methacrylic acid copolymer dispersion, polyethylene glycol 400, polysorbate 80, silicon
763
dioxide (25- and 50-mg tablets only), titanium dioxide, triethyl citrate, carmine (250-mg tablet
764
only), iron oxide black (50-, 250-, and 300-mg tablets only), iron oxide yellow (25-, 50-, and
765
100-mg tablets only), iron oxide red (100-mg tablet only), FD&C Blue No. 2 Aluminum Lake
766
(200- and 250-mg tablets only). Tablets are printed with edible black ink.
767
LAMICTAL XR Extended-Release Tablets contain a modified-release eroding
768
formulation as the core. The tablets are coated with a clear enteric coat and have an aperture
769
drilled through the coats on both faces of the tablet (DiffCORE™) to enable a controlled release
770
of drug in the acidic environment of the stomach. The combination of this and the modified
771
release core are designed to control the dissolution rate of lamotrigine over a period of
772
approximately 12 to 15 hours, leading to a gradual increase in serum lamotrigine levels.
773
12
CLINICAL PHARMACOLOGY
774
12.1 Mechanism of Action
775
The precise mechanism(s) by which lamotrigine exerts its anticonvulsant action are
776
unknown. In animal models designed to detect anticonvulsant activity, lamotrigine was effective
777
in preventing seizure spread in the maximum electroshock (MES) and pentylenetetrazol (scMet)
778
tests, and prevented seizures in the visually and electrically evoked after-discharge (EEAD) tests
779
for antiepileptic activity. Lamotrigine also displayed inhibitory properties in the kindling model
780
in rats both during kindling development and in the fully kindled state. The relevance of these
781
models to human epilepsy, however, is not known.
782
One proposed mechanism of action of lamotrigine, the relevance of which remains to be
783
established in humans, involves an effect on sodium channels. In vitro pharmacological studies
784
suggest that lamotrigine inhibits voltage-sensitive sodium channels, thereby stabilizing neuronal
785
membranes and consequently modulating presynaptic transmitter release of excitatory amino
786
acids (e.g., glutamate and aspartate).
25
Reference ID: 3677876
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Page 26
787
Effect of Lamotrigine on N-Methyl d-Aspartate-Receptor Mediated Activity:
788
Lamotrigine did not inhibit N-methyl d-aspartate (NMDA)-induced depolarizations in rat cortical
789
slices or NMDA-induced cyclic GMP formation in immature rat cerebellum, nor did lamotrigine
790
displace compounds that are either competitive or noncompetitive ligands at this glutamate
791
receptor complex (CNQX, CGS, TCHP). The IC50 for lamotrigine effects on NMDA-induced
792
currents (in the presence of 3 µM of glycine) in cultured hippocampal neurons exceeded
793
100 µM.
794
12.2 Pharmacodynamics
795
Folate Metabolism: In vitro, lamotrigine inhibited dihydrofolate reductase, the enzyme
796
that catalyzes the reduction of dihydrofolate to tetrahydrofolate. Inhibition of this enzyme may
797
interfere with the biosynthesis of nucleic acids and proteins. When oral daily doses of
798
lamotrigine were given to pregnant rats during organogenesis, fetal, placental, and maternal
799
folate concentrations were reduced. Significantly reduced concentrations of folate are associated
800
with teratogenesis [see Use in Specific Populations (8.1)]. Folate concentrations were also
801
reduced in male rats given repeated oral doses of lamotrigine. Reduced concentrations were
802
partially returned to normal when supplemented with folinic acid.
803
Cardiovascular: In dogs, lamotrigine is extensively metabolized to a 2-N-methyl
804
metabolite. This metabolite causes dose-dependent prolongation of the PR interval, widening of
805
the QRS complex, and, at higher doses, complete AV conduction block. Similar cardiovascular
806
effects are not anticipated in humans because only trace amounts of the 2-N-methyl metabolite
807
(<0.6% of lamotrigine dose) have been found in human urine [see Clinical Pharmacology
808
(12.3)]. However, it is conceivable that plasma concentrations of this metabolite could be
809
increased in patients with a reduced capacity to glucuronidate lamotrigine (e.g., in patients with
810
liver disease, patients taking concomitant medications that inhibit glucuronidation).
811
12.3 Pharmacokinetics
812
In comparison with immediate-release lamotrigine, the plasma lamotrigine levels
813
following administration of LAMICTAL XR are not associated with any significant changes in
814
trough plasma concentrations, and are characterized by lower peaks, longer time to peaks, and
815
lower peak-to-trough fluctuation, as described in detail below.
816
Absorption: Lamotrigine is absorbed after oral administration with negligible first-pass
817
metabolism. The bioavailability of lamotrigine is not affected by food.
818
In an open-label, crossover study of 44 subjects with epilepsy receiving concomitant
819
AEDs, the steady-state pharmacokinetics of lamotrigine were compared following administration
820
of equivalent total doses of LAMICTAL XR given once daily with those of lamotrigine
821
immediate-release given twice daily. In this study, the median time to peak concentration (Tmax)
822
following administration of LAMICTAL XR was 4 to 6 hours in subjects taking carbamazepine,
823
phenytoin, phenobarbital, or primidone; 9 to 11 hours in subjects taking valproate; and 6 to
824
10 hours in subjects taking AEDs other than carbamazepine, phenytoin, phenobarbital,
825
primidone, or valproate. In comparison, the median Tmax following administration of immediate
826
release lamotrigine was between 1 and 1.5 hours.
26
Reference ID: 3677876
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For current labeling information, please visit https://www.fda.gov/drugsatfda
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Page 27
827
The steady-state trough concentrations for extended-release lamotrigine were similar to
828
or higher than those of immediate-release lamotrigine depending on concomitant AED (Table 6).
829
A mean reduction in the lamotrigine Cmax by 11% to 29% was observed for LAMICTAL XR
830
compared with immediate-release lamotrigine, resulting in a decrease in the peak-to-trough
831
fluctuation in serum lamotrigine concentrations. However, in some subjects receiving enzyme
832
inducing AEDs, a reduction in Cmax of 44% to 77% was observed. The degree of fluctuation was
833
reduced by 17% in subjects taking enzyme-inducing AEDs; 34% in subjects taking valproate;
834
and 37% in subjects taking AEDs other than carbamazepine, phenytoin, phenobarbital,
835
primidone, or valproate. LAMICTAL XR and immediate-release lamotrigine regimens were
836
similar with respect to area under the curve (AUC, a measure of the extent of bioavailability) for
837
subjects receiving AEDs other than those known to induce the metabolism of lamotrigine. The
838
relative bioavailability of extended-release lamotrigine was approximately 21% lower than
839
immediate-release lamotrigine in subjects receiving enzyme-inducing AEDs. However, a
840
reduction in exposure of up to 70% was observed in some subjects in this group when they
841
switched to LAMICTAL XR. Therefore, doses may need to be adjusted in some patients based
842
on therapeutic response.
843
844
Table 6. Steady-State Bioavailability of LAMICTAL XR Relative to Immediate-Release
845
Lamotrigine at Equivalent Daily Doses (Ratio of Extended-Release to Immediate-Release
846
90% CI)
Concomitant Antiepileptic Drug
AUC(0-24ss)
Cmax
Cmin
Enzyme-inducing antiepileptic
drugsa
0.79 (0.69, 0.90)
0.71 (0.61, 0.82)
0.99 (0.89, 1.09)
Valproate
0.94 (0.81, 1.08)
0.88 (0.75, 1.03)
0.99 (0.88, 1.10)
Antiepileptic drugs other than
enzyme-inducing antiepileptic
drugsa or valproate
1.00 (0.88, 1.14)
0.89 (0.78, 1.03)
1.14 (1.03, 1.25)
847
a Enzyme-inducing antiepileptic drugs include carbamazepine, phenytoin, phenobarbital, and
848
primidone.
849
850
Dose Proportionality: In healthy volunteers not receiving any other medications and
851
given LAMICTAL XR once daily, the systemic exposure to lamotrigine increased in direct
852
proportion to the dose administered over the range of 50 to 200 mg. At doses between 25 and
853
50 mg, the increase was less than dose proportional, with a 2-fold increase in dose resulting in an
854
approximately 1.6-fold increase in systemic exposure.
855
Distribution: Estimates of the mean apparent volume of distribution (Vd/F) of
856
lamotrigine following oral administration ranged from 0.9 to 1.3 L/kg. Vd/F is independent of
857
dose and is similar following single and multiple doses in both patients with epilepsy and in
858
healthy volunteers.
27
Reference ID: 3677876
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28
Reference ID: 3677876
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For current labeling information, please visit https://www.fda.gov/drugsatfda
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FDA Proposed Labeling Text dated 12/23/2014
Page 29
892
Table 7. Mean Pharmacokinetic Parametersa of Immediate-Release Lamotrigine in
893
Healthy Volunteers and Adult Subjects With Epilepsy
Adult Study Population
Number of
Subjects
t½:
Elimination
Half-life (h)
CL/F:
Apparent Plasma
Clearance
(mL/min/kg)
Healthy volunteers taking no
other medications:
Single-dose lamotrigine
Multiple-dose lamotrigine
179
36
32.8
(14.0-103.0)
25.4
(11.6-61.6)
0.44
(0.12-1.10)
0.58
(0.24-1.15)
Healthy volunteers taking
valproate:
Single-dose lamotrigine
Multiple-dose lamotrigine
6
18
48.3
(31.5-88.6)
70.3
(41.9-113.5)
0.30
(0.14-0.42)
0.18
(0.12-0.33)
Subjects with epilepsy taking
valproate only:
Single-dose lamotrigine
4
58.8
(30.5-88.8)
0.28
(0.16-0.40)
Subjects with epilepsy taking
carbamazepine, phenytoin,
phenobarbital, or primidoneb
plus valproate:
Single-dose lamotrigine
25
27.2
(11.2-51.6)
0.53
(0.27-1.04)
Subjects with epilepsy taking
carbamazepine, phenytoin,
phenobarbital, or primidone:b
Single-dose lamotrigine
Multiple-dose lamotrigine
24
17
14.4
(6.4-30.4)
12.6
(7.5-23.1)
1.10
(0.51-2.22)
1.21
(0.66-1.82)
894
a The majority of parameter means determined in each study had coefficients of variation
895
between 20% and 40% for half-life and CL/F and between 30% and 70% for Tmax. The
896
overall mean values were calculated from individual study means that were weighted based
897
on the number of volunteers/subjects in each study. The numbers in parentheses below each
898
parameter mean represent the range of individual volunteer/subject values across studies.
29
Reference ID: 3677876
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Page 30
899
b Carbamazepine, phenytoin, phenobarbital, and primidone have been shown to increase the
900
apparent clearance of lamotrigine. Estrogen-containing oral contraceptives and other drugs,
901
such as rifampin and protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir, that
902
induce lamotrigine glucuronidation have also been shown to increase the apparent clearance
903
of lamotrigine [see Drug Interactions (7)].
904
905
Drug Interactions: The apparent clearance of lamotrigine is affected by the
906
coadministration of certain medications [see Warnings and Precautions (5.7, 5.11), Drug
907
Interactions (7)].
908
The net effects of drug interactions with lamotrigine, based on drug interaction studies
909
using immediate-release lamotrigine, are summarized in Tables 5 and 8, followed by details of
910
the drug interaction studies below.
911
912
Table 8. Summary of Drug Interactions With Lamotrigine
Drug
Drug Plasma
Concentration With
Adjunctive Lamotriginea
Lamotrigine Plasma
Concentration With
Adjunctive Drugsb
Oral contraceptives (e.g.,
ethinylestradiol/levonorgestrel)c
Atazanavir/ritonavir
Bupropion
Carbamazepine
Carbamazepine epoxidef
Felbamate
Gabapentin
Levetiracetam
Lithium
Lopinavir/ritonavir
Olanzapine
Oxcarbazepine
10-Monohydroxy oxcarbazepine
metaboliteh
Phenobarbital/primidone
Phenytoin
Pregabalin
Rifampin
Risperidone
9-hydroxyrisperidonei
Topiramate
Valproate
↔d
↔e
Not assessed
↔
?
Not assessed
Not assessed
↔
↔
↔e
↔
↔
↔
↔
↔
↔
Not assessed
↔
↔
↔j
↓
↓
↓
↔
↓
↔
↔
↔
Not assessed
↓
↔g
↔
↓
↓
↔
↓
Not assessed
↔
↑
30
Reference ID: 3677876
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Page 31
Valproate + phenytoin and/or
Not assessed
↔
carbamazepine
Zonisamide
Not assessed
↔
913
a From adjunctive clinical trials and volunteer trials.
914
b Net effects were estimated by comparing the mean clearance values obtained in adjunctive
915
clinical trials and volunteer trials.
916
c The effect of other hormonal contraceptive preparations or hormone replacement therapy on
917
the pharmacokinetics of lamotrigine has not been systematically evaluated in clinical trials,
918
although the effect may be similar to that seen with the ethinylestradiol/levonorgestrel
919
combinations.
920
d Modest decrease in levonorgestrel.
921
e Compared to historical controls.
922
f Not administered, but an active metabolite of carbamazepine.
923
g Slight decrease, not expected to be clinically relevant.
924
h Not administered, but an active metabolite of oxcarbazepine.
925
i Not administered, but an active metabolite of risperidone.
j
926
Slight increase, not expected to be clinically relevant.
927
↔ = No significant effect.
928
? = Conflicting data.
929
930
Estrogen-Containing Oral Contraceptives: In 16 female volunteers, an oral
931
contraceptive preparation containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel
932
increased the apparent clearance of lamotrigine (300 mg/day) by approximately 2-fold with mean
933
decreases in AUC of 52% and in Cmax of 39%. In this study, trough serum lamotrigine
934
concentrations gradually increased and were approximately 2-fold higher on average at the end
935
of the week of the inactive hormone preparation compared with trough lamotrigine
936
concentrations at the end of the active hormone cycle.
937
Gradual transient increases in lamotrigine plasma levels (approximate 2-fold increase)
938
occurred during the week of inactive hormone preparation (pill-free week) for women not also
939
taking a drug that increased the clearance of lamotrigine (carbamazepine, phenytoin,
940
phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors
941
lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation) [see Drug
942
Interactions (7)]. The increase in lamotrigine plasma levels will be greater if the dose of
943
LAMICTAL XR is increased in the few days before or during the pill-free week. Increases in
944
lamotrigine plasma levels could result in dose-dependent adverse reactions.
945
In the same study, coadministration of lamotrigine (300 mg/day) in 16 female volunteers
946
did not affect the pharmacokinetics of the ethinylestradiol component of the oral contraceptive
947
preparation. There were mean decreases in the AUC and Cmax of the levonorgestrel component of
948
19% and 12%, respectively. Measurement of serum progesterone indicated that there was no
949
hormonal evidence of ovulation in any of the 16 volunteers, although measurement of serum
31
Reference ID: 3677876
This label may not be the latest approved by FDA.
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NDA 022115/S-004 & S-014
FDA Proposed Labeling Text dated 12/23/2014
Page 32
950
FSH, LH, and estradiol indicated that there was some loss of suppression of the hypothalamic
951
pituitary-ovarian axis.
952
The effects of doses of lamotrigine other than 300 mg/day have not been systematically
953
evaluated in controlled clinical trials.
954
The clinical significance of the observed hormonal changes on ovulatory activity is
955
unknown. However, the possibility of decreased contraceptive efficacy in some patients cannot
956
be excluded. Therefore, patients should be instructed to promptly report changes in their
957
menstrual pattern (e.g., break-through bleeding).
958
Dosage adjustments may be necessary for women receiving estrogen-containing oral
959
contraceptive preparations [see Dosage and Administration (2.1)].
960
Other Hormonal Contraceptives or Hormone Replacement Therapy: The effect of
961
other hormonal contraceptive preparations or hormone replacement therapy on the
962
pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that
963
ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the
964
progestin-only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the
965
dosage of LAMICTAL XR in the presence of progestogens alone will likely not be needed.
966
Atazanavir/Ritonavir: In a study in healthy volunteers, daily doses of
967
atazanavir/ritonavir (300 mg/100 mg) reduced the plasma AUC and Cmax of lamotrigine (single
968
100-mg dose) by an average of 32% and 6%, respectively, and shortened the elimination half
969
lives by 27%. In the presence of atazanavir/ritonavir (300 mg/100 mg), the metabolite-to
970
lamotrigine ratio was increased from 0.45 to 0.71 consistent with induction of glucuronidation.
971
The pharmacokinetics of atazanavir/ritonavir were similar in the presence of concomitant
972
lamotrigine to the historical data of the pharmacokinetics in the absence of lamotrigine.
973
Bupropion: The pharmacokinetics of a 100-mg single dose of lamotrigine in healthy
974
volunteers (n = 12) were not changed by coadministration of bupropion sustained-release
975
formulation (150 mg twice daily) starting 11 days before lamotrigine.
976
Carbamazepine: Lamotrigine has no appreciable effect on steady-state carbamazepine
977
plasma concentration. Limited clinical data suggest there is a higher incidence of dizziness,
978
diplopia, ataxia, and blurred vision in patients receiving carbamazepine with lamotrigine than in
979
patients receiving other AEDs with lamotrigine [see Adverse Reactions (6.1)]. The mechanism
980
of this interaction is unclear. The effect of lamotrigine on plasma concentrations of
981
carbamazepine-epoxide is unclear. In a small subset of patients (n = 7) studied in a placebo
982
controlled trial, lamotrigine had no effect on carbamazepine-epoxide plasma concentrations, but
983
in a small, uncontrolled study (n = 9), carbamazepine-epoxide levels increased.
984
The addition of carbamazepine decreases lamotrigine steady-state concentrations by
985
approximately 40%.
986
Esomeprazole: In a study of 30 subjects, coadministration of LAMICTAL XR with
987
esomeprazole resulted in no significant change in lamotrigine levels and a small decrease in Tmax.
988
The levels of gastric pH were not altered compared with pre-lamotrigine dosing.
32
Reference ID: 3677876
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 022115/S-004 & S-014
FDA Proposed Labeling Text dated 12/23/2014
Page 33
989
Felbamate: In a trial in 21 healthy volunteers, coadministration of felbamate (1,200 mg
990
twice daily) with lamotrigine (100 mg twice daily for 10 days) appeared to have no clinically
991
relevant effects on the pharmacokinetics of lamotrigine.
992
Folate Inhibitors: Lamotrigine is a weak inhibitor of dihydrofolate reductase. Prescribers
993
should be aware of this action when prescribing other medications that inhibit folate metabolism.
994
Gabapentin: Based on a retrospective analysis of plasma levels in 34 subjects who
995
received lamotrigine both with and without gabapentin, gabapentin does not appear to change the
996
apparent clearance of lamotrigine.
997
Levetiracetam: Potential drug interactions between levetiracetam and lamotrigine were
998
assessed by evaluating serum concentrations of both agents during placebo-controlled clinical
999
trials. These data indicate that lamotrigine does not influence the pharmacokinetics of
1000
levetiracetam and that levetiracetam does not influence the pharmacokinetics of lamotrigine.
1001
Lithium: The pharmacokinetics of lithium were not altered in healthy subjects (n = 20) by
1002
coadministration of lamotrigine (100 mg/day) for 6 days.
1003
Lopinavir/Ritonavir: The addition of lopinavir (400 mg twice daily)/ritonavir (100 mg
1004
twice daily) decreased the AUC, Cmax, and elimination half-life of lamotrigine by approximately
1005
50% to 55.4% in 18 healthy subjects. The pharmacokinetics of lopinavir/ritonavir were similar
1006
with concomitant lamotrigine, compared to that in historical controls.
1007
Olanzapine: The AUC and Cmax of olanzapine were similar following the addition of
1008
olanzapine (15 mg once daily) to lamotrigine (200 mg once daily) in healthy male volunteers
1009
(n = 16) compared with the AUC and Cmax in healthy male volunteers receiving olanzapine alone
1010
(n = 16).
1011
In the same trial, the AUC and Cmax of lamotrigine were reduced on average by 24% and
1012
20%, respectively, following the addition of olanzapine to lamotrigine in healthy male volunteers
1013
compared with those receiving lamotrigine alone. This reduction in lamotrigine plasma
1014
concentrations is not expected to be clinically relevant.
1015
Oxcarbazepine: The AUC and Cmax of oxcarbazepine and its active 10-monohydroxy
1016
oxcarbazepine metabolite were not significantly different following the addition of
1017
oxcarbazepine (600 mg twice daily) to lamotrigine (200 mg once daily) in healthy male
1018
volunteers (n = 13) compared with healthy male volunteers receiving oxcarbazepine alone
1019
(n = 13).
1020
In the same trial, the AUC and Cmax of lamotrigine were similar following the addition of
1021
oxcarbazepine (600 mg twice daily) to lamotrigine in healthy male volunteers compared with
1022
those receiving lamotrigine alone. Limited clinical data suggest a higher incidence of headache,
1023
dizziness, nausea, and somnolence with coadministration of lamotrigine and oxcarbazepine
1024
compared with lamotrigine alone or oxcarbazepine alone.
1025
Phenobarbital, Primidone: The addition of phenobarbital or primidone decreases
1026
lamotrigine steady-state concentrations by approximately 40%.
33
Reference ID: 3677876
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 022115/S-004 & S-014
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Page 34
1027
Phenytoin: Lamotrigine has no appreciable effect on steady-state phenytoin plasma
1028
concentrations in patients with epilepsy. The addition of phenytoin decreases lamotrigine steady
1029
state concentrations by approximately 40%.
1030
Pregabalin: Steady-state trough plasma concentrations of lamotrigine were not affected
1031
by concomitant pregabalin (200 mg 3 times daily) administration. There are no pharmacokinetic
1032
interactions between lamotrigine and pregabalin.
1033
Rifampin: In 10 male volunteers, rifampin (600 mg/day for 5 days) significantly
1034
increased the apparent clearance of a single 25-mg dose of lamotrigine by approximately 2-fold
1035
(AUC decreased by approximately 40%).
1036
Risperidone: In a 14 healthy volunteers study, multiple oral doses of lamotrigine 400 mg
1037
daily had no clinically significant effect on the single-dose pharmacokinetics of risperidone 2 mg
1038
and its active metabolite 9-OH risperidone. Following the coadministration of risperidone 2 mg
1039
with lamotrigine, 12 of the 14 volunteers reported somnolence compared with 1 out of 20 when
1040
risperidone was given alone, and none when lamotrigine was administered alone.
1041
Topiramate: Topiramate resulted in no change in plasma concentrations of lamotrigine.
1042
Administration of lamotrigine resulted in a 15% increase in topiramate concentrations.
1043
Valproate: When lamotrigine was administered to healthy volunteers (n = 18) receiving
1044
valproate, the trough steady-state valproate plasma concentrations decreased by an average of
1045
25% over a 3-week period, and then stabilized. However, adding lamotrigine to the existing
1046
therapy did not cause a change in valproate plasma concentrations in either adult or pediatric
1047
patients in controlled clinical trials.
1048
The addition of valproate increased lamotrigine steady-state concentrations in normal
1049
volunteers by slightly more than 2-fold. In 1 trial, maximal inhibition of lamotrigine clearance
1050
was reached at valproate doses between 250 and 500 mg/day and did not increase as the
1051
valproate dose was further increased.
1052
Zonisamide: In a study in 18 patients with epilepsy, coadministration of zonisamide
1053
(200 to 400 mg/day) with lamotrigine (150 to 500 mg/day for 35 days) had no significant effect
1054
on the pharmacokinetics of lamotrigine.
1055
Known Inducers or Inhibitors of Glucuronidation: Drugs other than those listed above
1056
have not been systematically evaluated in combination with lamotrigine. Since lamotrigine is
1057
metabolized predominately by glucuronic acid conjugation, drugs that are known to induce or
1058
inhibit glucuronidation may affect the apparent clearance of lamotrigine, and doses of
1059
LAMICTAL XR may require adjustment based on clinical response.
1060
Other: Results of in vitro experiments suggest that clearance of lamotrigine is unlikely to
1061
be reduced by concomitant administration of amitriptyline, clonazepam, clozapine, fluoxetine,
1062
haloperidol, lorazepam, phenelzine, sertraline, or trazodone.
1063
Results of in vitro experiments suggest that lamotrigine does not reduce the clearance of
1064
drugs eliminated predominantly by CYP2D6.
1065
Specific Populations: Subjects With Renal Impairment: Twelve volunteers with
1066
chronic renal failure (mean creatinine clearance: 13 mL/min, range: 6 to 23) and another 6
34
Reference ID: 3677876
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 022115/S-004 & S-014
FDA Proposed Labeling Text dated 12/23/2014
Page 35
1067
individuals undergoing hemodialysis were each given a single 100-mg dose of immediate-release
1068
lamotrigine. The mean plasma half-lives determined in the study were 42.9 hours (chronic renal
1069
failure), 13.0 hours (during hemodialysis), and 57.4 hours (between hemodialysis) compared
1070
with 26.2 hours in healthy volunteers. On average, approximately 20% (range: 5.6 to 35.1) of the
1071
amount of lamotrigine present in the body was eliminated by hemodialysis during a 4-hour
1072
session [see Dosage and Administration (2.1)].
1073
Hepatic Disease: The pharmacokinetics of lamotrigine following a single 100-mg
1074
dose of immediate-release lamotrigine were evaluated in 24 subjects with mild, moderate, and
1075
severe hepatic impairment (Child-Pugh Classification system) and compared with 12 subjects
1076
without hepatic impairment. The subjects with severe hepatic impairment were without ascites
1077
(n = 2) or with ascites (n = 5). The mean apparent clearances of lamotrigine in subjects with mild
1078
(n = 12), moderate (n = 5), severe without ascites (n = 2), and severe with ascites (n = 5) liver
1079
impairment were 0.30 ± 0.09, 0.24 ± 0.1, 0.21 ± 0.04, and 0.15 ± 0.09 mL/min/kg, respectively,
1080
as compared with 0.37 ± 0.1 mL/min/kg in the healthy controls. Mean half-lives of lamotrigine
1081
in subjects with mild, moderate, severe without ascites, and severe with ascites hepatic
1082
impairment were 46 ± 20, 72 ± 44, 67 ± 11, and 100 ± 48 hours, respectively, as compared with
1083
33 ± 7 hours in healthy controls [see Dosage and Administration (2.1)].
1084
Elderly: The pharmacokinetics of lamotrigine following a single 150-mg dose of
1085
immediate-release lamotrigine were evaluated in 12 elderly volunteers between the ages of 65
1086
and 76 years (mean creatinine clearance: 61 mL/min, range: 33 to 108 mL/min). The mean
1087
half-life of lamotrigine in these subjects was 31.2 hours (range: 24.5 to 43.4 hours), and the mean
1088
clearance was 0.40 mL/min/kg (range: 0.26 to 0.48 mL/min/kg).
1089
Gender: The clearance of lamotrigine is not affected by gender. However, during
1090
dose escalation of immediate-release lamotrigine in 1 clinical trial in patients with epilepsy on a
1091
stable dose of valproate (n = 77), mean trough lamotrigine concentrations unadjusted for weight
1092
were 24% to 45% higher (0.3 to 1.7 mcg/mL) in females than in males.
1093
Race: The apparent oral clearance of lamotrigine was 25% lower in non-Caucasians
1094
than Caucasians.
1095
Pediatric Patients: Safety and effectiveness of LAMICTAL XR for use in patients
1096
younger than 13 years have not been established.
1097
13
NONCLINICAL TOXICOLOGY
1098
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
1099
No evidence of carcinogenicity was seen in mouse or rat following oral administration of
1100
lamotrigine for up to 2 years at doses up to 30 mg/kg/day and 10 to 15 mg/kg/day in mouse and
1101
rat, respectively. The highest doses tested are less than the human dose of 400 mg/day on a body
1102
surface area (mg/m2) basis.
1103
Lamotrigine was negative in in vitro gene mutation (Ames and mouse lymphoma tk)
1104
assays and in clastogenicity (in vitro human lymphocyte and in vivo rat bone marrow) assays.
35
Reference ID: 3677876
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 022115/S-004 & S-014
FDA Proposed Labeling Text dated 12/23/2014
Page 36
1105
No evidence of impaired fertility was detected in rats given oral doses of lamotrigine up
1106
to 20 mg/kg/day. The highest dose tested is less than the human dose of 400 mg/day on a mg/m2
1107
basis.
1108
14
CLINICAL STUDIES
1109
14.1 Adjunctive Therapy for Primary Generalized Tonic-Clonic Seizures
1110
The effectiveness of LAMICTAL XR as adjunctive therapy in subjects with PGTC
1111
seizures was established in a 19-week, international, multicenter, double-blind, randomized,
1112
placebo-controlled trial in 143 patients aged 13 years and older (n = 70 on LAMICTAL XR, n =
1113
73 on placebo). Patients with at least 3 PGTC seizures during an 8-week baseline phase were
1114
randomized to 19 weeks of treatment with LAMICTAL XR or placebo added to their current
1115
AED regimen of up to 2 drugs. Patients were dosed on a fixed-dose regimen, with target doses
1116
ranging from 200 to 500 mg/day of LAMICTAL XR based on concomitant AEDs (target dose =
1117
200 mg for valproate, 300 mg for AEDs not altering plasma lamotrigine levels, and 500 mg for
1118
enzyme-inducing AEDs).
1119
The primary efficacy endpoint was percent change from baseline in PGTC seizure
1120
frequency during the double-blind treatment phase. For the intent-to-treat population, the median
1121
percent reduction in PGTC seizure frequency was 75% in patients treated with LAMICTAL XR
1122
and 32% in patients treated with placebo, a difference that was statistically significant, defined as
1123
a 2-sided P value <0.05.
1124
Figure 1 presents the percentage of patients (X-axis) with a percent reduction in PGTC
1125
seizure frequency (responder rate) from baseline through the entire treatment period at least as
1126
great as that represented on the Y-axis. A positive value on the Y-axis indicates an improvement
1127
from baseline (i.e., a decrease in seizure frequency), while a negative value indicates a worsening
1128
from baseline (i.e., an increase in seizure frequency). Thus, in a display of this type, a curve for
1129
an effective treatment is shifted to the left of the curve for placebo. The proportion of patients
1130
achieving any particular level of reduction in PGTC seizure frequency was consistently higher
1131
for the group treated with LAMICTAL XR compared with the placebo group. For example, 70%
1132
of patients randomized to LAMICTAL XR experienced a 50% or greater reduction in PGTC
1133
seizure frequency, compared with 32% of patients randomized to placebo. Patients with an
1134
increase in seizure frequency >100% are represented on the Y-axis as equal to or greater than
1135
-100%.
1136
36
Reference ID: 3677876
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 022115/S-004 & S-014
FDA Proposed Labeling Text dated 12/23/2014
Page 37
1137
Figure 1. Proportion of Patients by Responder Rate for LAMICTAL XR and Placebo
1138
Group (Primary Generalized Tonic-Clonic Seizures Study)
graph
1140
14.2 Adjunctive Therapy for Partial-Onset Seizures
1141
The effectiveness of immediate-release lamotrigine as adjunctive therapy was initially
1142
established in 3 pivotal, multicenter, placebo-controlled, double-blind clinical trials in 355 adults
1143
with refractory partial-onset seizures.
1144
The effectiveness of LAMICTAL XR as adjunctive therapy in partial-onset seizures, with
1145
or without secondary generalization, was established in a 19-week, multicenter, double-blind,
1146
placebo-controlled trial in 236 patients aged 13 years and older (approximately 93% of patients
1147
were aged 16 to 65 years). Approximately 36% were from the U.S. and approximately 64% were
1148
from other countries including Argentina, Brazil, Chile, Germany, India, Korea, Russian
1149
Federation, and Ukraine. Patients with at least 8 partial-onset seizures during an 8-week
1150
prospective baseline phase (or 4-week prospective baseline coupled with a 4-week historical
1151
baseline documented with seizure diary data) were randomized to treatment with
1152
LAMICTAL XR (n = 116) or placebo (n = 120) added to their current regimen of 1 or 2 AEDs.
1153
Approximately half of the patients were taking 2 concomitant AEDs at baseline. Target doses
1154
ranged from 200 to 500 mg/day of LAMICTAL XR based on concomitant AED (target dose =
1155
200 mg for valproate, 300 mg for AEDs not altering plasma lamotrigine, and 500 mg for
1156
enzyme-inducing AEDs). The median partial seizure frequency per week at baseline was 2.3 for
1157
LAMICTAL XR and 2.1 for placebo.
37
Reference ID: 3677876
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 022115/S-004 & S-014
FDA Proposed Labeling Text dated 12/23/2014
Page 38
1158
The primary endpoint was the median percent change from baseline in partial-onset
1159
seizure frequency during the entire double-blind treatment phase. The median percent reductions
1160
in weekly partial-onset seizures were 47% in patients treated with LAMICTAL XR and 25% on
1161
placebo, a difference that was statistically significant, defined as a 2-sided P value ≤0.05.
1162
Figure 2 presents the percentage of patients (X-axis) with a percent reduction in partial
1163
onset seizure frequency (responder rate) from baseline through the entire treatment period at
1164
least as great as that represented on the Y-axis. The proportion of patients achieving any
1165
particular level of reduction in partial-onset seizure frequency was consistently higher for the
1166
group treated with LAMICTAL XR compared with the placebo group. For example, 44% of
1167
patients randomized to LAMICTAL XR experienced a 50% or greater reduction in partial-onset
1168
seizure frequency compared with 21% of patients randomized to placebo.
1169
1170
Figure 2. Proportion of Patients by Responder Rate for LAMICTAL XR and Placebo
1171
Group (Partial-Onset Seizure Study)
graph
1173
1174
14.3 Conversion to Monotherapy for Partial-Onset Seizures
1175
The effectiveness of LAMICTAL XR as monotherapy for partial-onset seizures was
1176
established in a historical control trial in 223 adults with partial-onset seizures. The historical
1177
control methodology is described in a publication by French, et al. [see References (15)]. Briefly,
1178
in this study, patients were randomized to ultimately receive either LAMICTAL XR 300 or
38
Reference ID: 3677876
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 022115/S-004 & S-014
FDA Proposed Labeling Text dated 12/23/2014
Page 39
1179
250 mg once a day, and their responses were compared with those of a historical control group.
1180
The historical control consisted of a pooled analysis of the control groups from 8 studies of
1181
similar design, which utilized a subtherapeutic dose of an AED as a comparator. Statistical
1182
superiority to the historical control was considered to be demonstrated if the upper 95%
1183
confidence interval for the proportion of patients meeting escape criteria in patients receiving
1184
LAMICTAL XR remained below the lower 95% prediction interval of 65.3% derived from the
1185
historical control data.
1186
In this study, patients aged 13 years and older experienced at least 4 partial-onset seizures
1187
during an 8-week baseline period with at least 2 seizures occurring during each of 2 consecutive
1188
4-week periods while receiving valproate or a non–enzyme-inducing AED. LAMICTAL XR was
1189
added to either valproate or a non–enzyme-inducing AED over a 6- to 7-week period followed
1190
by the gradual withdrawal of the background AED. Patients were then continued on
1191
monotherapy with LAMICTAL XR for 12 weeks. The escape criteria were 1 or more of the
1192
following: (1) doubling of average monthly seizure count during any 28 consecutive days,
1193
(2) doubling of highest consecutive 2-day seizure frequency during the entire treatment phase,
1194
(3) emergence of a new seizure type compared with baseline (4) clinically significant
1195
prolongation of generalized tonic-clonic seizures or worsening of seizure considered by the
1196
investigator to require intervention. These criteria were similar to those in the 8 controlled trials
1197
from which the historical control group was constituted.
1198
The upper 95% confidence limits of the proportion of subjects meeting escape criteria
1199
(40.2% at 300 mg/day and 44.5% at 250 mg/day) were below the threshold of 65.3% derived
1200
from the historical control data.
1201
Although the study population was not fully comparable with the historical controlled
1202
population and the study was not fully blinded, numerous sensitivity analyses supported the
1203
primary results. Efficacy was further supported by the established effectiveness of the
1204
immediate-release formulation as monotherapy.
1205
15
REFERENCES
1206
1. French JA, Wang S, Warnock B, Temkin N. Historical control monotherapy design in the
1207
treatment of epilepsy. Epilepsia. 2010; 51(10):1936-1943.
1208
16
HOW SUPPLIED/STORAGE AND HANDLING
1209
LAMICTAL XR (lamotrigine) Extended-Release Tablets
1210
25 mg, yellow with a white center, round, biconvex, film-coated tablets printed on one
1211
face in black ink with “LAMICTAL” and “XR 25”, unit-of-use bottles of 30 with orange caps
1212
(NDC 0173-0754-00).
1213
50 mg, green with a white center, round, biconvex, film-coated tablets printed on one
1214
face in black ink with “LAMICTAL” and “XR 50”, unit-of-use bottles of 30 with orange caps
1215
(NDC 0173-0755-00).
39
Reference ID: 3677876
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 022115/S-004 & S-014
FDA Proposed Labeling Text dated 12/23/2014
Page 40
1216
100 mg, orange with a white center, round, biconvex, film-coated tablets printed on one
1217
face in black ink with “LAMICTAL” and “XR 100”, unit-of-use bottles of 30 with orange caps
1218
(NDC 0173-0756-00).
1219
200 mg, blue with a white center, round, biconvex, film-coated tablets printed on one
1220
face in black ink with “LAMICTAL” and “XR 200”, unit-of-use bottles of 30 with orange caps
1221
(NDC 0173-0757-00).
1222
250 mg, purple with a white center, caplet-shaped, film-coated tablets printed on one face
1223
in black ink with “LAMICTAL” and “XR 250”, unit-of-use bottles of 30 with orange caps (NDC
1224
0173-0781-00).
1225
300 mg, gray with a white center, caplet-shaped, film-coated tablets printed on one face
1226
in black ink with “LAMICTAL” and “XR 300”, unit-of-use bottles of 30 with orange caps (NDC
1227
0173-0761-00).
1228
LAMICTAL XR (lamotrigine) Patient Titration Kit for Patients Taking Valproate
1229
(Blue XR Kit)
1230
25 mg, yellow with a white center, round, biconvex, film-coated tablets printed on one
1231
face in black ink with “LAMICTAL” and “XR 25” and 50 mg, green with a white center, round,
1232
biconvex, film-coated tablets printed on one face in black ink with “LAMICTAL” and “XR 50”;
1233
blisterpack of 21/25-mg tablets and 7/50-mg tablets (NDC 0173-0758-00).
1234
LAMICTAL XR (lamotrigine) Patient Titration Kit for Patients Taking
1235
Carbamazepine, Phenytoin, Phenobarbital, or Primidone, and Not Taking Valproate
1236
(Green XR Kit)
1237
50 mg, green with a white center, round, biconvex, film-coated tablets printed on one
1238
face in black ink with “LAMICTAL” and “XR 50”; 100 mg, orange with a white center, round,
1239
biconvex, film-coated tablets printed on one face in black ink with “LAMICTAL” and “XR
1240
100”; and 200 mg, blue with a white center, round, biconvex, film-coated tablets printed on one
1241
face in black ink with “LAMICTAL” and “XR 200”; blisterpack of 14/50-mg tablets, 14/100-mg
1242
tablets, and 7/200-mg tablets (NDC 0173-0759-00).
1243
LAMICTAL XR (lamotrigine) Patient Titration Kit for Patients Not Taking
1244
Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate (Orange XR Kit)
1245
25 mg, yellow with a white center, round, biconvex, film-coated tablets printed on one
1246
face in black ink with “LAMICTAL” and “XR 25”; 50 mg, green with a white center, round,
1247
biconvex, film-coated tablets printed on one face in black ink with “LAMICTAL” and “XR 50”;
1248
and 100 mg, orange with a white center, round, biconvex, film-coated tablets printed on one face
1249
in black ink with “LAMICTAL” and “XR 100”; blisterpack of 14/25-mg tablets, 14/50-mg
1250
tablets, and 7/100-mg tablets (NDC 0173-0760-00).
1251
Storage: Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see
1252
USP Controlled Room Temperature].
1253
17
PATIENT COUNSELING INFORMATION
1254
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
40
Reference ID: 3677876
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 022115/S-004 & S-014
FDA Proposed Labeling Text dated 12/23/2014
Page 41
1255
Rash: Prior to initiation of treatment with LAMICTAL XR, inform patients that a rash or
1256
other signs or symptoms of hypersensitivity (e.g., fever, lymphadenopathy) may herald a serious
1257
medical event and instruct them to report any such occurrence to their physician immediately.
1258
Multiorgan Hypersensitivity Reactions, Blood Dyscrasias, and Organ Failure:
1259
Inform patients that multiorgan hypersensitivity reactions and acute multiorgan failure may
1260
occur with LAMICTAL. Isolated organ failure or isolated blood dyscrasias without evidence of
1261
multiorgan hypersensitivity may also occur. Instruct patients to contact their physician
1262
immediately if they experience any signs or symptoms of these conditions [see Warnings and
1263
Precautions (5.2, 5.3)].
1264
Suicidal Thinking and Behavior: Inform patients, their caregivers, and families that
1265
AEDs, including LAMICTAL XR, may increase the risk of suicidal thoughts and behavior.
1266
Instruct them to be alert for the emergence or worsening of symptoms of depression, any unusual
1267
changes in mood or behavior, or the emergence of suicidal thoughts or behavior or thoughts
1268
about self-harm. They should immediately report behaviors of concern to their physician.
1269
Worsening of Seizures: Advise patients to notify their physician if worsening of
1270
seizure control occurs.
1271
Central Nervous System Adverse Effects: Inform patients that LAMICTAL XR may
1272
cause dizziness, somnolence, and other symptoms and signs of central nervous system
1273
depression. Accordingly, instruct them neither to drive a car nor to operate other complex
1274
machinery until they have gained sufficient experience on LAMICTAL XR to gauge whether or
1275
not it adversely affects their mental and/or motor performance.
1276
Pregnancy and Nursing: Instruct patients to notify their physician if they become
1277
pregnant or intend to become pregnant during therapy and if they intend to breastfeed or are
1278
breastfeeding an infant.
1279
Encourage patients to enroll in the NAAED Pregnancy Registry if they become pregnant.
1280
This registry is collecting information about the safety of antiepileptic drugs during pregnancy.
1281
To enroll, patients can call the toll-free number 1-888-233-2334 [see Use in Specific Populations
1282
(8.1)].
1283
Inform patients who intend to breastfeed that LAMICTAL XR is present in breast milk
1284
and advise them to monitor their child for potential adverse effects of this drug. Discuss the
1285
benefits and risks of continuing breastfeeding.
1286
Oral Contraceptive Use: Instruct women to notify their physician if they plan to start or
1287
stop use of oral contraceptives or other female hormonal preparations. Starting estrogen
1288
containing oral contraceptives may significantly decrease lamotrigine plasma levels and stopping
1289
estrogen-containing oral contraceptives (including the pill-free week) may significantly increase
1290
lamotrigine plasma levels [see Warnings and Precautions (5.7), Clinical Pharmacology (12.3)].
1291
Also instruct women to promptly notify their physician if they experience adverse reactions or
1292
changes in menstrual pattern (e.g., break-through bleeding) while receiving LAMICTAL XR in
1293
combination with these medications.
41
Reference ID: 3677876
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 022115/S-004 & S-014
FDA Proposed Labeling Text dated 12/23/2014
Page 42
1294
Discontinuing LAMICTAL XR: Instruct patients to notify their physician if they stop
1295
taking LAMICTAL XR for any reason and not to resume LAMICTAL XR without consulting
1296
their physician.
1297
Aseptic Meningitis: Inform patients that LAMICTAL XR may cause aseptic meningitis.
1298
Instruct them to notify their physician immediately if they develop signs and symptoms of
1299
meningitis such as headache, fever, nausea, vomiting, stiff neck, rash, abnormal sensitivity to
1300
light, myalgia, chills, confusion, or drowsiness while taking LAMICTAL XR.
1301
Potential Medication Errors: Medication errors involving LAMICTAL have occurred.
1302
In particular the names LAMICTAL or lamotrigine can be confused with the names of other
1303
commonly used medications. Medication errors may also occur between the different
1304
formulations of LAMICTAL. To reduce the potential of medication errors, write and say
1305
LAMICTAL XR clearly. Depictions of the LAMICTAL XR Extended-Release Tablets can be
1306
found in the Medication Guide. Each LAMICTAL XR tablet has a distinct color and white
1307
center, and is printed with “LAMICTAL XR” and the tablet strength. These distinctive features
1308
serve to identify the different presentations of the drug and thus may help reduce the risk of
1309
medication errors. LAMICTAL XR is supplied in round, unit-of-use bottles with orange caps
1310
containing 30 tablets. The label on the bottle includes a depiction of the tablets that further
1311
communicates to patients and pharmacists that the medication is LAMICTAL XR and the
1312
specific tablet strength included in the bottle. The unit-of-use bottle with a distinctive orange cap
1313
and distinctive bottle label features serves to identify the different presentations of the drug and
1314
thus may help to reduce the risk of medication errors. To avoid a medication error of using the
1315
wrong drug or formulation, strongly advise patients to visually inspect their tablets to
1316
verify that they are LAMICTAL XR each time they fill their prescription and to
1317
immediately talk to their doctor/pharmacist if they receive a LAMICTAL XR tablet
1318
without a white center and without “LAMICTAL XR” and the strength printed on the
1319
tablet as they may have received the wrong medication [see Dosage Forms and Strengths (3),
1320
How Supplied/Storage and Handling (16)].
1321
1322
LAMICTAL XR and DiffCORE are trademarks of the GSK group of companies.
1323
1324
1325 company logo
1326
GlaxoSmithKline
1327
Research Triangle Park, NC 27709
1328
1329
2014, the GSK group of companies. All rights reserved.
1330
1331
LXR:xPI
42
Reference ID: 3677876
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 022115/S-004 & S-014
FDA Proposed Labeling Text dated 12/23/2014
Page 43
1332
1333
1334
MEDICATION GUIDE
1335
1336
LAMICTAL® (la-MIK-tal) XR™ (lamotrigine) Extended-Release Tablets
1337
1338
Read this Medication Guide before you start taking LAMICTAL XR and each time you
1339
get a refill. There may be new information. This information does not take the place
1340
of talking with your healthcare provider about your medical condition or treatment.
1341
If you have questions about LAMICTAL XR, ask your healthcare provider or
1342
pharmacist.
1343
1344
What is the most important information I should know about LAMICTAL
1345
XR?
1346
1. LAMICTAL XR may cause a serious skin rash that may cause you to be
1347
hospitalized or even cause death.
1348
There is no way to tell if a mild rash will become more serious. A serious skin
1349
rash can happen at any time during your treatment with LAMICTAL XR, but is
1350
more likely to happen within the first 2 to 8 weeks of treatment. Children aged
1351
between 2 and 16 years have a higher chance of getting this serious skin rash
1352
while taking LAMICTAL XR. LAMICTAL XR is not approved for use in children
1353
younger than 13 years .
1354
The risk of getting a serious skin rash is higher if you:
1355
•
take LAMICTAL XR while taking valproate [DEPAKENE® (valproic acid) or
1356
DEPAKOTE® (divalproex sodium)].
1357
•
take a higher starting dose of LAMICTAL XR than your healthcare provider
1358
prescribed.
1359
•
increase your dose of LAMICTAL XR faster than prescribed.
1360
Call your healthcare provider right away if you have any of the
1361
following:
1362
•
a skin rash
1363
•
blistering or peeling of your skin
1364
•
hives
1365
•
painful sores in your mouth or around your eyes
1366
These symptoms may be the first signs of a serious skin reaction. A healthcare
1367
provider should examine you to decide if you should continue taking LAMICTAL
1368
XR.
43
Reference ID: 3677876
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 022115/S-004 & S-014
FDA Proposed Labeling Text dated 12/23/2014
Page 44
1369
2. Other serious reactions, including serious blood problems or liver
1370
problems. LAMICTAL XR can also cause other types of allergic reactions or
1371
serious problems that may affect organs and other parts of your body like your
1372
liver or blood cells. You may or may not have a rash with these types of
1373
reactions. Call your healthcare provider right away if you have any of these
1374
symptoms:
1375
•
fever
1376
•
frequent infections
1377
•
severe muscle pain
1378
•
swelling of your face, eyes, lips, or tongue
1379
•
swollen lymph glands
1380
•
unusual bruising or bleeding
1381
•
weakness, fatigue
1382
•
yellowing of your skin or the white part of your eyes
1383
3. Like other antiepileptic drugs, LAMICTAL XR may cause suicidal
1384
thoughts or actions in a very small number of people, about 1 in 500.
1385
Call a healthcare provider right away if you have any of these
1386
symptoms, especially if they are new, worse, or worry you:
1387
•
thoughts about suicide or dying
1388
•
attempt to commit suicide
1389
•
new or worse depression
1390
•
new or worse anxiety
1391
•
feeling agitated or restless
1392
•
panic attacks
1393
•
trouble sleeping (insomnia)
1394
•
new or worse irritability
1395
•
acting aggressive, being angry, or violent
1396
•
acting on dangerous impulses
1397
•
an extreme increase in activity and talking (mania)
1398
•
other unusual changes in behavior or mood
1399
Do not stop LAMICTAL XR without first talking to a healthcare provider.
1400
•
Stopping LAMICTAL XR suddenly can cause serious problems.
1401
•
Suicidal thoughts or actions can be caused by things other than medicines. If
1402
you have suicidal thoughts or actions, your healthcare provider may check
1403
for other causes.
1404
How can I watch for early symptoms of suicidal thoughts and actions?
1405
•
Pay attention to any changes, especially sudden changes, in mood,
1406
behaviors, thoughts, or feelings.
44
Reference ID: 3677876
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 022115/S-004 & S-014
FDA Proposed Labeling Text dated 12/23/2014
Page 45
1407
•
Keep all follow-up visits with your healthcare provider as scheduled.
1408
•
Call your healthcare provider between visits as needed, especially if you are
1409
worried about symptoms.
1410
4. LAMICTAL XR may rarely cause aseptic meningitis, a serious
1411
inflammation of the protective membrane that covers the brain and
1412
spinal cord.
1413
Call your healthcare provider right away if you have any of the following
1414
symptoms:
1415
•
headache
1416
•
fever
1417
•
nausea
1418
•
vomiting
1419
•
stiff neck
1420
•
rash
1421
•
unusual sensitivity to light
1422
•
muscle pains
1423
•
chills
1424
•
confusion
1425
•
drowsiness
1426
Meningitis has many causes other than LAMICTAL XR, which your doctor would
1427
check for if you developed meningitis while taking LAMICTAL XR.
1428
LAMICTAL XR can have other serious side effects. For more information
1429
ask your healthcare provider or pharmacist. Tell your healthcare provider if you
1430
have any side effect that bothers you. Be sure to read the section below entitled
1431
“What are the possible side effects of LAMICTAL XR?”
1432
5. Patients prescribed LAMICTAL have sometimes been given the wrong
1433
medicine because many medicines have names similar to LAMICTAL, so
1434
always check that you receive LAMICTAL XR.
1435
Taking the wrong medication can cause serious health problems. When your
1436
healthcare provider gives you a prescription for LAMICTAL XR:
1437
•
Make sure you can read it clearly.
1438
•
Talk to your pharmacist to check that you are given the correct medicine.
1439
•
Each time you fill your prescription, check the tablets you receive against the
1440
pictures of the tablets below.
1441
These pictures show the distinct wording, colors, and shapes of the tablets
1442
that help to identify the right strength of LAMICTAL XR. Immediately call your
45
Reference ID: 3677876
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 022115/S-004 & S-014
FDA Proposed Labeling Text dated 12/23/2014
Page 46
1443
pharmacist if you receive a LAMICTAL XR tablet that does not look like one of
1444
the tablets shown below, as you may have received the wrong medication.
1445
1446
LAMICTAL XR (lamotrigine) Extended-Release Tablets
25 mg, yellow
with white center
Imprinted with
LAMICTAL
XR 25
50 mg, green
with white center
Imprinted with
LAMICTAL
XR 50
100 mg, orange
with white center
Imprinted with
LAMICTAL
XR 100
200 mg, blue
with white center
Imprinted with
LAMICTAL
XR 200
250 mg, purple
with white center
Imprinted with
LAMICTAL
XR 250
300 mg, gray
with white center
Imprinted with
LAMICTAL
XR 300
1447
1448
What is LAMICTAL XR?
1449
LAMICTAL XR is a prescription medicine used:
1450
•
together with other medicines to treat primary generalized tonic-clonic seizures
1451
and partial onset seizures in people aged 13 years and older.
1452
•
alone when changing from 1 other medicine used to treat partial-onset seizures
1453
in people aged 13 years and older.
1454
It is not known if LAMICTAL XR is safe or effective in children younger than 13
1455
years. Other forms of LAMICTAL can be used in children aged 2 to 12 years.
1456
It is not known if LAMICTAL XR is safe or effective when used alone as the first
1457
treatment of seizures.
1458
1459
Who should not take LAMICTAL XR?
1460
You should not take LAMICTAL XR if you have had an allergic reaction to
1461
lamotrigine or to any of the inactive ingredients in LAMICTAL XR. See the end of
1462
this leaflet for a complete list of ingredients in LAMICTAL XR.
1463
1464
What should I tell my healthcare provider before taking LAMICTAL XR?
46
Reference ID: 3677876
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 022115/S-004 & S-014
FDA Proposed Labeling Text dated 12/23/2014
Page 47
1465
Before taking LAMICTAL XR, tell your healthcare provider about all of your medical
1466
conditions, including if you:
1467
•
have had a rash or allergic reaction to another antiseizure medicine.
1468
•
have or have had depression, mood problems, or suicidal thoughts or behavior.
1469
•
have had aseptic meningitis after taking LAMICTAL (lamotrigine) or LAMICTAL
1470
XR.
1471
•
are taking oral contraceptives (birth control pills) or other female hormonal
1472
medicines. Do not start or stop taking birth control pills or other female
1473
hormonal medicine until you have talked with your healthcare provider. Tell your
1474
healthcare provider if you have any changes in your menstrual pattern such as
1475
breakthrough bleeding. Stopping these medicines may cause side effects (such
1476
as dizziness, lack of coordination, or double vision). Starting these medicines
1477
may lessen how well LAMICTAL XR works.
1478
•
are pregnant or plan to become pregnant. It is not known if LAMICTAL XR will
1479
harm your unborn baby. If you become pregnant while taking LAMICTAL XR, talk
1480
to your healthcare provider about registering with the North American
1481
Antiepileptic Drug Pregnancy Registry. You can enroll in this registry by calling
1482
1-888-233-2334. The purpose of this registry is to collect information about the
1483
safety of antiepileptic drugs during pregnancy.
1484
•
are breastfeeding. LAMICTAL XR passes into breast milk and may cause side
1485
effects in a breastfed baby. If you breastfeed while taking LAMICTAL XR, watch
1486
your baby closely for trouble breathing, episodes of temporarily stopping
1487
breathing, sleepiness, or poor sucking. Call your baby’s healthcare provider right
1488
away if you see any of these problems. Talk to your healthcare provider about
1489
the best way to feed your baby if you take LAMICTAL XR.
1490
Tell your healthcare provider about all the medicines you take or if you are planning
1491
to take a new medicine, including prescription and non-prescription medicines,
1492
vitamins, and herbal supplements. If you use LAMICTAL XR with certain other
1493
medicines, they can affect each other, causing side effects.
1494
1495
How should I take LAMICTAL XR?
1496
•
Take LAMICTAL XR exactly as prescribed.
1497
•
Your healthcare provider may change your dose. Do not change your dose
1498
without talking to your healthcare provider.
1499
•
Do not stop taking LAMICTAL XR without talking to your healthcare provider.
1500
Stopping LAMICTAL XR suddenly may cause serious problems. For example, if
1501
you have epilepsy and you stop taking LAMICTAL XR suddenly, you may have
1502
seizures that do not stop. Talk with your healthcare provider about how to stop
1503
LAMICTAL XR slowly.
47
Reference ID: 3677876
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 022115/S-004 & S-014
FDA Proposed Labeling Text dated 12/23/2014
Page 48
1504
•
If you miss a dose of LAMICTAL XR, take it as soon as you remember. If it is
1505
almost time for your next dose, just skip the missed dose. Take the next dose at
1506
your regular time. Do not take 2 doses at the same time.
1507
•
If you take too much LAMICTAL XR, call your healthcare provider or your local
1508
Poison Control Center or go to the nearest hospital emergency room right away.
1509
•
You may not feel the full effect of LAMICTAL XR for several weeks.
1510
•
If you have epilepsy, tell your healthcare provider if your seizures get worse or if
1511
you have any new types of seizures.
1512
•
LAMICTAL XR can be taken with or without food.
1513
•
Do not chew, crush, or divide LAMICTAL XR.
1514
•
Swallow LAMICTAL XR Tablets whole.
1515
•
If you have trouble swallowing LAMICTAL XR Tablets, tell your healthcare
1516
provider because there may be another form of LAMICTAL you can take.
1517
•
If you receive LAMICTAL XR in a blisterpack, examine the blisterpack before use.
1518
Do not use if blisters are torn, broken, or missing.
1519
1520
What should I avoid while taking LAMICTAL XR?
1521
Do not drive a car or operate complex, hazardous machinery until you know how
1522
LAMICTAL XR affects you.
1523
1524
What are the possible side effects of LAMICTAL XR?
1525
See “What is the most important information I should know about LAMICTAL XR?”
1526
Common side effects of LAMICTAL XR include:
1527
•
dizziness
1528
•
tremor
1529
•
double vision
1530
•
nausea
1531
•
vomiting
1532
•
trouble with balance and coordination
1533
•
anxiety
1534
Other common side effects that have been reported with another form of LAMICTAL
1535
include headache, sleepiness, blurred vision, runny nose, and rash.
1536
Tell your healthcare provider about any side effect that bothers you or that does
1537
not go away.
1538
These are not all the possible side effects of LAMICTAL XR. For more information,
1539
ask your healthcare provider or pharmacist.
1540
Call your doctor for medical advice about side effects. You may report side effects
1541
to FDA at 1-800-FDA-1088.
48
Reference ID: 3677876
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 022115/S-004 & S-014
FDA Proposed Labeling Text dated 12/23/2014
Page 49
1542
1543
How should I store LAMICTAL XR?
1544
•
Store LAMICTAL XR at room temperature between 59oF and 86oF (15oC and
1545
30oC).
1546
•
Keep LAMICTAL XR and all medicines out of the reach of children.
1547
1548
General information about LAMICTAL XR
1549
Medicines are sometimes prescribed for purposes other than those listed in a
1550
Medication Guide. Do not use LAMICTAL XR for a condition for which it was not
1551
prescribed. Do not give LAMICTAL XR to other people, even if they have the same
1552
symptoms you have. It may harm them.
1553
This Medication Guide summarizes the most important information about LAMICTAL
1554
XR. If you would like more information, talk with your healthcare provider. You can
1555
ask your healthcare provider or pharmacist for information about LAMICTAL XR that
1556
is written for healthcare professionals.
1557
For more information, go to www.lamictalxr.com or call 1-888-825-5249.
1558
1559
What are the ingredients in LAMICTAL XR?
1560
Active ingredient: lamotrigine.
1561
Inactive ingredients: glycerol monostearate, hypromellose, lactose monohydrate,
1562
magnesium stearate, methacrylic acid copolymer dispersion, polyethylene glycol
1563
400, polysorbate 80, silicon dioxide (25- and 50-mg tablets only), titanium dioxide,
1564
triethyl citrate, carmine (250-mg tablet only), iron oxide black (50-, 250-, and 300
1565
mg tablets only), iron oxide yellow (25-, 50-, and 100-mg tablets only), iron oxide
1566
red (100-mg tablet only), FD&C Blue No. 2 Aluminum Lake (200- and 250-mg
1567
tablets only). Tablets are printed with edible black ink.
1568
1569
This Medication Guide has been approved by the U.S. Food and Drug
1570
Administration.
1571
1572
LAMICTAL XR is a trademark of the GSK group of companies. The other brands
1573
listed are trademarks of their respective owners and are not trademarks of the GSK
1574
group of companies. The makers of these brands are not affiliated with and do not
1575
endorse the GSK group of companies or its products.
1576
1577
49
Reference ID: 3677876
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 022115/S-004 & S-014
FDA Proposed Labeling Text dated 12/23/2014
Page 50 company logo
1578
1579
GlaxoSmithKline
1580
Research Triangle Park, NC 27709
1581
1582
2014, the GSK group of companies. All rights reserved.
1583
1584
December 2014
1585
LXR:xMG
50
Reference ID: 3677876
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:47:12.719703
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/020241s035s040,020764s028s033,022251s002s009lbl.pdf', 'application_number': 20241, 'submission_type': 'SUPPL ', 'submission_number': 35}
|
12,365
|
NDA 020241/S-045 & S-051
NDA 020764/S-038 & S-044
NDA 022251/S-007 & S-014
FDA Approved Labeling Text dated 3/24/2015
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
LAMICTAL safely and effectively. See full prescribing information for
LAMICTAL.
LAMICTAL (lamotrigine) tablets, for oral use
LAMICTAL (lamotrigine) chewable dispersible tablets, for oral use
LAMICTAL ODT (lamotrigine) orally disintegrating tablets, for oral use
Initial U.S. Approval: 1994
WARNING: SERIOUS SKIN RASHES
See full prescribing information for complete boxed warning.
• Cases of life-threatening serious rashes, including Stevens-Johnson
syndrome and toxic epidermal necrolysis, and/or rash-related death
have been caused by lamotrigine. The rate of serious rash is greater in
pediatric patients than in adults. Additional factors that may increase
the risk of rash include:
• coadministration with valproate.
• exceeding recommended initial dose of LAMICTAL.
• exceeding recommended dose escalation for LAMICTAL. (5.1)
• Benign rashes are also caused by lamotrigine; however, it is not
possible to predict which rashes will prove to be serious or life
threatening. LAMICTAL should be discontinued at the first sign of
rash, unless the rash is clearly not drug related. (5.1)
---------------------------RECENT MAJOR CHANGES --------------------------
Dosage and Administration (2.1, 2.2, 2.4)
12/2014
Warnings and Precautions, Laboratory Tests (5.14)
3/2015
--------------------------- INDICATIONS AND USAGE---------------------------
LAMICTAL is indicated for:
Epilepsy—adjunctive therapy in patients aged 2 years and older:
• partial-onset seizures.
• primary generalized tonic-clonic seizures.
• generalized seizures of Lennox-Gastaut syndrome. (1.1)
Epilepsy—monotherapy in patients aged 16 years and older: Conversion to
monotherapy in patients with partial-onset seizures who are receiving
treatment with carbamazepine, phenytoin, phenobarbital, primidone, or
valproate as the single AED. (1.1)
Bipolar disorder in patients aged 18 years and older: Maintenance treatment of
bipolar I disorder to delay the time to occurrence of mood episodes in patients
treated for acute mood episodes with standard therapy. (1.2)
-----------------------DOSAGE AND ADMINISTRATION ----------------------
• Dosing is based on concomitant medications, indication, and patient age.
(2.1, 2.2, 2.3, 2.4)
• To avoid an increased risk of rash, the recommended initial dose and
subsequent dose escalations should not be exceeded. LAMICTAL Starter
Kits and LAMICTAL ODT Patient Titration Kits are available for the first
5 weeks of treatment. (2.1, 16)
• Do not restart LAMICTAL in patients who discontinued due to rash unless
the potential benefits clearly outweigh the risks. (2.1, 5.1)
• Adjustments to maintenance doses will be necessary in most patients
starting or stopping estrogen-containing oral contraceptives. (2.1, 5.8)
• Discontinuation: Taper over a period of at least 2 weeks (approximately
50% dose reduction per week). (2.1, 5.9)
Epilepsy:
• Adjunctive therapy—See Table 1 for patients older than 12 years and
Tables 2 and 3 for patients aged 2 to 12 years. (2.2)
• Conversion to monotherapy—See Table 4. (2.3)
Bipolar disorder: See Tables 5 and 6. (2.4)
--------------------- DOSAGE FORMS AND STRENGTHS---------------------
• Tablets: 25 mg, 100 mg, 150 mg, and 200 mg; scored. (3.1, 16)
• Chewable dispersible tablets: 2 mg, 5 mg, and 25 mg. (3.2, 16)
• Orally disintegrating tablets: 25 mg, 50 mg, 100 mg, and 200 mg. (3.3, 16)
------------------------------ CONTRAINDICATIONS -----------------------------
Hypersensitivity to the drug or its ingredients. (Boxed Warning, 4)
----------------------- WARNINGS AND PRECAUTIONS ----------------------
• Life-threatening serious rash and/or rash-related death: Discontinue at the
first sign of rash, unless the rash is clearly not drug related. (Boxed
Warning, 5.1)
• Fatal or life-threatening hypersensitivity reaction: Multiorgan
hypersensitivity reactions, also known as drug reaction with eosinophilia
and systemic symptoms (DRESS), may be fatal or life threatening. Early
signs may include rash, fever, and lymphadenopathy. These reactions may
be associated with other organ involvement, such as hepatitis, hepatic
failure, blood dyscrasias, or acute multiorgan failure. LAMICTAL should
be discontinued if alternate etiology for this reaction is not found. (5.2)
• Blood dyscrasias (e.g., neutropenia, thrombocytopenia, pancytopenia): May
occur, either with or without an associated hypersensitivity syndrome.
Monitor for signs of anemia, unexpected infection, or bleeding. (5.3)
• Suicidal behavior and ideation: Monitor for suicidal thoughts or behaviors.
(5.4)
• Clinical worsening, emergence of new symptoms, and suicidal
ideation/behaviors may be associated with treatment of bipolar disorder.
Patients should be closely monitored, particularly early in treatment or
during dosage changes. (5.5)
• Aseptic meningitis: Monitor for signs of meningitis. (5.6)
• Medication errors due to product name confusion: Strongly advise patients
to visually inspect tablets to verify the received drug is correct. (5.7, 16, 17)
------------------------------ ADVERSE REACTIONS -----------------------------
Epilepsy: Most common adverse reactions (incidence ≥10%) in adults were
dizziness, headache, diplopia, ataxia, nausea, blurred vision, somnolence,
rhinitis, pharyngitis, and rash. Additional adverse reactions (incidence ≥10%)
reported in children included vomiting, infection, fever, accidental injury,
diarrhea, abdominal pain, and tremor. (6.1)
Bipolar disorder: Most common adverse reactions (incidence >5%) were
nausea, insomnia, somnolence, back pain, fatigue, rash, rhinitis, abdominal
pain, and xerostomia. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact
GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
------------------------------ DRUG INTERACTIONS------------------------------
• Valproate increases lamotrigine concentrations more than 2-fold. (7, 12.3)
• Carbamazepine, phenytoin, phenobarbital, primidone, and rifampin
decrease lamotrigine concentrations by approximately 40%. (7, 12.3)
• Estrogen-containing oral contraceptives decrease lamotrigine
concentrations by approximately 50%. (7, 12.3)
• Protease inhibitors lopinavir/ritonavir and atazanavir/lopinavir decrease
lamotrigine exposure by approximately 50% and 32%, respectively. (7,
12.3)
• Coadministration with organic cationic transporter 2 substrates with narrow
therapeutic index is not recommended (7, 12.3)
----------------------- USE IN SPECIFIC POPULATIONS ----------------------
• Pregnancy: Based on animal data may cause fetal harm. (8.1)
• Efficacy of LAMICTAL, used as adjunctive treatment for partial-onset
seizures, was not demonstrated in a small, randomized, double-blind,
placebo-controlled trial in very young pediatric patients (1 to 24 months).
(8.4)
• Hepatic impairment: Dosage adjustments required in patients with
moderate and severe liver impairment. (2.1, 8.6)
• Renal impairment: Reduced maintenance doses may be effective for
patients with significant renal impairment. (2.1, 8.7)
See 17 for PATIENT COUNSELING INFORMATION and Medication
Guide.
Revised: 3/2015
1
Reference ID: 3720577
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-045 & S-051
NDA 020764/S-038 & S-044
NDA 022251/S-007 & S-014
FDA Approved Labeling Text dated 3/24/2015
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: SERIOUS SKIN RASHES
1
INDICATIONS AND USAGE
1.1
Epilepsy
1.2
Bipolar Disorder
2
DOSAGE AND ADMINISTRATION
2.1
General Dosing Considerations
2.2
Epilepsy—Adjunctive Therapy
2.3
Epilepsy—Conversion From Adjunctive Therapy
to Monotherapy
2.4
Bipolar Disorder
2.5
Administration of LAMICTAL Chewable
Dispersible Tablets
2.6
Administration of LAMICTAL ODT Orally
Disintegrating Tablets
3
DOSAGE FORMS AND STRENGTHS
3.1
Tablets
3.2
Chewable Dispersible Tablets
3.3
Orally Disintegrating Tablets
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1
Serious Skin Rashes [see Boxed Warning]
5.2
Multiorgan Hypersensitivity Reactions and Organ
Failure
5.3
Blood Dyscrasias
5.4
Suicidal Behavior and Ideation
5.5
Use in Patients With Bipolar Disorder
5.6
Aseptic Meningitis
5.7
Potential Medication Errors
5.8
Concomitant Use With Oral Contraceptives
5.9
Withdrawal Seizures
5.10
Status Epilepticus
5.11
Sudden Unexplained Death in Epilepsy (SUDEP)
5.12
Addition of LAMICTAL to a Multidrug Regimen
That Includes Valproate
5.13
Binding in the Eye and Other Melanin-Containing
Tissues
5.14
Laboratory Tests
6
ADVERSE REACTIONS
6.1
Clinical Trial Experience
6.2
Other Adverse Reactions Observed in All Clinical
Trials
6.3
Postmarketing Experience
7
DRUG INTERACTIONS
8
USE IN SPECIFIC POPULATIONS
8.2
Labor and Delivery
8.3
Nursing Mothers
8.4
Pediatric Use
8.5
Geriatric Use
8.6
Hepatic Impairment
8.7
Renal Impairment
10
OVERDOSAGE
10.1
Human Overdose Experience
10.2
Management of Overdose
11
DESCRIPTION
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
12.2
Pharmacodynamics
12.3
Pharmacokinetics
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of
Fertility
14
CLINICAL STUDIES
14.1
Epilepsy
14.2
Bipolar Disorder
16
HOW SUPPLIED/STORAGE AND HANDLING
17
PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information are not
listed.
FULL PRESCRIBING INFORMATION
WARNING: SERIOUS SKIN RASHES
LAMICTAL® can cause serious rashes requiring hospitalization and discontinuation of
treatment. The incidence of these rashes, which have included Stevens-Johnson syndrome,
is approximately 0.8% (8 per 1,000) in pediatric patients (aged 2 to 16 years) receiving
LAMICTAL as adjunctive therapy for epilepsy and 0.3% (3 per 1,000) in adults on
adjunctive therapy for epilepsy. In clinical trials of bipolar and other mood disorders, the
rate of serious rash was 0.08% (0.8 per 1,000) in adult patients receiving LAMICTAL as
initial monotherapy and 0.13% (1.3 per 1,000) in adult patients receiving LAMICTAL as
adjunctive therapy. In a prospectively followed cohort of 1,983 pediatric patients (aged 2 to
16 years) with epilepsy taking adjunctive LAMICTAL, there was 1 rash-related death. In
worldwide postmarketing experience, rare cases of toxic epidermal necrolysis and/or rash-
related death have been reported in adult and pediatric patients, but their numbers are too
few to permit a precise estimate of the rate.
Other than age, there are as yet no factors identified that are known to predict the risk of
occurrence or the severity of rash caused by LAMICTAL. There are suggestions, yet to be
2
Reference ID: 3720577
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-045 & S-051
NDA 020764/S-038 & S-044
NDA 022251/S-007 & S-014
FDA Approved Labeling Text dated 3/24/2015
proven, that the risk of rash may also be increased by (1) coadministration of LAMICTAL
with valproate (includes valproic acid and divalproex sodium), (2) exceeding the
recommended initial dose of LAMICTAL, or (3) exceeding the recommended dose
escalation for LAMICTAL. However, cases have occurred in the absence of these factors.
Nearly all cases of life-threatening rashes caused by LAMICTAL have occurred within 2 to
8 weeks of treatment initiation. However, isolated cases have occurred after prolonged
treatment (e.g., 6 months). Accordingly, duration of therapy cannot be relied upon as
means to predict the potential risk heralded by the first appearance of a rash.
Although benign rashes are also caused by LAMICTAL, it is not possible to predict
reliably which rashes will prove to be serious or life threatening. Accordingly, LAMICTAL
should ordinarily be discontinued at the first sign of rash, unless the rash is clearly not
drug related. Discontinuation of treatment may not prevent a rash from becoming life
threatening or permanently disabling or disfiguring [see Warnings and Precautions (5.1)].
1
INDICATIONS AND USAGE
1.1
Epilepsy
Adjunctive Therapy
LAMICTAL is indicated as adjunctive therapy for the following seizure types in patients aged 2
years and older:
• partial-onset seizures.
• primary generalized tonic-clonic (PGTC) seizures.
• generalized seizures of Lennox-Gastaut syndrome.
Monotherapy
LAMICTAL is indicated for conversion to monotherapy in adults (aged 16 years and older) with
partial-onset seizures who are receiving treatment with carbamazepine, phenytoin, phenobarbital,
primidone, or valproate as the single antiepileptic drug (AED).
Safety and effectiveness of LAMICTAL have not been established (1) as initial monotherapy;
(2) for conversion to monotherapy from AEDs other than carbamazepine, phenytoin,
phenobarbital, primidone, or valproate; or (3) for simultaneous conversion to monotherapy from
2 or more concomitant AEDs.
1.2
Bipolar Disorder
LAMICTAL is indicated for the maintenance treatment of bipolar I disorder to delay the time to
occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in adults (aged 18
years and older) treated for acute mood episodes with standard therapy. The effectiveness of
LAMICTAL in the acute treatment of mood episodes has not been established.
3
Reference ID: 3720577
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-045 & S-051
NDA 020764/S-038 & S-044
NDA 022251/S-007 & S-014
FDA Approved Labeling Text dated 3/24/2015
The effectiveness of LAMICTAL as maintenance treatment was established in 2 placebo-
controlled trials in patients with bipolar I disorder as defined by DSM-IV [see Clinical Studies
(14.2)]. The physician who elects to prescribe LAMICTAL for periods extending beyond 16
weeks should periodically re-evaluate the long-term usefulness of the drug for the individual
patient.
2
DOSAGE AND ADMINISTRATION
2.1
General Dosing Considerations
Rash
There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash
may be increased by (1) coadministration of LAMICTAL with valproate, (2) exceeding the
recommended initial dose of LAMICTAL, or (3) exceeding the recommended dose escalation
for LAMICTAL. However, cases have occurred in the absence of these factors [see Boxed
Warning]. Therefore, it is important that the dosing recommendations be followed closely.
The risk of nonserious rash may be increased when the recommended initial dose and/or the rate
of dose escalation for LAMICTAL is exceeded and in patients with a history of allergy or rash to
other AEDs.
LAMICTAL Starter Kits and LAMICTAL ODT® Patient Titration Kits provide LAMICTAL at
doses consistent with the recommended titration schedule for the first 5 weeks of treatment,
based upon concomitant medications, for patients with epilepsy (older than 12 years) and bipolar
I disorder (aged 18 years and older) and are intended to help reduce the potential for rash. The
use of LAMICTAL Starter Kits and LAMICTAL ODT Patient Titration Kits is recommended
for appropriate patients who are starting or restarting LAMICTAL [see How Supplied/Storage
and Handling (16)].
It is recommended that LAMICTAL not be restarted in patients who discontinued due to rash
associated with prior treatment with lamotrigine unless the potential benefits clearly outweigh
the risks. If the decision is made to restart a patient who has discontinued LAMICTAL, the need
to restart with the initial dosing recommendations should be assessed. The greater the interval of
time since the previous dose, the greater consideration should be given to restarting with the
initial dosing recommendations. If a patient has discontinued lamotrigine for a period of more
than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be
followed. The half-life of lamotrigine is affected by other concomitant medications [see Clinical
Pharmacology (12.3)].
LAMICTAL Added to Drugs Known to Induce or Inhibit Glucuronidation
Because lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are
known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine.
Drugs that induce glucuronidation include carbamazepine, phenytoin, phenobarbital, primidone,
4
Reference ID: 3720577
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-045 & S-051
NDA 020764/S-038 & S-044
NDA 022251/S-007 & S-014
FDA Approved Labeling Text dated 3/24/2015
rifampin, estrogen-containing oral contraceptives, and the protease inhibitors lopinavir/ritonavir
and atazanavir/ritonavir. Valproate inhibits glucuronidation. For dosing considerations for
LAMICTAL in patients on estrogen-containing contraceptives and atazanavir/ritonavir, see
below and Table 13. For dosing considerations for LAMICTAL in patients on other drugs known
to induce or inhibit glucuronidation, see Table 1, Table 2, Table 5, Table 6, and Table 13.
Target Plasma Levels for Patients With Epilepsy or Bipolar Disorder
A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of
LAMICTAL should be based on therapeutic response [see Clinical Pharmacology (12.3)].
Women Taking Estrogen-Containing Oral Contraceptives
Starting LAMICTAL in Women Taking Estrogen-Containing Oral Contraceptives: Although
estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine
[see Clinical Pharmacology (12.3)], no adjustments to the recommended dose-escalation
guidelines for LAMICTAL should be necessary solely based on the use of estrogen-containing
oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for
initiating adjunctive therapy with LAMICTAL based on the concomitant AED or other
concomitant medications (see Table 1 or Table 5). See below for adjustments to maintenance
doses of LAMICTAL in women taking estrogen-containing oral contraceptives.
Adjustments to the Maintenance Dose of LAMICTAL in Women Taking Estrogen-Containing
Oral Contraceptives:
(1) Taking Estrogen-Containing Oral Contraceptives: In women not taking
carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the
protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine
glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance
dose of LAMICTAL will in most cases need to be increased by as much as 2-fold over the
recommended target maintenance dose to maintain a consistent lamotrigine plasma level.
(2) Starting Estrogen-Containing Oral Contraceptives: In women taking a stable dose of
LAMICTAL and not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs
such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that
induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)],
the maintenance dose will in most cases need to be increased by as much as 2-fold to maintain a
consistent lamotrigine plasma level. The dose increases should begin at the same time that the
oral contraceptive is introduced and continue, based on clinical response, no more rapidly than
50 to 100 mg/day every week. Dose increases should not exceed the recommended rate (see
Table 1 or Table 5) unless lamotrigine plasma levels or clinical response support larger
increases. Gradual transient increases in lamotrigine plasma levels may occur during the week of
inactive hormonal preparation (pill-free week), and these increases will be greater if dose
increases are made in the days before or during the week of inactive hormonal preparation.
5
Reference ID: 3720577
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-045 & S-051
NDA 020764/S-038 & S-044
NDA 022251/S-007 & S-014
FDA Approved Labeling Text dated 3/24/2015
Increased lamotrigine plasma levels could result in additional adverse reactions, such as
dizziness, ataxia, and diplopia. If adverse reactions attributable to LAMICTAL consistently
occur during the pill-free week, dose adjustments to the overall maintenance dose may be
necessary. Dose adjustments limited to the pill-free week are not recommended. For women
taking LAMICTAL in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other
drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir
that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology
(12.3)], no adjustment to the dose of LAMICTAL should be necessary.
(3) Stopping Estrogen-Containing Oral Contraceptives: In women not taking
carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the
protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine
glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance
dose of LAMICTAL will in most cases need to be decreased by as much as 50% in order to
maintain a consistent lamotrigine plasma level. The decrease in dose of LAMICTAL should not
exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or
lamotrigine plasma levels indicate otherwise [see Clinical Pharmacology (12.3)]. In women
taking LAMICTAL in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other
drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir
that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology
(12.3)], no adjustment to the dose of LAMICTAL should be necessary.
Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy
The effect of other hormonal contraceptive preparations or hormone replacement therapy on the
pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that
ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the
progestin-only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the
dosage of LAMICTAL in the presence of progestogens alone will likely not be needed.
Patients Taking Atazanavir/Ritonavir
While atazanavir/ritonavir does reduce the lamotrigine plasma concentration, no adjustments to
the recommended dose-escalation guidelines for LAMICTAL should be necessary solely based
on the use of atazanavir/ritonavir. Dose escalation should follow the recommended guidelines for
initiating adjunctive therapy with LAMICTAL based on concomitant AED or other concomitant
medications (see Tables 1, 2, and 5). In patients already taking maintenance doses of
LAMICTAL and not taking glucuronidation inducers, the dose of LAMICTAL may need to be
increased if atazanavir/ritonavir is added, or decreased if atazanavir/ritonavir is discontinued [see
Clinical Pharmacology (12.3)].
Patients With Hepatic Impairment
6
Reference ID: 3720577
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NDA 020241/S-045 & S-051
NDA 020764/S-038 & S-044
NDA 022251/S-007 & S-014
FDA Approved Labeling Text dated 3/24/2015
Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology
study in 24 subjects with mild, moderate, and severe liver impairment [see Use in Specific
Populations (8.6), Clinical Pharmacology (12.3)], the following general recommendations can
be made. No dosage adjustment is needed in patients with mild liver impairment. Initial,
escalation, and maintenance doses should generally be reduced by approximately 25% in patients
with moderate and severe liver impairment without ascites and 50% in patients with severe liver
impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical
response.
Patients With Renal Impairment
Initial doses of LAMICTAL should be based on patients’ concomitant medications (see Tables
1-3 or Table 5); reduced maintenance doses may be effective for patients with significant renal
impairment [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]. Few patients
with severe renal impairment have been evaluated during chronic treatment with LAMICTAL.
Because there is inadequate experience in this population, LAMICTAL should be used with
caution in these patients.
Discontinuation Strategy
Epilepsy: For patients receiving LAMICTAL in combination with other AEDs, a re-evaluation
of all AEDs in the regimen should be considered if a change in seizure control or an appearance
or worsening of adverse reactions is observed.
If a decision is made to discontinue therapy with LAMICTAL, a step-wise reduction of dose
over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns
require a more rapid withdrawal [see Warnings and Precautions (5.9)].
Discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as
rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce
lamotrigine glucuronidation should prolong the half-life of lamotrigine; discontinuing valproate
should shorten the half-life of lamotrigine.
Bipolar Disorder: In the controlled clinical trials, there was no increase in the incidence, type, or
severity of adverse reactions following abrupt termination of LAMICTAL. In clinical trials in
patients with bipolar disorder, 2 patients experienced seizures shortly after abrupt withdrawal of
LAMICTAL. However, there were confounding factors that may have contributed to the
occurrence of seizures in these patients with bipolar disorder. Discontinuation of LAMICTAL
should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per
week) unless safety concerns require a more rapid withdrawal [see Warnings and Precautions
(5.9)].
2.2
Epilepsy—Adjunctive Therapy
This section provides specific dosing recommendations for patients older than 12 years and
patients aged 2 to 12 years. Within each of these age-groups, specific dosing recommendations
7
Reference ID: 3720577
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-045 & S-051
NDA 020764/S-038 & S-044
NDA 022251/S-007 & S-014
FDA Approved Labeling Text dated 3/24/2015
are provided depending upon concomitant AEDs or other concomitant medications (see Table 1
for patients older than 12 years and Table 2 for patients aged 2 to 12 years). A weight-based
dosing guide for patients aged 2 to 12 years on concomitant valproate is provided in Table 3.
Patients Older Than 12 Years
Recommended dosing guidelines are summarized in Table 1.
Table 1. Escalation Regimen for LAMICTAL in Patients Older Than 12 Years With
Epilepsy
In Patients
TAKING Valproatea
In Patients
NOT TAKING
Carbamazepine,
Phenytoin,
Phenobarbital,
Primidone,b or
Valproatea
In Patients TAKING
Carbamazepine,
Phenytoin,
Phenobarbital, or
Primidoneb and NOT
TAKING Valproatea
Weeks 1 and 2
25 mg every other day
25 mg every day
50 mg/day
Weeks 3 and 4
25 mg every day
50 mg/day
100 mg/day
(in 2 divided doses)
Week 5 onward
to maintenance
Increase by
25 to 50 mg/day
every 1 to 2 weeks.
Increase by
50 mg/day
every 1 to 2 weeks.
Increase by
100 mg/day
every 1 to 2 weeks.
Usual
maintenance dose
100 to 200 mg/day
with valproate alone
100 to 400 mg/day
with valproate and
other drugs that
induce glucuronidation
(in 1 or 2 divided doses)
225 to 375 mg/day
(in 2 divided doses)
300 to 500 mg/day
(in 2 divided doses)
a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of
lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].
b Drugs that induce lamotrigine glucuronidation and increase clearance, other than the specified
antiepileptic drugs, include estrogen-containing oral contraceptives, rifampin, and the protease
inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Dosing recommendations for oral
contraceptives and the protease inhibitor atazanavir/ritonavir can be found in General Dosing
Considerations [see Dosage and Administration (2.1)]. Patients on rifampin and the protease
inhibitor lopinavir/ritonavir should follow the same dosing titration/maintenance regimen used
with antiepileptic drugs that induce glucuronidation and increase clearance [see Dosage and
Administration (2.1), Drug Interactions (7), and Clinical Pharmacology (12.3)].
8
Reference ID: 3720577
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-045 & S-051
NDA 020764/S-038 & S-044
NDA 022251/S-007 & S-014
FDA Approved Labeling Text dated 3/24/2015
Patients Aged 2 to 12 Years
Recommended dosing guidelines are summarized in Table 2.
Smaller starting doses and slower dose escalations than those used in clinical trials are
recommended because of the suggestion that the risk of rash may be decreased by smaller
starting doses and slower dose escalations. Therefore, maintenance doses will take longer to
reach in clinical practice than in clinical trials. It may take several weeks to months to achieve an
individualized maintenance dose. Maintenance doses in patients weighing less than 30 kg,
regardless of age or concomitant AED, may need to be increased as much as 50%, based on
clinical response.
The smallest available strength of LAMICTAL chewable dispersible tablets is 2 mg, and only
whole tablets should be administered. If the calculated dose cannot be achieved using whole
tablets, the dose should be rounded down to the nearest whole tablet [see How Supplied/Storage
and Handling (16) and Medication Guide].
Table 2. Escalation Regimen for LAMICTAL in Patients Aged 2 to 12 Years With Epilepsy
In Patients TAKING
Valproatea
In Patients
NOT TAKING
Carbamazepine,
Phenytoin,
Phenobarbital,
Primidone,b or
Valproatea
In Patients TAKING
Carbamazepine,
Phenytoin,
Phenobarbital, or
Primidoneb and NOT
TAKING Valproatea
Weeks 1 and 2
0.15 mg/kg/day
in 1 or 2 divided doses,
rounded down to the
nearest whole tablet
(see Table 3 for
weight-based dosing
guide)
0.3 mg/kg/day
in 1 or 2 divided doses,
rounded down to the
nearest whole tablet
0.6 mg/kg/day
in 2 divided doses,
rounded down to the
nearest whole tablet
Weeks 3 and 4
0.3 mg/kg/day
in 1 or 2 divided doses,
rounded down to the
nearest whole tablet
(see Table 3 for
weight-based dosing
guide)
0.6 mg/kg/day
in 2 divided doses,
rounded down to the
nearest whole tablet
1.2 mg/kg/day
in 2 divided doses,
rounded down to the
nearest whole tablet
9
Reference ID: 3720577
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-045 & S-051
NDA 020764/S-038 & S-044
NDA 022251/S-007 & S-014
FDA Approved Labeling Text dated 3/24/2015
Week 5 onward to
maintenance
The dose should be
increased every 1 to 2
weeks as follows:
calculate
0.3 mg/kg/day,
round this amount
down to the nearest
whole tablet, and add
this amount to the
previously
administered daily
dose.
The dose should be
increased every 1 to 2
weeks as follows:
calculate
0.6 mg/kg/day,
round this amount
down to the nearest
whole tablet, and add
this amount to the
previously
administered daily
dose.
The dose should be
increased every 1 to 2
weeks as follows:
calculate
1.2 mg/kg/day,
round this amount
down to the nearest
whole tablet, and add
this amount to the
previously
administered daily
dose.
Usual
maintenance dose
1 to 5 mg/kg/day
(maximum
200 mg/day in 1 or 2
divided doses)
1 to 3 mg/kg/day
with valproate alone
4.5 to 7.5 mg/kg/day
(maximum
300 mg/day in 2
divided doses)
5 to 15 mg/kg/day
(maximum
400 mg/day in 2
divided doses)
Maintenance dose
May need to be
May need to be
May need to be
in patients less
increased by as much
increased by as much
increased by as much
than 30 kg
as 50%, based on
clinical response.
as 50%, based on
clinical response.
as 50%, based on
clinical response.
Note: Only whole tablets should be used for dosing.
a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of
lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].
b Drugs that induce lamotrigine glucuronidation and increase clearance, other than the specified
antiepileptic drugs, include estrogen-containing oral contraceptives, rifampin, and the protease
inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Dosing recommendations for oral
contraceptives and the protease inhibitor atazanavir/ritonavir can be found in General Dosing
Considerations [see Dosage and Administration (2.1)]. Patients on rifampin and the protease
inhibitor lopinavir/ritonavir should follow the same dosing titration/maintenance regimen used
with antiepileptic drugs that induce glucuronidation and increase clearance [see Dosage and
Administration (2.1), Drug Interactions (7), and Clinical Pharmacology (12.3)].
10
Reference ID: 3720577
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-045 & S-051
NDA 020764/S-038 & S-044
NDA 022251/S-007 & S-014
FDA Approved Labeling Text dated 3/24/2015
Table 3. The Initial Weight-Based Dosing Guide for Patients Aged 2 to 12 Years Taking
Valproate (Weeks 1 to 4) With Epilepsy
If the patient’s weight is
Give this daily dose, using the most appropriate
combination of LAMICTAL 2- and 5-mg tablets
Greater than
And less than
Weeks 1 and 2
Weeks 3 and 4
6.7 kg
14 kg
2 mg every other day
2 mg every day
14.1 kg
27 kg
2 mg every day
4 mg every day
27.1 kg
34 kg
4 mg every day
8 mg every day
34.1 kg
40 kg
5 mg every day
10 mg every day
Usual Adjunctive Maintenance Dose for Epilepsy
The usual maintenance doses identified in Tables 1 and 2 are derived from dosing regimens
employed in the placebo-controlled adjunctive trials in which the efficacy of LAMICTAL was
established. In patients receiving multidrug regimens employing carbamazepine, phenytoin,
phenobarbital, or primidone without valproate, maintenance doses of adjunctive LAMICTAL as
high as 700 mg/day have been used. In patients receiving valproate alone, maintenance doses of
adjunctive LAMICTAL as high as 200 mg/day have been used. The advantage of using doses
above those recommended in Tables 1-4 has not been established in controlled trials.
2.3
Epilepsy—Conversion From Adjunctive Therapy to Monotherapy
The goal of the transition regimen is to attempt to maintain seizure control while mitigating the
risk of serious rash associated with the rapid titration of LAMICTAL.
The recommended maintenance dose of LAMICTAL as monotherapy is 500 mg/day given in 2
divided doses.
To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations
for LAMICTAL should not be exceeded [see Boxed Warning].
Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin, Phenobarbital, or
Primidone to Monotherapy With LAMICTAL
After achieving a dose of 500 mg/day of LAMICTAL using the guidelines in Table 1, the
concomitant enzyme-inducing AED should be withdrawn by 20% decrements each week over a
4-week period. The regimen for the withdrawal of the concomitant AED is based on experience
gained in the controlled monotherapy clinical trial.
Conversion From Adjunctive Therapy With Valproate to Monotherapy With LAMICTAL
The conversion regimen involves the 4 steps outlined in Table 4.
11
Reference ID: 3720577
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-045 & S-051
NDA 020764/S-038 & S-044
NDA 022251/S-007 & S-014
FDA Approved Labeling Text dated 3/24/2015
Table 4. Conversion From Adjunctive Therapy With Valproate to Monotherapy With
LAMICTAL in Patients Aged 16 Years and Older With Epilepsy
LAMICTAL
Valproate
Step 1
Achieve a dose of 200 mg/day according
to guidelines in Table 1.
Maintain established stable dose.
Step 2
Maintain at 200 mg/day.
Decrease dose by decrements no
greater than 500 mg/day/week to
500 mg/day and then maintain for 1
week.
Step 3
Increase to 300 mg/day and maintain for 1
week.
Simultaneously decrease to
250 mg/day and maintain for 1 week.
Step 4
Increase by 100 mg/day every week to
achieve maintenance dose of 500 mg/day.
Discontinue.
Conversion From Adjunctive Therapy With Antiepileptic Drugs Other Than Carbamazepine,
Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy With LAMICTAL
No specific dosing guidelines can be provided for conversion to monotherapy with LAMICTAL
with AEDs other than carbamazepine, phenytoin, phenobarbital, primidone, or valproate.
2.4
Bipolar Disorder
The goal of maintenance treatment with LAMICTAL is to delay the time to occurrence of mood
episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood
episodes with standard therapy. The target dose of LAMICTAL is 200 mg/day (100 mg/day in
patients taking valproate, which decreases the apparent clearance of lamotrigine, and 400 mg/day
in patients not taking valproate and taking either carbamazepine, phenytoin, phenobarbital,
primidone, or other drugs such as rifampin and the protease inhibitor lopinavir/ritonavir that
increase the apparent clearance of lamotrigine). In the clinical trials, doses up to 400 mg/day as
monotherapy were evaluated; however, no additional benefit was seen at 400 mg/day compared
with 200 mg/day [see Clinical Studies (14.2)]. Accordingly, doses above 200 mg/day are not
recommended. Treatment with LAMICTAL is introduced, based on concurrent medications,
according to the regimen outlined in Table 5. If other psychotropic medications are withdrawn
following stabilization, the dose of LAMICTAL should be adjusted. For patients discontinuing
valproate, the dose of LAMICTAL should be doubled over a 2-week period in equal weekly
increments (see Table 6). For patients discontinuing carbamazepine, phenytoin, phenobarbital,
primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and
atazanavir/ritonavir that induce lamotrigine glucuronidation, the dose of LAMICTAL should
remain constant for the first week and then should be decreased by half over a 2-week period in
equal weekly decrements (see Table 6). The dose of LAMICTAL may then be further adjusted to
the target dose (200 mg) as clinically indicated.
12
Reference ID: 3720577
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-045 & S-051
NDA 020764/S-038 & S-044
NDA 022251/S-007 & S-014
FDA Approved Labeling Text dated 3/24/2015
If other drugs are subsequently introduced, the dose of LAMICTAL may need to be adjusted. In
particular, the introduction of valproate requires reduction in the dose of LAMICTAL [see Drug
Interactions (7), Clinical Pharmacology (12.3)].
To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations
of LAMICTAL should not be exceeded [see Boxed Warning].
Table 5. Escalation Regimen for LAMICTAL in Patients With Bipolar Disorder
In Patients TAKING
Valproatea
In Patients
NOT TAKING
Carbamazepine,
Phenytoin,
Phenobarbital,
Primidone,b or
Valproatea
In Patients TAKING
Carbamazepine,
Phenytoin,
Phenobarbital, or
Primidoneb and NOT
TAKING Valproatea
Weeks 1 and 2
25 mg every other day
25 mg daily
50 mg daily
Weeks 3 and 4
25 mg daily
50 mg daily
100 mg daily,
in divided doses
Week 5
50 mg daily
100 mg daily
200 mg daily,
in divided doses
Week 6
100 mg daily
200 mg daily
300 mg daily,
in divided doses
Week 7
100 mg daily
200 mg daily
up to 400 mg daily,
in divided doses
a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of
lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].
b Drugs that induce lamotrigine glucuronidation and increase clearance, other than the
specified antiepileptic drugs, include estrogen-containing oral contraceptives, rifampin, and
the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Dosing
recommendations for oral contraceptives and the protease inhibitor atazanavir/ritonavir can
be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients
on rifampin and the protease inhibitor lopinavir/ritonavir should follow the same dosing
titration/maintenance regimen used with antiepileptic drugs that induce glucuronidation and
increase clearance [see Dosage and Administration (2.1), Drug Interactions (7), and
Clinical Pharmacology (12.3)].
13
Reference ID: 3720577
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-045 & S-051
NDA 020764/S-038 & S-044
NDA 022251/S-007 & S-014
FDA Approved Labeling Text dated 3/24/2015
Table 6. Dosage Adjustments to LAMICTAL in Patients With Bipolar Disorder Following
Discontinuation of Psychotropic Medications
Discontinuation
of Psychotropic Drugs
(excluding Valproate,a
Carbamazepine,
Phenytoin, Phenobarbital,
or Primidoneb)
After Discontinuation
of Valproatea
After Discontinuation of
Carbamazepine,
Phenytoin, Phenobarbital,
or Primidoneb
Current dose of
LAMICTAL (mg/day)
100
Current dose of
LAMICTAL (mg/day)
400
Week 1
Maintain current dose
of LAMICTAL
150
400
Week 2
Maintain current dose
of LAMICTAL
200
300
Week 3
onward
Maintain current dose
of LAMICTAL
200
200
a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of
lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].
b Drugs that induce lamotrigine glucuronidation and increase clearance, other than the specified
antiepileptic drugs, include estrogen-containing oral contraceptives, rifampin, and the protease
inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Dosing recommendations for oral
contraceptives and the protease inhibitor atazanavir/ritonavir can be found in General Dosing
Considerations [see Dosage and Administration (2.1)]. Patients on rifampin and the protease
inhibitor lopinavir/ritonavir should follow the same dosing titration/maintenance regimen used
with antiepileptic drugs that induce glucuronidation and increase clearance [see Dosage and
Administration (2.1), Drug Interactions (7), and Clinical Pharmacology (12.3)].
The benefit of continuing treatment in patients who had been stabilized in an 8- to 16-week
open-label phase with LAMICTAL was established in 2 randomized, placebo-controlled clinical
maintenance trials [see Clinical Studies (14.2)]. However, the optimal duration of treatment with
LAMICTAL has not been established. Thus, patients should be periodically reassessed to
determine the need for maintenance treatment.
2.5
Administration of LAMICTAL Chewable Dispersible Tablets
LAMICTAL chewable dispersible tablets may be swallowed whole, chewed, or dispersed in
water or diluted fruit juice. If the tablets are chewed, consume a small amount of water or diluted
fruit juice to aid in swallowing.
To disperse LAMICTAL chewable dispersible tablets, add the tablets to a small amount of liquid
(1 teaspoon, or enough to cover the medication). Approximately 1 minute later, when the tablets
are completely dispersed, swirl the solution and consume the entire quantity immediately. No
attempt should be made to administer partial quantities of the dispersed tablets.
14
Reference ID: 3720577
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-045 & S-051
NDA 020764/S-038 & S-044
NDA 022251/S-007 & S-014
FDA Approved Labeling Text dated 3/24/2015
2.6
Administration of LAMICTAL ODT Orally Disintegrating Tablets
LAMICTAL ODT orally disintegrating tablets should be placed onto the tongue and moved
around in the mouth. The tablet will disintegrate rapidly, can be swallowed with or without
water, and can be taken with or without food.
3
DOSAGE FORMS AND STRENGTHS
3.1
Tablets
25 mg, white, scored, shield-shaped tablets debossed with “LAMICTAL” and “25.”
100 mg, peach, scored, shield-shaped tablets debossed with “LAMICTAL” and “100.”
150 mg, cream, scored, shield-shaped tablets debossed with “LAMICTAL” and “150.”
200 mg, blue, scored, shield-shaped tablets debossed with “LAMICTAL” and “200.”
3.2
Chewable Dispersible Tablets
2 mg, white to off-white, round tablets debossed with “LTG” over “2.”
5 mg, white to off-white, caplet-shaped tablets debossed with “GX CL2.”
25 mg, white, super elliptical-shaped tablets debossed with “GX CL5.”
3.3
Orally Disintegrating Tablets
25 mg, white to off-white, round, flat-faced, radius-edged tablets debossed with “LMT” on one
side and “25” on the other side.
50 mg, white to off-white, round, flat-faced, radius-edged tablets debossed with “LMT” on one
side and “50” on the other side.
100 mg, white to off-white, round, flat-faced, radius-edged tablets debossed with “LAMICTAL”
on one side and “100” on the other side.
200 mg, white to off-white, round, flat-faced, radius-edged tablets debossed with “LAMICTAL”
on one side and “200” on the other side.
4
CONTRAINDICATIONS
LAMICTAL is contraindicated in patients who have demonstrated hypersensitivity (e.g., rash,
angioedema, acute urticaria, extensive pruritus, mucosal ulceration) to the drug or its ingredients
[see Boxed Warning, Warnings and Precautions (5.1, 5.2)].
15
Reference ID: 3720577
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-045 & S-051
NDA 020764/S-038 & S-044
NDA 022251/S-007 & S-014
FDA Approved Labeling Text dated 3/24/2015
5
WARNINGS AND PRECAUTIONS
5.1
Serious Skin Rashes [see Boxed Warning]
Pediatric Population
The incidence of serious rash associated with hospitalization and discontinuation of LAMICTAL
in a prospectively followed cohort of pediatric patients (aged 2 to 16 years) with epilepsy
receiving adjunctive therapy was approximately 0.8% (16 of 1,983). When 14 of these cases
were reviewed by 3 expert dermatologists, there was considerable disagreement as to their proper
classification. To illustrate, one dermatologist considered none of the cases to be Stevens-
Johnson syndrome; another assigned 7 of the 14 to this diagnosis. There was 1 rash-related death
in this 1,983-patient cohort. Additionally, there have been rare cases of toxic epidermal
necrolysis with and without permanent sequelae and/or death in US and foreign postmarketing
experience.
There is evidence that the inclusion of valproate in a multidrug regimen increases the risk of
serious, potentially life-threatening rash in pediatric patients. In pediatric patients who used
valproate concomitantly, 1.2% (6 of 482) experienced a serious rash compared with 0.6% (6 of
952) patients not taking valproate.
Adult Population
Serious rash associated with hospitalization and discontinuation of LAMICTAL occurred in
0.3% (11 of 3,348) of adult patients who received LAMICTAL in premarketing clinical trials of
epilepsy. In the bipolar and other mood disorders clinical trials, the rate of serious rash was
0.08% (1 of 1,233) of adult patients who received LAMICTAL as initial monotherapy and
0.13% (2 of 1,538) of adult patients who received LAMICTAL as adjunctive therapy. No
fatalities occurred among these individuals. However, in worldwide postmarketing experience,
rare cases of rash-related death have been reported, but their numbers are too few to permit a
precise estimate of the rate.
Among the rashes leading to hospitalization were Stevens-Johnson syndrome, toxic epidermal
necrolysis, angioedema, and those associated with multiorgan hypersensitivity [see Warnings
and Precautions (5.2)].
There is evidence that the inclusion of valproate in a multidrug regimen increases the risk of
serious, potentially life-threatening rash in adults. Specifically, of 584 patients administered
LAMICTAL with valproate in epilepsy clinical trials, 6 (1%) were hospitalized in association
with rash; in contrast, 4 (0.16%) of 2,398 clinical trial patients and volunteers administered
LAMICTAL in the absence of valproate were hospitalized.
16
Reference ID: 3720577
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-045 & S-051
NDA 020764/S-038 & S-044
NDA 022251/S-007 & S-014
FDA Approved Labeling Text dated 3/24/2015
Patients With History of Allergy or Rash to Other Antiepileptic Drugs
The risk of nonserious rash may be increased when the recommended initial dose and/or the rate
of dose escalation for LAMICTAL is exceeded and in patients with a history of allergy or rash to
other AEDs.
5.2
Multiorgan Hypersensitivity Reactions and Organ Failure
Multiorgan hypersensitivity reactions, also known as drug reaction with eosinophilia and
systemic symptoms (DRESS), have occurred with lamotrigine. Some have been fatal or life
threatening. DRESS typically, although not exclusively, presents with fever, rash, and/or
lymphadenopathy in association with other organ system involvement, such as hepatitis,
nephritis, hematologic abnormalities, myocarditis, or myositis, sometimes resembling an acute
viral infection. Eosinophilia is often present. This disorder is variable in its expression, and other
organ systems not noted here may be involved.
Fatalities associated with acute multiorgan failure and various degrees of hepatic failure have
been reported in 2 of 3,796 adult patients and 4 of 2,435 pediatric patients who received
lamotrigine in epilepsy clinical trials. Rare fatalities from multiorgan failure have also been
reported in postmarketing use.
Isolated liver failure without rash or involvement of other organs has also been reported with
lamotrigine.
It is important to note that early manifestations of hypersensitivity (e.g., fever,
lymphadenopathy) may be present even though a rash is not evident. If such signs or symptoms
are present, the patient should be evaluated immediately. LAMICTAL should be discontinued if
an alternative etiology for the signs or symptoms cannot be established.
Prior to initiation of treatment with LAMICTAL, the patient should be instructed that a rash or
other signs or symptoms of hypersensitivity (e.g., fever, lymphadenopathy) may herald a serious
medical event and that the patient should report any such occurrence to a physician immediately.
5.3
Blood Dyscrasias
There have been reports of blood dyscrasias that may or may not be associated with multiorgan
hypersensitivity (also known as DRESS) [see Warnings and Precautions (5.2)]. These have
included neutropenia, leukopenia, anemia, thrombocytopenia, pancytopenia, and, rarely, aplastic
anemia and pure red cell aplasia.
5.4
Suicidal Behavior and Ideation
AEDs, including LAMICTAL, increase the risk of suicidal thoughts or behavior in patients
taking these drugs for any indication. Patients treated with any AED for any indication should be
monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or
any unusual changes in mood or behavior.
17
Reference ID: 3720577
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-045 & S-051
NDA 020764/S-038 & S-044
NDA 022251/S-007 & S-014
FDA Approved Labeling Text dated 3/24/2015
Pooled analyses of 199 placebo-controlled clinical trials (monotherapy and adjunctive therapy)
of 11 different AEDs showed that patients randomized to 1 of the AEDs had approximately
twice the risk (adjusted Relative Risk 1.8, 95% CI: 1.2, 2.7) of suicidal thinking or behavior
compared with patients randomized to placebo. In these trials, which had a median treatment
duration of 12 weeks, the estimated incidence of suicidal behavior or ideation among 27,863
AED-treated patients was 0.43%, compared with 0.24% among 16,029 placebo-treated patients,
representing an increase of approximately 1 case of suicidal thinking or behavior for every 530
patients treated. There were 4 suicides in drug-treated patients in the trials and none in placebo-
treated patients, but the number of events is too small to allow any conclusion about drug effect
on suicide.
The increased risk of suicidal thoughts or behavior with AEDs was observed as early as 1 week
after starting treatment with AEDs and persisted for the duration of treatment assessed. Because
most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts
or behavior beyond 24 weeks could not be assessed.
The risk of suicidal thoughts or behavior was generally consistent among drugs in the data
analyzed. The finding of increased risk with AEDs of varying mechanism of action and across a
range of indications suggests that the risk applies to all AEDs used for any indication. The risk
did not vary substantially by age (5 to 100 years) in the clinical trials analyzed.
Table 7 shows absolute and relative risk by indication for all evaluated AEDs.
Table 7. Risk by Indication for Antiepileptic Drugs in the Pooled Analysis
Indication
Placebo
Patients With
Events per
1,000 Patients
Drug Patients
With Events
per 1,000
Patients
Relative Risk:
Incidence of
Events in Drug
Patients/
Incidence in
Placebo Patients
Risk Difference:
Additional Drug
Patients With
Events per
1,000 Patients
Epilepsy
1.0
3.4
3.5
2.4
Psychiatric
5.7
8.5
1.5
2.9
Other
1.0
1.8
1.9
0.9
Total
2.4
4.3
1.8
1.9
The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in
clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for
the epilepsy and psychiatric indications.
Anyone considering prescribing LAMICTAL or any other AED must balance the risk of suicidal
thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for
which AEDs are prescribed are themselves associated with morbidity and mortality and an
increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge
18
Reference ID: 3720577
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-045 & S-051
NDA 020764/S-038 & S-044
NDA 022251/S-007 & S-014
FDA Approved Labeling Text dated 3/24/2015
during treatment, the prescriber needs to consider whether the emergence of these symptoms in
any given patient may be related to the illness being treated.
Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal
thoughts and behavior and should be advised of the need to be alert for the emergence or
worsening of the signs and symptoms of depression, any unusual changes in mood or behavior,
the emergence of suicidal thoughts or suicidal behavior, or thoughts about self-harm. Behaviors
of concern should be reported immediately to healthcare providers.
5.5
Use in Patients With Bipolar Disorder
Acute Treatment of Mood Episodes
Safety and effectiveness of LAMICTAL in the acute treatment of mood episodes have not been
established.
Children and Adolescents (younger than 18 years)
Safety and effectiveness of LAMICTAL in patients younger than 18 years with mood disorders
have not been established [see Warnings and Precautions (5.4)].
Clinical Worsening and Suicide Risk Associated With Bipolar Disorder
Patients with bipolar disorder may experience worsening of their depressive symptoms and/or
the emergence of suicidal ideation and behaviors (suicidality) whether or not they are taking
medications for bipolar disorder. Patients should be closely monitored for clinical worsening
(including development of new symptoms) and suicidality, especially at the beginning of a
course of treatment or at the time of dose changes.
In addition, patients with a history of suicidal behavior or thoughts, those patients exhibiting a
significant degree of suicidal ideation prior to commencement of treatment, and young adults are
at an increased risk of suicidal thoughts or suicide attempts and should receive careful
monitoring during treatment [see Warnings and Precautions (5.4)].
Consideration should be given to changing the therapeutic regimen, including possibly
discontinuing the medication, in patients who experience clinical worsening (including
development of new symptoms) and/or the emergence of suicidal ideation/behavior, especially if
these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting
symptoms.
Prescriptions for LAMICTAL should be written for the smallest quantity of tablets consistent
with good patient management in order to reduce the risk of overdose. Overdoses have been
reported for LAMICTAL, some of which have been fatal [see Overdosage (10.1)].
19
Reference ID: 3720577
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-045 & S-051
NDA 020764/S-038 & S-044
NDA 022251/S-007 & S-014
FDA Approved Labeling Text dated 3/24/2015
5.6
Aseptic Meningitis
Therapy with lamotrigine increases the risk of developing aseptic meningitis. Because of the
potential for serious outcomes of untreated meningitis due to other causes, patients should also
be evaluated for other causes of meningitis and treated as appropriate.
Postmarketing cases of aseptic meningitis have been reported in pediatric and adult patients
taking lamotrigine for various indications. Symptoms upon presentation have included headache,
fever, nausea, vomiting, and nuchal rigidity. Rash, photophobia, myalgia, chills, altered
consciousness, and somnolence were also noted in some cases. Symptoms have been reported to
occur within 1 day to one and a half months following the initiation of treatment. In most cases,
symptoms were reported to resolve after discontinuation of lamotrigine. Re-exposure resulted in
a rapid return of symptoms (from within 30 minutes to 1 day following re-initiation of treatment)
that were frequently more severe. Some of the patients treated with lamotrigine who developed
aseptic meningitis had underlying diagnoses of systemic lupus erythematosus or other
autoimmune diseases.
Cerebrospinal fluid (CSF) analyzed at the time of clinical presentation in reported cases was
characterized by a mild to moderate pleocytosis, normal glucose levels, and mild to moderate
increase in protein. CSF white blood cell count differentials showed a predominance of
neutrophils in a majority of the cases, although a predominance of lymphocytes was reported in
approximately one third of the cases. Some patients also had new onset of signs and symptoms
of involvement of other organs (predominantly hepatic and renal involvement), which may
suggest that in these cases the aseptic meningitis observed was part of a hypersensitivity reaction
[see Warnings and Precautions (5.2)].
5.7
Potential Medication Errors
Medication errors involving LAMICTAL have occurred. In particular, the names LAMICTAL or
lamotrigine can be confused with the names of other commonly used medications. Medication
errors may also occur between the different formulations of LAMICTAL. To reduce the potential
of medication errors, write and say LAMICTAL clearly. Depictions of the LAMICTAL tablets,
chewable dispersible tablets, and orally disintegrating tablets can be found in the Medication
Guide that accompanies the product to highlight the distinctive markings, colors, and shapes that
serve to identify the different presentations of the drug and thus may help reduce the risk of
medication errors. To avoid the medication error of using the wrong drug or formulation, patients
should be strongly advised to visually inspect their tablets to verify that they are LAMICTAL, as
well as the correct formulation of LAMICTAL, each time they fill their prescription.
5.8
Concomitant Use With Oral Contraceptives
Some estrogen-containing oral contraceptives have been shown to decrease serum concentrations
of lamotrigine [see Clinical Pharmacology (12.3)]. Dosage adjustments will be necessary in
most patients who start or stop estrogen-containing oral contraceptives while taking LAMICTAL
20
Reference ID: 3720577
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-045 & S-051
NDA 020764/S-038 & S-044
NDA 022251/S-007 & S-014
FDA Approved Labeling Text dated 3/24/2015
[see Dosage and Administration (2.1)]. During the week of inactive hormone preparation (pill-
free week) of oral contraceptive therapy, plasma lamotrigine levels are expected to rise, as much
as doubling at the end of the week. Adverse reactions consistent with elevated levels of
lamotrigine, such as dizziness, ataxia, and diplopia, could occur.
5.9
Withdrawal Seizures
As with other AEDs, LAMICTAL should not be abruptly discontinued. In patients with epilepsy
there is a possibility of increasing seizure frequency. In clinical trials in patients with bipolar
disorder, 2 patients experienced seizures shortly after abrupt withdrawal of LAMICTAL;
however, there were confounding factors that may have contributed to the occurrence of seizures
in these patients with bipolar disorder. Unless safety concerns require a more rapid withdrawal,
the dose of LAMICTAL should be tapered over a period of at least 2 weeks (approximately 50%
reduction per week) [see Dosage and Administration (2.1)].
5.10
Status Epilepticus
Valid estimates of the incidence of treatment-emergent status epilepticus among patients treated
with LAMICTAL are difficult to obtain because reporters participating in clinical trials did not
all employ identical rules for identifying cases. At a minimum, 7 of 2,343 adult patients had
episodes that could unequivocally be described as status epilepticus. In addition, a number of
reports of variably defined episodes of seizure exacerbation (e.g., seizure clusters, seizure
flurries) were made.
5.11
Sudden Unexplained Death in Epilepsy (SUDEP)
During the premarketing development of LAMICTAL, 20 sudden and unexplained deaths were
recorded among a cohort of 4,700 patients with epilepsy (5,747 patient-years of exposure).
Some of these could represent seizure-related deaths in which the seizure was not observed, e.g.,
at night. This represents an incidence of 0.0035 deaths per patient-year. Although this rate
exceeds that expected in a healthy population matched for age and sex, it is within the range of
estimates for the incidence of sudden unexplained death in epilepsy (SUDEP) in patients not
receiving LAMICTAL (ranging from 0.0005 for the general population of patients with epilepsy,
to 0.004 for a recently studied clinical trial population similar to that in the clinical development
program for LAMICTAL, to 0.005 for patients with refractory epilepsy). Consequently, whether
these figures are reassuring or suggest concern depends on the comparability of the populations
reported upon with the cohort receiving LAMICTAL and the accuracy of the estimates provided.
Probably most reassuring is the similarity of estimated SUDEP rates in patients receiving
LAMICTAL and those receiving other AEDs, chemically unrelated to each other, that underwent
clinical testing in similar populations. Importantly, that drug is chemically unrelated to
LAMICTAL. This evidence suggests, although it certainly does not prove, that the high SUDEP
rates reflect population rates, not a drug effect.
21
Reference ID: 3720577
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-045 & S-051
NDA 020764/S-038 & S-044
NDA 022251/S-007 & S-014
FDA Approved Labeling Text dated 3/24/2015
5.12
Addition of LAMICTAL to a Multidrug Regimen That Includes Valproate
Because valproate reduces the clearance of lamotrigine, the dosage of lamotrigine in the presence
of valproate is less than half of that required in its absence [see Dosage and Administration (2.2,
2.3, 2.4), Drug Interactions (7)].
5.13
Binding in the Eye and Other Melanin-Containing Tissues
Because lamotrigine binds to melanin, it could accumulate in melanin-rich tissues over time.
This raises the possibility that lamotrigine may cause toxicity in these tissues after extended use.
Although ophthalmological testing was performed in 1 controlled clinical trial, the testing was
inadequate to exclude subtle effects or injury occurring after long-term exposure. Moreover, the
capacity of available tests to detect potentially adverse consequences, if any, of lamotrigine’s
binding to melanin is unknown [see Clinical Pharmacology (12.2)].
Accordingly, although there are no specific recommendations for periodic ophthalmological
monitoring, prescribers should be aware of the possibility of long-term ophthalmologic effects.
5.14
Laboratory Tests
False-Positive Drug Test Results
Lamotrigine has been reported to interfere with the assay used in some rapid urine drug screens,
which can result in false-positive readings, particularly for phencyclidine (PCP). A more specific
analytical method should be used to confirm a positive result.
Plasma Concentrations of Lamotrigine
The value of monitoring plasma concentrations of lamotrigine in patients treated with
LAMICTAL has not been established. Because of the possible pharmacokinetic interactions
between lamotrigine and other drugs, including AEDs (see Table 15), monitoring of the plasma
levels of lamotrigine and concomitant drugs may be indicated, particularly during dosage
adjustments. In general, clinical judgment should be exercised regarding monitoring of plasma
levels of lamotrigine and other drugs and whether or not dosage adjustments are necessary.
6
ADVERSE REACTIONS
The following adverse reactions are described in more detail in the Warnings and Precautions
section of the label:
• Serious skin rashes [see Warnings and Precautions (5.1)]
• Multiorgan hypersensitivity reactions and organ failure [see Warnings and Precautions (5.2)]
• Blood dyscrasias [see Warnings and Precautions (5.3)]
• Suicidal behavior and ideation [see Warnings and Precautions (5.4)]
• Aseptic meningitis [see Warnings and Precautions (5.6)]
22
Reference ID: 3720577
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-045 & S-051
NDA 020764/S-038 & S-044
NDA 022251/S-007 & S-014
FDA Approved Labeling Text dated 3/24/2015
• Withdrawal seizures [see Warnings and Precautions (5.9)]
• Status epilepticus [see Warnings and Precautions (5.10)]
• Sudden unexplained death in epilepsy [see Warnings and Precautions (5.11)]
6.1
Clinical Trial Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates
observed in the clinical trials of a drug cannot be directly compared with rates in the clinical
trials of another drug and may not reflect the rates observed in practice.
Epilepsy
Most Common Adverse Reactions in All Clinical Trials: Adjunctive Therapy in Adults With
Epilepsy: The most commonly observed (≥5% for LAMICTAL and more common on drug than
placebo) adverse reactions seen in association with LAMICTAL during adjunctive therapy in
adults and not seen at an equivalent frequency among placebo-treated patients were: dizziness,
ataxia, somnolence, headache, diplopia, blurred vision, nausea, vomiting, and rash. Dizziness,
diplopia, ataxia, blurred vision, nausea, and vomiting were dose related. Dizziness, diplopia,
ataxia, and blurred vision occurred more commonly in patients receiving carbamazepine with
LAMICTAL than in patients receiving other AEDs with LAMICTAL. Clinical data suggest a
higher incidence of rash, including serious rash, in patients receiving concomitant valproate than
in patients not receiving valproate [see Warnings and Precautions (5.1)].
Approximately 11% of the 3,378 adult patients who received LAMICTAL as adjunctive therapy
in premarketing clinical trials discontinued treatment because of an adverse reaction. The
adverse reactions most commonly associated with discontinuation were rash (3.0%), dizziness
(2.8%), and headache (2.5%).
In a dose-response trial in adults, the rate of discontinuation of LAMICTAL for dizziness, ataxia,
diplopia, blurred vision, nausea, and vomiting was dose related.
Monotherapy in Adults With Epilepsy: The most commonly observed (≥5% for
LAMICTAL and more common on drug than placebo) adverse reactions seen in association with
the use of LAMICTAL during the monotherapy phase of the controlled trial in adults not seen at
an equivalent rate in the control group were vomiting, coordination abnormality, dyspepsia,
nausea, dizziness, rhinitis, anxiety, insomnia, infection, pain, weight decrease, chest pain, and
dysmenorrhea. The most commonly observed (≥5% for LAMICTAL and more common on drug
than placebo) adverse reactions associated with the use of LAMICTAL during the conversion to
monotherapy (add-on) period, not seen at an equivalent frequency among low-dose valproate-
treated patients, were dizziness, headache, nausea, asthenia, coordination abnormality, vomiting,
rash, somnolence, diplopia, ataxia, accidental injury, tremor, blurred vision, insomnia,
nystagmus, diarrhea, lymphadenopathy, pruritus, and sinusitis.
23
Reference ID: 3720577
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-045 & S-051
NDA 020764/S-038 & S-044
NDA 022251/S-007 & S-014
FDA Approved Labeling Text dated 3/24/2015
Approximately 10% of the 420 adult patients who received LAMICTAL as monotherapy in
premarketing clinical trials discontinued treatment because of an adverse reaction. The adverse
reactions most commonly associated with discontinuation were rash (4.5%), headache (3.1%),
and asthenia (2.4%).
Adjunctive Therapy in Pediatric Patients With Epilepsy: The most commonly observed
(≥5% for LAMICTAL and more common on drug than placebo) adverse reactions seen in
association with the use of LAMICTAL as adjunctive treatment in pediatric patients aged 2 to 16
years and not seen at an equivalent rate in the control group were infection, vomiting, rash, fever,
somnolence, accidental injury, dizziness, diarrhea, abdominal pain, nausea, ataxia, tremor,
asthenia, bronchitis, flu syndrome, and diplopia.
In 339 patients aged 2 to 16 years with partial-onset seizures or generalized seizures of Lennox-
Gastaut syndrome, 4.2% of patients on LAMICTAL and 2.9% of patients on placebo
discontinued due to adverse reactions. The most commonly reported adverse reaction that led to
discontinuation of LAMICTAL was rash.
Approximately 11.5% of the 1,081 pediatric patients aged 2 to 16 years who received
LAMICTAL as adjunctive therapy in premarketing clinical trials discontinued treatment because
of an adverse reaction. The adverse reactions most commonly associated with discontinuation
were rash (4.4%), reaction aggravated (1.7%), and ataxia (0.6%).
Controlled Adjunctive Clinical Trials in Adults With Epilepsy: Table 8 lists adverse
reactions that occurred in adult patients with epilepsy treated with LAMICTAL in placebo-
controlled trials. In these studies, either LAMICTAL or placebo was added to the patient’s
current AED therapy.
Table 8. Adverse Reactions in Pooled, Placebo-Controlled Adjunctive Trials in Adult
Patients With Epilepsya,b
Body System/
Adverse Reaction
Percent of Patients
Receiving Adjunctive
LAMICTAL
(n = 711)
Percent of Patients
Receiving Adjunctive
Placebo
(n = 419)
Body as a whole
Headache
Flu syndrome
Fever
Abdominal pain
Neck pain
Reaction aggravated
(seizure exacerbation)
29
7
6
5
2
2
19
6
4
4
1
1
24
Reference ID: 3720577
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-045 & S-051
NDA 020764/S-038 & S-044
NDA 022251/S-007 & S-014
FDA Approved Labeling Text dated 3/24/2015
Digestive
Nausea
19
10
Vomiting
9
4
Diarrhea
6
4
Dyspepsia
5
2
Constipation
4
3
Anorexia
2
1
Musculoskeletal
Arthralgia
2
0
Nervous
Dizziness
38
13
Ataxia
22
6
Somnolence
14
7
Incoordination
6
2
Insomnia
6
2
Tremor
4
1
Depression
4
3
Anxiety
4
3
Convulsion
3
1
Irritability
3
2
Speech disorder
3
0
Concentration disturbance
2
1
Respiratory
Rhinitis
14
9
Pharyngitis
10
9
Cough increased
8
6
Skin and appendages
Rash
Pruritus
10
3
5
2
Special senses
Diplopia
28
7
Blurred vision
16
5
Vision abnormality
3
1
Urogenital
Female patients only
Dysmenorrhea
Vaginitis
Amenorrhea
(n = 365)
7
4
2
(n = 207)
6
1
1
a Adverse reactions that occurred in at least 2% of patients treated with LAMICTAL and at a
greater incidence than placebo.
25
Reference ID: 3720577
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-045 & S-051
NDA 020764/S-038 & S-044
NDA 022251/S-007 & S-014
FDA Approved Labeling Text dated 3/24/2015
b Patients in these adjunctive trials were receiving 1 to 3 of the concomitant antiepileptic drugs
carbamazepine, phenytoin, phenobarbital, or primidone in addition to LAMICTAL or
placebo. Patients may have reported multiple adverse reactions during the trial or at
discontinuation; thus, patients may be included in more than 1 category.
In a randomized, parallel trial comparing placebo with 300 and 500 mg/day of LAMICTAL,
some of the more common drug-related adverse reactions were dose related (see Table 9).
Table 9. Dose-Related Adverse Reactions From a Randomized, Placebo-Controlled,
Adjunctive Trial in Adults With Epilepsy
Adverse Reaction
Percent of Patients Experiencing Adverse Reactions
Placebo
(n = 73)
LAMICTAL
300 mg
(n = 71)
LAMICTAL
500 mg
(n = 72)
Ataxia
Blurred vision
Diplopia
Dizziness
Nausea
Vomiting
10
10
8
27
11
4
10
11
24
a
31
18
11
28
a,b
25
a,b
49
a,b
54
a,b
25
a
18
a
a Significantly greater than placebo group (P<0.05).
b Significantly greater than group receiving LAMICTAL 300 mg (P<0.05).
The overall adverse reaction profile for LAMICTAL was similar between females and males and
was independent of age. Because the largest non-Caucasian racial subgroup was only 6% of
patients exposed to LAMICTAL in placebo-controlled trials, there are insufficient data to
support a statement regarding the distribution of adverse reaction reports by race. Generally,
females receiving either LAMICTAL as adjunctive therapy or placebo were more likely to report
adverse reactions than males. The only adverse reaction for which the reports on LAMICTAL
were greater than 10% more frequent in females than males (without a corresponding difference
by gender on placebo) was dizziness (difference = 16.5%). There was little difference between
females and males in the rates of discontinuation of LAMICTAL for individual adverse
reactions.
Controlled Monotherapy Trial in Adults With Partial-Onset Seizures: Table 10 lists
adverse reactions that occurred in patients with epilepsy treated with monotherapy with
LAMICTAL in a double-blind trial following discontinuation of either concomitant
carbamazepine or phenytoin not seen at an equivalent frequency in the control group.
26
Reference ID: 3720577
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-045 & S-051
NDA 020764/S-038 & S-044
NDA 022251/S-007 & S-014
FDA Approved Labeling Text dated 3/24/2015
Table 10. Adverse Reactions in a Controlled Monotherapy Trial in Adult Patients With
Partial-Onset Seizuresa,b
Body System/
Adverse Reaction
Percent of Patients
Receiving LAMICTALc as
Monotherapy
(n = 43)
Percent of Patients
Receiving Low-Dose
Valproated Monotherapy
(n = 44)
Body as a whole
Pain
Infection
Chest pain
5
5
5
0
2
2
Digestive
Vomiting
Dyspepsia
Nausea
9
7
7
0
2
2
Metabolic and nutritional
Weight decrease
5
2
Nervous
Coordination abnormality
Dizziness
Anxiety
Insomnia
7
7
5
5
0
0
0
2
Respiratory
Rhinitis
7
2
Urogenital (female patients
only)
Dysmenorrhea
(n = 21)
5
(n = 28)
0
a Adverse reactions that occurred in at least 5% of patients treated with LAMICTAL and at a
greater incidence than valproate-treated patients.
b Patients in this trial were converted to LAMICTAL or valproate monotherapy from
adjunctive therapy with carbamazepine or phenytoin. Patients may have reported multiple
adverse reactions during the trial; thus, patients may be included in more than 1 category.
c Up to 500 mg/day.
d 1,000 mg/day.
Adverse reactions that occurred with a frequency of less than 5% and greater than 2% of patients
receiving LAMICTAL and numerically more frequent than placebo were:
Body as a Whole: Asthenia, fever.
Digestive: Anorexia, dry mouth, rectal hemorrhage, peptic ulcer.
Metabolic and Nutritional: Peripheral edema.
27
Reference ID: 3720577
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-045 & S-051
NDA 020764/S-038 & S-044
NDA 022251/S-007 & S-014
FDA Approved Labeling Text dated 3/24/2015
Nervous System: Amnesia, ataxia, depression, hypesthesia, libido increase, decreased reflexes,
increased reflexes, nystagmus, irritability, suicidal ideation.
Respiratory: Epistaxis, bronchitis, dyspnea.
Skin and Appendages: Contact dermatitis, dry skin, sweating.
Special Senses: Vision abnormality.
Incidence in Controlled Adjunctive Trials in Pediatric Patients With Epilepsy: Table 11
lists adverse reactions that occurred in 339 pediatric patients with partial-onset seizures or
generalized seizures of Lennox-Gastaut syndrome who received LAMICTAL up to 15
mg/kg/day or a maximum of 750 mg/day.
Table 11. Adverse Reactions in Pooled, Placebo-Controlled Adjunctive Trials in Pediatric
Patients With Epilepsya
Body System/Adverse Reaction
Percent of Patients
Receiving LAMICTAL
(n = 168)
Percent of Patients
Receiving Placebo
(n = 171)
Body as a whole
Infection
20
17
Fever
15
14
Accidental injury
14
12
Abdominal pain
10
5
Asthenia
8
4
Flu syndrome
7
6
Pain
5
4
Facial edema
2
1
Photosensitivity
2
0
Cardiovascular
Hemorrhage
2
1
Digestive
Vomiting
20
16
Diarrhea
11
9
Nausea
10
2
Constipation
4
2
Dyspepsia
2
1
Hemic and lymphatic
Lymphadenopathy
2
1
Metabolic and nutritional
Edema
2
0
28
Reference ID: 3720577
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-045 & S-051
NDA 020764/S-038 & S-044
NDA 022251/S-007 & S-014
FDA Approved Labeling Text dated 3/24/2015
Nervous system
Somnolence
17
15
Dizziness
14
4
Ataxia
11
3
Tremor
10
1
Emotional lability
4
2
Gait abnormality
4
2
Thinking abnormality
3
2
Convulsions
2
1
Nervousness
2
1
Vertigo
2
1
Respiratory
Pharyngitis
14
11
Bronchitis
7
5
Increased cough
7
6
Sinusitis
2
1
Bronchospasm
2
1
Skin
Rash
14
12
Eczema
2
1
Pruritus
2
1
Special senses
Diplopia
5
1
Blurred vision
4
1
Visual abnormality
2
0
Urogenital
Male and female patients
Urinary tract infection
3
0
a Adverse reactions that occurred in at least 2% of patients treated with LAMICTAL and at a
greater incidence than placebo.
Bipolar Disorder
The most common adverse reactions seen in association with the use of LAMICTAL as
monotherapy (100 to 400 mg/day) in adult patients (aged 18 years and older) with bipolar
disorder in the 2 double-blind, placebo-controlled trials of 18 months’ duration are included in
Table 12. Adverse reactions that occurred in at least 5% of patients and were numerically more
frequent during the dose-escalation phase of LAMICTAL in these trials (when patients may have
been receiving concomitant medications) compared with the monotherapy phase were: headache
(25%), rash (11%), dizziness (10%), diarrhea (8%), dream abnormality (6%), and pruritus (6%).
29
Reference ID: 3720577
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-045 & S-051
NDA 020764/S-038 & S-044
NDA 022251/S-007 & S-014
FDA Approved Labeling Text dated 3/24/2015
During the monotherapy phase of the double-blind, placebo-controlled trials of 18 months’
duration, 13% of 227 patients who received LAMICTAL (100 to 400 mg/day), 16% of 190
patients who received placebo, and 23% of 166 patients who received lithium discontinued
therapy because of an adverse reaction. The adverse reactions which most commonly led to
discontinuation of LAMICTAL were rash (3%) and mania/hypomania/mixed mood adverse
reactions (2%). Approximately 16% of 2,401 patients who received LAMICTAL (50 to
500 mg/day) for bipolar disorder in premarketing trials discontinued therapy because of an
adverse reaction, most commonly due to rash (5%) and mania/hypomania/mixed mood adverse
reactions (2%).
The overall adverse reaction profile for LAMICTAL was similar between females and males,
between elderly and nonelderly patients, and among racial groups.
Table 12. Adverse Reactions in 2 Placebo-Controlled Trials in Adult Patients With Bipolar
I Disordera,b
Body System/
Adverse Reaction
Percent of Patients
Receiving LAMICTAL
(n = 227)
Percent of Patients
Receiving Placebo
(n = 190)
General
Back pain
Fatigue
Abdominal pain
8
8
6
6
5
3
Digestive
Nausea
Constipation
Vomiting
14
5
5
11
2
2
Nervous System
Insomnia
Somnolence
Xerostomia (dry mouth)
10
9
6
6
7
4
Respiratory
Rhinitis
Exacerbation of cough
Pharyngitis
7
5
5
4
3
4
Skin
Rash (nonserious)c
7
5
a Adverse reactions that occurred in at least 5% of patients treated with LAMICTAL and at a
greater incidence than placebo.
b Patients in these trials were converted to LAMICTAL (100 to 400 mg/day) or placebo
monotherapy from add-on therapy with other psychotropic medications. Patients may have
reported multiple adverse reactions during the trial; thus, patients may be included in more
30
Reference ID: 3720577
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-045 & S-051
NDA 020764/S-038 & S-044
NDA 022251/S-007 & S-014
FDA Approved Labeling Text dated 3/24/2015
than 1 category.
c In the overall bipolar and other mood disorders clinical trials, the rate of serious rash was
0.08% (1 of 1,233) of adult patients who received LAMICTAL as initial monotherapy and
0.13% (2 of 1,538) of adult patients who received LAMICTAL as adjunctive therapy [see
Warnings and Precautions (5.1)].
Other reactions that occurred in 5% or more patients but equally or more frequently in the
placebo group included: dizziness, mania, headache, infection, influenza, pain, accidental injury,
diarrhea, and dyspepsia.
Adverse reactions that occurred with a frequency of less than 5% and greater than 1% of patients
receiving LAMICTAL and numerically more frequent than placebo were:
General: Fever, neck pain.
Cardiovascular: Migraine.
Digestive: Flatulence.
Metabolic and Nutritional: Weight gain, edema.
Musculoskeletal: Arthralgia, myalgia.
Nervous System: Amnesia, depression, agitation, emotional lability, dyspraxia, abnormal
thoughts, dream abnormality, hypoesthesia.
Respiratory: Sinusitis.
Urogenital: Urinary frequency.
Adverse Reactions Following Abrupt Discontinuation: In the 2 maintenance trials, there was no
increase in the incidence, severity, or type of adverse reactions in patients with bipolar disorder
after abruptly terminating therapy with LAMICTAL. In clinical trials in patients with bipolar
disorder, 2 patients experienced seizures shortly after abrupt withdrawal of LAMICTAL.
However, there were confounding factors that may have contributed to the occurrence of seizures
in these patients with bipolar disorder [see Warnings and Precautions (5.9)].
Mania/Hypomania/Mixed Episodes: During the double-blind, placebo-controlled clinical trials in
bipolar I disorder in which patients were converted to monotherapy with LAMICTAL (100 to
400 mg/day) from other psychotropic medications and followed for up to 18 months, the rates of
manic or hypomanic or mixed mood episodes reported as adverse reactions were 5% for patients
treated with LAMICTAL (n = 227), 4% for patients treated with lithium (n = 166), and 7% for
patients treated with placebo (n = 190). In all bipolar controlled trials combined, adverse
reactions of mania (including hypomania and mixed mood episodes) were reported in 5% of
patients treated with LAMICTAL (n = 956), 3% of patients treated with lithium (n = 280), and
4% of patients treated with placebo (n = 803).
6.2
Other Adverse Reactions Observed in All Clinical Trials
31
Reference ID: 3720577
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NDA 020241/S-045 & S-051
NDA 020764/S-038 & S-044
NDA 022251/S-007 & S-014
FDA Approved Labeling Text dated 3/24/2015
LAMICTAL has been administered to 6,694 individuals for whom complete adverse reaction
data was captured during all clinical trials, only some of which were placebo controlled. During
these trials, all adverse reactions were recorded by the clinical investigators using terminology of
their own choosing. To provide a meaningful estimate of the proportion of individuals having
adverse reactions, similar types of adverse reactions were grouped into a smaller number of
standardized categories using modified COSTART dictionary terminology. The frequencies
presented represent the proportion of the 6,694 individuals exposed to LAMICTAL who
experienced an event of the type cited on at least 1 occasion while receiving LAMICTAL. All
reported adverse reactions are included except those already listed in the previous tables or
elsewhere in the labeling, those too general to be informative, and those not reasonably
associated with the use of the drug.
Adverse reactions are further classified within body system categories and enumerated in order
of decreasing frequency using the following definitions: frequent adverse reactions are defined as
those occurring in at least 1/100 patients; infrequent adverse reactions are those occurring in
1/100 to 1/1,000 patients; rare adverse reactions are those occurring in fewer than 1/1,000
patients.
Body as a Whole
Infrequent: Allergic reaction, chills, malaise.
Cardiovascular System
Infrequent: Flushing, hot flashes, hypertension, palpitations, postural hypotension, syncope,
tachycardia, vasodilation.
Dermatological
Infrequent: Acne, alopecia, hirsutism, maculopapular rash, skin discoloration, urticaria.
Rare: Angioedema, erythema, exfoliative dermatitis, fungal dermatitis, herpes zoster,
leukoderma, multiforme erythema, petechial rash, pustular rash, Stevens-Johnson syndrome,
vesiculobullous rash.
Digestive System
Infrequent: Dysphagia, eructation, gastritis, gingivitis, increased appetite, increased salivation,
liver function tests abnormal, mouth ulceration.
Rare: Gastrointestinal hemorrhage, glossitis, gum hemorrhage, gum hyperplasia, hematemesis,
hemorrhagic colitis, hepatitis, melena, stomach ulcer, stomatitis, tongue edema.
Endocrine System
Rare: Goiter, hypothyroidism.
Hematologic and Lymphatic System
32
Reference ID: 3720577
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-045 & S-051
NDA 020764/S-038 & S-044
NDA 022251/S-007 & S-014
FDA Approved Labeling Text dated 3/24/2015
Infrequent: Ecchymosis, leukopenia.
Rare: Anemia, eosinophilia, fibrin decrease, fibrinogen decrease, iron deficiency anemia,
leukocytosis, lymphocytosis, macrocytic anemia, petechia, thrombocytopenia.
Metabolic and Nutritional Disorders
Infrequent: Aspartate transaminase increased.
Rare: Alcohol intolerance, alkaline phosphatase increase, alanine transaminase increase,
bilirubinemia, general edema, gamma glutamyl transpeptidase increase, hyperglycemia.
Musculoskeletal System
Infrequent: Arthritis, leg cramps, myasthenia, twitching.
Rare: Bursitis, muscle atrophy, pathological fracture, tendinous contracture.
Nervous System
Frequent: Confusion, paresthesia.
Infrequent: Akathisia, apathy, aphasia, central nervous system depression, depersonalization,
dysarthria, dyskinesia, euphoria, hallucinations, hostility, hyperkinesia, hypertonia, libido
decreased, memory decrease, mind racing, movement disorder, myoclonus, panic attack,
paranoid reaction, personality disorder, psychosis, sleep disorder, stupor, suicidal ideation.
Rare: Choreoathetosis, delirium, delusions, dysphoria, dystonia, extrapyramidal syndrome,
faintness, grand mal convulsions, hemiplegia, hyperalgesia, hyperesthesia, hypokinesia,
hypotonia, manic depression reaction, muscle spasm, neuralgia, neurosis, paralysis, peripheral
neuritis.
Respiratory System
Infrequent: Yawn.
Rare: Hiccup, hyperventilation.
Special Senses
Frequent: Amblyopia.
Infrequent: Abnormality of accommodation, conjunctivitis, dry eyes, ear pain, photophobia, taste
perversion, tinnitus.
Rare: Deafness, lacrimation disorder, oscillopsia, parosmia, ptosis, strabismus, taste loss, uveitis,
visual field defect.
Urogenital System
Infrequent: Abnormal ejaculation, hematuria, impotence, menorrhagia, polyuria, urinary
incontinence.
33
Reference ID: 3720577
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-045 & S-051
NDA 020764/S-038 & S-044
NDA 022251/S-007 & S-014
FDA Approved Labeling Text dated 3/24/2015
Rare: Acute kidney failure, anorgasmia, breast abscess, breast neoplasm, creatinine increase,
cystitis, dysuria, epididymitis, female lactation, kidney failure, kidney pain, nocturia, urinary
retention, urinary urgency.
6.3
Postmarketing Experience
The following adverse events (not listed above in clinical trials or other sections of the
prescribing information) have been identified during postapproval use of LAMICTAL. Because
these events are reported voluntarily from a population of uncertain size, it is not always possible
to reliably estimate their frequency or establish a causal relationship to drug exposure.
Blood and Lymphatic
Agranulocytosis, hemolytic anemia, lymphadenopathy not associated with hypersensitivity
disorder.
Gastrointestinal
Esophagitis.
Hepatobiliary Tract and Pancreas
Pancreatitis.
Immunologic
Lupus-like reaction, vasculitis.
Lower Respiratory
Apnea.
Musculoskeletal
Rhabdomyolysis has been observed in patients experiencing hypersensitivity reactions.
Nervous System
Aggression, exacerbation of Parkinsonian symptoms in patients with pre-existing Parkinson’s
disease, tics.
Non-site Specific
Progressive immunosuppression.
7
DRUG INTERACTIONS
Significant drug interactions with LAMICTAL are summarized in this section. Additional details
of these drug interaction studies are provided in the Clinical Pharmacology section [see Clinical
Pharmacology (12.3)].
34
Reference ID: 3720577
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-045 & S-051
NDA 020764/S-038 & S-044
NDA 022251/S-007 & S-014
FDA Approved Labeling Text dated 3/24/2015
Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug
Effect on
Concentration of
Lamotrigine or
Concomitant Drug
Clinical Comment
Estrogen-containing oral
contraceptive
preparations containing
30 mcg ethinylestradiol
and 150 mcg
levonorgestrel
↓ lamotrigine
↓ levonorgestrel
Decreased lamotrigine concentrations
approximately 50%.
Decrease in levonorgestrel component by
19%.
Carbamazepine and
carbamazepine epoxide
↓ lamotrigine
? carbamazepine
epoxide
Addition of carbamazepine decreases
lamotrigine concentration approximately
40%.
May increase carbamazepine epoxide
levels.
Lopinavir/ritonavir
↓ lamotrigine
Decreased lamotrigine concentration
approximately 50%.
Atazanavir/ritonavir
↓ lamotrigine
Decreased lamotrigine AUC
approximately 32%.
Phenobarbital/primidone
↓ lamotrigine
Decreased lamotrigine concentration
approximately 40%.
Phenytoin
↓ lamotrigine
Decreased lamotrigine concentration
approximately 40%.
Rifampin
↓ lamotrigine
Decreased lamotrigine AUC
approximately 40%.
Valproate
↑ lamotrigine
? valproate
Increased lamotrigine concentrations
slightly more than 2-fold.
There are conflicting study results
regarding effect of lamotrigine on
valproate concentrations: 1) a mean 25%
decrease in valproate concentrations in
healthy volunteers, 2) no change in
valproate concentrations in controlled
clinical trials in patients with epilepsy.
↓ = Decreased (induces lamotrigine glucuronidation).
↑ = Increased (inhibits lamotrigine glucuronidation).
? = Conflicting data.
35
Reference ID: 3720577
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For current labeling information, please visit https://www.fda.gov/drugsatfda
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NDA 020764/S-038 & S-044
NDA 022251/S-007 & S-014
FDA Approved Labeling Text dated 3/24/2015
Effect of LAMICTAL on Organic Cationic Transporter 2 Substrates
Lamotrigine is an inhibitor of renal tubular secretion via organic cationic transporter 2 (OCT2)
proteins [see Clinical Pharmacology (12.3)]. This may result in increased plasma levels of
certain drugs that are substantially excreted via this route. Coadministration of LAMICTAL with
OCT2 substrates with a narrow therapeutic index (e.g., dofetilide) is not recommended.
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
As with other AEDs, physiological changes during pregnancy may affect lamotrigine
concentrations and/or therapeutic effect. There have been reports of decreased lamotrigine
concentrations during pregnancy and restoration of pre-partum concentrations after delivery.
Dosage adjustments may be necessary to maintain clinical response.
Pregnancy Category C
There are no adequate and well-controlled studies in pregnant women. In animal studies,
lamotrigine was developmentally toxic at doses lower than those administered clinically.
LAMICTAL should be used during pregnancy only if the potential benefit justifies the potential
risk to the fetus. When lamotrigine was administered to pregnant mice, rats, or rabbits during the
period of organogenesis (oral doses of up to 125, 25, and 30 mg/kg, respectively), reduced fetal
body weight and increased incidences of fetal skeletal variations were seen in mice and rats at
doses that were also maternally toxic. The no-effect doses for embryofetal developmental
toxicity in mice, rats, and rabbits (75, 6.25, and 30 mg/kg, respectively) are similar to (mice and
rabbits) or less than (rats) the human dose of 400 mg/day on a body surface area (mg/m2) basis.
In a study in which pregnant rats were administered lamotrigine (oral doses of 5 or 25 mg/kg)
during the period of organogenesis and offspring were evaluated postnatally, behavioral
abnormalities were observed in exposed offspring at both doses. The lowest effect dose for
developmental neurotoxicity in rats is less than the human dose of 400 mg/day on a mg/m2 basis.
Maternal toxicity was observed at the higher dose tested.
When pregnant rats were administered lamotrigine (oral doses of 5, 10, or 20 mg/kg) during the
latter part of gestation, increased offspring mortality (including stillbirths) was seen at all doses.
The lowest effect dose for peri/postnatal developmental toxicity in rats is less than the human
dose of 400 mg/day on a mg/m2 basis. Maternal toxicity was observed at the 2 highest doses
tested.
Lamotrigine decreases fetal folate concentrations in rat, an effect known to be associated with
adverse pregnancy outcomes in animals and humans.
Pregnancy Registry
36
Reference ID: 3720577
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-045 & S-051
NDA 020764/S-038 & S-044
NDA 022251/S-007 & S-014
FDA Approved Labeling Text dated 3/24/2015
To provide information regarding the effects of in utero exposure to LAMICTAL, physicians are
advised to recommend that pregnant patients taking LAMICTAL enroll in the North American
Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll-free
number 1-888-233-2334 and must be done by patients themselves. Information on the registry
can also be found at the website http://www.aedpregnancyregistry.org.
8.2
Labor and Delivery
The effect of LAMICTAL on labor and delivery in humans is unknown.
8.3
Nursing Mothers
Lamotrigine is present in milk from lactating women taking LAMICTAL. Data from multiple
small studies indicate that lamotrigine plasma levels in human milk-fed infants have been
reported to be as high as 50% of the maternal serum levels. Neonates and young infants are at
risk for high serum levels because maternal serum and milk levels can rise to high levels
postpartum if lamotrigine dosage has been increased during pregnancy but not later reduced to
the pre-pregnancy dosage. Lamotrigine exposure is further increased due to the immaturity of the
infant glucuronidation capacity needed for drug clearance. Events including apnea, drowsiness,
and poor sucking have been reported in infants who have been human milk-fed by mothers using
lamotrigine; whether or not these events were caused by lamotrigine is unknown. Human milk-
fed infants should be closely monitored for adverse events resulting from lamotrigine.
Measurement of infant serum levels should be performed to rule out toxicity if concerns arise.
Human milk-feeding should be discontinued in infants with lamotrigine toxicity. Caution should
be exercised when LAMICTAL is administered to a nursing woman.
8.4
Pediatric Use
LAMICTAL is indicated for adjunctive therapy in patients aged 2 years and older for partial-
onset seizures, the generalized seizures of Lennox-Gastaut syndrome, and PGTC seizures.
Safety and efficacy of LAMICTAL used as adjunctive treatment for partial-onset seizures were
not demonstrated in a small, randomized, double-blind, placebo-controlled withdrawal trial in
very young pediatric patients (aged 1 to 24 months). LAMICTAL was associated with an
increased risk for infectious adverse reactions (LAMICTAL 37%, placebo 5%), and respiratory
adverse reactions (LAMICTAL 26%, placebo 5%). Infectious adverse reactions included
bronchiolitis, bronchitis, ear infection, eye infection, otitis externa, pharyngitis, urinary tract
infection, and viral infection. Respiratory adverse reactions included nasal congestion, cough,
and apnea.
Safety and effectiveness in patients younger than 18 years with bipolar disorder have not been
established.
In a juvenile animal study in which lamotrigine (oral doses of 5, 15, or 30 mg/kg) was
administered to young rats (postnatal days 7 to 62), decreased viability and growth were seen at
the highest dose tested and long-term behavioral abnormalities (decreased locomotor activity,
37
Reference ID: 3720577
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-045 & S-051
NDA 020764/S-038 & S-044
NDA 022251/S-007 & S-014
FDA Approved Labeling Text dated 3/24/2015
increased reactivity, and learning deficits in animals tested as adults) were observed at the 2
highest doses. The no-effect dose for adverse effects on neurobehavioral development is less
than the human dose of 400 mg/day on a mg/m2 basis.
8.5
Geriatric Use
Clinical trials of LAMICTAL for epilepsy and bipolar disorder did not include sufficient
numbers of patients aged 65 years and older to determine whether they respond differently from
younger patients or exhibit a different safety profile than that of younger patients. In general,
dose selection for an elderly patient should be cautious, usually starting at the low end of the
dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and
of concomitant disease or other drug therapy.
8.6
Hepatic Impairment
Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology
study in 24 subjects with mild, moderate, and severe liver impairment [see Clinical
Pharmacology (12.3)], the following general recommendations can be made. No dosage
adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance
doses should generally be reduced by approximately 25% in patients with moderate and severe
liver impairment without ascites and 50% in patients with severe liver impairment with ascites.
Escalation and maintenance doses may be adjusted according to clinical response [see Dosage
and Administration (2.1)].
8.7
Renal Impairment
Lamotrigine is metabolized mainly by glucuronic acid conjugation, with the majority of the
metabolites being recovered in the urine. In a small study comparing a single dose of lamotrigine
in subjects with varying degrees of renal impairment with healthy volunteers, the plasma half-life
of lamotrigine was approximately twice as long in the subjects with chronic renal failure [see
Clinical Pharmacology (12.3)].
Initial doses of LAMICTAL should be based on patients’ AED regimens; reduced maintenance
doses may be effective for patients with significant renal impairment. Few patients with severe
renal impairment have been evaluated during chronic treatment with lamotrigine. Because there
is inadequate experience in this population, LAMICTAL should be used with caution in these
patients [see Dosage and Administration (2.1)].
10
OVERDOSAGE
10.1
Human Overdose Experience
Overdoses involving quantities up to 15 g have been reported for LAMICTAL, some of which
have been fatal. Overdose has resulted in ataxia, nystagmus, seizures (including tonic-clonic
seizures), decreased level of consciousness, coma, and intraventricular conduction delay.
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10.2
Management of Overdose
There are no specific antidotes for lamotrigine. Following a suspected overdose, hospitalization
of the patient is advised. General supportive care is indicated, including frequent monitoring of
vital signs and close observation of the patient. If indicated, emesis should be induced; usual
precautions should be taken to protect the airway. It should be kept in mind that immediate-
release lamotrigine is rapidly absorbed [see Clinical Pharmacology (12.3)]. It is uncertain
whether hemodialysis is an effective means of removing lamotrigine from the blood. In 6 renal
failure patients, about 20% of the amount of lamotrigine in the body was removed by
hemodialysis during a 4-hour session. A Poison Control Center should be contacted for
information on the management of overdosage of LAMICTAL.
11
DESCRIPTION
LAMICTAL (lamotrigine), an AED of the phenyltriazine class, is chemically unrelated to
existing AEDs. Lamotrigine’s chemical name is 3,5-diamino-6-(2,3-dichlorophenyl)-as-triazine,
its molecular formula is C9H7N5Cl2, and its molecular weight is 256.09. Lamotrigine is a white to
pale cream-colored powder and has a pKa of 5.7. Lamotrigine is very slightly soluble in water
(0.17 mg/mL at 25°C) and slightly soluble in 0.1 M HCl (4.1 mg/mL at 25°C). The structural
formula is:
LAMICTAL tablets are supplied for oral administration as 25-mg (white), 100-mg (peach), 150-
mg (cream), and 200-mg (blue) tablets. Each tablet contains the labeled amount of lamotrigine
and the following inactive ingredients: lactose; magnesium stearate; microcrystalline cellulose;
povidone; sodium starch glycolate; FD&C Yellow No. 6 Lake (100-mg tablet only); ferric oxide,
yellow (150-mg tablet only); and FD&C Blue No. 2 Lake (200-mg tablet only).
LAMICTAL chewable dispersible tablets are supplied for oral administration. The tablets
contain 2 mg (white), 5 mg (white), or 25 mg (white) of lamotrigine and the following inactive
ingredients: blackcurrant flavor, calcium carbonate, low-substituted hydroxypropylcellulose,
magnesium aluminum silicate, magnesium stearate, povidone, saccharin sodium, and sodium
starch glycolate. The chewable dispersible tablets meet Organic Impurities Procedure 2 as
published in the current USP monograph for Lamotrigine Tablets for Oral Suspension.
LAMICTAL ODT orally disintegrating tablets are supplied for oral administration. The tablets
contain 25 mg (white to off-white), 50 mg (white to off-white), 100 mg (white to off-white), or
200 mg (white to off-white) of lamotrigine and the following inactive ingredients: artificial
cherry flavor, crospovidone, ethylcellulose, magnesium stearate, mannitol, polyethylene, and
sucralose.
39
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LAMICTAL ODT orally disintegrating tablets are formulated using technologies (Microcaps®
and AdvaTab®) designed to mask the bitter taste of lamotrigine and achieve a rapid dissolution
profile. Tablet characteristics including flavor, mouth-feel, after-taste, and ease of use were rated
as favorable in a study in 108 healthy volunteers.
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
The precise mechanism(s) by which lamotrigine exerts its anticonvulsant action are unknown. In
animal models designed to detect anticonvulsant activity, lamotrigine was effective in preventing
seizure spread in the maximum electroshock (MES) and pentylenetetrazol (scMet) tests, and
prevented seizures in the visually and electrically evoked after-discharge (EEAD) tests for
antiepileptic activity. Lamotrigine also displayed inhibitory properties in the kindling model in
rats both during kindling development and in the fully kindled state. The relevance of these
models to human epilepsy, however, is not known.
One proposed mechanism of action of lamotrigine, the relevance of which remains to be
established in humans, involves an effect on sodium channels. In vitro pharmacological studies
suggest that lamotrigine inhibits voltage-sensitive sodium channels, thereby stabilizing neuronal
membranes and consequently modulating presynaptic transmitter release of excitatory amino
acids (e.g., glutamate and aspartate).
Effect of Lamotrigine on N-Methyl d-Aspartate-Receptor Mediated Activity
Lamotrigine did not inhibit N-methyl d-aspartate (NMDA)-induced depolarizations in rat cortical
slices or NMDA-induced cyclic GMP formation in immature rat cerebellum, nor did lamotrigine
displace compounds that are either competitive or noncompetitive ligands at this glutamate
receptor complex (CNQX, CGS, TCHP). The IC50 for lamotrigine effects on NMDA-induced
currents (in the presence of 3 µM of glycine) in cultured hippocampal neurons exceeded 100
µM.
The mechanisms by which lamotrigine exerts its therapeutic action in bipolar disorder have not
been established.
12.2
Pharmacodynamics
Folate Metabolism
In vitro, lamotrigine inhibited dihydrofolate reductase, the enzyme that catalyzes the reduction of
dihydrofolate to tetrahydrofolate. Inhibition of this enzyme may interfere with the biosynthesis
of nucleic acids and proteins. When oral daily doses of lamotrigine were given to pregnant rats
during organogenesis, fetal, placental, and maternal folate concentrations were reduced.
Significantly reduced concentrations of folate are associated with teratogenesis [see Use in
Specific Populations (8.1)]. Folate concentrations were also reduced in male rats given repeated
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oral doses of lamotrigine. Reduced concentrations were partially returned to normal when
supplemented with folinic acid.
Accumulation in Kidneys
Lamotrigine accumulated in the kidney of the male rat, causing chronic progressive nephrosis,
necrosis, and mineralization. These findings are attributed to α-2 microglobulin, a species- and
sex-specific protein that has not been detected in humans or other animal species.
Melanin Binding
Lamotrigine binds to melanin-containing tissues, e.g., in the eye and pigmented skin. It has been
found in the uveal tract up to 52 weeks after a single dose in rodents.
Cardiovascular
In dogs, lamotrigine is extensively metabolized to a 2-N-methyl metabolite. This metabolite
causes dose-dependent prolongation of the PR interval, widening of the QRS complex, and, at
higher doses, complete AV conduction block. Similar cardiovascular effects are not anticipated
in humans because only trace amounts of the 2-N-methyl metabolite (<0.6% of lamotrigine dose)
have been found in human urine [see Clinical Pharmacology (12.3)]. However, it is conceivable
that plasma concentrations of this metabolite could be increased in patients with a reduced
capacity to glucuronidate lamotrigine (e.g., in patients with liver disease, patients taking
concomitant medications that inhibit glucuronidation).
12.3
Pharmacokinetics
The pharmacokinetics of lamotrigine have been studied in subjects with epilepsy, healthy young
and elderly volunteers, and volunteers with chronic renal failure. Lamotrigine pharmacokinetic
parameters for adult and pediatric subjects and healthy normal volunteers are summarized in
Tables 14 and 16.
Table 14. Mean Pharmacokinetic Parametersa in Healthy Volunteers and Adult Subjects
With Epilepsy
Adult Study Population
Number
of
Subjects
Tmax: Time of
Maximum
Plasma
Concentration
(h)
t½:
Elimination
Half-life
(h)
CL/F:
Apparent
Plasma
Clearance
(mL/min/kg)
Healthy volunteers taking no
other medications:
Single-dose LAMICTAL
Multiple-dose LAMICTAL
179
36
2.2
(0.25-12.0)
1.7
(0.5-4.0)
32.8
(14.0-103.0)
25.4
(11.6-61.6)
0.44
(0.12-1.10)
0.58
(0.24-1.15)
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Healthy volunteers taking
valproate:
Single-dose LAMICTAL
Multiple-dose LAMICTAL
6
18
1.8
(1.0-4.0)
1.9
(0.5-3.5)
48.3
(31.5-88.6)
70.3
(41.9-113.5)
0.30
(0.14-0.42)
0.18
(0.12-0.33)
Subjects with epilepsy taking
valproate only:
Single-dose LAMICTAL
4
4.8
(1.8-8.4)
58.8
(30.5-88.8)
0.28
(0.16-0.40)
Subjects with epilepsy taking
carbamazepine, phenytoin,
phenobarbital, or primidoneb
plus valproate:
Single-dose LAMICTAL
25
3.8
(1.0-10.0)
27.2
(11.2-51.6)
0.53
(0.27-1.04)
Subjects with epilepsy taking
carbamazepine, phenytoin,
phenobarbital, or primidone:b
Single-dose LAMICTAL
Multiple-dose LAMICTAL
24
17
2.3
(0.5-5.0)
2.0
(0.75-5.93)
14.4
(6.4-30.4)
12.6
(7.5-23.1)
1.10
(0.51-2.22)
1.21
(0.66-1.82)
a The majority of parameter means determined in each study had coefficients of variation
between 20% and 40% for half-life and CL/F and between 30% and 70% for Tmax. The overall
mean values were calculated from individual study means that were weighted based on the
number of volunteers/subjects in each study. The numbers in parentheses below each
parameter mean represent the range of individual volunteer/subject values across studies.
b Carbamazepine, phenytoin, phenobarbital, and primidone have been shown to increase the
apparent clearance of lamotrigine. Estrogen-containing oral contraceptives and other drugs,
such as rifampin and protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir, that
induce lamotrigine glucuronidation have also been shown to increase the apparent clearance
of lamotrigine [see Drug Interactions (7)].
Absorption
Lamotrigine is rapidly and completely absorbed after oral administration with negligible first-
pass metabolism (absolute bioavailability is 98%). The bioavailability is not affected by food.
Peak plasma concentrations occur anywhere from 1.4 to 4.8 hours following drug administration.
The lamotrigine chewable/dispersible tablets were found to be equivalent whether administered
as dispersed in water, chewed and swallowed, or swallowed as whole, to the lamotrigine
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compressed tablets in terms of rate and extent of absorption. In terms of rate and extent of
absorption, lamotrigine orally disintegrating tablets whether disintegrated in the mouth or
swallowed whole with water were equivalent to the lamotrigine compressed tablets swallowed
with water.
Dose Proportionality
In healthy volunteers not receiving any other medications and given single doses, the plasma
concentrations of lamotrigine increased in direct proportion to the dose administered over the
range of 50 to 400 mg. In 2 small studies (n = 7 and 8) of patients with epilepsy who were
maintained on other AEDs, there also was a linear relationship between dose and lamotrigine
plasma concentrations at steady state following doses of 50 to 350 mg twice daily.
Distribution
Estimates of the mean apparent volume of distribution (Vd/F) of lamotrigine following oral
administration ranged from 0.9 to 1.3 L/kg. Vd/F is independent of dose and is similar following
single and multiple doses in both patients with epilepsy and in healthy volunteers.
Protein Binding
Data from in vitro studies indicate that lamotrigine is approximately 55% bound to human
plasma proteins at plasma lamotrigine concentrations from 1 to 10 mcg/mL (10 mcg/mL is 4 to 6
times the trough plasma concentration observed in the controlled efficacy trials). Because
lamotrigine is not highly bound to plasma proteins, clinically significant interactions with other
drugs through competition for protein binding sites are unlikely. The binding of lamotrigine to
plasma proteins did not change in the presence of therapeutic concentrations of phenytoin,
phenobarbital, or valproate. Lamotrigine did not displace other AEDs (carbamazepine,
phenytoin, phenobarbital) from protein-binding sites.
Metabolism
Lamotrigine is metabolized predominantly by glucuronic acid conjugation; the major metabolite
is an inactive 2-N-glucuronide conjugate. After oral administration of 240 mg of 14C-lamotrigine
(15 µCi) to 6 healthy volunteers, 94% was recovered in the urine and 2% was recovered in the
feces. The radioactivity in the urine consisted of unchanged lamotrigine (10%), the 2-N-
glucuronide (76%), a 5-N-glucuronide (10%), a 2-N-methyl metabolite (0.14%), and other
unidentified minor metabolites (4%).
Enzyme Induction
The effects of lamotrigine on the induction of specific families of mixed-function oxidase
isozymes have not been systematically evaluated.
Following multiple administrations (150 mg twice daily) to normal volunteers taking no other
medications, lamotrigine induced its own metabolism, resulting in a 25% decrease in t½ and a
37% increase in CL/F at steady state compared with values obtained in the same volunteers
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following a single dose. Evidence gathered from other sources suggests that self-induction by
lamotrigine may not occur when lamotrigine is given as adjunctive therapy in patients receiving
enzyme-inducing drugs such as carbamazepine, phenytoin, phenobarbital, primidone, or other
drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir
that induce lamotrigine glucuronidation [see Drug Interactions (7)].
Elimination
The elimination half-life and apparent clearance of lamotrigine following oral administration of
LAMICTAL to adult subjects with epilepsy and healthy volunteers is summarized in Table 14.
Half-life and apparent oral clearance vary depending on concomitant AEDs.
Drug Interactions
The apparent clearance of lamotrigine is affected by the coadministration of certain medications
[see Warnings and Precautions (5.8, 5.12), Drug Interactions (7)].
The net effects of drug interactions with lamotrigine are summarized in Tables 13 and 15,
followed by details of the drug interaction studies below.
Table 15. Summary of Drug Interactions With Lamotrigine
Drug
Drug Plasma
Concentration With
Adjunctive Lamotriginea
Lamotrigine Plasma
Concentration With
Adjunctive Drugsb
Oral contraceptives (e.g.,
ethinylestradiol/levonorgestrel)c
Aripiprazole
Atazanavir/ritonavir
Bupropion
Carbamazepine
Carbamazepine epoxideg
Felbamate
Gabapentin
Levetiracetam
Lithium
Lopinavir/ritonavir
Olanzapine
Oxcarbazepine
10-Monohydroxy oxcarbazepine
metaboliteh
Phenobarbital/primidone
Phenytoin
Pregabalin
↔d
Not assessed
↔f
Not assessed
↔
?
Not assessed
Not assessed
↔
↔
↔e
↔
↔
↔
↔
↔
↔
↓
↔e
↓
↔
↓
↔
↔
↔
Not assessed
↓
↔e
↔
↓
↓
↔
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Rifampin
Risperidone
9-hydroxyrisperidonei
Topiramate
Valproate
Valproate + phenytoin and/or
carbamazepine
Zonisamide
Not assessed
↔
↔
↔j
↓
Not assessed
Not assessed
↓
Not assessed
↔
↑
↔
↔
a From adjunctive clinical trials and volunteer trials.
b Net effects were estimated by comparing the mean clearance values obtained in adjunctive
clinical trials and volunteer trials.
c The effect of other hormonal contraceptive preparations or hormone replacement therapy on
the pharmacokinetics of lamotrigine has not been systematically evaluated in clinical trials,
although the effect may be similar to that seen with the ethinylestradiol/levonorgestrel
combinations.
d Modest decrease in levonorgestrel.
e Slight decrease, not expected to be clinically meaningful.
f Compared to historical controls.
g Not administered, but an active metabolite of carbamazepine.
h Not administered, but an active metabolite of oxcarbazepine.
i Not administered, but an active metabolite of risperidone.
j Slight increase, not expected to be clinically meaningful.
↔ = No significant effect.
? = Conflicting data.
Estrogen-Containing Oral Contraceptives
In 16 female volunteers, an oral contraceptive preparation containing 30 mcg ethinylestradiol
and 150 mcg levonorgestrel increased the apparent clearance of lamotrigine (300 mg/day) by
approximately 2-fold with mean decreases in AUC of 52% and in Cmax of 39%. In this study,
trough serum lamotrigine concentrations gradually increased and were approximately 2-fold
higher on average at the end of the week of the inactive hormone preparation compared with
trough lamotrigine concentrations at the end of the active hormone cycle.
Gradual transient increases in lamotrigine plasma levels (approximate 2-fold increase) occurred
during the week of inactive hormone preparation (pill-free week) for women not also taking a
drug that increased the clearance of lamotrigine (carbamazepine, phenytoin, phenobarbital,
primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and
atazanavir/ritonavir that induce lamotrigine glucuronidation) [see Drug Interactions (7)]. The
increase in lamotrigine plasma levels will be greater if the dose of LAMICTAL is increased in
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the few days before or during the pill-free week. Increases in lamotrigine plasma levels could
result in dose-dependent adverse reactions.
In the same study, coadministration of lamotrigine (300 mg/day) in 16 female volunteers did not
affect the pharmacokinetics of the ethinylestradiol component of the oral contraceptive
preparation. There were mean decreases in the AUC and Cmax of the levonorgestrel component of
19% and 12%, respectively. Measurement of serum progesterone indicated that there was no
hormonal evidence of ovulation in any of the 16 volunteers, although measurement of serum
FSH, LH, and estradiol indicated that there was some loss of suppression of the hypothalamic-
pituitary-ovarian axis.
The effects of doses of lamotrigine other than 300 mg/day have not been systematically
evaluated in controlled clinical trials.
The clinical significance of the observed hormonal changes on ovulatory activity is unknown.
However, the possibility of decreased contraceptive efficacy in some patients cannot be
excluded. Therefore, patients should be instructed to promptly report changes in their menstrual
pattern (e.g., break-through bleeding).
Dosage adjustments may be necessary for women receiving estrogen-containing oral
contraceptive preparations [see Dosage and Administration (2.1)].
Other Hormonal Contraceptives or Hormone Replacement Therapy
The effect of other hormonal contraceptive preparations or hormone replacement therapy on the
pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that
ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the
progestin-only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the
dosage of LAMICTAL in the presence of progestogens alone will likely not be needed.
Aripiprazole
In 18 patients with bipolar disorder on a stable regimen of 100 to 400 mg/day of lamotrigine, the
lamotrigine AUC and Cmax were reduced by approximately 10% in patients who received
aripiprazole 10 to 30 mg/day for 7 days, followed by 30 mg/day for an additional 7 days. This
reduction in lamotrigine exposure is not considered clinically meaningful.
Atazanavir/Ritonavir
In a study in healthy volunteers, daily doses of atazanavir/ritonavir (300 mg/100 mg) reduced the
plasma AUC and Cmax of lamotrigine (single 100-mg dose) by an average of 32% and 6%,
respectively, and shortened the elimination half-lives by 27%. In the presence of
atazanavir/ritonavir (300 mg/100 mg), the metabolite-to-lamotrigine ratio was increased from
0.45 to 0.71 consistent with induction of glucuronidation. The pharmacokinetics of
atazanavir/ritonavir were similar in the presence of concomitant lamotrigine to the historical data
of the pharmacokinetics in the absence of lamotrigine.
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Bupropion
The pharmacokinetics of a 100-mg single dose of lamotrigine in healthy volunteers (n = 12) were
not changed by coadministration of bupropion sustained-release formulation (150 mg twice
daily) starting 11 days before lamotrigine.
Carbamazepine
Lamotrigine has no appreciable effect on steady-state carbamazepine plasma concentration.
Limited clinical data suggest there is a higher incidence of dizziness, diplopia, ataxia, and
blurred vision in patients receiving carbamazepine with lamotrigine than in patients receiving
other AEDs with lamotrigine [see Adverse Reactions (6.1)]. The mechanism of this interaction is
unclear. The effect of lamotrigine on plasma concentrations of carbamazepine-epoxide is
unclear. In a small subset of patients (n = 7) studied in a placebo-controlled trial, lamotrigine had
no effect on carbamazepine-epoxide plasma concentrations, but in a small, uncontrolled study
(n = 9), carbamazepine-epoxide levels increased.
The addition of carbamazepine decreases lamotrigine steady-state concentrations by
approximately 40%.
Felbamate
In a trial in 21 healthy volunteers, coadministration of felbamate (1,200 mg twice daily) with
lamotrigine (100 mg twice daily for 10 days) appeared to have no clinically relevant effects on
the pharmacokinetics of lamotrigine.
Folate Inhibitors
Lamotrigine is a weak inhibitor of dihydrofolate reductase. Prescribers should be aware of this
action when prescribing other medications that inhibit folate metabolism.
Gabapentin
Based on a retrospective analysis of plasma levels in 34 subjects who received lamotrigine both
with and without gabapentin, gabapentin does not appear to change the apparent clearance of
lamotrigine.
Levetiracetam
Potential drug interactions between levetiracetam and lamotrigine were assessed by evaluating
serum concentrations of both agents during placebo-controlled clinical trials. These data indicate
that lamotrigine does not influence the pharmacokinetics of levetiracetam and that levetiracetam
does not influence the pharmacokinetics of lamotrigine.
Lithium
The pharmacokinetics of lithium were not altered in healthy subjects (n = 20) by
coadministration of lamotrigine (100 mg/day) for 6 days.
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Lopinavir/Ritonavir
The addition of lopinavir (400 mg twice daily)/ritonavir (100 mg twice daily) decreased the
AUC, Cmax, and elimination half-life of lamotrigine by approximately 50% to 55.4% in 18
healthy subjects. The pharmacokinetics of lopinavir/ritonavir were similar with concomitant
lamotrigine, compared to that in historical controls.
Olanzapine
The AUC and Cmax of olanzapine were similar following the addition of olanzapine (15 mg once
daily) to lamotrigine (200 mg once daily) in healthy male volunteers (n = 16) compared with the
AUC and Cmax in healthy male volunteers receiving olanzapine alone (n = 16).
In the same trial, the AUC and Cmax of lamotrigine were reduced on average by 24% and 20%,
respectively, following the addition of olanzapine to lamotrigine in healthy male volunteers
compared with those receiving lamotrigine alone. This reduction in lamotrigine plasma
concentrations is not expected to be clinically meaningful.
Oxcarbazepine
The AUC and Cmax of oxcarbazepine and its active 10-monohydroxy oxcarbazepine metabolite
were not significantly different following the addition of oxcarbazepine (600 mg twice daily) to
lamotrigine (200 mg once daily) in healthy male volunteers (n = 13) compared with healthy male
volunteers receiving oxcarbazepine alone (n = 13).
In the same trial, the AUC and Cmax of lamotrigine were similar following the addition of
oxcarbazepine (600 mg twice daily) to lamotrigine in healthy male volunteers compared with
those receiving lamotrigine alone. Limited clinical data suggest a higher incidence of headache,
dizziness, nausea, and somnolence with coadministration of lamotrigine and oxcarbazepine
compared with lamotrigine alone or oxcarbazepine alone.
Phenobarbital, Primidone
The addition of phenobarbital or primidone decreases lamotrigine steady-state concentrations by
approximately 40%.
Phenytoin
Lamotrigine has no appreciable effect on steady-state phenytoin plasma concentrations in
patients with epilepsy. The addition of phenytoin decreases lamotrigine steady-state
concentrations by approximately 40%.
Pregabalin
Steady-state trough plasma concentrations of lamotrigine were not affected by concomitant
pregabalin (200 mg 3 times daily) administration. There are no pharmacokinetic interactions
between lamotrigine and pregabalin.
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Rifampin
In 10 male volunteers, rifampin (600 mg/day for 5 days) significantly increased the apparent
clearance of a single 25-mg dose of lamotrigine by approximately 2-fold (AUC decreased by
approximately 40%).
Risperidone
In a 14 healthy volunteers study, multiple oral doses of lamotrigine 400 mg daily had no
clinically significant effect on the single-dose pharmacokinetics of risperidone 2 mg and its
active metabolite 9-OH risperidone. Following the coadministration of risperidone 2 mg with
lamotrigine, 12 of the 14 volunteers reported somnolence compared with 1 out of 20 when
risperidone was given alone, and none when lamotrigine was administered alone.
Topiramate
Topiramate resulted in no change in plasma concentrations of lamotrigine. Administration of
lamotrigine resulted in a 15% increase in topiramate concentrations.
Valproate
When lamotrigine was administered to healthy volunteers (n = 18) receiving valproate, the
trough steady-state valproate plasma concentrations decreased by an average of 25% over a 3-
week period, and then stabilized. However, adding lamotrigine to the existing therapy did not
cause a change in valproate plasma concentrations in either adult or pediatric patients in
controlled clinical trials.
The addition of valproate increased lamotrigine steady-state concentrations in normal volunteers
by slightly more than 2-fold. In 1 trial, maximal inhibition of lamotrigine clearance was reached
at valproate doses between 250 and 500 mg/day and did not increase as the valproate dose was
further increased.
Zonisamide
In a study in 18 patients with epilepsy, coadministration of zonisamide (200 to 400 mg/day) with
lamotrigine (150 to 500 mg/day for 35 days) had no significant effect on the pharmacokinetics of
lamotrigine.
Known Inducers or Inhibitors of Glucuronidation
Drugs other than those listed above have not been systematically evaluated in combination with
lamotrigine. Since lamotrigine is metabolized predominately by glucuronic acid conjugation,
drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of
lamotrigine and doses of lamotrigine may require adjustment based on clinical response.
49
Reference ID: 3720577
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-045 & S-051
NDA 020764/S-038 & S-044
NDA 022251/S-007 & S-014
FDA Approved Labeling Text dated 3/24/2015
Other
In vitro assessment of the inhibitory effect of lamotrigine at OCT2 demonstrate that lamotrigine,
but not the N(2)-glucuronide metabolite, is an inhibitor of OCT2 at potentially clinically relevant
concentrations, with IC50 value of 53.8 µM [see Drug Interactions (7)].
Results of in vitro experiments suggest that clearance of lamotrigine is unlikely to be reduced by
concomitant administration of amitriptyline, clonazepam, clozapine, fluoxetine, haloperidol,
lorazepam, phenelzine, sertraline, or trazodone.
Results of in vitro experiments suggest that lamotrigine does not reduce the clearance of drugs
eliminated predominantly by CYP2D6.
Specific Populations
Renal Impairment: Twelve volunteers with chronic renal failure (mean creatinine clearance: 13
mL/min, range: 6 to 23) and another 6 individuals undergoing hemodialysis were each given a
single 100-mg dose of lamotrigine. The mean plasma half-lives determined in the study were
42.9 hours (chronic renal failure), 13.0 hours (during hemodialysis), and 57.4 hours (between
hemodialysis) compared with 26.2 hours in healthy volunteers. On average, approximately 20%
(range: 5.6 to 35.1) of the amount of lamotrigine present in the body was eliminated by
hemodialysis during a 4-hour session [see Dosage and Administration (2.1)].
Hepatic Disease: The pharmacokinetics of lamotrigine following a single 100-mg dose of
lamotrigine were evaluated in 24 subjects with mild, moderate, and severe hepatic impairment
(Child-Pugh Classification system) and compared with 12 subjects without hepatic impairment.
The subjects with severe hepatic impairment were without ascites (n = 2) or with ascites (n = 5).
The mean apparent clearances of lamotrigine in subjects with mild (n = 12), moderate (n = 5),
severe without ascites (n = 2), and severe with ascites (n = 5) liver impairment were 0.30 ± 0.09,
0.24 ± 0.1, 0.21 ± 0.04, and 0.15 ± 0.09 mL/min/kg, respectively, as compared with 0.37 ± 0.1
mL/min/kg in the healthy controls. Mean half-lives of lamotrigine in subjects with mild,
moderate, severe without ascites, and severe with ascites hepatic impairment were 46 ± 20, 72 ±
44, 67 ± 11, and 100 ± 48 hours, respectively, as compared with 33 ± 7 hours in healthy controls
[see Dosage and Administration (2.1)].
Age: Pediatric Subjects: The pharmacokinetics of lamotrigine following a single 2-mg/kg dose
were evaluated in 2 studies in pediatric subjects (n = 29 for subjects aged 10 months to 5.9 years
and n = 26 for subjects aged 5 to 11 years). Forty-three subjects received concomitant therapy
with other AEDs and 12 subjects received lamotrigine as monotherapy. Lamotrigine
pharmacokinetic parameters for pediatric patients are summarized in Table 16.
Population pharmacokinetic analyses involving subjects aged 2 to 18 years demonstrated that
lamotrigine clearance was influenced predominantly by total body weight and concurrent AED
therapy. The oral clearance of lamotrigine was higher, on a body weight basis, in pediatric
patients than in adults. Weight-normalized lamotrigine clearance was higher in those subjects
50
Reference ID: 3720577
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NDA 020764/S-038 & S-044
NDA 022251/S-007 & S-014
FDA Approved Labeling Text dated 3/24/2015
weighing less than 30 kg compared with those weighing greater than 30 kg. Accordingly,
patients weighing less than 30 kg may need an increase of as much as 50% in maintenance doses,
based on clinical response, as compared with subjects weighing more than 30 kg being
administered the same AEDs [see Dosage and Administration (2.2)]. These analyses also
revealed that, after accounting for body weight, lamotrigine clearance was not significantly
influenced by age. Thus, the same weight-adjusted doses should be administered to children
irrespective of differences in age. Concomitant AEDs which influence lamotrigine clearance in
adults were found to have similar effects in children.
Table 16. Mean Pharmacokinetic Parameters in Pediatric Subjects With Epilepsy
Pediatric Study Population
Number of
Subjects
Tmax
(h)
t½
(h)
CL/F
(mL/min/kg)
Ages 10 months-5.3 years
Subjects taking carbamazepine,
10
3.0
7.7
3.62
phenytoin, phenobarbital, or
primidonea
(1.0-5.9)
(5.7-11.4)
(2.44-5.28)
Subjects taking AEDs with no
7
5.2
19.0
1.2
known effect on the apparent
clearance of lamotrigine
(2.9-6.1)
(12.9-27.1)
(0.75-2.42)
Subjects taking valproate only
8
2.9
44.9
0.47
(1.0-6.0)
(29.5-52.5)
(0.23-0.77)
Ages 5-11 years
Subjects taking carbamazepine,
7
1.6
7.0
2.54
phenytoin, phenobarbital, or
primidonea
(1.0-3.0)
(3.8-9.8)
(1.35-5.58)
Subjects taking carbamazepine,
8
3.3
19.1
0.89
phenytoin, phenobarbital, or
primidonea plus valproate
(1.0-6.4)
(7.0-31.2)
(0.39-1.93)
Subjects taking valproate only
b
3
4.5
65.8
0.24
(3.0-6.0)
(50.7-73.7)
(0.21-0.26)
Ages 13-18 years
Subjects taking carbamazepine,
phenytoin, phenobarbital, or
primidonea
11
___ c
___ c
1.3
Subjects taking carbamazepine,
phenytoin, phenobarbital, or
primidonea plus valproate
8
___ c
___ c
0.5
Subjects taking valproate only
4
___ c
___ c
0.3
a Carbamazepine, phenytoin, phenobarbital, and primidone have been shown to increase the
apparent clearance of lamotrigine. Estrogen-containing oral contraceptives, rifampin, and the
51
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protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir have also been shown to
increase the apparent clearance of lamotrigine [see Drug Interactions (7)].
b Two subjects were included in the calculation for mean Tmax.
c Parameter not estimated.
Elderly: The pharmacokinetics of lamotrigine following a single 150-mg dose of
lamotrigine were evaluated in 12 elderly volunteers between the ages of 65 and 76 years (mean
creatinine clearance = 61 mL/min, range: 33 to 108 mL/min). The mean half-life of lamotrigine
in these subjects was 31.2 hours (range: 24.5 to 43.4 hours), and the mean clearance was
0.40 mL/min/kg (range: 0.26 to 0.48 mL/min/kg).
Gender: The clearance of lamotrigine is not affected by gender. However, during dose escalation
of lamotrigine in 1 clinical trial in patients with epilepsy on a stable dose of valproate (n = 77),
mean trough lamotrigine concentrations unadjusted for weight were 24% to 45% higher (0.3 to
1.7 mcg/mL) in females than in males.
Race: The apparent oral clearance of lamotrigine was 25% lower in non-Caucasians than
Caucasians.
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
No evidence of carcinogenicity was seen in mouse or rat following oral administration of
lamotrigine for up to 2 years at doses up to 30 mg/kg/day and 10 to 15 mg/kg/day in mouse and
rat, respectively. The highest doses tested are less than the human dose of 400 mg/day on a body
surface area (mg/m2) basis.
Lamotrigine was negative in in vitro gene mutation (Ames and mouse lymphoma tk) assays and
in clastogenicity (in vitro human lymphocyte and in vivo rat bone marrow) assays.
No evidence of impaired fertility was detected in rats given oral doses of lamotrigine up to 20
mg/kg/day. The highest dose tested is less than the human dose of 400 mg/day on a mg/m2 basis.
14
CLINICAL STUDIES
14.1
Epilepsy
Monotherapy With LAMICTAL in Adults With Partial-Onset Seizures Already Receiving
Treatment With Carbamazepine, Phenytoin, Phenobarbital, or Primidone as the Single
Antiepileptic Drug
The effectiveness of monotherapy with LAMICTAL was established in a multicenter, double-
blind clinical trial enrolling 156 adult outpatients with partial-onset seizures. The patients
experienced at least 4 simple partial-onset, complex partial-onset, and/or secondarily generalized
seizures during each of 2 consecutive 4-week periods while receiving carbamazepine or
52
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phenytoin monotherapy during baseline. LAMICTAL (target dose of 500 mg/day) or valproate
(1,000 mg/day) was added to either carbamazepine or phenytoin monotherapy over a 4-week
period. Patients were then converted to monotherapy with LAMICTAL or valproate during the
next 4 weeks, then continued on monotherapy for an additional 12-week period.
Trial endpoints were completion of all weeks of trial treatment or meeting an escape criterion.
Criteria for escape relative to baseline were: (1) doubling of average monthly seizure count, (2)
doubling of highest consecutive 2-day seizure frequency, (3) emergence of a new seizure type
(defined as a seizure that did not occur during the 8-week baseline) that is more severe than
seizure types that occur during study treatment, or (4) clinically significant prolongation of
generalized tonic-clonic seizures. The primary efficacy variable was the proportion of patients in
each treatment group who met escape criteria.
The percentages of patients who met escape criteria were 42% (32/76) in the group receiving
LAMICTAL and 69% (55/80) in the valproate group. The difference in the percentage of
patients meeting escape criteria was statistically significant (P = 0.0012) in favor of
LAMICTAL. No differences in efficacy based on age, sex, or race were detected.
Patients in the control group were intentionally treated with a relatively low dose of valproate; as
such, the sole objective of this trial was to demonstrate the effectiveness and safety of
monotherapy with LAMICTAL, and cannot be interpreted to imply the superiority of
LAMICTAL to an adequate dose of valproate.
Adjunctive Therapy With LAMICTAL in Adults With Partial-Onset Seizures
The effectiveness of LAMICTAL as adjunctive therapy (added to other AEDs) was initially
established in 3 pivotal, multicenter, placebo-controlled, double-blind clinical trials in 355 adults
with refractory partial-onset seizures. The patients had a history of at least 4 partial-onset
seizures per month in spite of receiving 1 or more AEDs at therapeutic concentrations and in 2 of
the trials were observed on their established AED regimen during baselines that varied between 8
to 12 weeks. In the third trial, patients were not observed in a prospective baseline. In patients
continuing to have at least 4 seizures per month during the baseline, LAMICTAL or placebo was
then added to the existing therapy. In all 3 trials, change from baseline in seizure frequency was
the primary measure of effectiveness. The results given below are for all partial-onset seizures in
the intent-to-treat population (all patients who received at least 1 dose of treatment) in each trial,
unless otherwise indicated. The median seizure frequency at baseline was 3 per week while the
mean at baseline was 6.6 per week for all patients enrolled in efficacy trials.
One trial (n = 216) was a double-blind, placebo-controlled, parallel trial consisting of a 24-week
treatment period. Patients could not be on more than 2 other anticonvulsants and valproate was
not allowed. Patients were randomized to receive placebo, a target dose of 300 mg/day of
LAMICTAL, or a target dose of 500 mg/day of LAMICTAL. The median reductions in the
frequency of all partial-onset seizures relative to baseline were 8% in patients receiving placebo,
20% in patients receiving 300 mg/day of LAMICTAL, and 36% in patients receiving 500
53
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mg/day of LAMICTAL. The seizure frequency reduction was statistically significant in the 500-
mg/day group compared with the placebo group, but not in the 300-mg/day group.
A second trial (n = 98) was a double-blind, placebo-controlled, randomized, crossover trial
consisting of two 14-week treatment periods (the last 2 weeks of which consisted of dose
tapering) separated by a 4-week washout period. Patients could not be on more than 2 other
anticonvulsants and valproate was not allowed. The target dose of LAMICTAL was 400 mg/day.
When the first 12 weeks of the treatment periods were analyzed, the median change in seizure
frequency was a 25% reduction on LAMICTAL compared with placebo (P<0.001).
The third trial (n = 41) was a double-blind, placebo-controlled, crossover trial consisting of two
12-week treatment periods separated by a 4-week washout period. Patients could not be on more
than 2 other anticonvulsants. Thirteen patients were on concomitant valproate; these patients
received 150 mg/day of LAMICTAL. The 28 other patients had a target dose of 300 mg/day of
LAMICTAL. The median change in seizure frequency was a 26% reduction on LAMICTAL
compared with placebo (P<0.01).
No differences in efficacy based on age, sex, or race, as measured by change in seizure
frequency, were detected.
Adjunctive Therapy With LAMICTAL in Pediatric Patients With Partial-Onset Seizures
The effectiveness of LAMICTAL as adjunctive therapy in pediatric patients with partial-onset
seizures was established in a multicenter, double-blind, placebo-controlled trial in 199 patients
aged 2 to 16 years (n = 98 on LAMICTAL, n = 101 on placebo). Following an 8-week baseline
phase, patients were randomized to 18 weeks of treatment with LAMICTAL or placebo added to
their current AED regimen of up to 2 drugs. Patients were dosed based on body weight and
valproate use. Target doses were designed to approximate 5 mg/kg/day for patients taking
valproate (maximum dose: 250 mg/day) and 15 mg/kg/day for the patients not taking valproate
(maximum dose: 750 mg/day). The primary efficacy endpoint was percentage change from
baseline in all partial-onset seizures. For the intent-to-treat population, the median reduction of
all partial-onset seizures was 36% in patients treated with LAMICTAL and 7% on placebo, a
difference that was statistically significant (P<0.01).
Adjunctive Therapy With LAMICTAL in Pediatric and Adult Patients With Lennox-Gastaut
Syndrome
The effectiveness of LAMICTAL as adjunctive therapy in patients with Lennox-Gastaut
syndrome was established in a multicenter, double-blind, placebo-controlled trial in 169 patients
aged 3 to 25 years (n = 79 on LAMICTAL, n = 90 on placebo). Following a 4-week, single-
blind, placebo phase, patients were randomized to 16 weeks of treatment with LAMICTAL or
placebo added to their current AED regimen of up to 3 drugs. Patients were dosed on a fixed-
dose regimen based on body weight and valproate use. Target doses were designed to
approximate 5 mg/kg/day for patients taking valproate (maximum dose: 200 mg/day) and 15
54
Reference ID: 3720577
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mg/kg/day for patients not taking valproate (maximum dose: 400 mg/day). The primary efficacy
endpoint was percentage change from baseline in major motor seizures (atonic, tonic, major
myoclonic, and tonic-clonic seizures). For the intent-to-treat population, the median reduction of
major motor seizures was 32% in patients treated with LAMICTAL and 9% on placebo, a
difference that was statistically significant (P<0.05). Drop attacks were significantly reduced by
LAMICTAL (34%) compared with placebo (9%), as were tonic-clonic seizures (36% reduction
versus 10% increase for LAMICTAL and placebo, respectively).
Adjunctive Therapy With LAMICTAL in Pediatric and Adult Patients With Primary Generalized
Tonic-Clonic Seizures
The effectiveness of LAMICTAL as adjunctive therapy in patients with PGTC seizures was
established in a multicenter, double-blind, placebo-controlled trial in 117 pediatric and adult
patients aged 2 years and older (n = 58 on LAMICTAL, n = 59 on placebo). Patients with at least
3 PGTC seizures during an 8-week baseline phase were randomized to 19 to 24 weeks of
treatment with LAMICTAL or placebo added to their current AED regimen of up to 2 drugs.
Patients were dosed on a fixed-dose regimen, with target doses ranging from 3 to 12 mg/kg/day
for pediatric patients and from 200 to 400 mg/day for adult patients based on concomitant AEDs.
The primary efficacy endpoint was percentage change from baseline in PGTC seizures. For the
intent-to-treat population, the median percent reduction in PGTC seizures was 66% in patients
treated with LAMICTAL and 34% on placebo, a difference that was statistically significant
(P = 0.006).
14.2
Bipolar Disorder
The effectiveness of LAMICTAL in the maintenance treatment of bipolar I disorder was
established in 2 multicenter, double-blind, placebo-controlled trials in adult patients who met
DSM-IV criteria for bipolar I disorder. Trial 1 enrolled patients with a current or recent (within
60 days) depressive episode as defined by DSM-IV and Trial 2 included patients with a current
or recent (within 60 days) episode of mania or hypomania as defined by DSM-IV. Both trials
included a cohort of patients (30% of 404 subjects in Trial 1 and 28% of 171 patients in Trial 2)
with rapid cycling bipolar disorder (4 to 6 episodes per year).
In both trials, patients were titrated to a target dose of 200 mg of LAMICTAL as add-on therapy
or as monotherapy with gradual withdrawal of any psychotropic medications during an 8- to 16-
week open-label period. Overall 81% of 1,305 patients participating in the open-label period
were receiving 1 or more other psychotropic medications, including benzodiazepines, selective
serotonin reuptake inhibitors (SSRIs), atypical antipsychotics (including olanzapine), valproate,
or lithium, during titration of LAMICTAL. Patients with a CGI-severity score of 3 or less
maintained for at least 4 continuous weeks, including at least the final week on monotherapy
with LAMICTAL, were randomized to a placebo-controlled, double-blind treatment period for
up to 18 months. The primary endpoint was TIME (time to intervention for a mood episode or
one that was emerging, time to discontinuation for either an adverse event that was judged to be
55
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related to bipolar disorder, or for lack of efficacy). The mood episode could be depression,
mania, hypomania, or a mixed episode.
In Trial 1, patients received double-blind monotherapy with LAMICTAL 50 mg/day (n = 50),
LAMICTAL 200 mg/day (n = 124), LAMICTAL 400 mg/day (n = 47), or placebo (n = 121).
LAMICTAL (200- and 400-mg/day treatment groups combined) was superior to placebo in
delaying the time to occurrence of a mood episode. Separate analyses of the 200- and 400-
mg/day dose groups revealed no added benefit from the higher dose.
In Trial 2, patients received double-blind monotherapy with LAMICTAL (100 to 400 mg/day, n
= 59), or placebo (n = 70). LAMICTAL was superior to placebo in delaying time to occurrence
of a mood episode. The mean dose of LAMICTAL was about 211 mg/day.
Although these trials were not designed to separately evaluate time to the occurrence of
depression or mania, a combined analysis for the 2 trials revealed a statistically significant
benefit for LAMICTAL over placebo in delaying the time to occurrence of both depression and
mania, although the finding was more robust for depression.
16
HOW SUPPLIED/STORAGE AND HANDLING
LAMICTAL (lamotrigine) tablets
25 mg, white, scored, shield-shaped tablets debossed with “LAMICTAL” and “25”, bottles of
100 (NDC 0173-0633-02).
Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled
Room Temperature] in a dry place.
100 mg, peach, scored, shield-shaped tablets debossed with “LAMICTAL” and “100”, bottles of
100 (NDC 0173-0642-55).
150 mg, cream, scored, shield-shaped tablets debossed with “LAMICTAL” and “150”, bottles of
60 (NDC 0173-0643-60).
200 mg, blue, scored, shield-shaped tablets debossed with “LAMICTAL” and “200”, bottles of
60 (NDC 0173-0644-60).
Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled
Room Temperature] in a dry place and protect from light.
LAMICTAL (lamotrigine) Starter Kit for Patients Taking Valproate (Blue Kit)
25 mg, white, scored, shield-shaped tablets debossed with “LAMICTAL” and “25”, blisterpack
of 35 tablets (NDC 0173-0633-10).
Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled
Room Temperature] in a dry place.
56
Reference ID: 3720577
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-045 & S-051
NDA 020764/S-038 & S-044
NDA 022251/S-007 & S-014
FDA Approved Labeling Text dated 3/24/2015
LAMICTAL (lamotrigine) Starter Kit for Patients Taking Carbamazepine, Phenytoin,
Phenobarbital, or Primidone and Not Taking Valproate (Green Kit)
25 mg, white, scored, shield-shaped tablets debossed with “LAMICTAL” and “25” and 100 mg,
peach, scored, shield-shaped tablets debossed with “LAMICTAL” and “100”, blisterpack of 98
tablets (84/25-mg tablets and 14/100-mg tablets) (NDC 0173-0817-28).
Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled
Room Temperature] in a dry place and protect from light.
LAMICTAL (lamotrigine) Starter Kit for Patients Not Taking Carbamazepine, Phenytoin,
Phenobarbital, Primidone, or Valproate (Orange Kit)
25 mg, white, scored, shield-shaped tablets debossed with “LAMICTAL” and “25” and 100 mg,
peach, scored, shield-shaped tablets debossed with “LAMICTAL” and “100”, blisterpack of 49
tablets (42/25-mg tablets and 7/100-mg tablets) (NDC 0173-0594-02).
Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled
Room Temperature] in a dry place and protect from light.
LAMICTAL (lamotrigine) chewable dispersible tablets
2 mg, white to off-white, round tablets debossed with “LTG” over “2”, bottles of 30 (NDC 0173-
0699-00). ORDER DIRECTLY FROM GlaxoSmithKline 1-800-334-4153.
5 mg, white to off-white, caplet-shaped tablets debossed with “GX CL2”, bottles of 100 (NDC
0173-0526-00).
25 mg, white, super elliptical-shaped tablets debossed with “GX CL5”, bottles of 100 (NDC
0173-0527-00).
Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled
Room Temperature] in a dry place.
LAMICTAL ODT (lamotrigine) orally disintegrating tablets
25 mg, white to off-white, round, flat-faced, radius-edged tablets debossed with “LMT” on one
side and “25” on the other, Maintenance Packs of 30 (NDC 0173-0772-02).
50 mg, white to off-white, round, flat-faced, radius-edged tablets debossed with “LMT” on one
side and “50” on the other, Maintenance Packs of 30 (NDC 0173-0774-02).
100 mg, white to off-white, round, flat-faced, radius-edged tablets debossed with “LAMICTAL”
on one side and “100” on the other, Maintenance Packs of 30 (NDC 0173-0776-02).
200 mg, white to off-white, round, flat-faced, radius-edged tablets debossed with “LAMICTAL”
on one side and “200” on the other, Maintenance Packs of 30 (NDC 0173-0777-02).
Store between 20°C and 25°C (68°F and 77°F); with excursions permitted between 15°C and
30°C (59°F and 86°F).
57
Reference ID: 3720577
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-045 & S-051
NDA 020764/S-038 & S-044
NDA 022251/S-007 & S-014
FDA Approved Labeling Text dated 3/24/2015
LAMICTAL ODT (lamotrigine) Patient Titration Kit for Patients Taking Valproate (Blue ODT
Kit)
25 mg, white to off-white, round, flat-faced, radius-edged tablets debossed with “LMT” on one
side and “25” on the other, and 50 mg, white to off-white, round, flat-faced, radius-edged tablets
debossed with “LMT” on one side and “50” on the other, blisterpack of 28 tablets (21/25-mg
tablets and 7/50-mg tablets) (NDC 0173-0779-00).
Store between 20°C and 25°C (68°F and 77°F); with excursions permitted between 15°C and
30°C (59°F and 86°F).
LAMICTAL ODT (lamotrigine) Patient Titration Kit for Patients Taking Carbamazepine,
Phenytoin, Phenobarbital, or Primidone and Not Taking Valproate (Green ODT Kit)
50 mg, white to off-white, round, flat-faced, radius-edged tablets debossed with “LMT” on one
side and “50” on the other, and 100 mg, white to off-white, round, flat-faced, radius-edged
tablets debossed with “LAMICTAL” on one side and “100” on the other, blisterpack of 56
tablets (42/50-mg tablets and 14/100-mg tablets) (NDC 0173-0780-00).
Store between 20°C and 25°C (68°F and 77°F); with excursions permitted between 15°C and
30°C (59°F and 86°F).
LAMICTAL ODT (lamotrigine) Patient Titration Kit for Patients Not Taking Carbamazepine,
Phenytoin, Phenobarbital, Primidone, or Valproate (Orange ODT Kit)
25 mg, white to off-white, round, flat-faced, radius-edged tablets debossed with “LMT” on one
side and “25” on the other, 50 mg, white to off-white, round, flat-faced, radius-edged tablets
debossed with “LMT” on one side and “50” on the other, and 100 mg, white to off-white, round,
flat-faced, radius-edged tablets debossed with “LAMICTAL” on one side and “100” on the
other, blisterpack of 35 (14/25-mg tablets, 14/50-mg tablets, and 7/100-mg tablets) (NDC 0173-
0778-00).
Store between 20°C and 25°C (68°F and 77°F); with excursions permitted between 15°C and
30°C (59°F and 86°F).
Blisterpacks
If the product is dispensed in a blisterpack, the patient should be advised to examine the
blisterpack before use and not use if blisters are torn, broken, or missing.
17
PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Rash
Prior to initiation of treatment with LAMICTAL, inform patients that a rash or other signs or
symptoms of hypersensitivity (e.g., fever, lymphadenopathy) may herald a serious medical event
and instruct them to report any such occurrence to their physician immediately.
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NDA 022251/S-007 & S-014
FDA Approved Labeling Text dated 3/24/2015
Multiorgan Hypersensitivity Reactions, Blood Dyscrasias, and Organ Failure
Inform patients that multiorgan hypersensitivity reactions and acute multiorgan failure may
occur with LAMICTAL. Isolated organ failure or isolated blood dyscrasias without evidence of
multiorgan hypersensitivity may also occur. Instruct patients to contact their physician
immediately if they experience any signs or symptoms of these conditions [see Warnings and
Precautions (5.2, 5.3)].
Suicidal Thinking and Behavior
Inform patients, their caregivers, and families that AEDs, including LAMICTAL, may increase
the risk of suicidal thoughts and behavior. Instruct them to be alert for the emergence or
worsening of symptoms of depression, any unusual changes in mood or behavior, or the
emergence of suicidal thoughts or behavior or thoughts about self-harm. Instruct them to
immediately report behaviors of concern to their physician.
Worsening of Seizures
Advise patients to notify their physician if worsening of seizure control occurs.
Central Nervous System Adverse Effects
Inform patients that LAMICTAL may cause dizziness, somnolence, and other symptoms and
signs of central nervous system depression. Accordingly, instruct them neither to drive a car nor
to operate other complex machinery until they have gained sufficient experience on LAMICTAL
to gauge whether or not it adversely affects their mental and/or motor performance.
Pregnancy and Nursing
Instruct patients to notify their physician if they become pregnant or intend to become pregnant
during therapy and if they intend to breastfeed or are breastfeeding an infant.
Encourage patients to enroll in the NAAED Pregnancy Registry if they become pregnant. This
registry is collecting information about the safety of antiepileptic drugs during pregnancy. To
enroll, patients can call the toll-free number 1-888-233-2334 [see Use in Specific Populations
(8.1)].
Inform patients who intend to breastfeed that LAMICTAL is present in breast milk and advise
them to monitor their child for potential adverse effects of this drug. Discuss the benefits and
risks of continuing breastfeeding.
Oral Contraceptive Use
Instruct women to notify their physician if they plan to start or stop use of oral contraceptives or
other female hormonal preparations. Starting estrogen-containing oral contraceptives may
significantly decrease lamotrigine plasma levels and stopping estrogen-containing oral
contraceptives (including the pill-free week) may significantly increase lamotrigine plasma
levels [see Warnings and Precautions (5.8), Clinical Pharmacology (12.3)]. Also instruct
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NDA 022251/S-007 & S-014
FDA Approved Labeling Text dated 3/24/2015
women to promptly notify their physician if they experience adverse reactions or changes in
menstrual pattern (e.g., break-through bleeding) while receiving LAMICTAL in combination
with these medications.
Discontinuing LAMICTAL
Instruct patients to notify their physician if they stop taking LAMICTAL for any reason and not
to resume LAMICTAL without consulting their physician.
Aseptic Meningitis
Inform patients that LAMICTAL may cause aseptic meningitis. Instruct them to notify their
physician immediately if they develop signs and symptoms of meningitis such as headache,
fever, nausea, vomiting, stiff neck, rash, abnormal sensitivity to light, myalgia, chills, confusion,
or drowsiness while taking LAMICTAL.
Potential Medication Errors
To avoid a medication error of using the wrong drug or formulation, strongly advise patients to
visually inspect their tablets to verify that they are LAMICTAL, as well as the correct
formulation of LAMICTAL, each time they fill their prescription [see Dosage Forms and
Strengths (3.1, 3.2, 3.3), How Supplied/Storage and Handling (16)]. Refer the patient to the
Medication Guide that provides depictions of the LAMICTAL tablets, chewable dispersible
tablets, and orally disintegrating tablets.
LAMICTAL and LAMICTAL ODT are registered trademarks of the GSK group of companies.
The other brands listed are trademarks of their respective owners and are not trademarks of the
GSK group of companies. The makers of these brands are not affiliated with and do not endorse
the GSK group of companies or its products.
Distributed by
GlaxoSmithKline
Research Triangle Park, NC 27709
2015, the GSK group of companies. All rights reserved.
LMT:xPI
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NDA 020241/S-045 & S-051
NDA 020764/S-038 & S-044
NDA 022251/S-007 & S-014
FDA Approved Labeling Text dated 3/24/2015
MEDICATION GUIDE
LAMICTAL® (la-MIK-tal) (lamotrigine) tablets
and chewable dispersible tablets
LAMICTAL ODT® (lamotrigine) orally disintegrating tablets
Read this Medication Guide before you start taking LAMICTAL and each time you
get a refill. There may be new information. This information does not take the place
of talking with your healthcare provider about your medical condition or treatment.
If you have questions about LAMICTAL, ask your healthcare provider or pharmacist.
What is the most important information I should know about LAMICTAL?
1. LAMICTAL may cause a serious skin rash that may cause you to be
hospitalized or even cause death.
There is no way to tell if a mild rash will become more serious. A serious skin
rash can happen at any time during your treatment with LAMICTAL, but is more
likely to happen within the first 2 to 8 weeks of treatment. Children aged
between 2 and 16 years have a higher chance of getting this serious skin rash
while taking LAMICTAL.
The risk of getting a serious skin rash is higher if you:
• take LAMICTAL while taking valproate [DEPAKENE® (valproic acid) or
DEPAKOTE® (divalproex sodium)].
• take a higher starting dose of LAMICTAL than your healthcare provider
prescribed.
• increase your dose of LAMICTAL faster than prescribed.
Call your healthcare provider right away if you have any of the
following:
• a skin rash
• blistering or peeling of your skin
• hives
• painful sores in your mouth or around your eyes
These symptoms may be the first signs of a serious skin reaction. A healthcare
provider should examine you to decide if you should continue taking LAMICTAL.
2. Other serious reactions, including serious blood problems or liver
problems. LAMICTAL can also cause other types of allergic reactions or serious
problems that may affect organs and other parts of your body like your liver or
blood cells. You may or may not have a rash with these types of reactions. Call
your healthcare provider right away if you have any of these symptoms:
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NDA 022251/S-007 & S-014
FDA Approved Labeling Text dated 3/24/2015
• fever
• frequent infections
• severe muscle pain
• swelling of your face, eyes, lips, or tongue
• swollen lymph glands
• unusual bruising or bleeding
• weakness, fatigue
• yellowing of your skin or the white part of your eyes
3. Like other antiepileptic drugs, LAMICTAL may cause suicidal thoughts or
actions in a very small number of people, about 1 in 500.
Call a healthcare provider right away if you have any of these
symptoms, especially if they are new, worse, or worry you:
• thoughts about suicide or dying
• attempt to commit suicide
• new or worse depression
• new or worse anxiety
• feeling agitated or restless
• panic attacks
• trouble sleeping (insomnia)
• new or worse irritability
• acting aggressive, being angry, or violent
• acting on dangerous impulses
•
an extreme increase in activity and talking (mania)
•
other unusual changes in behavior or mood
Do not stop LAMICTAL without first talking to a healthcare provider.
• Stopping LAMICTAL suddenly can cause serious problems.
• Suicidal thoughts or actions can be caused by things other than medicines. If
you have suicidal thoughts or actions, your healthcare provider may check
for other causes.
How can I watch for early symptoms of suicidal thoughts and actions?
• Pay attention to any changes, especially sudden changes, in mood,
behaviors, thoughts, or feelings.
• Keep all follow-up visits with your healthcare provider as scheduled.
• Call your healthcare provider between visits as needed, especially if you are
worried about symptoms.
4. LAMICTAL may rarely cause aseptic meningitis, a serious inflammation
of the protective membrane that covers the brain and spinal cord.
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NDA 022251/S-007 & S-014
FDA Approved Labeling Text dated 3/24/2015
Call your healthcare provider right away if you have any of the following
symptoms:
• headache
• fever
• nausea
• vomiting
• stiff neck
• rash
• unusual sensitivity to light
• muscle pains
• chills
• confusion
• drowsiness
Meningitis has many causes other than LAMICTAL, which your doctor would
check for if you developed meningitis while taking LAMICTAL.
LAMICTAL can have other serious side effects. For more information ask
your healthcare provider or pharmacist. Tell your healthcare provider if you have
any side effect that bothers you. Be sure to read the section below entitled
“What are the possible side effects of LAMICTAL?”
5. Patients prescribed LAMICTAL have sometimes been given the wrong
medicine because many medicines have names similar to LAMICTAL, so
always check that you receive LAMICTAL.
Taking the wrong medication can cause serious health problems. When your
healthcare provider gives you a prescription for LAMICTAL:
• Make sure you can read it clearly.
• Talk to your pharmacist to check that you are given the correct medicine.
• Each time you fill your prescription, check the tablets you receive against the
pictures of the tablets below.
These pictures show the distinct wording, colors, and shapes of the tablets
that help to identify the right strength of LAMICTAL Tablets, Chewable
Dispersible Tablets, and Orally Disintegrating Tablets. Immediately call your
pharmacist if you receive a LAMICTAL tablet that does not look like one of the
tablets shown below, as you may have received the wrong medication.
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NDA 020241/S-045 & S-051
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NDA 022251/S-007 & S-014
FDA Approved Labeling Text dated 3/24/2015
LAMICTAL (lamotrigine) tablets
25 mg, white
100 mg, peach
150 mg, cream
200 mg, blue
Imprinted with
Imprinted with
Imprinted with
Imprinted with
LAMICTAL 25
LAMICTAL 100
LAMICTAL 150
LAMICTAL 200
LAMICTAL (lamotrigine) chewable dispersible
tablets
2 mg, white
5 mg, white
25 mg, white
Imprinted with
Imprinted with
Imprinted with
LTG 2
GX CL2
GX CL5
LAMICTAL ODT (lamotrigine) orally disintegrating tablets
25 mg, white
50 mg, white
100 mg, white
200 mg, white
to off-white
to off-white
to off-white
to off-white
Imprinted with
Imprinted with
Imprinted with
Imprinted with
LMT on one
LMT on one
LAMICTAL on
LAMICTAL on
side
side
one side
one side
25 on the other 50 on the other
100 on the
200 on the
other
other
What is LAMICTAL?
LAMICTAL is a prescription medicine used:
1. together with other medicines to treat certain types of seizures (partial-onset
seizures, primary generalized tonic-clonic seizures, generalized seizures of
Lennox-Gastaut syndrome) in people aged 2 years and older.
2. alone when changing from 1 other medicine used to treat partial-onset seizures
in people aged 16 years and older.
3. for the long-term treatment of bipolar I disorder to lengthen the time between
mood episodes in people aged 18 years and older who have been treated for
mood episodes with other medicine.
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NDA 020241/S-045 & S-051
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NDA 022251/S-007 & S-014
FDA Approved Labeling Text dated 3/24/2015
It is not known if LAMICTAL is safe or effective in children or teenagers younger
than 18 years with mood disorders such as bipolar disorder or depression.
It is not known if LAMICTAL is safe or effective when used alone as the first
treatment of seizures.
Who should not take LAMICTAL?
You should not take LAMICTAL if you have had an allergic reaction to lamotrigine or
to any of the inactive ingredients in LAMICTAL. See the end of this leaflet for a
complete list of ingredients in LAMICTAL.
What should I tell my healthcare provider before taking LAMICTAL?
Before taking LAMICTAL, tell your healthcare provider about all of your medical
conditions, including if you:
• have had a rash or allergic reaction to another antiseizure medicine.
• have or have had depression, mood problems, or suicidal thoughts or behavior.
• have had aseptic meningitis after taking LAMICTAL or LAMICTAL XR
(lamotrigine).
• are taking oral contraceptives (birth control pills) or other female hormonal
medicines. Do not start or stop taking birth control pills or other female
hormonal medicine until you have talked with your healthcare provider. Tell your
healthcare provider if you have any changes in your menstrual pattern such as
breakthrough bleeding. Stopping these medicines may cause side effects (such
as dizziness, lack of coordination, or double vision). Starting these medicines
may lessen how well LAMICTAL works.
• are pregnant or plan to become pregnant. It is not known if LAMICTAL will harm
your unborn baby. If you become pregnant while taking LAMICTAL, talk to your
healthcare provider about registering with the North American Antiepileptic Drug
Pregnancy Registry. You can enroll in this registry by calling 1-888-233-2334.
The purpose of this registry is to collect information about the safety of
antiepileptic drugs during pregnancy.
• are breastfeeding. LAMICTAL passes into breast milk and may cause side effects
in a breastfed baby. If you breastfeed while taking LAMICTAL, watch your baby
closely for trouble breathing, episodes of temporarily stopping breathing,
sleepiness, or poor sucking. Call your baby’s healthcare provider right away if
you see any of these problems. Talk to your healthcare provider about the best
way to feed your baby if you take LAMICTAL.
Tell your healthcare provider about all the medicines you take or if you are planning
to take a new medicine, including prescription and non-prescription medicines,
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NDA 022251/S-007 & S-014
FDA Approved Labeling Text dated 3/24/2015
vitamins, and herbal supplements. If you use LAMICTAL with certain other
medicines, they can affect each other, causing side effects.
How should I take LAMICTAL?
• Take LAMICTAL exactly as prescribed.
• Your healthcare provider may change your dose. Do not change your dose
without talking to your healthcare provider.
• Do not stop taking LAMICTAL without talking to your healthcare provider.
Stopping LAMICTAL suddenly may cause serious problems. For example, if you
have epilepsy and you stop taking LAMICTAL suddenly, you may have seizures
that do not stop. Talk with your healthcare provider about how to stop
LAMICTAL slowly.
• If you miss a dose of LAMICTAL, take it as soon as you remember. If it is almost
time for your next dose, just skip the missed dose. Take the next dose at your
regular time. Do not take 2 doses at the same time.
• If you take too much LAMICTAL, call your healthcare provider or your local
Poison Control Center or go to the nearest hospital emergency room right away.
• You may not feel the full effect of LAMICTAL for several weeks.
• If you have epilepsy, tell your healthcare provider if your seizures get worse or if
you have any new types of seizures.
• Swallow LAMICTAL Tablets whole.
• If you have trouble swallowing LAMICTAL Tablets, tell your healthcare provider
because there may be another form of LAMICTAL you can take.
• LAMICTAL ODT should be placed on the tongue and moved around the mouth.
The tablet will rapidly disintegrate, can be swallowed with or without water, and
can be taken with or without food.
• LAMICTAL chewable dispersible tablets may be swallowed whole, chewed, or
mixed in water or diluted fruit juice. If the tablets are chewed, drink a small
amount of water or diluted fruit juice to help in swallowing. To break up
LAMICTAL chewable dispersible tablets, add the tablets to a small amount of
liquid (1 teaspoon, or enough to cover the medicine) in a glass or spoon. Wait at
least 1 minute or until the tablets are completely broken up, mix the solution
together, and take the whole amount right away.
• If you receive LAMICTAL in a blisterpack, examine the blisterpack before use. Do
not use if blisters are torn, broken, or missing.
What should I avoid while taking LAMICTAL?
Do not drive a car or operate complex, hazardous machinery until you know how
LAMICTAL affects you.
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NDA 020241/S-045 & S-051
NDA 020764/S-038 & S-044
NDA 022251/S-007 & S-014
FDA Approved Labeling Text dated 3/24/2015
What are the possible side effects of LAMICTAL?
See “What is the most important information I should know about LAMICTAL?”
Common side effects of LAMICTAL include:
•
dizziness
•
tremor
•
headache
•
rash
•
blurred or double vision
•
fever
•
lack of coordination
•
abdominal pain
•
sleepiness
•
back pain
•
nausea, vomiting, diarrhea
•
tiredness
•
insomnia
•
dry mouth
Tell your healthcare provider about any side effect that bothers you or that does
not go away.
These are not all the possible side effects of LAMICTAL. For more information, ask
your healthcare provider or pharmacist.
Call your doctor for medical advice about side effects. You may report side effects
to FDA at 1-800-FDA-1088.
How should I store LAMICTAL?
•
Store LAMICTAL at room temperature between 68oF and 77oF (20oC and 25oC).
•
Keep LAMICTAL and all medicines out of the reach of children.
General information about LAMICTAL
Medicines are sometimes prescribed for purposes other than those listed in a
Medication Guide. Do not use LAMICTAL for a condition for which it was not
prescribed. Do not give LAMICTAL to other people, even if they have the same
symptoms you have. It may harm them.
If you take a urine drug screening test, LAMICTAL may make the test result positive
for another drug. If you require a urine drug screening test, tell the healthcare
professional administering the test that you are taking LAMICTAL.
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NDA 020241/S-045 & S-051
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NDA 022251/S-007 & S-014
FDA Approved Labeling Text dated 3/24/2015
This Medication Guide summarizes the most important information about
LAMICTAL. If you would like more information, talk with your healthcare provider.
You can ask your healthcare provider or pharmacist for information about
LAMICTAL that is written for healthcare professionals.
For more information, go to www.lamictal.com or call 1-888-825-5249.
What are the ingredients in LAMICTAL?
LAMICTAL tablets
Active ingredient: lamotrigine.
Inactive ingredients: lactose; magnesium stearate, microcrystalline cellulose,
povidone, sodium starch glycolate, FD&C Yellow No. 6 Lake (100-mg tablet only),
ferric oxide, yellow (150-mg tablet only), and FD&C Blue No. 2 Lake (200-mg tablet
only).
LAMICTAL chewable dispersible tablets
Active ingredient: lamotrigine.
Inactive ingredients: blackcurrant flavor, calcium carbonate, low-substituted
hydroxypropylcellulose, magnesium aluminum silicate, magnesium stearate,
povidone, saccharin sodium, and sodium starch glycolate.
LAMICTAL ODT orally disintegrating tablets
Active ingredient: lamotrigine.
Inactive ingredients: artificial cherry flavor, crospovidone, ethylcellulose,
magnesium stearate, mannitol, polyethylene, and sucralose.
This Medication Guide has been approved by the U.S. Food and Drug
Administration.
LAMICTAL and LAMICTAL ODT are registered trademarks of the GSK group of
companies. The other brands listed are trademarks of their respective owners and
are not trademarks of the GSK group of companies. The makers of these brands
are not affiliated with and do not endorse the GSK group of companies or its
products.
Distributed by
68
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NDA 020241/S-045 & S-051
NDA 020764/S-038 & S-044
NDA 022251/S-007 & S-014
FDA Approved Labeling Text dated 3/24/2015
GlaxoSmithKline
Research Triangle Park, NC 27709
2015, the GSK group of companies. All rights reserved.
March 2015
LMT:xMG
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For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:47:12.986737
|
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|
12,366
|
NDA 020241/S-045 & S-051
NDA 020764/S-038 & S-044
NDA 022251/S-007 & S-014
FDA Approved Labeling Text dated 3/24/2015
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
LAMICTAL safely and effectively. See full prescribing information for
LAMICTAL.
LAMICTAL (lamotrigine) tablets, for oral use
LAMICTAL (lamotrigine) chewable dispersible tablets, for oral use
LAMICTAL ODT (lamotrigine) orally disintegrating tablets, for oral use
Initial U.S. Approval: 1994
WARNING: SERIOUS SKIN RASHES
See full prescribing information for complete boxed warning.
• Cases of life-threatening serious rashes, including Stevens-Johnson
syndrome and toxic epidermal necrolysis, and/or rash-related death
have been caused by lamotrigine. The rate of serious rash is greater in
pediatric patients than in adults. Additional factors that may increase
the risk of rash include:
• coadministration with valproate.
• exceeding recommended initial dose of LAMICTAL.
• exceeding recommended dose escalation for LAMICTAL. (5.1)
• Benign rashes are also caused by lamotrigine; however, it is not
possible to predict which rashes will prove to be serious or life
threatening. LAMICTAL should be discontinued at the first sign of
rash, unless the rash is clearly not drug related. (5.1)
---------------------------RECENT MAJOR CHANGES --------------------------
Dosage and Administration (2.1, 2.2, 2.4)
12/2014
Warnings and Precautions, Laboratory Tests (5.14)
3/2015
--------------------------- INDICATIONS AND USAGE---------------------------
LAMICTAL is indicated for:
Epilepsy—adjunctive therapy in patients aged 2 years and older:
• partial-onset seizures.
• primary generalized tonic-clonic seizures.
• generalized seizures of Lennox-Gastaut syndrome. (1.1)
Epilepsy—monotherapy in patients aged 16 years and older: Conversion to
monotherapy in patients with partial-onset seizures who are receiving
treatment with carbamazepine, phenytoin, phenobarbital, primidone, or
valproate as the single AED. (1.1)
Bipolar disorder in patients aged 18 years and older: Maintenance treatment of
bipolar I disorder to delay the time to occurrence of mood episodes in patients
treated for acute mood episodes with standard therapy. (1.2)
-----------------------DOSAGE AND ADMINISTRATION ----------------------
• Dosing is based on concomitant medications, indication, and patient age.
(2.1, 2.2, 2.3, 2.4)
• To avoid an increased risk of rash, the recommended initial dose and
subsequent dose escalations should not be exceeded. LAMICTAL Starter
Kits and LAMICTAL ODT Patient Titration Kits are available for the first
5 weeks of treatment. (2.1, 16)
• Do not restart LAMICTAL in patients who discontinued due to rash unless
the potential benefits clearly outweigh the risks. (2.1, 5.1)
• Adjustments to maintenance doses will be necessary in most patients
starting or stopping estrogen-containing oral contraceptives. (2.1, 5.8)
• Discontinuation: Taper over a period of at least 2 weeks (approximately
50% dose reduction per week). (2.1, 5.9)
Epilepsy:
• Adjunctive therapy—See Table 1 for patients older than 12 years and
Tables 2 and 3 for patients aged 2 to 12 years. (2.2)
• Conversion to monotherapy—See Table 4. (2.3)
Bipolar disorder: See Tables 5 and 6. (2.4)
--------------------- DOSAGE FORMS AND STRENGTHS---------------------
• Tablets: 25 mg, 100 mg, 150 mg, and 200 mg; scored. (3.1, 16)
• Chewable dispersible tablets: 2 mg, 5 mg, and 25 mg. (3.2, 16)
• Orally disintegrating tablets: 25 mg, 50 mg, 100 mg, and 200 mg. (3.3, 16)
------------------------------ CONTRAINDICATIONS -----------------------------
Hypersensitivity to the drug or its ingredients. (Boxed Warning, 4)
----------------------- WARNINGS AND PRECAUTIONS ----------------------
• Life-threatening serious rash and/or rash-related death: Discontinue at the
first sign of rash, unless the rash is clearly not drug related. (Boxed
Warning, 5.1)
• Fatal or life-threatening hypersensitivity reaction: Multiorgan
hypersensitivity reactions, also known as drug reaction with eosinophilia
and systemic symptoms (DRESS), may be fatal or life threatening. Early
signs may include rash, fever, and lymphadenopathy. These reactions may
be associated with other organ involvement, such as hepatitis, hepatic
failure, blood dyscrasias, or acute multiorgan failure. LAMICTAL should
be discontinued if alternate etiology for this reaction is not found. (5.2)
• Blood dyscrasias (e.g., neutropenia, thrombocytopenia, pancytopenia): May
occur, either with or without an associated hypersensitivity syndrome.
Monitor for signs of anemia, unexpected infection, or bleeding. (5.3)
• Suicidal behavior and ideation: Monitor for suicidal thoughts or behaviors.
(5.4)
• Clinical worsening, emergence of new symptoms, and suicidal
ideation/behaviors may be associated with treatment of bipolar disorder.
Patients should be closely monitored, particularly early in treatment or
during dosage changes. (5.5)
• Aseptic meningitis: Monitor for signs of meningitis. (5.6)
• Medication errors due to product name confusion: Strongly advise patients
to visually inspect tablets to verify the received drug is correct. (5.7, 16, 17)
------------------------------ ADVERSE REACTIONS -----------------------------
Epilepsy: Most common adverse reactions (incidence ≥10%) in adults were
dizziness, headache, diplopia, ataxia, nausea, blurred vision, somnolence,
rhinitis, pharyngitis, and rash. Additional adverse reactions (incidence ≥10%)
reported in children included vomiting, infection, fever, accidental injury,
diarrhea, abdominal pain, and tremor. (6.1)
Bipolar disorder: Most common adverse reactions (incidence >5%) were
nausea, insomnia, somnolence, back pain, fatigue, rash, rhinitis, abdominal
pain, and xerostomia. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact
GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
------------------------------ DRUG INTERACTIONS------------------------------
• Valproate increases lamotrigine concentrations more than 2-fold. (7, 12.3)
• Carbamazepine, phenytoin, phenobarbital, primidone, and rifampin
decrease lamotrigine concentrations by approximately 40%. (7, 12.3)
• Estrogen-containing oral contraceptives decrease lamotrigine
concentrations by approximately 50%. (7, 12.3)
• Protease inhibitors lopinavir/ritonavir and atazanavir/lopinavir decrease
lamotrigine exposure by approximately 50% and 32%, respectively. (7,
12.3)
• Coadministration with organic cationic transporter 2 substrates with narrow
therapeutic index is not recommended (7, 12.3)
----------------------- USE IN SPECIFIC POPULATIONS ----------------------
• Pregnancy: Based on animal data may cause fetal harm. (8.1)
• Efficacy of LAMICTAL, used as adjunctive treatment for partial-onset
seizures, was not demonstrated in a small, randomized, double-blind,
placebo-controlled trial in very young pediatric patients (1 to 24 months).
(8.4)
• Hepatic impairment: Dosage adjustments required in patients with
moderate and severe liver impairment. (2.1, 8.6)
• Renal impairment: Reduced maintenance doses may be effective for
patients with significant renal impairment. (2.1, 8.7)
See 17 for PATIENT COUNSELING INFORMATION and Medication
Guide.
Revised: 3/2015
1
Reference ID: 3720577
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-045 & S-051
NDA 020764/S-038 & S-044
NDA 022251/S-007 & S-014
FDA Approved Labeling Text dated 3/24/2015
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: SERIOUS SKIN RASHES
1
INDICATIONS AND USAGE
1.1
Epilepsy
1.2
Bipolar Disorder
2
DOSAGE AND ADMINISTRATION
2.1
General Dosing Considerations
2.2
Epilepsy—Adjunctive Therapy
2.3
Epilepsy—Conversion From Adjunctive Therapy
to Monotherapy
2.4
Bipolar Disorder
2.5
Administration of LAMICTAL Chewable
Dispersible Tablets
2.6
Administration of LAMICTAL ODT Orally
Disintegrating Tablets
3
DOSAGE FORMS AND STRENGTHS
3.1
Tablets
3.2
Chewable Dispersible Tablets
3.3
Orally Disintegrating Tablets
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1
Serious Skin Rashes [see Boxed Warning]
5.2
Multiorgan Hypersensitivity Reactions and Organ
Failure
5.3
Blood Dyscrasias
5.4
Suicidal Behavior and Ideation
5.5
Use in Patients With Bipolar Disorder
5.6
Aseptic Meningitis
5.7
Potential Medication Errors
5.8
Concomitant Use With Oral Contraceptives
5.9
Withdrawal Seizures
5.10
Status Epilepticus
5.11
Sudden Unexplained Death in Epilepsy (SUDEP)
5.12
Addition of LAMICTAL to a Multidrug Regimen
That Includes Valproate
5.13
Binding in the Eye and Other Melanin-Containing
Tissues
5.14
Laboratory Tests
6
ADVERSE REACTIONS
6.1
Clinical Trial Experience
6.2
Other Adverse Reactions Observed in All Clinical
Trials
6.3
Postmarketing Experience
7
DRUG INTERACTIONS
8
USE IN SPECIFIC POPULATIONS
8.2
Labor and Delivery
8.3
Nursing Mothers
8.4
Pediatric Use
8.5
Geriatric Use
8.6
Hepatic Impairment
8.7
Renal Impairment
10
OVERDOSAGE
10.1
Human Overdose Experience
10.2
Management of Overdose
11
DESCRIPTION
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
12.2
Pharmacodynamics
12.3
Pharmacokinetics
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of
Fertility
14
CLINICAL STUDIES
14.1
Epilepsy
14.2
Bipolar Disorder
16
HOW SUPPLIED/STORAGE AND HANDLING
17
PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information are not
listed.
FULL PRESCRIBING INFORMATION
WARNING: SERIOUS SKIN RASHES
LAMICTAL® can cause serious rashes requiring hospitalization and discontinuation of
treatment. The incidence of these rashes, which have included Stevens-Johnson syndrome,
is approximately 0.8% (8 per 1,000) in pediatric patients (aged 2 to 16 years) receiving
LAMICTAL as adjunctive therapy for epilepsy and 0.3% (3 per 1,000) in adults on
adjunctive therapy for epilepsy. In clinical trials of bipolar and other mood disorders, the
rate of serious rash was 0.08% (0.8 per 1,000) in adult patients receiving LAMICTAL as
initial monotherapy and 0.13% (1.3 per 1,000) in adult patients receiving LAMICTAL as
adjunctive therapy. In a prospectively followed cohort of 1,983 pediatric patients (aged 2 to
16 years) with epilepsy taking adjunctive LAMICTAL, there was 1 rash-related death. In
worldwide postmarketing experience, rare cases of toxic epidermal necrolysis and/or rash-
related death have been reported in adult and pediatric patients, but their numbers are too
few to permit a precise estimate of the rate.
Other than age, there are as yet no factors identified that are known to predict the risk of
occurrence or the severity of rash caused by LAMICTAL. There are suggestions, yet to be
2
Reference ID: 3720577
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-045 & S-051
NDA 020764/S-038 & S-044
NDA 022251/S-007 & S-014
FDA Approved Labeling Text dated 3/24/2015
proven, that the risk of rash may also be increased by (1) coadministration of LAMICTAL
with valproate (includes valproic acid and divalproex sodium), (2) exceeding the
recommended initial dose of LAMICTAL, or (3) exceeding the recommended dose
escalation for LAMICTAL. However, cases have occurred in the absence of these factors.
Nearly all cases of life-threatening rashes caused by LAMICTAL have occurred within 2 to
8 weeks of treatment initiation. However, isolated cases have occurred after prolonged
treatment (e.g., 6 months). Accordingly, duration of therapy cannot be relied upon as
means to predict the potential risk heralded by the first appearance of a rash.
Although benign rashes are also caused by LAMICTAL, it is not possible to predict
reliably which rashes will prove to be serious or life threatening. Accordingly, LAMICTAL
should ordinarily be discontinued at the first sign of rash, unless the rash is clearly not
drug related. Discontinuation of treatment may not prevent a rash from becoming life
threatening or permanently disabling or disfiguring [see Warnings and Precautions (5.1)].
1
INDICATIONS AND USAGE
1.1
Epilepsy
Adjunctive Therapy
LAMICTAL is indicated as adjunctive therapy for the following seizure types in patients aged 2
years and older:
• partial-onset seizures.
• primary generalized tonic-clonic (PGTC) seizures.
• generalized seizures of Lennox-Gastaut syndrome.
Monotherapy
LAMICTAL is indicated for conversion to monotherapy in adults (aged 16 years and older) with
partial-onset seizures who are receiving treatment with carbamazepine, phenytoin, phenobarbital,
primidone, or valproate as the single antiepileptic drug (AED).
Safety and effectiveness of LAMICTAL have not been established (1) as initial monotherapy;
(2) for conversion to monotherapy from AEDs other than carbamazepine, phenytoin,
phenobarbital, primidone, or valproate; or (3) for simultaneous conversion to monotherapy from
2 or more concomitant AEDs.
1.2
Bipolar Disorder
LAMICTAL is indicated for the maintenance treatment of bipolar I disorder to delay the time to
occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in adults (aged 18
years and older) treated for acute mood episodes with standard therapy. The effectiveness of
LAMICTAL in the acute treatment of mood episodes has not been established.
3
Reference ID: 3720577
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-045 & S-051
NDA 020764/S-038 & S-044
NDA 022251/S-007 & S-014
FDA Approved Labeling Text dated 3/24/2015
The effectiveness of LAMICTAL as maintenance treatment was established in 2 placebo-
controlled trials in patients with bipolar I disorder as defined by DSM-IV [see Clinical Studies
(14.2)]. The physician who elects to prescribe LAMICTAL for periods extending beyond 16
weeks should periodically re-evaluate the long-term usefulness of the drug for the individual
patient.
2
DOSAGE AND ADMINISTRATION
2.1
General Dosing Considerations
Rash
There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash
may be increased by (1) coadministration of LAMICTAL with valproate, (2) exceeding the
recommended initial dose of LAMICTAL, or (3) exceeding the recommended dose escalation
for LAMICTAL. However, cases have occurred in the absence of these factors [see Boxed
Warning]. Therefore, it is important that the dosing recommendations be followed closely.
The risk of nonserious rash may be increased when the recommended initial dose and/or the rate
of dose escalation for LAMICTAL is exceeded and in patients with a history of allergy or rash to
other AEDs.
LAMICTAL Starter Kits and LAMICTAL ODT® Patient Titration Kits provide LAMICTAL at
doses consistent with the recommended titration schedule for the first 5 weeks of treatment,
based upon concomitant medications, for patients with epilepsy (older than 12 years) and bipolar
I disorder (aged 18 years and older) and are intended to help reduce the potential for rash. The
use of LAMICTAL Starter Kits and LAMICTAL ODT Patient Titration Kits is recommended
for appropriate patients who are starting or restarting LAMICTAL [see How Supplied/Storage
and Handling (16)].
It is recommended that LAMICTAL not be restarted in patients who discontinued due to rash
associated with prior treatment with lamotrigine unless the potential benefits clearly outweigh
the risks. If the decision is made to restart a patient who has discontinued LAMICTAL, the need
to restart with the initial dosing recommendations should be assessed. The greater the interval of
time since the previous dose, the greater consideration should be given to restarting with the
initial dosing recommendations. If a patient has discontinued lamotrigine for a period of more
than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be
followed. The half-life of lamotrigine is affected by other concomitant medications [see Clinical
Pharmacology (12.3)].
LAMICTAL Added to Drugs Known to Induce or Inhibit Glucuronidation
Because lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are
known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine.
Drugs that induce glucuronidation include carbamazepine, phenytoin, phenobarbital, primidone,
4
Reference ID: 3720577
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-045 & S-051
NDA 020764/S-038 & S-044
NDA 022251/S-007 & S-014
FDA Approved Labeling Text dated 3/24/2015
rifampin, estrogen-containing oral contraceptives, and the protease inhibitors lopinavir/ritonavir
and atazanavir/ritonavir. Valproate inhibits glucuronidation. For dosing considerations for
LAMICTAL in patients on estrogen-containing contraceptives and atazanavir/ritonavir, see
below and Table 13. For dosing considerations for LAMICTAL in patients on other drugs known
to induce or inhibit glucuronidation, see Table 1, Table 2, Table 5, Table 6, and Table 13.
Target Plasma Levels for Patients With Epilepsy or Bipolar Disorder
A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of
LAMICTAL should be based on therapeutic response [see Clinical Pharmacology (12.3)].
Women Taking Estrogen-Containing Oral Contraceptives
Starting LAMICTAL in Women Taking Estrogen-Containing Oral Contraceptives: Although
estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine
[see Clinical Pharmacology (12.3)], no adjustments to the recommended dose-escalation
guidelines for LAMICTAL should be necessary solely based on the use of estrogen-containing
oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for
initiating adjunctive therapy with LAMICTAL based on the concomitant AED or other
concomitant medications (see Table 1 or Table 5). See below for adjustments to maintenance
doses of LAMICTAL in women taking estrogen-containing oral contraceptives.
Adjustments to the Maintenance Dose of LAMICTAL in Women Taking Estrogen-Containing
Oral Contraceptives:
(1) Taking Estrogen-Containing Oral Contraceptives: In women not taking
carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the
protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine
glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance
dose of LAMICTAL will in most cases need to be increased by as much as 2-fold over the
recommended target maintenance dose to maintain a consistent lamotrigine plasma level.
(2) Starting Estrogen-Containing Oral Contraceptives: In women taking a stable dose of
LAMICTAL and not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs
such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that
induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)],
the maintenance dose will in most cases need to be increased by as much as 2-fold to maintain a
consistent lamotrigine plasma level. The dose increases should begin at the same time that the
oral contraceptive is introduced and continue, based on clinical response, no more rapidly than
50 to 100 mg/day every week. Dose increases should not exceed the recommended rate (see
Table 1 or Table 5) unless lamotrigine plasma levels or clinical response support larger
increases. Gradual transient increases in lamotrigine plasma levels may occur during the week of
inactive hormonal preparation (pill-free week), and these increases will be greater if dose
increases are made in the days before or during the week of inactive hormonal preparation.
5
Reference ID: 3720577
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-045 & S-051
NDA 020764/S-038 & S-044
NDA 022251/S-007 & S-014
FDA Approved Labeling Text dated 3/24/2015
Increased lamotrigine plasma levels could result in additional adverse reactions, such as
dizziness, ataxia, and diplopia. If adverse reactions attributable to LAMICTAL consistently
occur during the pill-free week, dose adjustments to the overall maintenance dose may be
necessary. Dose adjustments limited to the pill-free week are not recommended. For women
taking LAMICTAL in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other
drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir
that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology
(12.3)], no adjustment to the dose of LAMICTAL should be necessary.
(3) Stopping Estrogen-Containing Oral Contraceptives: In women not taking
carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the
protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine
glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance
dose of LAMICTAL will in most cases need to be decreased by as much as 50% in order to
maintain a consistent lamotrigine plasma level. The decrease in dose of LAMICTAL should not
exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or
lamotrigine plasma levels indicate otherwise [see Clinical Pharmacology (12.3)]. In women
taking LAMICTAL in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other
drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir
that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology
(12.3)], no adjustment to the dose of LAMICTAL should be necessary.
Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy
The effect of other hormonal contraceptive preparations or hormone replacement therapy on the
pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that
ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the
progestin-only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the
dosage of LAMICTAL in the presence of progestogens alone will likely not be needed.
Patients Taking Atazanavir/Ritonavir
While atazanavir/ritonavir does reduce the lamotrigine plasma concentration, no adjustments to
the recommended dose-escalation guidelines for LAMICTAL should be necessary solely based
on the use of atazanavir/ritonavir. Dose escalation should follow the recommended guidelines for
initiating adjunctive therapy with LAMICTAL based on concomitant AED or other concomitant
medications (see Tables 1, 2, and 5). In patients already taking maintenance doses of
LAMICTAL and not taking glucuronidation inducers, the dose of LAMICTAL may need to be
increased if atazanavir/ritonavir is added, or decreased if atazanavir/ritonavir is discontinued [see
Clinical Pharmacology (12.3)].
Patients With Hepatic Impairment
6
Reference ID: 3720577
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-045 & S-051
NDA 020764/S-038 & S-044
NDA 022251/S-007 & S-014
FDA Approved Labeling Text dated 3/24/2015
Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology
study in 24 subjects with mild, moderate, and severe liver impairment [see Use in Specific
Populations (8.6), Clinical Pharmacology (12.3)], the following general recommendations can
be made. No dosage adjustment is needed in patients with mild liver impairment. Initial,
escalation, and maintenance doses should generally be reduced by approximately 25% in patients
with moderate and severe liver impairment without ascites and 50% in patients with severe liver
impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical
response.
Patients With Renal Impairment
Initial doses of LAMICTAL should be based on patients’ concomitant medications (see Tables
1-3 or Table 5); reduced maintenance doses may be effective for patients with significant renal
impairment [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]. Few patients
with severe renal impairment have been evaluated during chronic treatment with LAMICTAL.
Because there is inadequate experience in this population, LAMICTAL should be used with
caution in these patients.
Discontinuation Strategy
Epilepsy: For patients receiving LAMICTAL in combination with other AEDs, a re-evaluation
of all AEDs in the regimen should be considered if a change in seizure control or an appearance
or worsening of adverse reactions is observed.
If a decision is made to discontinue therapy with LAMICTAL, a step-wise reduction of dose
over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns
require a more rapid withdrawal [see Warnings and Precautions (5.9)].
Discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as
rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce
lamotrigine glucuronidation should prolong the half-life of lamotrigine; discontinuing valproate
should shorten the half-life of lamotrigine.
Bipolar Disorder: In the controlled clinical trials, there was no increase in the incidence, type, or
severity of adverse reactions following abrupt termination of LAMICTAL. In clinical trials in
patients with bipolar disorder, 2 patients experienced seizures shortly after abrupt withdrawal of
LAMICTAL. However, there were confounding factors that may have contributed to the
occurrence of seizures in these patients with bipolar disorder. Discontinuation of LAMICTAL
should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per
week) unless safety concerns require a more rapid withdrawal [see Warnings and Precautions
(5.9)].
2.2
Epilepsy—Adjunctive Therapy
This section provides specific dosing recommendations for patients older than 12 years and
patients aged 2 to 12 years. Within each of these age-groups, specific dosing recommendations
7
Reference ID: 3720577
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-045 & S-051
NDA 020764/S-038 & S-044
NDA 022251/S-007 & S-014
FDA Approved Labeling Text dated 3/24/2015
are provided depending upon concomitant AEDs or other concomitant medications (see Table 1
for patients older than 12 years and Table 2 for patients aged 2 to 12 years). A weight-based
dosing guide for patients aged 2 to 12 years on concomitant valproate is provided in Table 3.
Patients Older Than 12 Years
Recommended dosing guidelines are summarized in Table 1.
Table 1. Escalation Regimen for LAMICTAL in Patients Older Than 12 Years With
Epilepsy
In Patients
TAKING Valproatea
In Patients
NOT TAKING
Carbamazepine,
Phenytoin,
Phenobarbital,
Primidone,b or
Valproatea
In Patients TAKING
Carbamazepine,
Phenytoin,
Phenobarbital, or
Primidoneb and NOT
TAKING Valproatea
Weeks 1 and 2
25 mg every other day
25 mg every day
50 mg/day
Weeks 3 and 4
25 mg every day
50 mg/day
100 mg/day
(in 2 divided doses)
Week 5 onward
to maintenance
Increase by
25 to 50 mg/day
every 1 to 2 weeks.
Increase by
50 mg/day
every 1 to 2 weeks.
Increase by
100 mg/day
every 1 to 2 weeks.
Usual
maintenance dose
100 to 200 mg/day
with valproate alone
100 to 400 mg/day
with valproate and
other drugs that
induce glucuronidation
(in 1 or 2 divided doses)
225 to 375 mg/day
(in 2 divided doses)
300 to 500 mg/day
(in 2 divided doses)
a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of
lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].
b Drugs that induce lamotrigine glucuronidation and increase clearance, other than the specified
antiepileptic drugs, include estrogen-containing oral contraceptives, rifampin, and the protease
inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Dosing recommendations for oral
contraceptives and the protease inhibitor atazanavir/ritonavir can be found in General Dosing
Considerations [see Dosage and Administration (2.1)]. Patients on rifampin and the protease
inhibitor lopinavir/ritonavir should follow the same dosing titration/maintenance regimen used
with antiepileptic drugs that induce glucuronidation and increase clearance [see Dosage and
Administration (2.1), Drug Interactions (7), and Clinical Pharmacology (12.3)].
8
Reference ID: 3720577
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-045 & S-051
NDA 020764/S-038 & S-044
NDA 022251/S-007 & S-014
FDA Approved Labeling Text dated 3/24/2015
Patients Aged 2 to 12 Years
Recommended dosing guidelines are summarized in Table 2.
Smaller starting doses and slower dose escalations than those used in clinical trials are
recommended because of the suggestion that the risk of rash may be decreased by smaller
starting doses and slower dose escalations. Therefore, maintenance doses will take longer to
reach in clinical practice than in clinical trials. It may take several weeks to months to achieve an
individualized maintenance dose. Maintenance doses in patients weighing less than 30 kg,
regardless of age or concomitant AED, may need to be increased as much as 50%, based on
clinical response.
The smallest available strength of LAMICTAL chewable dispersible tablets is 2 mg, and only
whole tablets should be administered. If the calculated dose cannot be achieved using whole
tablets, the dose should be rounded down to the nearest whole tablet [see How Supplied/Storage
and Handling (16) and Medication Guide].
Table 2. Escalation Regimen for LAMICTAL in Patients Aged 2 to 12 Years With Epilepsy
In Patients TAKING
Valproatea
In Patients
NOT TAKING
Carbamazepine,
Phenytoin,
Phenobarbital,
Primidone,b or
Valproatea
In Patients TAKING
Carbamazepine,
Phenytoin,
Phenobarbital, or
Primidoneb and NOT
TAKING Valproatea
Weeks 1 and 2
0.15 mg/kg/day
in 1 or 2 divided doses,
rounded down to the
nearest whole tablet
(see Table 3 for
weight-based dosing
guide)
0.3 mg/kg/day
in 1 or 2 divided doses,
rounded down to the
nearest whole tablet
0.6 mg/kg/day
in 2 divided doses,
rounded down to the
nearest whole tablet
Weeks 3 and 4
0.3 mg/kg/day
in 1 or 2 divided doses,
rounded down to the
nearest whole tablet
(see Table 3 for
weight-based dosing
guide)
0.6 mg/kg/day
in 2 divided doses,
rounded down to the
nearest whole tablet
1.2 mg/kg/day
in 2 divided doses,
rounded down to the
nearest whole tablet
9
Reference ID: 3720577
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-045 & S-051
NDA 020764/S-038 & S-044
NDA 022251/S-007 & S-014
FDA Approved Labeling Text dated 3/24/2015
Week 5 onward to
maintenance
The dose should be
increased every 1 to 2
weeks as follows:
calculate
0.3 mg/kg/day,
round this amount
down to the nearest
whole tablet, and add
this amount to the
previously
administered daily
dose.
The dose should be
increased every 1 to 2
weeks as follows:
calculate
0.6 mg/kg/day,
round this amount
down to the nearest
whole tablet, and add
this amount to the
previously
administered daily
dose.
The dose should be
increased every 1 to 2
weeks as follows:
calculate
1.2 mg/kg/day,
round this amount
down to the nearest
whole tablet, and add
this amount to the
previously
administered daily
dose.
Usual
maintenance dose
1 to 5 mg/kg/day
(maximum
200 mg/day in 1 or 2
divided doses)
1 to 3 mg/kg/day
with valproate alone
4.5 to 7.5 mg/kg/day
(maximum
300 mg/day in 2
divided doses)
5 to 15 mg/kg/day
(maximum
400 mg/day in 2
divided doses)
Maintenance dose
May need to be
May need to be
May need to be
in patients less
increased by as much
increased by as much
increased by as much
than 30 kg
as 50%, based on
clinical response.
as 50%, based on
clinical response.
as 50%, based on
clinical response.
Note: Only whole tablets should be used for dosing.
a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of
lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].
b Drugs that induce lamotrigine glucuronidation and increase clearance, other than the specified
antiepileptic drugs, include estrogen-containing oral contraceptives, rifampin, and the protease
inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Dosing recommendations for oral
contraceptives and the protease inhibitor atazanavir/ritonavir can be found in General Dosing
Considerations [see Dosage and Administration (2.1)]. Patients on rifampin and the protease
inhibitor lopinavir/ritonavir should follow the same dosing titration/maintenance regimen used
with antiepileptic drugs that induce glucuronidation and increase clearance [see Dosage and
Administration (2.1), Drug Interactions (7), and Clinical Pharmacology (12.3)].
10
Reference ID: 3720577
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-045 & S-051
NDA 020764/S-038 & S-044
NDA 022251/S-007 & S-014
FDA Approved Labeling Text dated 3/24/2015
Table 3. The Initial Weight-Based Dosing Guide for Patients Aged 2 to 12 Years Taking
Valproate (Weeks 1 to 4) With Epilepsy
If the patient’s weight is
Give this daily dose, using the most appropriate
combination of LAMICTAL 2- and 5-mg tablets
Greater than
And less than
Weeks 1 and 2
Weeks 3 and 4
6.7 kg
14 kg
2 mg every other day
2 mg every day
14.1 kg
27 kg
2 mg every day
4 mg every day
27.1 kg
34 kg
4 mg every day
8 mg every day
34.1 kg
40 kg
5 mg every day
10 mg every day
Usual Adjunctive Maintenance Dose for Epilepsy
The usual maintenance doses identified in Tables 1 and 2 are derived from dosing regimens
employed in the placebo-controlled adjunctive trials in which the efficacy of LAMICTAL was
established. In patients receiving multidrug regimens employing carbamazepine, phenytoin,
phenobarbital, or primidone without valproate, maintenance doses of adjunctive LAMICTAL as
high as 700 mg/day have been used. In patients receiving valproate alone, maintenance doses of
adjunctive LAMICTAL as high as 200 mg/day have been used. The advantage of using doses
above those recommended in Tables 1-4 has not been established in controlled trials.
2.3
Epilepsy—Conversion From Adjunctive Therapy to Monotherapy
The goal of the transition regimen is to attempt to maintain seizure control while mitigating the
risk of serious rash associated with the rapid titration of LAMICTAL.
The recommended maintenance dose of LAMICTAL as monotherapy is 500 mg/day given in 2
divided doses.
To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations
for LAMICTAL should not be exceeded [see Boxed Warning].
Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin, Phenobarbital, or
Primidone to Monotherapy With LAMICTAL
After achieving a dose of 500 mg/day of LAMICTAL using the guidelines in Table 1, the
concomitant enzyme-inducing AED should be withdrawn by 20% decrements each week over a
4-week period. The regimen for the withdrawal of the concomitant AED is based on experience
gained in the controlled monotherapy clinical trial.
Conversion From Adjunctive Therapy With Valproate to Monotherapy With LAMICTAL
The conversion regimen involves the 4 steps outlined in Table 4.
11
Reference ID: 3720577
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-045 & S-051
NDA 020764/S-038 & S-044
NDA 022251/S-007 & S-014
FDA Approved Labeling Text dated 3/24/2015
Table 4. Conversion From Adjunctive Therapy With Valproate to Monotherapy With
LAMICTAL in Patients Aged 16 Years and Older With Epilepsy
LAMICTAL
Valproate
Step 1
Achieve a dose of 200 mg/day according
to guidelines in Table 1.
Maintain established stable dose.
Step 2
Maintain at 200 mg/day.
Decrease dose by decrements no
greater than 500 mg/day/week to
500 mg/day and then maintain for 1
week.
Step 3
Increase to 300 mg/day and maintain for 1
week.
Simultaneously decrease to
250 mg/day and maintain for 1 week.
Step 4
Increase by 100 mg/day every week to
achieve maintenance dose of 500 mg/day.
Discontinue.
Conversion From Adjunctive Therapy With Antiepileptic Drugs Other Than Carbamazepine,
Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy With LAMICTAL
No specific dosing guidelines can be provided for conversion to monotherapy with LAMICTAL
with AEDs other than carbamazepine, phenytoin, phenobarbital, primidone, or valproate.
2.4
Bipolar Disorder
The goal of maintenance treatment with LAMICTAL is to delay the time to occurrence of mood
episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood
episodes with standard therapy. The target dose of LAMICTAL is 200 mg/day (100 mg/day in
patients taking valproate, which decreases the apparent clearance of lamotrigine, and 400 mg/day
in patients not taking valproate and taking either carbamazepine, phenytoin, phenobarbital,
primidone, or other drugs such as rifampin and the protease inhibitor lopinavir/ritonavir that
increase the apparent clearance of lamotrigine). In the clinical trials, doses up to 400 mg/day as
monotherapy were evaluated; however, no additional benefit was seen at 400 mg/day compared
with 200 mg/day [see Clinical Studies (14.2)]. Accordingly, doses above 200 mg/day are not
recommended. Treatment with LAMICTAL is introduced, based on concurrent medications,
according to the regimen outlined in Table 5. If other psychotropic medications are withdrawn
following stabilization, the dose of LAMICTAL should be adjusted. For patients discontinuing
valproate, the dose of LAMICTAL should be doubled over a 2-week period in equal weekly
increments (see Table 6). For patients discontinuing carbamazepine, phenytoin, phenobarbital,
primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and
atazanavir/ritonavir that induce lamotrigine glucuronidation, the dose of LAMICTAL should
remain constant for the first week and then should be decreased by half over a 2-week period in
equal weekly decrements (see Table 6). The dose of LAMICTAL may then be further adjusted to
the target dose (200 mg) as clinically indicated.
12
Reference ID: 3720577
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-045 & S-051
NDA 020764/S-038 & S-044
NDA 022251/S-007 & S-014
FDA Approved Labeling Text dated 3/24/2015
If other drugs are subsequently introduced, the dose of LAMICTAL may need to be adjusted. In
particular, the introduction of valproate requires reduction in the dose of LAMICTAL [see Drug
Interactions (7), Clinical Pharmacology (12.3)].
To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations
of LAMICTAL should not be exceeded [see Boxed Warning].
Table 5. Escalation Regimen for LAMICTAL in Patients With Bipolar Disorder
In Patients TAKING
Valproatea
In Patients
NOT TAKING
Carbamazepine,
Phenytoin,
Phenobarbital,
Primidone,b or
Valproatea
In Patients TAKING
Carbamazepine,
Phenytoin,
Phenobarbital, or
Primidoneb and NOT
TAKING Valproatea
Weeks 1 and 2
25 mg every other day
25 mg daily
50 mg daily
Weeks 3 and 4
25 mg daily
50 mg daily
100 mg daily,
in divided doses
Week 5
50 mg daily
100 mg daily
200 mg daily,
in divided doses
Week 6
100 mg daily
200 mg daily
300 mg daily,
in divided doses
Week 7
100 mg daily
200 mg daily
up to 400 mg daily,
in divided doses
a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of
lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].
b Drugs that induce lamotrigine glucuronidation and increase clearance, other than the
specified antiepileptic drugs, include estrogen-containing oral contraceptives, rifampin, and
the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Dosing
recommendations for oral contraceptives and the protease inhibitor atazanavir/ritonavir can
be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients
on rifampin and the protease inhibitor lopinavir/ritonavir should follow the same dosing
titration/maintenance regimen used with antiepileptic drugs that induce glucuronidation and
increase clearance [see Dosage and Administration (2.1), Drug Interactions (7), and
Clinical Pharmacology (12.3)].
13
Reference ID: 3720577
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-045 & S-051
NDA 020764/S-038 & S-044
NDA 022251/S-007 & S-014
FDA Approved Labeling Text dated 3/24/2015
Table 6. Dosage Adjustments to LAMICTAL in Patients With Bipolar Disorder Following
Discontinuation of Psychotropic Medications
Discontinuation
of Psychotropic Drugs
(excluding Valproate,a
Carbamazepine,
Phenytoin, Phenobarbital,
or Primidoneb)
After Discontinuation
of Valproatea
After Discontinuation of
Carbamazepine,
Phenytoin, Phenobarbital,
or Primidoneb
Current dose of
LAMICTAL (mg/day)
100
Current dose of
LAMICTAL (mg/day)
400
Week 1
Maintain current dose
of LAMICTAL
150
400
Week 2
Maintain current dose
of LAMICTAL
200
300
Week 3
onward
Maintain current dose
of LAMICTAL
200
200
a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of
lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].
b Drugs that induce lamotrigine glucuronidation and increase clearance, other than the specified
antiepileptic drugs, include estrogen-containing oral contraceptives, rifampin, and the protease
inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Dosing recommendations for oral
contraceptives and the protease inhibitor atazanavir/ritonavir can be found in General Dosing
Considerations [see Dosage and Administration (2.1)]. Patients on rifampin and the protease
inhibitor lopinavir/ritonavir should follow the same dosing titration/maintenance regimen used
with antiepileptic drugs that induce glucuronidation and increase clearance [see Dosage and
Administration (2.1), Drug Interactions (7), and Clinical Pharmacology (12.3)].
The benefit of continuing treatment in patients who had been stabilized in an 8- to 16-week
open-label phase with LAMICTAL was established in 2 randomized, placebo-controlled clinical
maintenance trials [see Clinical Studies (14.2)]. However, the optimal duration of treatment with
LAMICTAL has not been established. Thus, patients should be periodically reassessed to
determine the need for maintenance treatment.
2.5
Administration of LAMICTAL Chewable Dispersible Tablets
LAMICTAL chewable dispersible tablets may be swallowed whole, chewed, or dispersed in
water or diluted fruit juice. If the tablets are chewed, consume a small amount of water or diluted
fruit juice to aid in swallowing.
To disperse LAMICTAL chewable dispersible tablets, add the tablets to a small amount of liquid
(1 teaspoon, or enough to cover the medication). Approximately 1 minute later, when the tablets
are completely dispersed, swirl the solution and consume the entire quantity immediately. No
attempt should be made to administer partial quantities of the dispersed tablets.
14
Reference ID: 3720577
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-045 & S-051
NDA 020764/S-038 & S-044
NDA 022251/S-007 & S-014
FDA Approved Labeling Text dated 3/24/2015
2.6
Administration of LAMICTAL ODT Orally Disintegrating Tablets
LAMICTAL ODT orally disintegrating tablets should be placed onto the tongue and moved
around in the mouth. The tablet will disintegrate rapidly, can be swallowed with or without
water, and can be taken with or without food.
3
DOSAGE FORMS AND STRENGTHS
3.1
Tablets
25 mg, white, scored, shield-shaped tablets debossed with “LAMICTAL” and “25.”
100 mg, peach, scored, shield-shaped tablets debossed with “LAMICTAL” and “100.”
150 mg, cream, scored, shield-shaped tablets debossed with “LAMICTAL” and “150.”
200 mg, blue, scored, shield-shaped tablets debossed with “LAMICTAL” and “200.”
3.2
Chewable Dispersible Tablets
2 mg, white to off-white, round tablets debossed with “LTG” over “2.”
5 mg, white to off-white, caplet-shaped tablets debossed with “GX CL2.”
25 mg, white, super elliptical-shaped tablets debossed with “GX CL5.”
3.3
Orally Disintegrating Tablets
25 mg, white to off-white, round, flat-faced, radius-edged tablets debossed with “LMT” on one
side and “25” on the other side.
50 mg, white to off-white, round, flat-faced, radius-edged tablets debossed with “LMT” on one
side and “50” on the other side.
100 mg, white to off-white, round, flat-faced, radius-edged tablets debossed with “LAMICTAL”
on one side and “100” on the other side.
200 mg, white to off-white, round, flat-faced, radius-edged tablets debossed with “LAMICTAL”
on one side and “200” on the other side.
4
CONTRAINDICATIONS
LAMICTAL is contraindicated in patients who have demonstrated hypersensitivity (e.g., rash,
angioedema, acute urticaria, extensive pruritus, mucosal ulceration) to the drug or its ingredients
[see Boxed Warning, Warnings and Precautions (5.1, 5.2)].
15
Reference ID: 3720577
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-045 & S-051
NDA 020764/S-038 & S-044
NDA 022251/S-007 & S-014
FDA Approved Labeling Text dated 3/24/2015
5
WARNINGS AND PRECAUTIONS
5.1
Serious Skin Rashes [see Boxed Warning]
Pediatric Population
The incidence of serious rash associated with hospitalization and discontinuation of LAMICTAL
in a prospectively followed cohort of pediatric patients (aged 2 to 16 years) with epilepsy
receiving adjunctive therapy was approximately 0.8% (16 of 1,983). When 14 of these cases
were reviewed by 3 expert dermatologists, there was considerable disagreement as to their proper
classification. To illustrate, one dermatologist considered none of the cases to be Stevens-
Johnson syndrome; another assigned 7 of the 14 to this diagnosis. There was 1 rash-related death
in this 1,983-patient cohort. Additionally, there have been rare cases of toxic epidermal
necrolysis with and without permanent sequelae and/or death in US and foreign postmarketing
experience.
There is evidence that the inclusion of valproate in a multidrug regimen increases the risk of
serious, potentially life-threatening rash in pediatric patients. In pediatric patients who used
valproate concomitantly, 1.2% (6 of 482) experienced a serious rash compared with 0.6% (6 of
952) patients not taking valproate.
Adult Population
Serious rash associated with hospitalization and discontinuation of LAMICTAL occurred in
0.3% (11 of 3,348) of adult patients who received LAMICTAL in premarketing clinical trials of
epilepsy. In the bipolar and other mood disorders clinical trials, the rate of serious rash was
0.08% (1 of 1,233) of adult patients who received LAMICTAL as initial monotherapy and
0.13% (2 of 1,538) of adult patients who received LAMICTAL as adjunctive therapy. No
fatalities occurred among these individuals. However, in worldwide postmarketing experience,
rare cases of rash-related death have been reported, but their numbers are too few to permit a
precise estimate of the rate.
Among the rashes leading to hospitalization were Stevens-Johnson syndrome, toxic epidermal
necrolysis, angioedema, and those associated with multiorgan hypersensitivity [see Warnings
and Precautions (5.2)].
There is evidence that the inclusion of valproate in a multidrug regimen increases the risk of
serious, potentially life-threatening rash in adults. Specifically, of 584 patients administered
LAMICTAL with valproate in epilepsy clinical trials, 6 (1%) were hospitalized in association
with rash; in contrast, 4 (0.16%) of 2,398 clinical trial patients and volunteers administered
LAMICTAL in the absence of valproate were hospitalized.
16
Reference ID: 3720577
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-045 & S-051
NDA 020764/S-038 & S-044
NDA 022251/S-007 & S-014
FDA Approved Labeling Text dated 3/24/2015
Patients With History of Allergy or Rash to Other Antiepileptic Drugs
The risk of nonserious rash may be increased when the recommended initial dose and/or the rate
of dose escalation for LAMICTAL is exceeded and in patients with a history of allergy or rash to
other AEDs.
5.2
Multiorgan Hypersensitivity Reactions and Organ Failure
Multiorgan hypersensitivity reactions, also known as drug reaction with eosinophilia and
systemic symptoms (DRESS), have occurred with lamotrigine. Some have been fatal or life
threatening. DRESS typically, although not exclusively, presents with fever, rash, and/or
lymphadenopathy in association with other organ system involvement, such as hepatitis,
nephritis, hematologic abnormalities, myocarditis, or myositis, sometimes resembling an acute
viral infection. Eosinophilia is often present. This disorder is variable in its expression, and other
organ systems not noted here may be involved.
Fatalities associated with acute multiorgan failure and various degrees of hepatic failure have
been reported in 2 of 3,796 adult patients and 4 of 2,435 pediatric patients who received
lamotrigine in epilepsy clinical trials. Rare fatalities from multiorgan failure have also been
reported in postmarketing use.
Isolated liver failure without rash or involvement of other organs has also been reported with
lamotrigine.
It is important to note that early manifestations of hypersensitivity (e.g., fever,
lymphadenopathy) may be present even though a rash is not evident. If such signs or symptoms
are present, the patient should be evaluated immediately. LAMICTAL should be discontinued if
an alternative etiology for the signs or symptoms cannot be established.
Prior to initiation of treatment with LAMICTAL, the patient should be instructed that a rash or
other signs or symptoms of hypersensitivity (e.g., fever, lymphadenopathy) may herald a serious
medical event and that the patient should report any such occurrence to a physician immediately.
5.3
Blood Dyscrasias
There have been reports of blood dyscrasias that may or may not be associated with multiorgan
hypersensitivity (also known as DRESS) [see Warnings and Precautions (5.2)]. These have
included neutropenia, leukopenia, anemia, thrombocytopenia, pancytopenia, and, rarely, aplastic
anemia and pure red cell aplasia.
5.4
Suicidal Behavior and Ideation
AEDs, including LAMICTAL, increase the risk of suicidal thoughts or behavior in patients
taking these drugs for any indication. Patients treated with any AED for any indication should be
monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or
any unusual changes in mood or behavior.
17
Reference ID: 3720577
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-045 & S-051
NDA 020764/S-038 & S-044
NDA 022251/S-007 & S-014
FDA Approved Labeling Text dated 3/24/2015
Pooled analyses of 199 placebo-controlled clinical trials (monotherapy and adjunctive therapy)
of 11 different AEDs showed that patients randomized to 1 of the AEDs had approximately
twice the risk (adjusted Relative Risk 1.8, 95% CI: 1.2, 2.7) of suicidal thinking or behavior
compared with patients randomized to placebo. In these trials, which had a median treatment
duration of 12 weeks, the estimated incidence of suicidal behavior or ideation among 27,863
AED-treated patients was 0.43%, compared with 0.24% among 16,029 placebo-treated patients,
representing an increase of approximately 1 case of suicidal thinking or behavior for every 530
patients treated. There were 4 suicides in drug-treated patients in the trials and none in placebo-
treated patients, but the number of events is too small to allow any conclusion about drug effect
on suicide.
The increased risk of suicidal thoughts or behavior with AEDs was observed as early as 1 week
after starting treatment with AEDs and persisted for the duration of treatment assessed. Because
most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts
or behavior beyond 24 weeks could not be assessed.
The risk of suicidal thoughts or behavior was generally consistent among drugs in the data
analyzed. The finding of increased risk with AEDs of varying mechanism of action and across a
range of indications suggests that the risk applies to all AEDs used for any indication. The risk
did not vary substantially by age (5 to 100 years) in the clinical trials analyzed.
Table 7 shows absolute and relative risk by indication for all evaluated AEDs.
Table 7. Risk by Indication for Antiepileptic Drugs in the Pooled Analysis
Indication
Placebo
Patients With
Events per
1,000 Patients
Drug Patients
With Events
per 1,000
Patients
Relative Risk:
Incidence of
Events in Drug
Patients/
Incidence in
Placebo Patients
Risk Difference:
Additional Drug
Patients With
Events per
1,000 Patients
Epilepsy
1.0
3.4
3.5
2.4
Psychiatric
5.7
8.5
1.5
2.9
Other
1.0
1.8
1.9
0.9
Total
2.4
4.3
1.8
1.9
The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in
clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for
the epilepsy and psychiatric indications.
Anyone considering prescribing LAMICTAL or any other AED must balance the risk of suicidal
thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for
which AEDs are prescribed are themselves associated with morbidity and mortality and an
increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge
18
Reference ID: 3720577
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-045 & S-051
NDA 020764/S-038 & S-044
NDA 022251/S-007 & S-014
FDA Approved Labeling Text dated 3/24/2015
during treatment, the prescriber needs to consider whether the emergence of these symptoms in
any given patient may be related to the illness being treated.
Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal
thoughts and behavior and should be advised of the need to be alert for the emergence or
worsening of the signs and symptoms of depression, any unusual changes in mood or behavior,
the emergence of suicidal thoughts or suicidal behavior, or thoughts about self-harm. Behaviors
of concern should be reported immediately to healthcare providers.
5.5
Use in Patients With Bipolar Disorder
Acute Treatment of Mood Episodes
Safety and effectiveness of LAMICTAL in the acute treatment of mood episodes have not been
established.
Children and Adolescents (younger than 18 years)
Safety and effectiveness of LAMICTAL in patients younger than 18 years with mood disorders
have not been established [see Warnings and Precautions (5.4)].
Clinical Worsening and Suicide Risk Associated With Bipolar Disorder
Patients with bipolar disorder may experience worsening of their depressive symptoms and/or
the emergence of suicidal ideation and behaviors (suicidality) whether or not they are taking
medications for bipolar disorder. Patients should be closely monitored for clinical worsening
(including development of new symptoms) and suicidality, especially at the beginning of a
course of treatment or at the time of dose changes.
In addition, patients with a history of suicidal behavior or thoughts, those patients exhibiting a
significant degree of suicidal ideation prior to commencement of treatment, and young adults are
at an increased risk of suicidal thoughts or suicide attempts and should receive careful
monitoring during treatment [see Warnings and Precautions (5.4)].
Consideration should be given to changing the therapeutic regimen, including possibly
discontinuing the medication, in patients who experience clinical worsening (including
development of new symptoms) and/or the emergence of suicidal ideation/behavior, especially if
these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting
symptoms.
Prescriptions for LAMICTAL should be written for the smallest quantity of tablets consistent
with good patient management in order to reduce the risk of overdose. Overdoses have been
reported for LAMICTAL, some of which have been fatal [see Overdosage (10.1)].
19
Reference ID: 3720577
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-045 & S-051
NDA 020764/S-038 & S-044
NDA 022251/S-007 & S-014
FDA Approved Labeling Text dated 3/24/2015
5.6
Aseptic Meningitis
Therapy with lamotrigine increases the risk of developing aseptic meningitis. Because of the
potential for serious outcomes of untreated meningitis due to other causes, patients should also
be evaluated for other causes of meningitis and treated as appropriate.
Postmarketing cases of aseptic meningitis have been reported in pediatric and adult patients
taking lamotrigine for various indications. Symptoms upon presentation have included headache,
fever, nausea, vomiting, and nuchal rigidity. Rash, photophobia, myalgia, chills, altered
consciousness, and somnolence were also noted in some cases. Symptoms have been reported to
occur within 1 day to one and a half months following the initiation of treatment. In most cases,
symptoms were reported to resolve after discontinuation of lamotrigine. Re-exposure resulted in
a rapid return of symptoms (from within 30 minutes to 1 day following re-initiation of treatment)
that were frequently more severe. Some of the patients treated with lamotrigine who developed
aseptic meningitis had underlying diagnoses of systemic lupus erythematosus or other
autoimmune diseases.
Cerebrospinal fluid (CSF) analyzed at the time of clinical presentation in reported cases was
characterized by a mild to moderate pleocytosis, normal glucose levels, and mild to moderate
increase in protein. CSF white blood cell count differentials showed a predominance of
neutrophils in a majority of the cases, although a predominance of lymphocytes was reported in
approximately one third of the cases. Some patients also had new onset of signs and symptoms
of involvement of other organs (predominantly hepatic and renal involvement), which may
suggest that in these cases the aseptic meningitis observed was part of a hypersensitivity reaction
[see Warnings and Precautions (5.2)].
5.7
Potential Medication Errors
Medication errors involving LAMICTAL have occurred. In particular, the names LAMICTAL or
lamotrigine can be confused with the names of other commonly used medications. Medication
errors may also occur between the different formulations of LAMICTAL. To reduce the potential
of medication errors, write and say LAMICTAL clearly. Depictions of the LAMICTAL tablets,
chewable dispersible tablets, and orally disintegrating tablets can be found in the Medication
Guide that accompanies the product to highlight the distinctive markings, colors, and shapes that
serve to identify the different presentations of the drug and thus may help reduce the risk of
medication errors. To avoid the medication error of using the wrong drug or formulation, patients
should be strongly advised to visually inspect their tablets to verify that they are LAMICTAL, as
well as the correct formulation of LAMICTAL, each time they fill their prescription.
5.8
Concomitant Use With Oral Contraceptives
Some estrogen-containing oral contraceptives have been shown to decrease serum concentrations
of lamotrigine [see Clinical Pharmacology (12.3)]. Dosage adjustments will be necessary in
most patients who start or stop estrogen-containing oral contraceptives while taking LAMICTAL
20
Reference ID: 3720577
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-045 & S-051
NDA 020764/S-038 & S-044
NDA 022251/S-007 & S-014
FDA Approved Labeling Text dated 3/24/2015
[see Dosage and Administration (2.1)]. During the week of inactive hormone preparation (pill-
free week) of oral contraceptive therapy, plasma lamotrigine levels are expected to rise, as much
as doubling at the end of the week. Adverse reactions consistent with elevated levels of
lamotrigine, such as dizziness, ataxia, and diplopia, could occur.
5.9
Withdrawal Seizures
As with other AEDs, LAMICTAL should not be abruptly discontinued. In patients with epilepsy
there is a possibility of increasing seizure frequency. In clinical trials in patients with bipolar
disorder, 2 patients experienced seizures shortly after abrupt withdrawal of LAMICTAL;
however, there were confounding factors that may have contributed to the occurrence of seizures
in these patients with bipolar disorder. Unless safety concerns require a more rapid withdrawal,
the dose of LAMICTAL should be tapered over a period of at least 2 weeks (approximately 50%
reduction per week) [see Dosage and Administration (2.1)].
5.10
Status Epilepticus
Valid estimates of the incidence of treatment-emergent status epilepticus among patients treated
with LAMICTAL are difficult to obtain because reporters participating in clinical trials did not
all employ identical rules for identifying cases. At a minimum, 7 of 2,343 adult patients had
episodes that could unequivocally be described as status epilepticus. In addition, a number of
reports of variably defined episodes of seizure exacerbation (e.g., seizure clusters, seizure
flurries) were made.
5.11
Sudden Unexplained Death in Epilepsy (SUDEP)
During the premarketing development of LAMICTAL, 20 sudden and unexplained deaths were
recorded among a cohort of 4,700 patients with epilepsy (5,747 patient-years of exposure).
Some of these could represent seizure-related deaths in which the seizure was not observed, e.g.,
at night. This represents an incidence of 0.0035 deaths per patient-year. Although this rate
exceeds that expected in a healthy population matched for age and sex, it is within the range of
estimates for the incidence of sudden unexplained death in epilepsy (SUDEP) in patients not
receiving LAMICTAL (ranging from 0.0005 for the general population of patients with epilepsy,
to 0.004 for a recently studied clinical trial population similar to that in the clinical development
program for LAMICTAL, to 0.005 for patients with refractory epilepsy). Consequently, whether
these figures are reassuring or suggest concern depends on the comparability of the populations
reported upon with the cohort receiving LAMICTAL and the accuracy of the estimates provided.
Probably most reassuring is the similarity of estimated SUDEP rates in patients receiving
LAMICTAL and those receiving other AEDs, chemically unrelated to each other, that underwent
clinical testing in similar populations. Importantly, that drug is chemically unrelated to
LAMICTAL. This evidence suggests, although it certainly does not prove, that the high SUDEP
rates reflect population rates, not a drug effect.
21
Reference ID: 3720577
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-045 & S-051
NDA 020764/S-038 & S-044
NDA 022251/S-007 & S-014
FDA Approved Labeling Text dated 3/24/2015
5.12
Addition of LAMICTAL to a Multidrug Regimen That Includes Valproate
Because valproate reduces the clearance of lamotrigine, the dosage of lamotrigine in the presence
of valproate is less than half of that required in its absence [see Dosage and Administration (2.2,
2.3, 2.4), Drug Interactions (7)].
5.13
Binding in the Eye and Other Melanin-Containing Tissues
Because lamotrigine binds to melanin, it could accumulate in melanin-rich tissues over time.
This raises the possibility that lamotrigine may cause toxicity in these tissues after extended use.
Although ophthalmological testing was performed in 1 controlled clinical trial, the testing was
inadequate to exclude subtle effects or injury occurring after long-term exposure. Moreover, the
capacity of available tests to detect potentially adverse consequences, if any, of lamotrigine’s
binding to melanin is unknown [see Clinical Pharmacology (12.2)].
Accordingly, although there are no specific recommendations for periodic ophthalmological
monitoring, prescribers should be aware of the possibility of long-term ophthalmologic effects.
5.14
Laboratory Tests
False-Positive Drug Test Results
Lamotrigine has been reported to interfere with the assay used in some rapid urine drug screens,
which can result in false-positive readings, particularly for phencyclidine (PCP). A more specific
analytical method should be used to confirm a positive result.
Plasma Concentrations of Lamotrigine
The value of monitoring plasma concentrations of lamotrigine in patients treated with
LAMICTAL has not been established. Because of the possible pharmacokinetic interactions
between lamotrigine and other drugs, including AEDs (see Table 15), monitoring of the plasma
levels of lamotrigine and concomitant drugs may be indicated, particularly during dosage
adjustments. In general, clinical judgment should be exercised regarding monitoring of plasma
levels of lamotrigine and other drugs and whether or not dosage adjustments are necessary.
6
ADVERSE REACTIONS
The following adverse reactions are described in more detail in the Warnings and Precautions
section of the label:
• Serious skin rashes [see Warnings and Precautions (5.1)]
• Multiorgan hypersensitivity reactions and organ failure [see Warnings and Precautions (5.2)]
• Blood dyscrasias [see Warnings and Precautions (5.3)]
• Suicidal behavior and ideation [see Warnings and Precautions (5.4)]
• Aseptic meningitis [see Warnings and Precautions (5.6)]
22
Reference ID: 3720577
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-045 & S-051
NDA 020764/S-038 & S-044
NDA 022251/S-007 & S-014
FDA Approved Labeling Text dated 3/24/2015
• Withdrawal seizures [see Warnings and Precautions (5.9)]
• Status epilepticus [see Warnings and Precautions (5.10)]
• Sudden unexplained death in epilepsy [see Warnings and Precautions (5.11)]
6.1
Clinical Trial Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates
observed in the clinical trials of a drug cannot be directly compared with rates in the clinical
trials of another drug and may not reflect the rates observed in practice.
Epilepsy
Most Common Adverse Reactions in All Clinical Trials: Adjunctive Therapy in Adults With
Epilepsy: The most commonly observed (≥5% for LAMICTAL and more common on drug than
placebo) adverse reactions seen in association with LAMICTAL during adjunctive therapy in
adults and not seen at an equivalent frequency among placebo-treated patients were: dizziness,
ataxia, somnolence, headache, diplopia, blurred vision, nausea, vomiting, and rash. Dizziness,
diplopia, ataxia, blurred vision, nausea, and vomiting were dose related. Dizziness, diplopia,
ataxia, and blurred vision occurred more commonly in patients receiving carbamazepine with
LAMICTAL than in patients receiving other AEDs with LAMICTAL. Clinical data suggest a
higher incidence of rash, including serious rash, in patients receiving concomitant valproate than
in patients not receiving valproate [see Warnings and Precautions (5.1)].
Approximately 11% of the 3,378 adult patients who received LAMICTAL as adjunctive therapy
in premarketing clinical trials discontinued treatment because of an adverse reaction. The
adverse reactions most commonly associated with discontinuation were rash (3.0%), dizziness
(2.8%), and headache (2.5%).
In a dose-response trial in adults, the rate of discontinuation of LAMICTAL for dizziness, ataxia,
diplopia, blurred vision, nausea, and vomiting was dose related.
Monotherapy in Adults With Epilepsy: The most commonly observed (≥5% for
LAMICTAL and more common on drug than placebo) adverse reactions seen in association with
the use of LAMICTAL during the monotherapy phase of the controlled trial in adults not seen at
an equivalent rate in the control group were vomiting, coordination abnormality, dyspepsia,
nausea, dizziness, rhinitis, anxiety, insomnia, infection, pain, weight decrease, chest pain, and
dysmenorrhea. The most commonly observed (≥5% for LAMICTAL and more common on drug
than placebo) adverse reactions associated with the use of LAMICTAL during the conversion to
monotherapy (add-on) period, not seen at an equivalent frequency among low-dose valproate-
treated patients, were dizziness, headache, nausea, asthenia, coordination abnormality, vomiting,
rash, somnolence, diplopia, ataxia, accidental injury, tremor, blurred vision, insomnia,
nystagmus, diarrhea, lymphadenopathy, pruritus, and sinusitis.
23
Reference ID: 3720577
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-045 & S-051
NDA 020764/S-038 & S-044
NDA 022251/S-007 & S-014
FDA Approved Labeling Text dated 3/24/2015
Approximately 10% of the 420 adult patients who received LAMICTAL as monotherapy in
premarketing clinical trials discontinued treatment because of an adverse reaction. The adverse
reactions most commonly associated with discontinuation were rash (4.5%), headache (3.1%),
and asthenia (2.4%).
Adjunctive Therapy in Pediatric Patients With Epilepsy: The most commonly observed
(≥5% for LAMICTAL and more common on drug than placebo) adverse reactions seen in
association with the use of LAMICTAL as adjunctive treatment in pediatric patients aged 2 to 16
years and not seen at an equivalent rate in the control group were infection, vomiting, rash, fever,
somnolence, accidental injury, dizziness, diarrhea, abdominal pain, nausea, ataxia, tremor,
asthenia, bronchitis, flu syndrome, and diplopia.
In 339 patients aged 2 to 16 years with partial-onset seizures or generalized seizures of Lennox-
Gastaut syndrome, 4.2% of patients on LAMICTAL and 2.9% of patients on placebo
discontinued due to adverse reactions. The most commonly reported adverse reaction that led to
discontinuation of LAMICTAL was rash.
Approximately 11.5% of the 1,081 pediatric patients aged 2 to 16 years who received
LAMICTAL as adjunctive therapy in premarketing clinical trials discontinued treatment because
of an adverse reaction. The adverse reactions most commonly associated with discontinuation
were rash (4.4%), reaction aggravated (1.7%), and ataxia (0.6%).
Controlled Adjunctive Clinical Trials in Adults With Epilepsy: Table 8 lists adverse
reactions that occurred in adult patients with epilepsy treated with LAMICTAL in placebo-
controlled trials. In these studies, either LAMICTAL or placebo was added to the patient’s
current AED therapy.
Table 8. Adverse Reactions in Pooled, Placebo-Controlled Adjunctive Trials in Adult
Patients With Epilepsya,b
Body System/
Adverse Reaction
Percent of Patients
Receiving Adjunctive
LAMICTAL
(n = 711)
Percent of Patients
Receiving Adjunctive
Placebo
(n = 419)
Body as a whole
Headache
Flu syndrome
Fever
Abdominal pain
Neck pain
Reaction aggravated
(seizure exacerbation)
29
7
6
5
2
2
19
6
4
4
1
1
24
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FDA Approved Labeling Text dated 3/24/2015
Digestive
Nausea
19
10
Vomiting
9
4
Diarrhea
6
4
Dyspepsia
5
2
Constipation
4
3
Anorexia
2
1
Musculoskeletal
Arthralgia
2
0
Nervous
Dizziness
38
13
Ataxia
22
6
Somnolence
14
7
Incoordination
6
2
Insomnia
6
2
Tremor
4
1
Depression
4
3
Anxiety
4
3
Convulsion
3
1
Irritability
3
2
Speech disorder
3
0
Concentration disturbance
2
1
Respiratory
Rhinitis
14
9
Pharyngitis
10
9
Cough increased
8
6
Skin and appendages
Rash
Pruritus
10
3
5
2
Special senses
Diplopia
28
7
Blurred vision
16
5
Vision abnormality
3
1
Urogenital
Female patients only
Dysmenorrhea
Vaginitis
Amenorrhea
(n = 365)
7
4
2
(n = 207)
6
1
1
a Adverse reactions that occurred in at least 2% of patients treated with LAMICTAL and at a
greater incidence than placebo.
25
Reference ID: 3720577
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FDA Approved Labeling Text dated 3/24/2015
b Patients in these adjunctive trials were receiving 1 to 3 of the concomitant antiepileptic drugs
carbamazepine, phenytoin, phenobarbital, or primidone in addition to LAMICTAL or
placebo. Patients may have reported multiple adverse reactions during the trial or at
discontinuation; thus, patients may be included in more than 1 category.
In a randomized, parallel trial comparing placebo with 300 and 500 mg/day of LAMICTAL,
some of the more common drug-related adverse reactions were dose related (see Table 9).
Table 9. Dose-Related Adverse Reactions From a Randomized, Placebo-Controlled,
Adjunctive Trial in Adults With Epilepsy
Adverse Reaction
Percent of Patients Experiencing Adverse Reactions
Placebo
(n = 73)
LAMICTAL
300 mg
(n = 71)
LAMICTAL
500 mg
(n = 72)
Ataxia
Blurred vision
Diplopia
Dizziness
Nausea
Vomiting
10
10
8
27
11
4
10
11
24
a
31
18
11
28
a,b
25
a,b
49
a,b
54
a,b
25
a
18
a
a Significantly greater than placebo group (P<0.05).
b Significantly greater than group receiving LAMICTAL 300 mg (P<0.05).
The overall adverse reaction profile for LAMICTAL was similar between females and males and
was independent of age. Because the largest non-Caucasian racial subgroup was only 6% of
patients exposed to LAMICTAL in placebo-controlled trials, there are insufficient data to
support a statement regarding the distribution of adverse reaction reports by race. Generally,
females receiving either LAMICTAL as adjunctive therapy or placebo were more likely to report
adverse reactions than males. The only adverse reaction for which the reports on LAMICTAL
were greater than 10% more frequent in females than males (without a corresponding difference
by gender on placebo) was dizziness (difference = 16.5%). There was little difference between
females and males in the rates of discontinuation of LAMICTAL for individual adverse
reactions.
Controlled Monotherapy Trial in Adults With Partial-Onset Seizures: Table 10 lists
adverse reactions that occurred in patients with epilepsy treated with monotherapy with
LAMICTAL in a double-blind trial following discontinuation of either concomitant
carbamazepine or phenytoin not seen at an equivalent frequency in the control group.
26
Reference ID: 3720577
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Table 10. Adverse Reactions in a Controlled Monotherapy Trial in Adult Patients With
Partial-Onset Seizuresa,b
Body System/
Adverse Reaction
Percent of Patients
Receiving LAMICTALc as
Monotherapy
(n = 43)
Percent of Patients
Receiving Low-Dose
Valproated Monotherapy
(n = 44)
Body as a whole
Pain
Infection
Chest pain
5
5
5
0
2
2
Digestive
Vomiting
Dyspepsia
Nausea
9
7
7
0
2
2
Metabolic and nutritional
Weight decrease
5
2
Nervous
Coordination abnormality
Dizziness
Anxiety
Insomnia
7
7
5
5
0
0
0
2
Respiratory
Rhinitis
7
2
Urogenital (female patients
only)
Dysmenorrhea
(n = 21)
5
(n = 28)
0
a Adverse reactions that occurred in at least 5% of patients treated with LAMICTAL and at a
greater incidence than valproate-treated patients.
b Patients in this trial were converted to LAMICTAL or valproate monotherapy from
adjunctive therapy with carbamazepine or phenytoin. Patients may have reported multiple
adverse reactions during the trial; thus, patients may be included in more than 1 category.
c Up to 500 mg/day.
d 1,000 mg/day.
Adverse reactions that occurred with a frequency of less than 5% and greater than 2% of patients
receiving LAMICTAL and numerically more frequent than placebo were:
Body as a Whole: Asthenia, fever.
Digestive: Anorexia, dry mouth, rectal hemorrhage, peptic ulcer.
Metabolic and Nutritional: Peripheral edema.
27
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Nervous System: Amnesia, ataxia, depression, hypesthesia, libido increase, decreased reflexes,
increased reflexes, nystagmus, irritability, suicidal ideation.
Respiratory: Epistaxis, bronchitis, dyspnea.
Skin and Appendages: Contact dermatitis, dry skin, sweating.
Special Senses: Vision abnormality.
Incidence in Controlled Adjunctive Trials in Pediatric Patients With Epilepsy: Table 11
lists adverse reactions that occurred in 339 pediatric patients with partial-onset seizures or
generalized seizures of Lennox-Gastaut syndrome who received LAMICTAL up to 15
mg/kg/day or a maximum of 750 mg/day.
Table 11. Adverse Reactions in Pooled, Placebo-Controlled Adjunctive Trials in Pediatric
Patients With Epilepsya
Body System/Adverse Reaction
Percent of Patients
Receiving LAMICTAL
(n = 168)
Percent of Patients
Receiving Placebo
(n = 171)
Body as a whole
Infection
20
17
Fever
15
14
Accidental injury
14
12
Abdominal pain
10
5
Asthenia
8
4
Flu syndrome
7
6
Pain
5
4
Facial edema
2
1
Photosensitivity
2
0
Cardiovascular
Hemorrhage
2
1
Digestive
Vomiting
20
16
Diarrhea
11
9
Nausea
10
2
Constipation
4
2
Dyspepsia
2
1
Hemic and lymphatic
Lymphadenopathy
2
1
Metabolic and nutritional
Edema
2
0
28
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Nervous system
Somnolence
17
15
Dizziness
14
4
Ataxia
11
3
Tremor
10
1
Emotional lability
4
2
Gait abnormality
4
2
Thinking abnormality
3
2
Convulsions
2
1
Nervousness
2
1
Vertigo
2
1
Respiratory
Pharyngitis
14
11
Bronchitis
7
5
Increased cough
7
6
Sinusitis
2
1
Bronchospasm
2
1
Skin
Rash
14
12
Eczema
2
1
Pruritus
2
1
Special senses
Diplopia
5
1
Blurred vision
4
1
Visual abnormality
2
0
Urogenital
Male and female patients
Urinary tract infection
3
0
a Adverse reactions that occurred in at least 2% of patients treated with LAMICTAL and at a
greater incidence than placebo.
Bipolar Disorder
The most common adverse reactions seen in association with the use of LAMICTAL as
monotherapy (100 to 400 mg/day) in adult patients (aged 18 years and older) with bipolar
disorder in the 2 double-blind, placebo-controlled trials of 18 months’ duration are included in
Table 12. Adverse reactions that occurred in at least 5% of patients and were numerically more
frequent during the dose-escalation phase of LAMICTAL in these trials (when patients may have
been receiving concomitant medications) compared with the monotherapy phase were: headache
(25%), rash (11%), dizziness (10%), diarrhea (8%), dream abnormality (6%), and pruritus (6%).
29
Reference ID: 3720577
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For current labeling information, please visit https://www.fda.gov/drugsatfda
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NDA 022251/S-007 & S-014
FDA Approved Labeling Text dated 3/24/2015
During the monotherapy phase of the double-blind, placebo-controlled trials of 18 months’
duration, 13% of 227 patients who received LAMICTAL (100 to 400 mg/day), 16% of 190
patients who received placebo, and 23% of 166 patients who received lithium discontinued
therapy because of an adverse reaction. The adverse reactions which most commonly led to
discontinuation of LAMICTAL were rash (3%) and mania/hypomania/mixed mood adverse
reactions (2%). Approximately 16% of 2,401 patients who received LAMICTAL (50 to
500 mg/day) for bipolar disorder in premarketing trials discontinued therapy because of an
adverse reaction, most commonly due to rash (5%) and mania/hypomania/mixed mood adverse
reactions (2%).
The overall adverse reaction profile for LAMICTAL was similar between females and males,
between elderly and nonelderly patients, and among racial groups.
Table 12. Adverse Reactions in 2 Placebo-Controlled Trials in Adult Patients With Bipolar
I Disordera,b
Body System/
Adverse Reaction
Percent of Patients
Receiving LAMICTAL
(n = 227)
Percent of Patients
Receiving Placebo
(n = 190)
General
Back pain
Fatigue
Abdominal pain
8
8
6
6
5
3
Digestive
Nausea
Constipation
Vomiting
14
5
5
11
2
2
Nervous System
Insomnia
Somnolence
Xerostomia (dry mouth)
10
9
6
6
7
4
Respiratory
Rhinitis
Exacerbation of cough
Pharyngitis
7
5
5
4
3
4
Skin
Rash (nonserious)c
7
5
a Adverse reactions that occurred in at least 5% of patients treated with LAMICTAL and at a
greater incidence than placebo.
b Patients in these trials were converted to LAMICTAL (100 to 400 mg/day) or placebo
monotherapy from add-on therapy with other psychotropic medications. Patients may have
reported multiple adverse reactions during the trial; thus, patients may be included in more
30
Reference ID: 3720577
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-045 & S-051
NDA 020764/S-038 & S-044
NDA 022251/S-007 & S-014
FDA Approved Labeling Text dated 3/24/2015
than 1 category.
c In the overall bipolar and other mood disorders clinical trials, the rate of serious rash was
0.08% (1 of 1,233) of adult patients who received LAMICTAL as initial monotherapy and
0.13% (2 of 1,538) of adult patients who received LAMICTAL as adjunctive therapy [see
Warnings and Precautions (5.1)].
Other reactions that occurred in 5% or more patients but equally or more frequently in the
placebo group included: dizziness, mania, headache, infection, influenza, pain, accidental injury,
diarrhea, and dyspepsia.
Adverse reactions that occurred with a frequency of less than 5% and greater than 1% of patients
receiving LAMICTAL and numerically more frequent than placebo were:
General: Fever, neck pain.
Cardiovascular: Migraine.
Digestive: Flatulence.
Metabolic and Nutritional: Weight gain, edema.
Musculoskeletal: Arthralgia, myalgia.
Nervous System: Amnesia, depression, agitation, emotional lability, dyspraxia, abnormal
thoughts, dream abnormality, hypoesthesia.
Respiratory: Sinusitis.
Urogenital: Urinary frequency.
Adverse Reactions Following Abrupt Discontinuation: In the 2 maintenance trials, there was no
increase in the incidence, severity, or type of adverse reactions in patients with bipolar disorder
after abruptly terminating therapy with LAMICTAL. In clinical trials in patients with bipolar
disorder, 2 patients experienced seizures shortly after abrupt withdrawal of LAMICTAL.
However, there were confounding factors that may have contributed to the occurrence of seizures
in these patients with bipolar disorder [see Warnings and Precautions (5.9)].
Mania/Hypomania/Mixed Episodes: During the double-blind, placebo-controlled clinical trials in
bipolar I disorder in which patients were converted to monotherapy with LAMICTAL (100 to
400 mg/day) from other psychotropic medications and followed for up to 18 months, the rates of
manic or hypomanic or mixed mood episodes reported as adverse reactions were 5% for patients
treated with LAMICTAL (n = 227), 4% for patients treated with lithium (n = 166), and 7% for
patients treated with placebo (n = 190). In all bipolar controlled trials combined, adverse
reactions of mania (including hypomania and mixed mood episodes) were reported in 5% of
patients treated with LAMICTAL (n = 956), 3% of patients treated with lithium (n = 280), and
4% of patients treated with placebo (n = 803).
6.2
Other Adverse Reactions Observed in All Clinical Trials
31
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LAMICTAL has been administered to 6,694 individuals for whom complete adverse reaction
data was captured during all clinical trials, only some of which were placebo controlled. During
these trials, all adverse reactions were recorded by the clinical investigators using terminology of
their own choosing. To provide a meaningful estimate of the proportion of individuals having
adverse reactions, similar types of adverse reactions were grouped into a smaller number of
standardized categories using modified COSTART dictionary terminology. The frequencies
presented represent the proportion of the 6,694 individuals exposed to LAMICTAL who
experienced an event of the type cited on at least 1 occasion while receiving LAMICTAL. All
reported adverse reactions are included except those already listed in the previous tables or
elsewhere in the labeling, those too general to be informative, and those not reasonably
associated with the use of the drug.
Adverse reactions are further classified within body system categories and enumerated in order
of decreasing frequency using the following definitions: frequent adverse reactions are defined as
those occurring in at least 1/100 patients; infrequent adverse reactions are those occurring in
1/100 to 1/1,000 patients; rare adverse reactions are those occurring in fewer than 1/1,000
patients.
Body as a Whole
Infrequent: Allergic reaction, chills, malaise.
Cardiovascular System
Infrequent: Flushing, hot flashes, hypertension, palpitations, postural hypotension, syncope,
tachycardia, vasodilation.
Dermatological
Infrequent: Acne, alopecia, hirsutism, maculopapular rash, skin discoloration, urticaria.
Rare: Angioedema, erythema, exfoliative dermatitis, fungal dermatitis, herpes zoster,
leukoderma, multiforme erythema, petechial rash, pustular rash, Stevens-Johnson syndrome,
vesiculobullous rash.
Digestive System
Infrequent: Dysphagia, eructation, gastritis, gingivitis, increased appetite, increased salivation,
liver function tests abnormal, mouth ulceration.
Rare: Gastrointestinal hemorrhage, glossitis, gum hemorrhage, gum hyperplasia, hematemesis,
hemorrhagic colitis, hepatitis, melena, stomach ulcer, stomatitis, tongue edema.
Endocrine System
Rare: Goiter, hypothyroidism.
Hematologic and Lymphatic System
32
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Infrequent: Ecchymosis, leukopenia.
Rare: Anemia, eosinophilia, fibrin decrease, fibrinogen decrease, iron deficiency anemia,
leukocytosis, lymphocytosis, macrocytic anemia, petechia, thrombocytopenia.
Metabolic and Nutritional Disorders
Infrequent: Aspartate transaminase increased.
Rare: Alcohol intolerance, alkaline phosphatase increase, alanine transaminase increase,
bilirubinemia, general edema, gamma glutamyl transpeptidase increase, hyperglycemia.
Musculoskeletal System
Infrequent: Arthritis, leg cramps, myasthenia, twitching.
Rare: Bursitis, muscle atrophy, pathological fracture, tendinous contracture.
Nervous System
Frequent: Confusion, paresthesia.
Infrequent: Akathisia, apathy, aphasia, central nervous system depression, depersonalization,
dysarthria, dyskinesia, euphoria, hallucinations, hostility, hyperkinesia, hypertonia, libido
decreased, memory decrease, mind racing, movement disorder, myoclonus, panic attack,
paranoid reaction, personality disorder, psychosis, sleep disorder, stupor, suicidal ideation.
Rare: Choreoathetosis, delirium, delusions, dysphoria, dystonia, extrapyramidal syndrome,
faintness, grand mal convulsions, hemiplegia, hyperalgesia, hyperesthesia, hypokinesia,
hypotonia, manic depression reaction, muscle spasm, neuralgia, neurosis, paralysis, peripheral
neuritis.
Respiratory System
Infrequent: Yawn.
Rare: Hiccup, hyperventilation.
Special Senses
Frequent: Amblyopia.
Infrequent: Abnormality of accommodation, conjunctivitis, dry eyes, ear pain, photophobia, taste
perversion, tinnitus.
Rare: Deafness, lacrimation disorder, oscillopsia, parosmia, ptosis, strabismus, taste loss, uveitis,
visual field defect.
Urogenital System
Infrequent: Abnormal ejaculation, hematuria, impotence, menorrhagia, polyuria, urinary
incontinence.
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Rare: Acute kidney failure, anorgasmia, breast abscess, breast neoplasm, creatinine increase,
cystitis, dysuria, epididymitis, female lactation, kidney failure, kidney pain, nocturia, urinary
retention, urinary urgency.
6.3
Postmarketing Experience
The following adverse events (not listed above in clinical trials or other sections of the
prescribing information) have been identified during postapproval use of LAMICTAL. Because
these events are reported voluntarily from a population of uncertain size, it is not always possible
to reliably estimate their frequency or establish a causal relationship to drug exposure.
Blood and Lymphatic
Agranulocytosis, hemolytic anemia, lymphadenopathy not associated with hypersensitivity
disorder.
Gastrointestinal
Esophagitis.
Hepatobiliary Tract and Pancreas
Pancreatitis.
Immunologic
Lupus-like reaction, vasculitis.
Lower Respiratory
Apnea.
Musculoskeletal
Rhabdomyolysis has been observed in patients experiencing hypersensitivity reactions.
Nervous System
Aggression, exacerbation of Parkinsonian symptoms in patients with pre-existing Parkinson’s
disease, tics.
Non-site Specific
Progressive immunosuppression.
7
DRUG INTERACTIONS
Significant drug interactions with LAMICTAL are summarized in this section. Additional details
of these drug interaction studies are provided in the Clinical Pharmacology section [see Clinical
Pharmacology (12.3)].
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Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug
Effect on
Concentration of
Lamotrigine or
Concomitant Drug
Clinical Comment
Estrogen-containing oral
contraceptive
preparations containing
30 mcg ethinylestradiol
and 150 mcg
levonorgestrel
↓ lamotrigine
↓ levonorgestrel
Decreased lamotrigine concentrations
approximately 50%.
Decrease in levonorgestrel component by
19%.
Carbamazepine and
carbamazepine epoxide
↓ lamotrigine
? carbamazepine
epoxide
Addition of carbamazepine decreases
lamotrigine concentration approximately
40%.
May increase carbamazepine epoxide
levels.
Lopinavir/ritonavir
↓ lamotrigine
Decreased lamotrigine concentration
approximately 50%.
Atazanavir/ritonavir
↓ lamotrigine
Decreased lamotrigine AUC
approximately 32%.
Phenobarbital/primidone
↓ lamotrigine
Decreased lamotrigine concentration
approximately 40%.
Phenytoin
↓ lamotrigine
Decreased lamotrigine concentration
approximately 40%.
Rifampin
↓ lamotrigine
Decreased lamotrigine AUC
approximately 40%.
Valproate
↑ lamotrigine
? valproate
Increased lamotrigine concentrations
slightly more than 2-fold.
There are conflicting study results
regarding effect of lamotrigine on
valproate concentrations: 1) a mean 25%
decrease in valproate concentrations in
healthy volunteers, 2) no change in
valproate concentrations in controlled
clinical trials in patients with epilepsy.
↓ = Decreased (induces lamotrigine glucuronidation).
↑ = Increased (inhibits lamotrigine glucuronidation).
? = Conflicting data.
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Effect of LAMICTAL on Organic Cationic Transporter 2 Substrates
Lamotrigine is an inhibitor of renal tubular secretion via organic cationic transporter 2 (OCT2)
proteins [see Clinical Pharmacology (12.3)]. This may result in increased plasma levels of
certain drugs that are substantially excreted via this route. Coadministration of LAMICTAL with
OCT2 substrates with a narrow therapeutic index (e.g., dofetilide) is not recommended.
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
As with other AEDs, physiological changes during pregnancy may affect lamotrigine
concentrations and/or therapeutic effect. There have been reports of decreased lamotrigine
concentrations during pregnancy and restoration of pre-partum concentrations after delivery.
Dosage adjustments may be necessary to maintain clinical response.
Pregnancy Category C
There are no adequate and well-controlled studies in pregnant women. In animal studies,
lamotrigine was developmentally toxic at doses lower than those administered clinically.
LAMICTAL should be used during pregnancy only if the potential benefit justifies the potential
risk to the fetus. When lamotrigine was administered to pregnant mice, rats, or rabbits during the
period of organogenesis (oral doses of up to 125, 25, and 30 mg/kg, respectively), reduced fetal
body weight and increased incidences of fetal skeletal variations were seen in mice and rats at
doses that were also maternally toxic. The no-effect doses for embryofetal developmental
toxicity in mice, rats, and rabbits (75, 6.25, and 30 mg/kg, respectively) are similar to (mice and
rabbits) or less than (rats) the human dose of 400 mg/day on a body surface area (mg/m2) basis.
In a study in which pregnant rats were administered lamotrigine (oral doses of 5 or 25 mg/kg)
during the period of organogenesis and offspring were evaluated postnatally, behavioral
abnormalities were observed in exposed offspring at both doses. The lowest effect dose for
developmental neurotoxicity in rats is less than the human dose of 400 mg/day on a mg/m2 basis.
Maternal toxicity was observed at the higher dose tested.
When pregnant rats were administered lamotrigine (oral doses of 5, 10, or 20 mg/kg) during the
latter part of gestation, increased offspring mortality (including stillbirths) was seen at all doses.
The lowest effect dose for peri/postnatal developmental toxicity in rats is less than the human
dose of 400 mg/day on a mg/m2 basis. Maternal toxicity was observed at the 2 highest doses
tested.
Lamotrigine decreases fetal folate concentrations in rat, an effect known to be associated with
adverse pregnancy outcomes in animals and humans.
Pregnancy Registry
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To provide information regarding the effects of in utero exposure to LAMICTAL, physicians are
advised to recommend that pregnant patients taking LAMICTAL enroll in the North American
Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll-free
number 1-888-233-2334 and must be done by patients themselves. Information on the registry
can also be found at the website http://www.aedpregnancyregistry.org.
8.2
Labor and Delivery
The effect of LAMICTAL on labor and delivery in humans is unknown.
8.3
Nursing Mothers
Lamotrigine is present in milk from lactating women taking LAMICTAL. Data from multiple
small studies indicate that lamotrigine plasma levels in human milk-fed infants have been
reported to be as high as 50% of the maternal serum levels. Neonates and young infants are at
risk for high serum levels because maternal serum and milk levels can rise to high levels
postpartum if lamotrigine dosage has been increased during pregnancy but not later reduced to
the pre-pregnancy dosage. Lamotrigine exposure is further increased due to the immaturity of the
infant glucuronidation capacity needed for drug clearance. Events including apnea, drowsiness,
and poor sucking have been reported in infants who have been human milk-fed by mothers using
lamotrigine; whether or not these events were caused by lamotrigine is unknown. Human milk-
fed infants should be closely monitored for adverse events resulting from lamotrigine.
Measurement of infant serum levels should be performed to rule out toxicity if concerns arise.
Human milk-feeding should be discontinued in infants with lamotrigine toxicity. Caution should
be exercised when LAMICTAL is administered to a nursing woman.
8.4
Pediatric Use
LAMICTAL is indicated for adjunctive therapy in patients aged 2 years and older for partial-
onset seizures, the generalized seizures of Lennox-Gastaut syndrome, and PGTC seizures.
Safety and efficacy of LAMICTAL used as adjunctive treatment for partial-onset seizures were
not demonstrated in a small, randomized, double-blind, placebo-controlled withdrawal trial in
very young pediatric patients (aged 1 to 24 months). LAMICTAL was associated with an
increased risk for infectious adverse reactions (LAMICTAL 37%, placebo 5%), and respiratory
adverse reactions (LAMICTAL 26%, placebo 5%). Infectious adverse reactions included
bronchiolitis, bronchitis, ear infection, eye infection, otitis externa, pharyngitis, urinary tract
infection, and viral infection. Respiratory adverse reactions included nasal congestion, cough,
and apnea.
Safety and effectiveness in patients younger than 18 years with bipolar disorder have not been
established.
In a juvenile animal study in which lamotrigine (oral doses of 5, 15, or 30 mg/kg) was
administered to young rats (postnatal days 7 to 62), decreased viability and growth were seen at
the highest dose tested and long-term behavioral abnormalities (decreased locomotor activity,
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increased reactivity, and learning deficits in animals tested as adults) were observed at the 2
highest doses. The no-effect dose for adverse effects on neurobehavioral development is less
than the human dose of 400 mg/day on a mg/m2 basis.
8.5
Geriatric Use
Clinical trials of LAMICTAL for epilepsy and bipolar disorder did not include sufficient
numbers of patients aged 65 years and older to determine whether they respond differently from
younger patients or exhibit a different safety profile than that of younger patients. In general,
dose selection for an elderly patient should be cautious, usually starting at the low end of the
dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and
of concomitant disease or other drug therapy.
8.6
Hepatic Impairment
Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology
study in 24 subjects with mild, moderate, and severe liver impairment [see Clinical
Pharmacology (12.3)], the following general recommendations can be made. No dosage
adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance
doses should generally be reduced by approximately 25% in patients with moderate and severe
liver impairment without ascites and 50% in patients with severe liver impairment with ascites.
Escalation and maintenance doses may be adjusted according to clinical response [see Dosage
and Administration (2.1)].
8.7
Renal Impairment
Lamotrigine is metabolized mainly by glucuronic acid conjugation, with the majority of the
metabolites being recovered in the urine. In a small study comparing a single dose of lamotrigine
in subjects with varying degrees of renal impairment with healthy volunteers, the plasma half-life
of lamotrigine was approximately twice as long in the subjects with chronic renal failure [see
Clinical Pharmacology (12.3)].
Initial doses of LAMICTAL should be based on patients’ AED regimens; reduced maintenance
doses may be effective for patients with significant renal impairment. Few patients with severe
renal impairment have been evaluated during chronic treatment with lamotrigine. Because there
is inadequate experience in this population, LAMICTAL should be used with caution in these
patients [see Dosage and Administration (2.1)].
10
OVERDOSAGE
10.1
Human Overdose Experience
Overdoses involving quantities up to 15 g have been reported for LAMICTAL, some of which
have been fatal. Overdose has resulted in ataxia, nystagmus, seizures (including tonic-clonic
seizures), decreased level of consciousness, coma, and intraventricular conduction delay.
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10.2
Management of Overdose
There are no specific antidotes for lamotrigine. Following a suspected overdose, hospitalization
of the patient is advised. General supportive care is indicated, including frequent monitoring of
vital signs and close observation of the patient. If indicated, emesis should be induced; usual
precautions should be taken to protect the airway. It should be kept in mind that immediate-
release lamotrigine is rapidly absorbed [see Clinical Pharmacology (12.3)]. It is uncertain
whether hemodialysis is an effective means of removing lamotrigine from the blood. In 6 renal
failure patients, about 20% of the amount of lamotrigine in the body was removed by
hemodialysis during a 4-hour session. A Poison Control Center should be contacted for
information on the management of overdosage of LAMICTAL.
11
DESCRIPTION
LAMICTAL (lamotrigine), an AED of the phenyltriazine class, is chemically unrelated to
existing AEDs. Lamotrigine’s chemical name is 3,5-diamino-6-(2,3-dichlorophenyl)-as-triazine,
its molecular formula is C9H7N5Cl2, and its molecular weight is 256.09. Lamotrigine is a white to
pale cream-colored powder and has a pKa of 5.7. Lamotrigine is very slightly soluble in water
(0.17 mg/mL at 25°C) and slightly soluble in 0.1 M HCl (4.1 mg/mL at 25°C). The structural
formula is:
LAMICTAL tablets are supplied for oral administration as 25-mg (white), 100-mg (peach), 150-
mg (cream), and 200-mg (blue) tablets. Each tablet contains the labeled amount of lamotrigine
and the following inactive ingredients: lactose; magnesium stearate; microcrystalline cellulose;
povidone; sodium starch glycolate; FD&C Yellow No. 6 Lake (100-mg tablet only); ferric oxide,
yellow (150-mg tablet only); and FD&C Blue No. 2 Lake (200-mg tablet only).
LAMICTAL chewable dispersible tablets are supplied for oral administration. The tablets
contain 2 mg (white), 5 mg (white), or 25 mg (white) of lamotrigine and the following inactive
ingredients: blackcurrant flavor, calcium carbonate, low-substituted hydroxypropylcellulose,
magnesium aluminum silicate, magnesium stearate, povidone, saccharin sodium, and sodium
starch glycolate. The chewable dispersible tablets meet Organic Impurities Procedure 2 as
published in the current USP monograph for Lamotrigine Tablets for Oral Suspension.
LAMICTAL ODT orally disintegrating tablets are supplied for oral administration. The tablets
contain 25 mg (white to off-white), 50 mg (white to off-white), 100 mg (white to off-white), or
200 mg (white to off-white) of lamotrigine and the following inactive ingredients: artificial
cherry flavor, crospovidone, ethylcellulose, magnesium stearate, mannitol, polyethylene, and
sucralose.
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LAMICTAL ODT orally disintegrating tablets are formulated using technologies (Microcaps®
and AdvaTab®) designed to mask the bitter taste of lamotrigine and achieve a rapid dissolution
profile. Tablet characteristics including flavor, mouth-feel, after-taste, and ease of use were rated
as favorable in a study in 108 healthy volunteers.
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
The precise mechanism(s) by which lamotrigine exerts its anticonvulsant action are unknown. In
animal models designed to detect anticonvulsant activity, lamotrigine was effective in preventing
seizure spread in the maximum electroshock (MES) and pentylenetetrazol (scMet) tests, and
prevented seizures in the visually and electrically evoked after-discharge (EEAD) tests for
antiepileptic activity. Lamotrigine also displayed inhibitory properties in the kindling model in
rats both during kindling development and in the fully kindled state. The relevance of these
models to human epilepsy, however, is not known.
One proposed mechanism of action of lamotrigine, the relevance of which remains to be
established in humans, involves an effect on sodium channels. In vitro pharmacological studies
suggest that lamotrigine inhibits voltage-sensitive sodium channels, thereby stabilizing neuronal
membranes and consequently modulating presynaptic transmitter release of excitatory amino
acids (e.g., glutamate and aspartate).
Effect of Lamotrigine on N-Methyl d-Aspartate-Receptor Mediated Activity
Lamotrigine did not inhibit N-methyl d-aspartate (NMDA)-induced depolarizations in rat cortical
slices or NMDA-induced cyclic GMP formation in immature rat cerebellum, nor did lamotrigine
displace compounds that are either competitive or noncompetitive ligands at this glutamate
receptor complex (CNQX, CGS, TCHP). The IC50 for lamotrigine effects on NMDA-induced
currents (in the presence of 3 µM of glycine) in cultured hippocampal neurons exceeded 100
µM.
The mechanisms by which lamotrigine exerts its therapeutic action in bipolar disorder have not
been established.
12.2
Pharmacodynamics
Folate Metabolism
In vitro, lamotrigine inhibited dihydrofolate reductase, the enzyme that catalyzes the reduction of
dihydrofolate to tetrahydrofolate. Inhibition of this enzyme may interfere with the biosynthesis
of nucleic acids and proteins. When oral daily doses of lamotrigine were given to pregnant rats
during organogenesis, fetal, placental, and maternal folate concentrations were reduced.
Significantly reduced concentrations of folate are associated with teratogenesis [see Use in
Specific Populations (8.1)]. Folate concentrations were also reduced in male rats given repeated
40
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oral doses of lamotrigine. Reduced concentrations were partially returned to normal when
supplemented with folinic acid.
Accumulation in Kidneys
Lamotrigine accumulated in the kidney of the male rat, causing chronic progressive nephrosis,
necrosis, and mineralization. These findings are attributed to α-2 microglobulin, a species- and
sex-specific protein that has not been detected in humans or other animal species.
Melanin Binding
Lamotrigine binds to melanin-containing tissues, e.g., in the eye and pigmented skin. It has been
found in the uveal tract up to 52 weeks after a single dose in rodents.
Cardiovascular
In dogs, lamotrigine is extensively metabolized to a 2-N-methyl metabolite. This metabolite
causes dose-dependent prolongation of the PR interval, widening of the QRS complex, and, at
higher doses, complete AV conduction block. Similar cardiovascular effects are not anticipated
in humans because only trace amounts of the 2-N-methyl metabolite (<0.6% of lamotrigine dose)
have been found in human urine [see Clinical Pharmacology (12.3)]. However, it is conceivable
that plasma concentrations of this metabolite could be increased in patients with a reduced
capacity to glucuronidate lamotrigine (e.g., in patients with liver disease, patients taking
concomitant medications that inhibit glucuronidation).
12.3
Pharmacokinetics
The pharmacokinetics of lamotrigine have been studied in subjects with epilepsy, healthy young
and elderly volunteers, and volunteers with chronic renal failure. Lamotrigine pharmacokinetic
parameters for adult and pediatric subjects and healthy normal volunteers are summarized in
Tables 14 and 16.
Table 14. Mean Pharmacokinetic Parametersa in Healthy Volunteers and Adult Subjects
With Epilepsy
Adult Study Population
Number
of
Subjects
Tmax: Time of
Maximum
Plasma
Concentration
(h)
t½:
Elimination
Half-life
(h)
CL/F:
Apparent
Plasma
Clearance
(mL/min/kg)
Healthy volunteers taking no
other medications:
Single-dose LAMICTAL
Multiple-dose LAMICTAL
179
36
2.2
(0.25-12.0)
1.7
(0.5-4.0)
32.8
(14.0-103.0)
25.4
(11.6-61.6)
0.44
(0.12-1.10)
0.58
(0.24-1.15)
41
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Healthy volunteers taking
valproate:
Single-dose LAMICTAL
Multiple-dose LAMICTAL
6
18
1.8
(1.0-4.0)
1.9
(0.5-3.5)
48.3
(31.5-88.6)
70.3
(41.9-113.5)
0.30
(0.14-0.42)
0.18
(0.12-0.33)
Subjects with epilepsy taking
valproate only:
Single-dose LAMICTAL
4
4.8
(1.8-8.4)
58.8
(30.5-88.8)
0.28
(0.16-0.40)
Subjects with epilepsy taking
carbamazepine, phenytoin,
phenobarbital, or primidoneb
plus valproate:
Single-dose LAMICTAL
25
3.8
(1.0-10.0)
27.2
(11.2-51.6)
0.53
(0.27-1.04)
Subjects with epilepsy taking
carbamazepine, phenytoin,
phenobarbital, or primidone:b
Single-dose LAMICTAL
Multiple-dose LAMICTAL
24
17
2.3
(0.5-5.0)
2.0
(0.75-5.93)
14.4
(6.4-30.4)
12.6
(7.5-23.1)
1.10
(0.51-2.22)
1.21
(0.66-1.82)
a The majority of parameter means determined in each study had coefficients of variation
between 20% and 40% for half-life and CL/F and between 30% and 70% for Tmax. The overall
mean values were calculated from individual study means that were weighted based on the
number of volunteers/subjects in each study. The numbers in parentheses below each
parameter mean represent the range of individual volunteer/subject values across studies.
b Carbamazepine, phenytoin, phenobarbital, and primidone have been shown to increase the
apparent clearance of lamotrigine. Estrogen-containing oral contraceptives and other drugs,
such as rifampin and protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir, that
induce lamotrigine glucuronidation have also been shown to increase the apparent clearance
of lamotrigine [see Drug Interactions (7)].
Absorption
Lamotrigine is rapidly and completely absorbed after oral administration with negligible first-
pass metabolism (absolute bioavailability is 98%). The bioavailability is not affected by food.
Peak plasma concentrations occur anywhere from 1.4 to 4.8 hours following drug administration.
The lamotrigine chewable/dispersible tablets were found to be equivalent whether administered
as dispersed in water, chewed and swallowed, or swallowed as whole, to the lamotrigine
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compressed tablets in terms of rate and extent of absorption. In terms of rate and extent of
absorption, lamotrigine orally disintegrating tablets whether disintegrated in the mouth or
swallowed whole with water were equivalent to the lamotrigine compressed tablets swallowed
with water.
Dose Proportionality
In healthy volunteers not receiving any other medications and given single doses, the plasma
concentrations of lamotrigine increased in direct proportion to the dose administered over the
range of 50 to 400 mg. In 2 small studies (n = 7 and 8) of patients with epilepsy who were
maintained on other AEDs, there also was a linear relationship between dose and lamotrigine
plasma concentrations at steady state following doses of 50 to 350 mg twice daily.
Distribution
Estimates of the mean apparent volume of distribution (Vd/F) of lamotrigine following oral
administration ranged from 0.9 to 1.3 L/kg. Vd/F is independent of dose and is similar following
single and multiple doses in both patients with epilepsy and in healthy volunteers.
Protein Binding
Data from in vitro studies indicate that lamotrigine is approximately 55% bound to human
plasma proteins at plasma lamotrigine concentrations from 1 to 10 mcg/mL (10 mcg/mL is 4 to 6
times the trough plasma concentration observed in the controlled efficacy trials). Because
lamotrigine is not highly bound to plasma proteins, clinically significant interactions with other
drugs through competition for protein binding sites are unlikely. The binding of lamotrigine to
plasma proteins did not change in the presence of therapeutic concentrations of phenytoin,
phenobarbital, or valproate. Lamotrigine did not displace other AEDs (carbamazepine,
phenytoin, phenobarbital) from protein-binding sites.
Metabolism
Lamotrigine is metabolized predominantly by glucuronic acid conjugation; the major metabolite
is an inactive 2-N-glucuronide conjugate. After oral administration of 240 mg of 14C-lamotrigine
(15 µCi) to 6 healthy volunteers, 94% was recovered in the urine and 2% was recovered in the
feces. The radioactivity in the urine consisted of unchanged lamotrigine (10%), the 2-N-
glucuronide (76%), a 5-N-glucuronide (10%), a 2-N-methyl metabolite (0.14%), and other
unidentified minor metabolites (4%).
Enzyme Induction
The effects of lamotrigine on the induction of specific families of mixed-function oxidase
isozymes have not been systematically evaluated.
Following multiple administrations (150 mg twice daily) to normal volunteers taking no other
medications, lamotrigine induced its own metabolism, resulting in a 25% decrease in t½ and a
37% increase in CL/F at steady state compared with values obtained in the same volunteers
43
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following a single dose. Evidence gathered from other sources suggests that self-induction by
lamotrigine may not occur when lamotrigine is given as adjunctive therapy in patients receiving
enzyme-inducing drugs such as carbamazepine, phenytoin, phenobarbital, primidone, or other
drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir
that induce lamotrigine glucuronidation [see Drug Interactions (7)].
Elimination
The elimination half-life and apparent clearance of lamotrigine following oral administration of
LAMICTAL to adult subjects with epilepsy and healthy volunteers is summarized in Table 14.
Half-life and apparent oral clearance vary depending on concomitant AEDs.
Drug Interactions
The apparent clearance of lamotrigine is affected by the coadministration of certain medications
[see Warnings and Precautions (5.8, 5.12), Drug Interactions (7)].
The net effects of drug interactions with lamotrigine are summarized in Tables 13 and 15,
followed by details of the drug interaction studies below.
Table 15. Summary of Drug Interactions With Lamotrigine
Drug
Drug Plasma
Concentration With
Adjunctive Lamotriginea
Lamotrigine Plasma
Concentration With
Adjunctive Drugsb
Oral contraceptives (e.g.,
ethinylestradiol/levonorgestrel)c
Aripiprazole
Atazanavir/ritonavir
Bupropion
Carbamazepine
Carbamazepine epoxideg
Felbamate
Gabapentin
Levetiracetam
Lithium
Lopinavir/ritonavir
Olanzapine
Oxcarbazepine
10-Monohydroxy oxcarbazepine
metaboliteh
Phenobarbital/primidone
Phenytoin
Pregabalin
↔d
Not assessed
↔f
Not assessed
↔
?
Not assessed
Not assessed
↔
↔
↔e
↔
↔
↔
↔
↔
↔
↓
↔e
↓
↔
↓
↔
↔
↔
Not assessed
↓
↔e
↔
↓
↓
↔
44
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Rifampin
Risperidone
9-hydroxyrisperidonei
Topiramate
Valproate
Valproate + phenytoin and/or
carbamazepine
Zonisamide
Not assessed
↔
↔
↔j
↓
Not assessed
Not assessed
↓
Not assessed
↔
↑
↔
↔
a From adjunctive clinical trials and volunteer trials.
b Net effects were estimated by comparing the mean clearance values obtained in adjunctive
clinical trials and volunteer trials.
c The effect of other hormonal contraceptive preparations or hormone replacement therapy on
the pharmacokinetics of lamotrigine has not been systematically evaluated in clinical trials,
although the effect may be similar to that seen with the ethinylestradiol/levonorgestrel
combinations.
d Modest decrease in levonorgestrel.
e Slight decrease, not expected to be clinically meaningful.
f Compared to historical controls.
g Not administered, but an active metabolite of carbamazepine.
h Not administered, but an active metabolite of oxcarbazepine.
i Not administered, but an active metabolite of risperidone.
j Slight increase, not expected to be clinically meaningful.
↔ = No significant effect.
? = Conflicting data.
Estrogen-Containing Oral Contraceptives
In 16 female volunteers, an oral contraceptive preparation containing 30 mcg ethinylestradiol
and 150 mcg levonorgestrel increased the apparent clearance of lamotrigine (300 mg/day) by
approximately 2-fold with mean decreases in AUC of 52% and in Cmax of 39%. In this study,
trough serum lamotrigine concentrations gradually increased and were approximately 2-fold
higher on average at the end of the week of the inactive hormone preparation compared with
trough lamotrigine concentrations at the end of the active hormone cycle.
Gradual transient increases in lamotrigine plasma levels (approximate 2-fold increase) occurred
during the week of inactive hormone preparation (pill-free week) for women not also taking a
drug that increased the clearance of lamotrigine (carbamazepine, phenytoin, phenobarbital,
primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and
atazanavir/ritonavir that induce lamotrigine glucuronidation) [see Drug Interactions (7)]. The
increase in lamotrigine plasma levels will be greater if the dose of LAMICTAL is increased in
45
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the few days before or during the pill-free week. Increases in lamotrigine plasma levels could
result in dose-dependent adverse reactions.
In the same study, coadministration of lamotrigine (300 mg/day) in 16 female volunteers did not
affect the pharmacokinetics of the ethinylestradiol component of the oral contraceptive
preparation. There were mean decreases in the AUC and Cmax of the levonorgestrel component of
19% and 12%, respectively. Measurement of serum progesterone indicated that there was no
hormonal evidence of ovulation in any of the 16 volunteers, although measurement of serum
FSH, LH, and estradiol indicated that there was some loss of suppression of the hypothalamic-
pituitary-ovarian axis.
The effects of doses of lamotrigine other than 300 mg/day have not been systematically
evaluated in controlled clinical trials.
The clinical significance of the observed hormonal changes on ovulatory activity is unknown.
However, the possibility of decreased contraceptive efficacy in some patients cannot be
excluded. Therefore, patients should be instructed to promptly report changes in their menstrual
pattern (e.g., break-through bleeding).
Dosage adjustments may be necessary for women receiving estrogen-containing oral
contraceptive preparations [see Dosage and Administration (2.1)].
Other Hormonal Contraceptives or Hormone Replacement Therapy
The effect of other hormonal contraceptive preparations or hormone replacement therapy on the
pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that
ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the
progestin-only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the
dosage of LAMICTAL in the presence of progestogens alone will likely not be needed.
Aripiprazole
In 18 patients with bipolar disorder on a stable regimen of 100 to 400 mg/day of lamotrigine, the
lamotrigine AUC and Cmax were reduced by approximately 10% in patients who received
aripiprazole 10 to 30 mg/day for 7 days, followed by 30 mg/day for an additional 7 days. This
reduction in lamotrigine exposure is not considered clinically meaningful.
Atazanavir/Ritonavir
In a study in healthy volunteers, daily doses of atazanavir/ritonavir (300 mg/100 mg) reduced the
plasma AUC and Cmax of lamotrigine (single 100-mg dose) by an average of 32% and 6%,
respectively, and shortened the elimination half-lives by 27%. In the presence of
atazanavir/ritonavir (300 mg/100 mg), the metabolite-to-lamotrigine ratio was increased from
0.45 to 0.71 consistent with induction of glucuronidation. The pharmacokinetics of
atazanavir/ritonavir were similar in the presence of concomitant lamotrigine to the historical data
of the pharmacokinetics in the absence of lamotrigine.
46
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Bupropion
The pharmacokinetics of a 100-mg single dose of lamotrigine in healthy volunteers (n = 12) were
not changed by coadministration of bupropion sustained-release formulation (150 mg twice
daily) starting 11 days before lamotrigine.
Carbamazepine
Lamotrigine has no appreciable effect on steady-state carbamazepine plasma concentration.
Limited clinical data suggest there is a higher incidence of dizziness, diplopia, ataxia, and
blurred vision in patients receiving carbamazepine with lamotrigine than in patients receiving
other AEDs with lamotrigine [see Adverse Reactions (6.1)]. The mechanism of this interaction is
unclear. The effect of lamotrigine on plasma concentrations of carbamazepine-epoxide is
unclear. In a small subset of patients (n = 7) studied in a placebo-controlled trial, lamotrigine had
no effect on carbamazepine-epoxide plasma concentrations, but in a small, uncontrolled study
(n = 9), carbamazepine-epoxide levels increased.
The addition of carbamazepine decreases lamotrigine steady-state concentrations by
approximately 40%.
Felbamate
In a trial in 21 healthy volunteers, coadministration of felbamate (1,200 mg twice daily) with
lamotrigine (100 mg twice daily for 10 days) appeared to have no clinically relevant effects on
the pharmacokinetics of lamotrigine.
Folate Inhibitors
Lamotrigine is a weak inhibitor of dihydrofolate reductase. Prescribers should be aware of this
action when prescribing other medications that inhibit folate metabolism.
Gabapentin
Based on a retrospective analysis of plasma levels in 34 subjects who received lamotrigine both
with and without gabapentin, gabapentin does not appear to change the apparent clearance of
lamotrigine.
Levetiracetam
Potential drug interactions between levetiracetam and lamotrigine were assessed by evaluating
serum concentrations of both agents during placebo-controlled clinical trials. These data indicate
that lamotrigine does not influence the pharmacokinetics of levetiracetam and that levetiracetam
does not influence the pharmacokinetics of lamotrigine.
Lithium
The pharmacokinetics of lithium were not altered in healthy subjects (n = 20) by
coadministration of lamotrigine (100 mg/day) for 6 days.
47
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Lopinavir/Ritonavir
The addition of lopinavir (400 mg twice daily)/ritonavir (100 mg twice daily) decreased the
AUC, Cmax, and elimination half-life of lamotrigine by approximately 50% to 55.4% in 18
healthy subjects. The pharmacokinetics of lopinavir/ritonavir were similar with concomitant
lamotrigine, compared to that in historical controls.
Olanzapine
The AUC and Cmax of olanzapine were similar following the addition of olanzapine (15 mg once
daily) to lamotrigine (200 mg once daily) in healthy male volunteers (n = 16) compared with the
AUC and Cmax in healthy male volunteers receiving olanzapine alone (n = 16).
In the same trial, the AUC and Cmax of lamotrigine were reduced on average by 24% and 20%,
respectively, following the addition of olanzapine to lamotrigine in healthy male volunteers
compared with those receiving lamotrigine alone. This reduction in lamotrigine plasma
concentrations is not expected to be clinically meaningful.
Oxcarbazepine
The AUC and Cmax of oxcarbazepine and its active 10-monohydroxy oxcarbazepine metabolite
were not significantly different following the addition of oxcarbazepine (600 mg twice daily) to
lamotrigine (200 mg once daily) in healthy male volunteers (n = 13) compared with healthy male
volunteers receiving oxcarbazepine alone (n = 13).
In the same trial, the AUC and Cmax of lamotrigine were similar following the addition of
oxcarbazepine (600 mg twice daily) to lamotrigine in healthy male volunteers compared with
those receiving lamotrigine alone. Limited clinical data suggest a higher incidence of headache,
dizziness, nausea, and somnolence with coadministration of lamotrigine and oxcarbazepine
compared with lamotrigine alone or oxcarbazepine alone.
Phenobarbital, Primidone
The addition of phenobarbital or primidone decreases lamotrigine steady-state concentrations by
approximately 40%.
Phenytoin
Lamotrigine has no appreciable effect on steady-state phenytoin plasma concentrations in
patients with epilepsy. The addition of phenytoin decreases lamotrigine steady-state
concentrations by approximately 40%.
Pregabalin
Steady-state trough plasma concentrations of lamotrigine were not affected by concomitant
pregabalin (200 mg 3 times daily) administration. There are no pharmacokinetic interactions
between lamotrigine and pregabalin.
48
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Rifampin
In 10 male volunteers, rifampin (600 mg/day for 5 days) significantly increased the apparent
clearance of a single 25-mg dose of lamotrigine by approximately 2-fold (AUC decreased by
approximately 40%).
Risperidone
In a 14 healthy volunteers study, multiple oral doses of lamotrigine 400 mg daily had no
clinically significant effect on the single-dose pharmacokinetics of risperidone 2 mg and its
active metabolite 9-OH risperidone. Following the coadministration of risperidone 2 mg with
lamotrigine, 12 of the 14 volunteers reported somnolence compared with 1 out of 20 when
risperidone was given alone, and none when lamotrigine was administered alone.
Topiramate
Topiramate resulted in no change in plasma concentrations of lamotrigine. Administration of
lamotrigine resulted in a 15% increase in topiramate concentrations.
Valproate
When lamotrigine was administered to healthy volunteers (n = 18) receiving valproate, the
trough steady-state valproate plasma concentrations decreased by an average of 25% over a 3-
week period, and then stabilized. However, adding lamotrigine to the existing therapy did not
cause a change in valproate plasma concentrations in either adult or pediatric patients in
controlled clinical trials.
The addition of valproate increased lamotrigine steady-state concentrations in normal volunteers
by slightly more than 2-fold. In 1 trial, maximal inhibition of lamotrigine clearance was reached
at valproate doses between 250 and 500 mg/day and did not increase as the valproate dose was
further increased.
Zonisamide
In a study in 18 patients with epilepsy, coadministration of zonisamide (200 to 400 mg/day) with
lamotrigine (150 to 500 mg/day for 35 days) had no significant effect on the pharmacokinetics of
lamotrigine.
Known Inducers or Inhibitors of Glucuronidation
Drugs other than those listed above have not been systematically evaluated in combination with
lamotrigine. Since lamotrigine is metabolized predominately by glucuronic acid conjugation,
drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of
lamotrigine and doses of lamotrigine may require adjustment based on clinical response.
49
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Other
In vitro assessment of the inhibitory effect of lamotrigine at OCT2 demonstrate that lamotrigine,
but not the N(2)-glucuronide metabolite, is an inhibitor of OCT2 at potentially clinically relevant
concentrations, with IC50 value of 53.8 µM [see Drug Interactions (7)].
Results of in vitro experiments suggest that clearance of lamotrigine is unlikely to be reduced by
concomitant administration of amitriptyline, clonazepam, clozapine, fluoxetine, haloperidol,
lorazepam, phenelzine, sertraline, or trazodone.
Results of in vitro experiments suggest that lamotrigine does not reduce the clearance of drugs
eliminated predominantly by CYP2D6.
Specific Populations
Renal Impairment: Twelve volunteers with chronic renal failure (mean creatinine clearance: 13
mL/min, range: 6 to 23) and another 6 individuals undergoing hemodialysis were each given a
single 100-mg dose of lamotrigine. The mean plasma half-lives determined in the study were
42.9 hours (chronic renal failure), 13.0 hours (during hemodialysis), and 57.4 hours (between
hemodialysis) compared with 26.2 hours in healthy volunteers. On average, approximately 20%
(range: 5.6 to 35.1) of the amount of lamotrigine present in the body was eliminated by
hemodialysis during a 4-hour session [see Dosage and Administration (2.1)].
Hepatic Disease: The pharmacokinetics of lamotrigine following a single 100-mg dose of
lamotrigine were evaluated in 24 subjects with mild, moderate, and severe hepatic impairment
(Child-Pugh Classification system) and compared with 12 subjects without hepatic impairment.
The subjects with severe hepatic impairment were without ascites (n = 2) or with ascites (n = 5).
The mean apparent clearances of lamotrigine in subjects with mild (n = 12), moderate (n = 5),
severe without ascites (n = 2), and severe with ascites (n = 5) liver impairment were 0.30 ± 0.09,
0.24 ± 0.1, 0.21 ± 0.04, and 0.15 ± 0.09 mL/min/kg, respectively, as compared with 0.37 ± 0.1
mL/min/kg in the healthy controls. Mean half-lives of lamotrigine in subjects with mild,
moderate, severe without ascites, and severe with ascites hepatic impairment were 46 ± 20, 72 ±
44, 67 ± 11, and 100 ± 48 hours, respectively, as compared with 33 ± 7 hours in healthy controls
[see Dosage and Administration (2.1)].
Age: Pediatric Subjects: The pharmacokinetics of lamotrigine following a single 2-mg/kg dose
were evaluated in 2 studies in pediatric subjects (n = 29 for subjects aged 10 months to 5.9 years
and n = 26 for subjects aged 5 to 11 years). Forty-three subjects received concomitant therapy
with other AEDs and 12 subjects received lamotrigine as monotherapy. Lamotrigine
pharmacokinetic parameters for pediatric patients are summarized in Table 16.
Population pharmacokinetic analyses involving subjects aged 2 to 18 years demonstrated that
lamotrigine clearance was influenced predominantly by total body weight and concurrent AED
therapy. The oral clearance of lamotrigine was higher, on a body weight basis, in pediatric
patients than in adults. Weight-normalized lamotrigine clearance was higher in those subjects
50
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weighing less than 30 kg compared with those weighing greater than 30 kg. Accordingly,
patients weighing less than 30 kg may need an increase of as much as 50% in maintenance doses,
based on clinical response, as compared with subjects weighing more than 30 kg being
administered the same AEDs [see Dosage and Administration (2.2)]. These analyses also
revealed that, after accounting for body weight, lamotrigine clearance was not significantly
influenced by age. Thus, the same weight-adjusted doses should be administered to children
irrespective of differences in age. Concomitant AEDs which influence lamotrigine clearance in
adults were found to have similar effects in children.
Table 16. Mean Pharmacokinetic Parameters in Pediatric Subjects With Epilepsy
Pediatric Study Population
Number of
Subjects
Tmax
(h)
t½
(h)
CL/F
(mL/min/kg)
Ages 10 months-5.3 years
Subjects taking carbamazepine,
10
3.0
7.7
3.62
phenytoin, phenobarbital, or
primidonea
(1.0-5.9)
(5.7-11.4)
(2.44-5.28)
Subjects taking AEDs with no
7
5.2
19.0
1.2
known effect on the apparent
clearance of lamotrigine
(2.9-6.1)
(12.9-27.1)
(0.75-2.42)
Subjects taking valproate only
8
2.9
44.9
0.47
(1.0-6.0)
(29.5-52.5)
(0.23-0.77)
Ages 5-11 years
Subjects taking carbamazepine,
7
1.6
7.0
2.54
phenytoin, phenobarbital, or
primidonea
(1.0-3.0)
(3.8-9.8)
(1.35-5.58)
Subjects taking carbamazepine,
8
3.3
19.1
0.89
phenytoin, phenobarbital, or
primidonea plus valproate
(1.0-6.4)
(7.0-31.2)
(0.39-1.93)
Subjects taking valproate only
b
3
4.5
65.8
0.24
(3.0-6.0)
(50.7-73.7)
(0.21-0.26)
Ages 13-18 years
Subjects taking carbamazepine,
phenytoin, phenobarbital, or
primidonea
11
___ c
___ c
1.3
Subjects taking carbamazepine,
phenytoin, phenobarbital, or
primidonea plus valproate
8
___ c
___ c
0.5
Subjects taking valproate only
4
___ c
___ c
0.3
a Carbamazepine, phenytoin, phenobarbital, and primidone have been shown to increase the
apparent clearance of lamotrigine. Estrogen-containing oral contraceptives, rifampin, and the
51
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protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir have also been shown to
increase the apparent clearance of lamotrigine [see Drug Interactions (7)].
b Two subjects were included in the calculation for mean Tmax.
c Parameter not estimated.
Elderly: The pharmacokinetics of lamotrigine following a single 150-mg dose of
lamotrigine were evaluated in 12 elderly volunteers between the ages of 65 and 76 years (mean
creatinine clearance = 61 mL/min, range: 33 to 108 mL/min). The mean half-life of lamotrigine
in these subjects was 31.2 hours (range: 24.5 to 43.4 hours), and the mean clearance was
0.40 mL/min/kg (range: 0.26 to 0.48 mL/min/kg).
Gender: The clearance of lamotrigine is not affected by gender. However, during dose escalation
of lamotrigine in 1 clinical trial in patients with epilepsy on a stable dose of valproate (n = 77),
mean trough lamotrigine concentrations unadjusted for weight were 24% to 45% higher (0.3 to
1.7 mcg/mL) in females than in males.
Race: The apparent oral clearance of lamotrigine was 25% lower in non-Caucasians than
Caucasians.
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
No evidence of carcinogenicity was seen in mouse or rat following oral administration of
lamotrigine for up to 2 years at doses up to 30 mg/kg/day and 10 to 15 mg/kg/day in mouse and
rat, respectively. The highest doses tested are less than the human dose of 400 mg/day on a body
surface area (mg/m2) basis.
Lamotrigine was negative in in vitro gene mutation (Ames and mouse lymphoma tk) assays and
in clastogenicity (in vitro human lymphocyte and in vivo rat bone marrow) assays.
No evidence of impaired fertility was detected in rats given oral doses of lamotrigine up to 20
mg/kg/day. The highest dose tested is less than the human dose of 400 mg/day on a mg/m2 basis.
14
CLINICAL STUDIES
14.1
Epilepsy
Monotherapy With LAMICTAL in Adults With Partial-Onset Seizures Already Receiving
Treatment With Carbamazepine, Phenytoin, Phenobarbital, or Primidone as the Single
Antiepileptic Drug
The effectiveness of monotherapy with LAMICTAL was established in a multicenter, double-
blind clinical trial enrolling 156 adult outpatients with partial-onset seizures. The patients
experienced at least 4 simple partial-onset, complex partial-onset, and/or secondarily generalized
seizures during each of 2 consecutive 4-week periods while receiving carbamazepine or
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phenytoin monotherapy during baseline. LAMICTAL (target dose of 500 mg/day) or valproate
(1,000 mg/day) was added to either carbamazepine or phenytoin monotherapy over a 4-week
period. Patients were then converted to monotherapy with LAMICTAL or valproate during the
next 4 weeks, then continued on monotherapy for an additional 12-week period.
Trial endpoints were completion of all weeks of trial treatment or meeting an escape criterion.
Criteria for escape relative to baseline were: (1) doubling of average monthly seizure count, (2)
doubling of highest consecutive 2-day seizure frequency, (3) emergence of a new seizure type
(defined as a seizure that did not occur during the 8-week baseline) that is more severe than
seizure types that occur during study treatment, or (4) clinically significant prolongation of
generalized tonic-clonic seizures. The primary efficacy variable was the proportion of patients in
each treatment group who met escape criteria.
The percentages of patients who met escape criteria were 42% (32/76) in the group receiving
LAMICTAL and 69% (55/80) in the valproate group. The difference in the percentage of
patients meeting escape criteria was statistically significant (P = 0.0012) in favor of
LAMICTAL. No differences in efficacy based on age, sex, or race were detected.
Patients in the control group were intentionally treated with a relatively low dose of valproate; as
such, the sole objective of this trial was to demonstrate the effectiveness and safety of
monotherapy with LAMICTAL, and cannot be interpreted to imply the superiority of
LAMICTAL to an adequate dose of valproate.
Adjunctive Therapy With LAMICTAL in Adults With Partial-Onset Seizures
The effectiveness of LAMICTAL as adjunctive therapy (added to other AEDs) was initially
established in 3 pivotal, multicenter, placebo-controlled, double-blind clinical trials in 355 adults
with refractory partial-onset seizures. The patients had a history of at least 4 partial-onset
seizures per month in spite of receiving 1 or more AEDs at therapeutic concentrations and in 2 of
the trials were observed on their established AED regimen during baselines that varied between 8
to 12 weeks. In the third trial, patients were not observed in a prospective baseline. In patients
continuing to have at least 4 seizures per month during the baseline, LAMICTAL or placebo was
then added to the existing therapy. In all 3 trials, change from baseline in seizure frequency was
the primary measure of effectiveness. The results given below are for all partial-onset seizures in
the intent-to-treat population (all patients who received at least 1 dose of treatment) in each trial,
unless otherwise indicated. The median seizure frequency at baseline was 3 per week while the
mean at baseline was 6.6 per week for all patients enrolled in efficacy trials.
One trial (n = 216) was a double-blind, placebo-controlled, parallel trial consisting of a 24-week
treatment period. Patients could not be on more than 2 other anticonvulsants and valproate was
not allowed. Patients were randomized to receive placebo, a target dose of 300 mg/day of
LAMICTAL, or a target dose of 500 mg/day of LAMICTAL. The median reductions in the
frequency of all partial-onset seizures relative to baseline were 8% in patients receiving placebo,
20% in patients receiving 300 mg/day of LAMICTAL, and 36% in patients receiving 500
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mg/day of LAMICTAL. The seizure frequency reduction was statistically significant in the 500-
mg/day group compared with the placebo group, but not in the 300-mg/day group.
A second trial (n = 98) was a double-blind, placebo-controlled, randomized, crossover trial
consisting of two 14-week treatment periods (the last 2 weeks of which consisted of dose
tapering) separated by a 4-week washout period. Patients could not be on more than 2 other
anticonvulsants and valproate was not allowed. The target dose of LAMICTAL was 400 mg/day.
When the first 12 weeks of the treatment periods were analyzed, the median change in seizure
frequency was a 25% reduction on LAMICTAL compared with placebo (P<0.001).
The third trial (n = 41) was a double-blind, placebo-controlled, crossover trial consisting of two
12-week treatment periods separated by a 4-week washout period. Patients could not be on more
than 2 other anticonvulsants. Thirteen patients were on concomitant valproate; these patients
received 150 mg/day of LAMICTAL. The 28 other patients had a target dose of 300 mg/day of
LAMICTAL. The median change in seizure frequency was a 26% reduction on LAMICTAL
compared with placebo (P<0.01).
No differences in efficacy based on age, sex, or race, as measured by change in seizure
frequency, were detected.
Adjunctive Therapy With LAMICTAL in Pediatric Patients With Partial-Onset Seizures
The effectiveness of LAMICTAL as adjunctive therapy in pediatric patients with partial-onset
seizures was established in a multicenter, double-blind, placebo-controlled trial in 199 patients
aged 2 to 16 years (n = 98 on LAMICTAL, n = 101 on placebo). Following an 8-week baseline
phase, patients were randomized to 18 weeks of treatment with LAMICTAL or placebo added to
their current AED regimen of up to 2 drugs. Patients were dosed based on body weight and
valproate use. Target doses were designed to approximate 5 mg/kg/day for patients taking
valproate (maximum dose: 250 mg/day) and 15 mg/kg/day for the patients not taking valproate
(maximum dose: 750 mg/day). The primary efficacy endpoint was percentage change from
baseline in all partial-onset seizures. For the intent-to-treat population, the median reduction of
all partial-onset seizures was 36% in patients treated with LAMICTAL and 7% on placebo, a
difference that was statistically significant (P<0.01).
Adjunctive Therapy With LAMICTAL in Pediatric and Adult Patients With Lennox-Gastaut
Syndrome
The effectiveness of LAMICTAL as adjunctive therapy in patients with Lennox-Gastaut
syndrome was established in a multicenter, double-blind, placebo-controlled trial in 169 patients
aged 3 to 25 years (n = 79 on LAMICTAL, n = 90 on placebo). Following a 4-week, single-
blind, placebo phase, patients were randomized to 16 weeks of treatment with LAMICTAL or
placebo added to their current AED regimen of up to 3 drugs. Patients were dosed on a fixed-
dose regimen based on body weight and valproate use. Target doses were designed to
approximate 5 mg/kg/day for patients taking valproate (maximum dose: 200 mg/day) and 15
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Reference ID: 3720577
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-045 & S-051
NDA 020764/S-038 & S-044
NDA 022251/S-007 & S-014
FDA Approved Labeling Text dated 3/24/2015
mg/kg/day for patients not taking valproate (maximum dose: 400 mg/day). The primary efficacy
endpoint was percentage change from baseline in major motor seizures (atonic, tonic, major
myoclonic, and tonic-clonic seizures). For the intent-to-treat population, the median reduction of
major motor seizures was 32% in patients treated with LAMICTAL and 9% on placebo, a
difference that was statistically significant (P<0.05). Drop attacks were significantly reduced by
LAMICTAL (34%) compared with placebo (9%), as were tonic-clonic seizures (36% reduction
versus 10% increase for LAMICTAL and placebo, respectively).
Adjunctive Therapy With LAMICTAL in Pediatric and Adult Patients With Primary Generalized
Tonic-Clonic Seizures
The effectiveness of LAMICTAL as adjunctive therapy in patients with PGTC seizures was
established in a multicenter, double-blind, placebo-controlled trial in 117 pediatric and adult
patients aged 2 years and older (n = 58 on LAMICTAL, n = 59 on placebo). Patients with at least
3 PGTC seizures during an 8-week baseline phase were randomized to 19 to 24 weeks of
treatment with LAMICTAL or placebo added to their current AED regimen of up to 2 drugs.
Patients were dosed on a fixed-dose regimen, with target doses ranging from 3 to 12 mg/kg/day
for pediatric patients and from 200 to 400 mg/day for adult patients based on concomitant AEDs.
The primary efficacy endpoint was percentage change from baseline in PGTC seizures. For the
intent-to-treat population, the median percent reduction in PGTC seizures was 66% in patients
treated with LAMICTAL and 34% on placebo, a difference that was statistically significant
(P = 0.006).
14.2
Bipolar Disorder
The effectiveness of LAMICTAL in the maintenance treatment of bipolar I disorder was
established in 2 multicenter, double-blind, placebo-controlled trials in adult patients who met
DSM-IV criteria for bipolar I disorder. Trial 1 enrolled patients with a current or recent (within
60 days) depressive episode as defined by DSM-IV and Trial 2 included patients with a current
or recent (within 60 days) episode of mania or hypomania as defined by DSM-IV. Both trials
included a cohort of patients (30% of 404 subjects in Trial 1 and 28% of 171 patients in Trial 2)
with rapid cycling bipolar disorder (4 to 6 episodes per year).
In both trials, patients were titrated to a target dose of 200 mg of LAMICTAL as add-on therapy
or as monotherapy with gradual withdrawal of any psychotropic medications during an 8- to 16-
week open-label period. Overall 81% of 1,305 patients participating in the open-label period
were receiving 1 or more other psychotropic medications, including benzodiazepines, selective
serotonin reuptake inhibitors (SSRIs), atypical antipsychotics (including olanzapine), valproate,
or lithium, during titration of LAMICTAL. Patients with a CGI-severity score of 3 or less
maintained for at least 4 continuous weeks, including at least the final week on monotherapy
with LAMICTAL, were randomized to a placebo-controlled, double-blind treatment period for
up to 18 months. The primary endpoint was TIME (time to intervention for a mood episode or
one that was emerging, time to discontinuation for either an adverse event that was judged to be
55
Reference ID: 3720577
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-045 & S-051
NDA 020764/S-038 & S-044
NDA 022251/S-007 & S-014
FDA Approved Labeling Text dated 3/24/2015
related to bipolar disorder, or for lack of efficacy). The mood episode could be depression,
mania, hypomania, or a mixed episode.
In Trial 1, patients received double-blind monotherapy with LAMICTAL 50 mg/day (n = 50),
LAMICTAL 200 mg/day (n = 124), LAMICTAL 400 mg/day (n = 47), or placebo (n = 121).
LAMICTAL (200- and 400-mg/day treatment groups combined) was superior to placebo in
delaying the time to occurrence of a mood episode. Separate analyses of the 200- and 400-
mg/day dose groups revealed no added benefit from the higher dose.
In Trial 2, patients received double-blind monotherapy with LAMICTAL (100 to 400 mg/day, n
= 59), or placebo (n = 70). LAMICTAL was superior to placebo in delaying time to occurrence
of a mood episode. The mean dose of LAMICTAL was about 211 mg/day.
Although these trials were not designed to separately evaluate time to the occurrence of
depression or mania, a combined analysis for the 2 trials revealed a statistically significant
benefit for LAMICTAL over placebo in delaying the time to occurrence of both depression and
mania, although the finding was more robust for depression.
16
HOW SUPPLIED/STORAGE AND HANDLING
LAMICTAL (lamotrigine) tablets
25 mg, white, scored, shield-shaped tablets debossed with “LAMICTAL” and “25”, bottles of
100 (NDC 0173-0633-02).
Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled
Room Temperature] in a dry place.
100 mg, peach, scored, shield-shaped tablets debossed with “LAMICTAL” and “100”, bottles of
100 (NDC 0173-0642-55).
150 mg, cream, scored, shield-shaped tablets debossed with “LAMICTAL” and “150”, bottles of
60 (NDC 0173-0643-60).
200 mg, blue, scored, shield-shaped tablets debossed with “LAMICTAL” and “200”, bottles of
60 (NDC 0173-0644-60).
Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled
Room Temperature] in a dry place and protect from light.
LAMICTAL (lamotrigine) Starter Kit for Patients Taking Valproate (Blue Kit)
25 mg, white, scored, shield-shaped tablets debossed with “LAMICTAL” and “25”, blisterpack
of 35 tablets (NDC 0173-0633-10).
Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled
Room Temperature] in a dry place.
56
Reference ID: 3720577
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-045 & S-051
NDA 020764/S-038 & S-044
NDA 022251/S-007 & S-014
FDA Approved Labeling Text dated 3/24/2015
LAMICTAL (lamotrigine) Starter Kit for Patients Taking Carbamazepine, Phenytoin,
Phenobarbital, or Primidone and Not Taking Valproate (Green Kit)
25 mg, white, scored, shield-shaped tablets debossed with “LAMICTAL” and “25” and 100 mg,
peach, scored, shield-shaped tablets debossed with “LAMICTAL” and “100”, blisterpack of 98
tablets (84/25-mg tablets and 14/100-mg tablets) (NDC 0173-0817-28).
Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled
Room Temperature] in a dry place and protect from light.
LAMICTAL (lamotrigine) Starter Kit for Patients Not Taking Carbamazepine, Phenytoin,
Phenobarbital, Primidone, or Valproate (Orange Kit)
25 mg, white, scored, shield-shaped tablets debossed with “LAMICTAL” and “25” and 100 mg,
peach, scored, shield-shaped tablets debossed with “LAMICTAL” and “100”, blisterpack of 49
tablets (42/25-mg tablets and 7/100-mg tablets) (NDC 0173-0594-02).
Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled
Room Temperature] in a dry place and protect from light.
LAMICTAL (lamotrigine) chewable dispersible tablets
2 mg, white to off-white, round tablets debossed with “LTG” over “2”, bottles of 30 (NDC 0173-
0699-00). ORDER DIRECTLY FROM GlaxoSmithKline 1-800-334-4153.
5 mg, white to off-white, caplet-shaped tablets debossed with “GX CL2”, bottles of 100 (NDC
0173-0526-00).
25 mg, white, super elliptical-shaped tablets debossed with “GX CL5”, bottles of 100 (NDC
0173-0527-00).
Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled
Room Temperature] in a dry place.
LAMICTAL ODT (lamotrigine) orally disintegrating tablets
25 mg, white to off-white, round, flat-faced, radius-edged tablets debossed with “LMT” on one
side and “25” on the other, Maintenance Packs of 30 (NDC 0173-0772-02).
50 mg, white to off-white, round, flat-faced, radius-edged tablets debossed with “LMT” on one
side and “50” on the other, Maintenance Packs of 30 (NDC 0173-0774-02).
100 mg, white to off-white, round, flat-faced, radius-edged tablets debossed with “LAMICTAL”
on one side and “100” on the other, Maintenance Packs of 30 (NDC 0173-0776-02).
200 mg, white to off-white, round, flat-faced, radius-edged tablets debossed with “LAMICTAL”
on one side and “200” on the other, Maintenance Packs of 30 (NDC 0173-0777-02).
Store between 20°C and 25°C (68°F and 77°F); with excursions permitted between 15°C and
30°C (59°F and 86°F).
57
Reference ID: 3720577
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-045 & S-051
NDA 020764/S-038 & S-044
NDA 022251/S-007 & S-014
FDA Approved Labeling Text dated 3/24/2015
LAMICTAL ODT (lamotrigine) Patient Titration Kit for Patients Taking Valproate (Blue ODT
Kit)
25 mg, white to off-white, round, flat-faced, radius-edged tablets debossed with “LMT” on one
side and “25” on the other, and 50 mg, white to off-white, round, flat-faced, radius-edged tablets
debossed with “LMT” on one side and “50” on the other, blisterpack of 28 tablets (21/25-mg
tablets and 7/50-mg tablets) (NDC 0173-0779-00).
Store between 20°C and 25°C (68°F and 77°F); with excursions permitted between 15°C and
30°C (59°F and 86°F).
LAMICTAL ODT (lamotrigine) Patient Titration Kit for Patients Taking Carbamazepine,
Phenytoin, Phenobarbital, or Primidone and Not Taking Valproate (Green ODT Kit)
50 mg, white to off-white, round, flat-faced, radius-edged tablets debossed with “LMT” on one
side and “50” on the other, and 100 mg, white to off-white, round, flat-faced, radius-edged
tablets debossed with “LAMICTAL” on one side and “100” on the other, blisterpack of 56
tablets (42/50-mg tablets and 14/100-mg tablets) (NDC 0173-0780-00).
Store between 20°C and 25°C (68°F and 77°F); with excursions permitted between 15°C and
30°C (59°F and 86°F).
LAMICTAL ODT (lamotrigine) Patient Titration Kit for Patients Not Taking Carbamazepine,
Phenytoin, Phenobarbital, Primidone, or Valproate (Orange ODT Kit)
25 mg, white to off-white, round, flat-faced, radius-edged tablets debossed with “LMT” on one
side and “25” on the other, 50 mg, white to off-white, round, flat-faced, radius-edged tablets
debossed with “LMT” on one side and “50” on the other, and 100 mg, white to off-white, round,
flat-faced, radius-edged tablets debossed with “LAMICTAL” on one side and “100” on the
other, blisterpack of 35 (14/25-mg tablets, 14/50-mg tablets, and 7/100-mg tablets) (NDC 0173-
0778-00).
Store between 20°C and 25°C (68°F and 77°F); with excursions permitted between 15°C and
30°C (59°F and 86°F).
Blisterpacks
If the product is dispensed in a blisterpack, the patient should be advised to examine the
blisterpack before use and not use if blisters are torn, broken, or missing.
17
PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Rash
Prior to initiation of treatment with LAMICTAL, inform patients that a rash or other signs or
symptoms of hypersensitivity (e.g., fever, lymphadenopathy) may herald a serious medical event
and instruct them to report any such occurrence to their physician immediately.
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Reference ID: 3720577
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-045 & S-051
NDA 020764/S-038 & S-044
NDA 022251/S-007 & S-014
FDA Approved Labeling Text dated 3/24/2015
Multiorgan Hypersensitivity Reactions, Blood Dyscrasias, and Organ Failure
Inform patients that multiorgan hypersensitivity reactions and acute multiorgan failure may
occur with LAMICTAL. Isolated organ failure or isolated blood dyscrasias without evidence of
multiorgan hypersensitivity may also occur. Instruct patients to contact their physician
immediately if they experience any signs or symptoms of these conditions [see Warnings and
Precautions (5.2, 5.3)].
Suicidal Thinking and Behavior
Inform patients, their caregivers, and families that AEDs, including LAMICTAL, may increase
the risk of suicidal thoughts and behavior. Instruct them to be alert for the emergence or
worsening of symptoms of depression, any unusual changes in mood or behavior, or the
emergence of suicidal thoughts or behavior or thoughts about self-harm. Instruct them to
immediately report behaviors of concern to their physician.
Worsening of Seizures
Advise patients to notify their physician if worsening of seizure control occurs.
Central Nervous System Adverse Effects
Inform patients that LAMICTAL may cause dizziness, somnolence, and other symptoms and
signs of central nervous system depression. Accordingly, instruct them neither to drive a car nor
to operate other complex machinery until they have gained sufficient experience on LAMICTAL
to gauge whether or not it adversely affects their mental and/or motor performance.
Pregnancy and Nursing
Instruct patients to notify their physician if they become pregnant or intend to become pregnant
during therapy and if they intend to breastfeed or are breastfeeding an infant.
Encourage patients to enroll in the NAAED Pregnancy Registry if they become pregnant. This
registry is collecting information about the safety of antiepileptic drugs during pregnancy. To
enroll, patients can call the toll-free number 1-888-233-2334 [see Use in Specific Populations
(8.1)].
Inform patients who intend to breastfeed that LAMICTAL is present in breast milk and advise
them to monitor their child for potential adverse effects of this drug. Discuss the benefits and
risks of continuing breastfeeding.
Oral Contraceptive Use
Instruct women to notify their physician if they plan to start or stop use of oral contraceptives or
other female hormonal preparations. Starting estrogen-containing oral contraceptives may
significantly decrease lamotrigine plasma levels and stopping estrogen-containing oral
contraceptives (including the pill-free week) may significantly increase lamotrigine plasma
levels [see Warnings and Precautions (5.8), Clinical Pharmacology (12.3)]. Also instruct
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Reference ID: 3720577
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-045 & S-051
NDA 020764/S-038 & S-044
NDA 022251/S-007 & S-014
FDA Approved Labeling Text dated 3/24/2015
women to promptly notify their physician if they experience adverse reactions or changes in
menstrual pattern (e.g., break-through bleeding) while receiving LAMICTAL in combination
with these medications.
Discontinuing LAMICTAL
Instruct patients to notify their physician if they stop taking LAMICTAL for any reason and not
to resume LAMICTAL without consulting their physician.
Aseptic Meningitis
Inform patients that LAMICTAL may cause aseptic meningitis. Instruct them to notify their
physician immediately if they develop signs and symptoms of meningitis such as headache,
fever, nausea, vomiting, stiff neck, rash, abnormal sensitivity to light, myalgia, chills, confusion,
or drowsiness while taking LAMICTAL.
Potential Medication Errors
To avoid a medication error of using the wrong drug or formulation, strongly advise patients to
visually inspect their tablets to verify that they are LAMICTAL, as well as the correct
formulation of LAMICTAL, each time they fill their prescription [see Dosage Forms and
Strengths (3.1, 3.2, 3.3), How Supplied/Storage and Handling (16)]. Refer the patient to the
Medication Guide that provides depictions of the LAMICTAL tablets, chewable dispersible
tablets, and orally disintegrating tablets.
LAMICTAL and LAMICTAL ODT are registered trademarks of the GSK group of companies.
The other brands listed are trademarks of their respective owners and are not trademarks of the
GSK group of companies. The makers of these brands are not affiliated with and do not endorse
the GSK group of companies or its products.
Distributed by
GlaxoSmithKline
Research Triangle Park, NC 27709
2015, the GSK group of companies. All rights reserved.
LMT:xPI
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Reference ID: 3720577
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-045 & S-051
NDA 020764/S-038 & S-044
NDA 022251/S-007 & S-014
FDA Approved Labeling Text dated 3/24/2015
MEDICATION GUIDE
LAMICTAL® (la-MIK-tal) (lamotrigine) tablets
and chewable dispersible tablets
LAMICTAL ODT® (lamotrigine) orally disintegrating tablets
Read this Medication Guide before you start taking LAMICTAL and each time you
get a refill. There may be new information. This information does not take the place
of talking with your healthcare provider about your medical condition or treatment.
If you have questions about LAMICTAL, ask your healthcare provider or pharmacist.
What is the most important information I should know about LAMICTAL?
1. LAMICTAL may cause a serious skin rash that may cause you to be
hospitalized or even cause death.
There is no way to tell if a mild rash will become more serious. A serious skin
rash can happen at any time during your treatment with LAMICTAL, but is more
likely to happen within the first 2 to 8 weeks of treatment. Children aged
between 2 and 16 years have a higher chance of getting this serious skin rash
while taking LAMICTAL.
The risk of getting a serious skin rash is higher if you:
• take LAMICTAL while taking valproate [DEPAKENE® (valproic acid) or
DEPAKOTE® (divalproex sodium)].
• take a higher starting dose of LAMICTAL than your healthcare provider
prescribed.
• increase your dose of LAMICTAL faster than prescribed.
Call your healthcare provider right away if you have any of the
following:
• a skin rash
• blistering or peeling of your skin
• hives
• painful sores in your mouth or around your eyes
These symptoms may be the first signs of a serious skin reaction. A healthcare
provider should examine you to decide if you should continue taking LAMICTAL.
2. Other serious reactions, including serious blood problems or liver
problems. LAMICTAL can also cause other types of allergic reactions or serious
problems that may affect organs and other parts of your body like your liver or
blood cells. You may or may not have a rash with these types of reactions. Call
your healthcare provider right away if you have any of these symptoms:
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Reference ID: 3720577
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-045 & S-051
NDA 020764/S-038 & S-044
NDA 022251/S-007 & S-014
FDA Approved Labeling Text dated 3/24/2015
• fever
• frequent infections
• severe muscle pain
• swelling of your face, eyes, lips, or tongue
• swollen lymph glands
• unusual bruising or bleeding
• weakness, fatigue
• yellowing of your skin or the white part of your eyes
3. Like other antiepileptic drugs, LAMICTAL may cause suicidal thoughts or
actions in a very small number of people, about 1 in 500.
Call a healthcare provider right away if you have any of these
symptoms, especially if they are new, worse, or worry you:
• thoughts about suicide or dying
• attempt to commit suicide
• new or worse depression
• new or worse anxiety
• feeling agitated or restless
• panic attacks
• trouble sleeping (insomnia)
• new or worse irritability
• acting aggressive, being angry, or violent
• acting on dangerous impulses
•
an extreme increase in activity and talking (mania)
•
other unusual changes in behavior or mood
Do not stop LAMICTAL without first talking to a healthcare provider.
• Stopping LAMICTAL suddenly can cause serious problems.
• Suicidal thoughts or actions can be caused by things other than medicines. If
you have suicidal thoughts or actions, your healthcare provider may check
for other causes.
How can I watch for early symptoms of suicidal thoughts and actions?
• Pay attention to any changes, especially sudden changes, in mood,
behaviors, thoughts, or feelings.
• Keep all follow-up visits with your healthcare provider as scheduled.
• Call your healthcare provider between visits as needed, especially if you are
worried about symptoms.
4. LAMICTAL may rarely cause aseptic meningitis, a serious inflammation
of the protective membrane that covers the brain and spinal cord.
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Reference ID: 3720577
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-045 & S-051
NDA 020764/S-038 & S-044
NDA 022251/S-007 & S-014
FDA Approved Labeling Text dated 3/24/2015
Call your healthcare provider right away if you have any of the following
symptoms:
• headache
• fever
• nausea
• vomiting
• stiff neck
• rash
• unusual sensitivity to light
• muscle pains
• chills
• confusion
• drowsiness
Meningitis has many causes other than LAMICTAL, which your doctor would
check for if you developed meningitis while taking LAMICTAL.
LAMICTAL can have other serious side effects. For more information ask
your healthcare provider or pharmacist. Tell your healthcare provider if you have
any side effect that bothers you. Be sure to read the section below entitled
“What are the possible side effects of LAMICTAL?”
5. Patients prescribed LAMICTAL have sometimes been given the wrong
medicine because many medicines have names similar to LAMICTAL, so
always check that you receive LAMICTAL.
Taking the wrong medication can cause serious health problems. When your
healthcare provider gives you a prescription for LAMICTAL:
• Make sure you can read it clearly.
• Talk to your pharmacist to check that you are given the correct medicine.
• Each time you fill your prescription, check the tablets you receive against the
pictures of the tablets below.
These pictures show the distinct wording, colors, and shapes of the tablets
that help to identify the right strength of LAMICTAL Tablets, Chewable
Dispersible Tablets, and Orally Disintegrating Tablets. Immediately call your
pharmacist if you receive a LAMICTAL tablet that does not look like one of the
tablets shown below, as you may have received the wrong medication.
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Reference ID: 3720577
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NDA 020241/S-045 & S-051
NDA 020764/S-038 & S-044
NDA 022251/S-007 & S-014
FDA Approved Labeling Text dated 3/24/2015
LAMICTAL (lamotrigine) tablets
25 mg, white
100 mg, peach
150 mg, cream
200 mg, blue
Imprinted with
Imprinted with
Imprinted with
Imprinted with
LAMICTAL 25
LAMICTAL 100
LAMICTAL 150
LAMICTAL 200
LAMICTAL (lamotrigine) chewable dispersible
tablets
2 mg, white
5 mg, white
25 mg, white
Imprinted with
Imprinted with
Imprinted with
LTG 2
GX CL2
GX CL5
LAMICTAL ODT (lamotrigine) orally disintegrating tablets
25 mg, white
50 mg, white
100 mg, white
200 mg, white
to off-white
to off-white
to off-white
to off-white
Imprinted with
Imprinted with
Imprinted with
Imprinted with
LMT on one
LMT on one
LAMICTAL on
LAMICTAL on
side
side
one side
one side
25 on the other 50 on the other
100 on the
200 on the
other
other
What is LAMICTAL?
LAMICTAL is a prescription medicine used:
1. together with other medicines to treat certain types of seizures (partial-onset
seizures, primary generalized tonic-clonic seizures, generalized seizures of
Lennox-Gastaut syndrome) in people aged 2 years and older.
2. alone when changing from 1 other medicine used to treat partial-onset seizures
in people aged 16 years and older.
3. for the long-term treatment of bipolar I disorder to lengthen the time between
mood episodes in people aged 18 years and older who have been treated for
mood episodes with other medicine.
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Reference ID: 3720577
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-045 & S-051
NDA 020764/S-038 & S-044
NDA 022251/S-007 & S-014
FDA Approved Labeling Text dated 3/24/2015
It is not known if LAMICTAL is safe or effective in children or teenagers younger
than 18 years with mood disorders such as bipolar disorder or depression.
It is not known if LAMICTAL is safe or effective when used alone as the first
treatment of seizures.
Who should not take LAMICTAL?
You should not take LAMICTAL if you have had an allergic reaction to lamotrigine or
to any of the inactive ingredients in LAMICTAL. See the end of this leaflet for a
complete list of ingredients in LAMICTAL.
What should I tell my healthcare provider before taking LAMICTAL?
Before taking LAMICTAL, tell your healthcare provider about all of your medical
conditions, including if you:
• have had a rash or allergic reaction to another antiseizure medicine.
• have or have had depression, mood problems, or suicidal thoughts or behavior.
• have had aseptic meningitis after taking LAMICTAL or LAMICTAL XR
(lamotrigine).
• are taking oral contraceptives (birth control pills) or other female hormonal
medicines. Do not start or stop taking birth control pills or other female
hormonal medicine until you have talked with your healthcare provider. Tell your
healthcare provider if you have any changes in your menstrual pattern such as
breakthrough bleeding. Stopping these medicines may cause side effects (such
as dizziness, lack of coordination, or double vision). Starting these medicines
may lessen how well LAMICTAL works.
• are pregnant or plan to become pregnant. It is not known if LAMICTAL will harm
your unborn baby. If you become pregnant while taking LAMICTAL, talk to your
healthcare provider about registering with the North American Antiepileptic Drug
Pregnancy Registry. You can enroll in this registry by calling 1-888-233-2334.
The purpose of this registry is to collect information about the safety of
antiepileptic drugs during pregnancy.
• are breastfeeding. LAMICTAL passes into breast milk and may cause side effects
in a breastfed baby. If you breastfeed while taking LAMICTAL, watch your baby
closely for trouble breathing, episodes of temporarily stopping breathing,
sleepiness, or poor sucking. Call your baby’s healthcare provider right away if
you see any of these problems. Talk to your healthcare provider about the best
way to feed your baby if you take LAMICTAL.
Tell your healthcare provider about all the medicines you take or if you are planning
to take a new medicine, including prescription and non-prescription medicines,
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NDA 020241/S-045 & S-051
NDA 020764/S-038 & S-044
NDA 022251/S-007 & S-014
FDA Approved Labeling Text dated 3/24/2015
vitamins, and herbal supplements. If you use LAMICTAL with certain other
medicines, they can affect each other, causing side effects.
How should I take LAMICTAL?
• Take LAMICTAL exactly as prescribed.
• Your healthcare provider may change your dose. Do not change your dose
without talking to your healthcare provider.
• Do not stop taking LAMICTAL without talking to your healthcare provider.
Stopping LAMICTAL suddenly may cause serious problems. For example, if you
have epilepsy and you stop taking LAMICTAL suddenly, you may have seizures
that do not stop. Talk with your healthcare provider about how to stop
LAMICTAL slowly.
• If you miss a dose of LAMICTAL, take it as soon as you remember. If it is almost
time for your next dose, just skip the missed dose. Take the next dose at your
regular time. Do not take 2 doses at the same time.
• If you take too much LAMICTAL, call your healthcare provider or your local
Poison Control Center or go to the nearest hospital emergency room right away.
• You may not feel the full effect of LAMICTAL for several weeks.
• If you have epilepsy, tell your healthcare provider if your seizures get worse or if
you have any new types of seizures.
• Swallow LAMICTAL Tablets whole.
• If you have trouble swallowing LAMICTAL Tablets, tell your healthcare provider
because there may be another form of LAMICTAL you can take.
• LAMICTAL ODT should be placed on the tongue and moved around the mouth.
The tablet will rapidly disintegrate, can be swallowed with or without water, and
can be taken with or without food.
• LAMICTAL chewable dispersible tablets may be swallowed whole, chewed, or
mixed in water or diluted fruit juice. If the tablets are chewed, drink a small
amount of water or diluted fruit juice to help in swallowing. To break up
LAMICTAL chewable dispersible tablets, add the tablets to a small amount of
liquid (1 teaspoon, or enough to cover the medicine) in a glass or spoon. Wait at
least 1 minute or until the tablets are completely broken up, mix the solution
together, and take the whole amount right away.
• If you receive LAMICTAL in a blisterpack, examine the blisterpack before use. Do
not use if blisters are torn, broken, or missing.
What should I avoid while taking LAMICTAL?
Do not drive a car or operate complex, hazardous machinery until you know how
LAMICTAL affects you.
66
Reference ID: 3720577
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-045 & S-051
NDA 020764/S-038 & S-044
NDA 022251/S-007 & S-014
FDA Approved Labeling Text dated 3/24/2015
What are the possible side effects of LAMICTAL?
See “What is the most important information I should know about LAMICTAL?”
Common side effects of LAMICTAL include:
•
dizziness
•
tremor
•
headache
•
rash
•
blurred or double vision
•
fever
•
lack of coordination
•
abdominal pain
•
sleepiness
•
back pain
•
nausea, vomiting, diarrhea
•
tiredness
•
insomnia
•
dry mouth
Tell your healthcare provider about any side effect that bothers you or that does
not go away.
These are not all the possible side effects of LAMICTAL. For more information, ask
your healthcare provider or pharmacist.
Call your doctor for medical advice about side effects. You may report side effects
to FDA at 1-800-FDA-1088.
How should I store LAMICTAL?
•
Store LAMICTAL at room temperature between 68oF and 77oF (20oC and 25oC).
•
Keep LAMICTAL and all medicines out of the reach of children.
General information about LAMICTAL
Medicines are sometimes prescribed for purposes other than those listed in a
Medication Guide. Do not use LAMICTAL for a condition for which it was not
prescribed. Do not give LAMICTAL to other people, even if they have the same
symptoms you have. It may harm them.
If you take a urine drug screening test, LAMICTAL may make the test result positive
for another drug. If you require a urine drug screening test, tell the healthcare
professional administering the test that you are taking LAMICTAL.
67
Reference ID: 3720577
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-045 & S-051
NDA 020764/S-038 & S-044
NDA 022251/S-007 & S-014
FDA Approved Labeling Text dated 3/24/2015
This Medication Guide summarizes the most important information about
LAMICTAL. If you would like more information, talk with your healthcare provider.
You can ask your healthcare provider or pharmacist for information about
LAMICTAL that is written for healthcare professionals.
For more information, go to www.lamictal.com or call 1-888-825-5249.
What are the ingredients in LAMICTAL?
LAMICTAL tablets
Active ingredient: lamotrigine.
Inactive ingredients: lactose; magnesium stearate, microcrystalline cellulose,
povidone, sodium starch glycolate, FD&C Yellow No. 6 Lake (100-mg tablet only),
ferric oxide, yellow (150-mg tablet only), and FD&C Blue No. 2 Lake (200-mg tablet
only).
LAMICTAL chewable dispersible tablets
Active ingredient: lamotrigine.
Inactive ingredients: blackcurrant flavor, calcium carbonate, low-substituted
hydroxypropylcellulose, magnesium aluminum silicate, magnesium stearate,
povidone, saccharin sodium, and sodium starch glycolate.
LAMICTAL ODT orally disintegrating tablets
Active ingredient: lamotrigine.
Inactive ingredients: artificial cherry flavor, crospovidone, ethylcellulose,
magnesium stearate, mannitol, polyethylene, and sucralose.
This Medication Guide has been approved by the U.S. Food and Drug
Administration.
LAMICTAL and LAMICTAL ODT are registered trademarks of the GSK group of
companies. The other brands listed are trademarks of their respective owners and
are not trademarks of the GSK group of companies. The makers of these brands
are not affiliated with and do not endorse the GSK group of companies or its
products.
Distributed by
68
Reference ID: 3720577
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020241/S-045 & S-051
NDA 020764/S-038 & S-044
NDA 022251/S-007 & S-014
FDA Approved Labeling Text dated 3/24/2015
GlaxoSmithKline
Research Triangle Park, NC 27709
2015, the GSK group of companies. All rights reserved.
March 2015
LMT:xMG
69
Reference ID: 3720577
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:47:13.122189
|
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|
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HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
LAMICTAL safely and effectively. See full prescribing information for
LAMICTAL.
LAMICTAL (lamotrigine) tablets, for oral use
LAMICTAL (lamotrigine) chewable dispersible tablets, for oral use
LAMICTAL ODT (lamotrigine) orally disintegrating tablets, for oral use
Initial U.S. Approval: 1994
WARNING: SERIOUS SKIN RASHES
See full prescribing information for complete boxed warning.
• Cases of life-threatening serious rashes, including Stevens-Johnson
syndrome and toxic epidermal necrolysis, and/or rash-related death
have been caused by lamotrigine. The rate of serious rash is greater in
pediatric patients than in adults. Additional factors that may increase
the risk of rash include:
• coadministration with valproate.
• exceeding recommended initial dose of LAMICTAL.
• exceeding recommended dose escalation for LAMICTAL. (5.1)
• Benign rashes are also caused by lamotrigine; however, it is not
possible to predict which rashes will prove to be serious or life
threatening. LAMICTAL should be discontinued at the first sign of
rash, unless the rash is clearly not drug related. (5.1)
---------------------------RECENT MAJOR CHANGES --------------------------
Boxed Warning
5/2015
Indications and Usage, Bipolar Disorder (1.2)
5/2015
Warnings and Precautions, Serious Skin Rashes (5.1)
5/2015
Warnings and Precautions, Laboratory Tests (5.13)
3/2015
--------------------------- INDICATIONS AND USAGE---------------------------
LAMICTAL is indicated for:
Epilepsy—adjunctive therapy in patients aged 2 years and older:
• partial-onset seizures.
• primary generalized tonic-clonic seizures.
• generalized seizures of Lennox-Gastaut syndrome. (1.1)
Epilepsy—monotherapy in patients aged 16 years and older: Conversion to
monotherapy in patients with partial-onset seizures who are receiving
treatment with carbamazepine, phenytoin, phenobarbital, primidone, or
valproate as the single AED. (1.1)
Bipolar disorder: Maintenance treatment of bipolar I disorder to delay the time
to occurrence of mood episodes in patients treated for acute mood episodes
with standard therapy. (1.2)
Limitations of Use: Treatment of acute manic or mixed episodes is not
recommended. Effectiveness of LAMICTAL in the acute treatment of mood
episodes has not been established.
-----------------------DOSAGE AND ADMINISTRATION ----------------------
• Dosing is based on concomitant medications, indication, and patient age.
(2.1, 2.2, 2.3, 2.4)
• To avoid an increased risk of rash, the recommended initial dose and
subsequent dose escalations should not be exceeded. LAMICTAL Starter
Kits and LAMICTAL ODT Patient Titration Kits are available for the first
5 weeks of treatment. (2.1, 16)
• Do not restart LAMICTAL in patients who discontinued due to rash unless
the potential benefits clearly outweigh the risks. (2.1, 5.1)
• Adjustments to maintenance doses will be necessary in most patients
starting or stopping estrogen-containing oral contraceptives. (2.1, 5.7)
• Discontinuation: Taper over a period of at least 2 weeks (approximately
50% dose reduction per week). (2.1, 5.8)
Epilepsy:
• Adjunctive therapy—See Table 1 for patients older than 12 years and
Tables 2 and 3 for patients aged 2 to 12 years. (2.2)
• Conversion to monotherapy—See Table 4. (2.3)
Bipolar disorder: See Tables 5 and 6. (2.4)
--------------------- DOSAGE FORMS AND STRENGTHS---------------------
• Tablets: 25 mg, 100 mg, 150 mg, and 200 mg; scored. (3.1, 16)
• Chewable dispersible tablets: 2 mg, 5 mg, and 25 mg. (3.2, 16)
• Orally disintegrating tablets: 25 mg, 50 mg, 100 mg, and 200 mg. (3.3, 16)
------------------------------ CONTRAINDICATIONS -----------------------------
Hypersensitivity to the drug or its ingredients. (Boxed Warning, 4)
----------------------- WARNINGS AND PRECAUTIONS ----------------------
• Life-threatening serious rash and/or rash-related death: Discontinue at the
first sign of rash, unless the rash is clearly not drug related. (Boxed
Warning, 5.1)
• Fatal or life-threatening hypersensitivity reaction: Multiorgan
hypersensitivity reactions, also known as drug reaction with eosinophilia
and systemic symptoms, may be fatal or life threatening. Early signs may
include rash, fever, and lymphadenopathy. These reactions may be
associated with other organ involvement, such as hepatitis, hepatic failure,
blood dyscrasias, or acute multiorgan failure. LAMICTAL should be
discontinued if alternate etiology for this reaction is not found. (5.2)
• Blood dyscrasias (e.g., neutropenia, thrombocytopenia, pancytopenia): May
occur, either with or without an associated hypersensitivity syndrome.
Monitor for signs of anemia, unexpected infection, or bleeding. (5.3)
• Suicidal behavior and ideation: Monitor for suicidal thoughts or behaviors.
(5.4)
• Aseptic meningitis: Monitor for signs of meningitis. (5.5)
• Medication errors due to product name confusion: Strongly advise patients
to visually inspect tablets to verify the received drug is correct. (5.6, 16, 17)
------------------------------ ADVERSE REACTIONS -----------------------------
Epilepsy: Most common adverse reactions (incidence ≥10%) in adults were
dizziness, headache, diplopia, ataxia, nausea, blurred vision, somnolence,
rhinitis, pharyngitis, and rash. Additional adverse reactions (incidence ≥10%)
reported in children included vomiting, infection, fever, accidental injury,
diarrhea, abdominal pain, and tremor. (6.1)
Bipolar disorder: Most common adverse reactions (incidence >5%) in adults
were nausea, insomnia, somnolence, back pain, fatigue, rash, rhinitis,
abdominal pain, and xerostomia. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact
GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
------------------------------ DRUG INTERACTIONS------------------------------
• Valproate increases lamotrigine concentrations more than 2-fold. (7, 12.3)
• Carbamazepine, phenytoin, phenobarbital, primidone, and rifampin
decrease lamotrigine concentrations by approximately 40%. (7, 12.3)
• Estrogen-containing oral contraceptives decrease lamotrigine
concentrations by approximately 50%. (7, 12.3)
• Protease inhibitors lopinavir/ritonavir and atazanavir/lopinavir decrease
lamotrigine exposure by approximately 50% and 32%, respectively. (7,
12.3)
• Coadministration with organic cationic transporter 2 substrates with narrow
therapeutic index is not recommended (7, 12.3)
----------------------- USE IN SPECIFIC POPULATIONS ----------------------
• Pregnancy: Based on animal data may cause fetal harm. (8.1)
• Hepatic impairment: Dosage adjustments required in patients with
moderate and severe liver impairment. (2.1, 8.6)
• Renal impairment: Reduced maintenance doses may be effective for
patients with significant renal impairment. (2.1, 8.7)
See 17 for PATIENT COUNSELING INFORMATION and Medication
Guide.
Revised: 5/2015
FULL PRESCRIBING INFORMATION: CONTENTS*
2
DOSAGE AND ADMINISTRATION
WARNING: SERIOUS SKIN RASHES
2.1
General Dosing Considerations
INDICATIONS AND USAGE
2.2
Epilepsy—Adjunctive Therapy
1.1
Epilepsy
2.3
Epilepsy—Conversion from Adjunctive Therapy to
1.2
Bipolar Disorder
Monotherapy
2.4
Bipolar Disorder
1
Reference ID: 3757964
1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2.5
Administration of LAMICTAL Chewable
6.2
Other Adverse Reactions Observed in All Clinical
Dispersible Tablets
Trials
2.6
Administration of LAMICTAL ODT Orally
6.3
Postmarketing Experience
Disintegrating Tablets
7
DRUG INTERACTIONS
3
DOSAGE FORMS AND STRENGTHS
8
USE IN SPECIFIC POPULATIONS
3.1
Tablets
8.2
Labor and Delivery
3.2
Chewable Dispersible Tablets
8.3
Nursing Mothers
3.3
Orally Disintegrating Tablets
8.4
Pediatric Use
4
CONTRAINDICATIONS
8.5
Geriatric Use
5
WARNINGS AND PRECAUTIONS
8.6
Hepatic Impairment
5.1
Serious Skin Rashes [see Boxed Warning]
8.7
Renal Impairment
5.2
Multiorgan Hypersensitivity Reactions and Organ
10
OVERDOSAGE
Failure
10.1
Human Overdose Experience
5.3
Blood Dyscrasias
10.2
Management of Overdose
5.4
Suicidal Behavior and Ideation
11
DESCRIPTION
5.5
Aseptic Meningitis
12
CLINICAL PHARMACOLOGY
5.6
Potential Medication Errors
12.1
Mechanism of Action
5.7
Concomitant Use with Oral Contraceptives
12.2
Pharmacodynamics
5.8
Withdrawal Seizures
12.3
Pharmacokinetics
5.9
Status Epilepticus
13
NONCLINICAL TOXICOLOGY
5.10
Sudden Unexplained Death in Epilepsy (SUDEP)
13.1
Carcinogenesis, Mutagenesis, Impairment of
5.11
Addition of LAMICTAL to a Multidrug Regimen
Fertility
that Includes Valproate
14
CLINICAL STUDIES
5.12
Binding in the Eye and Other Melanin-Containing
14.1
Epilepsy
Tissues
14.2
Bipolar Disorder
5.13
Laboratory Tests
16
HOW SUPPLIED/STORAGE AND HANDLING
6
ADVERSE REACTIONS
17
PATIENT COUNSELING INFORMATION
6.1
Clinical Trial Experience
*Sections or subsections omitted from the full prescribing information are not
listed.
FULL PRESCRIBING INFORMATION
WARNING: SERIOUS SKIN RASHES
LAMICTAL® can cause serious rashes requiring hospitalization and discontinuation of
treatment. The incidence of these rashes, which have included Stevens-Johnson syndrome,
is approximately 0.3% to 0.8% in pediatric patients (aged 2 to 17 years) and 0.08% to 0.3%
in adults receiving LAMICTAL. One rash-related death was reported in a prospectively
followed cohort of 1,983 pediatric patients (aged 2 to 16 years) with epilepsy taking
LAMICTAL as adjunctive therapy. In worldwide postmarketing experience, rare cases of
toxic epidermal necrolysis and/or rash-related death have been reported in adult and
pediatric patients, but their numbers are too few to permit a precise estimate of the rate.
Other than age, there are as yet no factors identified that are known to predict the risk of
occurrence or the severity of rash caused by LAMICTAL. There are suggestions, yet to be
proven, that the risk of rash may also be increased by (1) coadministration of LAMICTAL
with valproate (includes valproic acid and divalproex sodium), (2) exceeding the
recommended initial dose of LAMICTAL, or (3) exceeding the recommended dose
escalation for LAMICTAL. However, cases have occurred in the absence of these factors.
Nearly all cases of life-threatening rashes caused by LAMICTAL have occurred within 2 to
8 weeks of treatment initiation. However, isolated cases have occurred after prolonged
treatment (e.g., 6 months). Accordingly, duration of therapy cannot be relied upon as
means to predict the potential risk heralded by the first appearance of a rash.
2
Reference ID: 3757964
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Although benign rashes are also caused by LAMICTAL, it is not possible to predict
reliably which rashes will prove to be serious or life threatening. Accordingly, LAMICTAL
should ordinarily be discontinued at the first sign of rash, unless the rash is clearly not
drug related. Discontinuation of treatment may not prevent a rash from becoming life
threatening or permanently disabling or disfiguring [see Warnings and Precautions (5.1)].
1
INDICATIONS AND USAGE
1.1
Epilepsy
Adjunctive Therapy
LAMICTAL is indicated as adjunctive therapy for the following seizure types in patients aged 2
years and older:
• partial-onset seizures.
• primary generalized tonic-clonic (PGTC) seizures.
• generalized seizures of Lennox-Gastaut syndrome.
Monotherapy
LAMICTAL is indicated for conversion to monotherapy in adults (aged 16 years and older) with
partial-onset seizures who are receiving treatment with carbamazepine, phenytoin, phenobarbital,
primidone, or valproate as the single antiepileptic drug (AED).
Safety and effectiveness of LAMICTAL have not been established (1) as initial monotherapy;
(2) for conversion to monotherapy from AEDs other than carbamazepine, phenytoin,
phenobarbital, primidone, or valproate; or (3) for simultaneous conversion to monotherapy from
2 or more concomitant AEDs.
1.2
Bipolar Disorder
LAMICTAL is indicated for the maintenance treatment of bipolar I disorder to delay the time to
occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated
for acute mood episodes with standard therapy [see Clinical Studies (14.1)].
Limitations of Use
Treatment of acute manic or mixed episodes is not recommended. Effectiveness of LAMICTAL
in the acute treatment of mood episodes has not been established.
2
DOSAGE AND ADMINISTRATION
2.1
General Dosing Considerations
Rash
There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash
may be increased by (1) coadministration of LAMICTAL with valproate, (2) exceeding the
recommended initial dose of LAMICTAL, or (3) exceeding the recommended dose escalation
3
Reference ID: 3757964
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
for LAMICTAL. However, cases have occurred in the absence of these factors [see Boxed
Warning]. Therefore, it is important that the dosing recommendations be followed closely.
The risk of nonserious rash may be increased when the recommended initial dose and/or the rate
of dose escalation for LAMICTAL is exceeded and in patients with a history of allergy or rash to
other AEDs.
LAMICTAL Starter Kits and LAMICTAL ODT® Patient Titration Kits provide LAMICTAL at
doses consistent with the recommended titration schedule for the first 5 weeks of treatment,
based upon concomitant medications, for patients with epilepsy (older than 12 years) and bipolar
I disorder (adults) and are intended to help reduce the potential for rash. The use of LAMICTAL
Starter Kits and LAMICTAL ODT Patient Titration Kits is recommended for appropriate
patients who are starting or restarting LAMICTAL [see How Supplied/Storage and Handling
(16)].
It is recommended that LAMICTAL not be restarted in patients who discontinued due to rash
associated with prior treatment with lamotrigine unless the potential benefits clearly outweigh
the risks. If the decision is made to restart a patient who has discontinued LAMICTAL, the need
to restart with the initial dosing recommendations should be assessed. The greater the interval of
time since the previous dose, the greater consideration should be given to restarting with the
initial dosing recommendations. If a patient has discontinued lamotrigine for a period of more
than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be
followed. The half-life of lamotrigine is affected by other concomitant medications [see Clinical
Pharmacology (12.3)].
LAMICTAL Added to Drugs Known to Induce or Inhibit Glucuronidation
Because lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are
known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine.
Drugs that induce glucuronidation include carbamazepine, phenytoin, phenobarbital, primidone,
rifampin, estrogen-containing oral contraceptives, and the protease inhibitors lopinavir/ritonavir
and atazanavir/ritonavir. Valproate inhibits glucuronidation. For dosing considerations for
LAMICTAL in patients on estrogen-containing contraceptives and atazanavir/ritonavir, see
below and Table 13. For dosing considerations for LAMICTAL in patients on other drugs known
to induce or inhibit glucuronidation, see Tables 1, 2, 5-6, and 13.
Target Plasma Levels for Patients with Epilepsy or Bipolar Disorder
A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of
LAMICTAL should be based on therapeutic response [see Clinical Pharmacology (12.3)].
Women Taking Estrogen-Containing Oral Contraceptives
Starting LAMICTAL in Women Taking Estrogen-Containing Oral Contraceptives: Although
estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine
[see Clinical Pharmacology (12.3)], no adjustments to the recommended dose-escalation
4
Reference ID: 3757964
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
guidelines for LAMICTAL should be necessary solely based on the use of estrogen-containing
oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for
initiating adjunctive therapy with LAMICTAL based on the concomitant AED or other
concomitant medications (see Tables 1, 5, and 7). See below for adjustments to maintenance
doses of LAMICTAL in women taking estrogen-containing oral contraceptives.
Adjustments to the Maintenance Dose of LAMICTAL in Women Taking Estrogen-Containing
Oral Contraceptives:
(1) Taking Estrogen-Containing Oral Contraceptives: In women not taking
carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the
protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine
glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance
dose of LAMICTAL will in most cases need to be increased by as much as 2-fold over the
recommended target maintenance dose to maintain a consistent lamotrigine plasma level.
(2) Starting Estrogen-Containing Oral Contraceptives: In women taking a stable dose of
LAMICTAL and not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs
such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that
induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)],
the maintenance dose will in most cases need to be increased by as much as 2-fold to maintain a
consistent lamotrigine plasma level. The dose increases should begin at the same time that the
oral contraceptive is introduced and continue, based on clinical response, no more rapidly than
50 to 100 mg/day every week. Dose increases should not exceed the recommended rate (see
Tables 1 and 5) unless lamotrigine plasma levels or clinical response support larger increases.
Gradual transient increases in lamotrigine plasma levels may occur during the week of inactive
hormonal preparation (pill-free week), and these increases will be greater if dose increases are
made in the days before or during the week of inactive hormonal preparation. Increased
lamotrigine plasma levels could result in additional adverse reactions, such as dizziness, ataxia,
and diplopia. If adverse reactions attributable to LAMICTAL consistently occur during the
pill-free week, dose adjustments to the overall maintenance dose may be necessary. Dose
adjustments limited to the pill-free week are not recommended. For women taking LAMICTAL
in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as
rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce
lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no
adjustment to the dose of LAMICTAL should be necessary.
(3) Stopping Estrogen-Containing Oral Contraceptives: In women not taking
carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the
protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine
glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance
dose of LAMICTAL will in most cases need to be decreased by as much as 50% in order to
maintain a consistent lamotrigine plasma level. The decrease in dose of LAMICTAL should not
5
Reference ID: 3757964
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or
lamotrigine plasma levels indicate otherwise [see Clinical Pharmacology (12.3)]. In women
taking LAMICTAL in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other
drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir
that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology
(12.3)], no adjustment to the dose of LAMICTAL should be necessary.
Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy
The effect of other hormonal contraceptive preparations or hormone replacement therapy on the
pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that
ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the
progestin-only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the
dosage of LAMICTAL in the presence of progestogens alone will likely not be needed.
Patients Taking Atazanavir/Ritonavir
While atazanavir/ritonavir does reduce the lamotrigine plasma concentration, no adjustments to
the recommended dose-escalation guidelines for LAMICTAL should be necessary solely based
on the use of atazanavir/ritonavir. Dose escalation should follow the recommended guidelines for
initiating adjunctive therapy with LAMICTAL based on concomitant AED or other concomitant
medications (see Tables 1, 2, and 5). In patients already taking maintenance doses of
LAMICTAL and not taking glucuronidation inducers, the dose of LAMICTAL may need to be
increased if atazanavir/ritonavir is added, or decreased if atazanavir/ritonavir is discontinued [see
Clinical Pharmacology (12.3)].
Patients with Hepatic Impairment
Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology
study in 24 subjects with mild, moderate, and severe liver impairment [see Use in Specific
Populations (8.6), Clinical Pharmacology (12.3)], the following general recommendations can
be made. No dosage adjustment is needed in patients with mild liver impairment. Initial,
escalation, and maintenance doses should generally be reduced by approximately 25% in patients
with moderate and severe liver impairment without ascites and 50% in patients with severe liver
impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical
response.
Patients with Renal Impairment
Initial doses of LAMICTAL should be based on patients’ concomitant medications (see Tables
1-3, and 5); reduced maintenance doses may be effective for patients with significant renal
impairment [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]. Few patients
with severe renal impairment have been evaluated during chronic treatment with LAMICTAL.
Because there is inadequate experience in this population, LAMICTAL should be used with
caution in these patients.
6
Reference ID: 3757964
This label may not be the latest approved by FDA.
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Discontinuation Strategy
Epilepsy: For patients receiving LAMICTAL in combination with other AEDs, a re-evaluation
of all AEDs in the regimen should be considered if a change in seizure control or an appearance
or worsening of adverse reactions is observed.
If a decision is made to discontinue therapy with LAMICTAL, a step-wise reduction of dose
over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns
require a more rapid withdrawal [see Warnings and Precautions (5.8)].
Discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as
rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce
lamotrigine glucuronidation should prolong the half-life of lamotrigine; discontinuing valproate
should shorten the half-life of lamotrigine.
Bipolar Disorder: In the controlled clinical trials, there was no increase in the incidence, type, or
severity of adverse reactions following abrupt termination of LAMICTAL. In the clinical
development program in adults with bipolar disorder, 2 patients experienced seizures shortly
after abrupt withdrawal of LAMICTAL. Discontinuation of LAMICTAL should involve a
step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety
concerns require a more rapid withdrawal [see Warnings and Precautions (5.8)].
2.2
Epilepsy—Adjunctive Therapy
This section provides specific dosing recommendations for patients older than 12 years and
patients aged 2 to 12 years. Within each of these age-groups, specific dosing recommendations
are provided depending upon concomitant AEDs or other concomitant medications (see Table 1
for patients older than 12 years and Table 2 for patients aged 2 to 12 years). A weight-based
dosing guide for patients aged 2 to 12 years on concomitant valproate is provided in Table 3.
Patients Older than 12 Years
Recommended dosing guidelines are summarized in Table 1.
7
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Table 1. Escalation Regimen for LAMICTAL in Patients Older than 12 Years with
Epilepsy
In Patients
TAKING Valproatea
In Patients
NOT TAKING
Carbamazepine,
Phenytoin,
Phenobarbital,
Primidone,b or
Valproatea
In Patients TAKING
Carbamazepine,
Phenytoin,
Phenobarbital, or
Primidoneb and NOT
TAKING Valproatea
Weeks 1 and 2
25 mg every other day
25 mg every day
50 mg/day
Weeks 3 and 4
25 mg every day
50 mg/day
100 mg/day
(in 2 divided doses)
Week 5 onward
to maintenance
Increase by
25 to 50 mg/day
every 1 to 2 weeks.
Increase by
50 mg/day
every 1 to 2 weeks.
Increase by
100 mg/day
every 1 to 2 weeks.
Usual
maintenance dose
100 to 200 mg/day
with valproate alone
100 to 400 mg/day
with valproate and
other drugs that
induce glucuronidation
(in 1 or 2 divided doses)
225 to 375 mg/day
(in 2 divided doses)
300 to 500 mg/day
(in 2 divided doses)
a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of
lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].
b Drugs that induce lamotrigine glucuronidation and increase clearance, other than the specified
antiepileptic drugs, include estrogen-containing oral contraceptives, rifampin, and the protease
inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Dosing recommendations for oral
contraceptives and the protease inhibitor atazanavir/ritonavir can be found in General Dosing
Considerations [see Dosage and Administration (2.1)]. Patients on rifampin and the protease
inhibitor lopinavir/ritonavir should follow the same dosing titration/maintenance regimen used
with antiepileptic drugs that induce glucuronidation and increase clearance [see Dosage and
Administration (2.1), Drug Interactions (7), and Clinical Pharmacology (12.3)].
Patients Aged 2 to 12 Years
Recommended dosing guidelines are summarized in Table 2.
Lower starting doses and slower dose escalations than those used in clinical trials are
recommended because of the suggestion that the risk of rash may be decreased by lower starting
doses and slower dose escalations. Therefore, maintenance doses will take longer to reach in
clinical practice than in clinical trials. It may take several weeks to months to achieve an
8
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individualized maintenance dose. Maintenance doses in patients weighing less than 30 kg,
regardless of age or concomitant AED, may need to be increased as much as 50%, based on
clinical response.
The smallest available strength of LAMICTAL chewable dispersible tablets is 2 mg, and only
whole tablets should be administered. If the calculated dose cannot be achieved using whole
tablets, the dose should be rounded down to the nearest whole tablet [see How Supplied/Storage
and Handling (16) and Medication Guide].
Table 2. Escalation Regimen for LAMICTAL in Patients Aged 2 to 12 Years with Epilepsy
In Patients TAKING
Valproatea
In Patients
NOT TAKING
Carbamazepine,
Phenytoin,
Phenobarbital,
Primidone,b or
Valproatea
In Patients TAKING
Carbamazepine,
Phenytoin,
Phenobarbital, or
Primidoneb and NOT
TAKING Valproatea
Weeks 1 and 2
0.15 mg/kg/day
in 1 or 2 divided doses,
rounded down to the
nearest whole tablet
(see Table 3 for
weight-based dosing
guide)
0.3 mg/kg/day
in 1 or 2 divided doses,
rounded down to the
nearest whole tablet
0.6 mg/kg/day
in 2 divided doses,
rounded down to the
nearest whole tablet
Weeks 3 and 4
0.3 mg/kg/day
in 1 or 2 divided doses,
rounded down to the
nearest whole tablet
(see Table 3 for
weight-based dosing
guide)
0.6 mg/kg/day
in 2 divided doses,
rounded down to the
nearest whole tablet
1.2 mg/kg/day
in 2 divided doses,
rounded down to the
nearest whole tablet
9
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Week 5 onward to
maintenance
The dose should be
increased every 1 to 2
weeks as follows:
calculate
0.3 mg/kg/day,
round this amount
down to the nearest
whole tablet, and add
this amount to the
previously
administered daily
dose.
The dose should be
increased every 1 to 2
weeks as follows:
calculate
0.6 mg/kg/day,
round this amount
down to the nearest
whole tablet, and add
this amount to the
previously
administered daily
dose.
The dose should be
increased every 1 to 2
weeks as follows:
calculate
1.2 mg/kg/day,
round this amount
down to the nearest
whole tablet, and add
this amount to the
previously
administered daily
dose.
Usual
maintenance dose
1 to 5 mg/kg/day
(maximum
200 mg/day in 1 or 2
divided doses)
1 to 3 mg/kg/day
with valproate alone
4.5 to 7.5 mg/kg/day
(maximum
300 mg/day in 2
divided doses)
5 to 15 mg/kg/day
(maximum
400 mg/day in 2
divided doses)
Maintenance dose
May need to be
May need to be
May need to be
in patients less
increased by as much
increased by as much
increased by as much
than 30 kg
as 50%, based on
clinical response.
as 50%, based on
clinical response.
as 50%, based on
clinical response.
Note: Only whole tablets should be used for dosing.
a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of
lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].
b Drugs that induce lamotrigine glucuronidation and increase clearance, other than the specified
antiepileptic drugs, include estrogen-containing oral contraceptives, rifampin, and the protease
inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Dosing recommendations for oral
contraceptives and the protease inhibitor atazanavir/ritonavir can be found in General Dosing
Considerations [see Dosage and Administration (2.1)]. Patients on rifampin and the protease
inhibitor lopinavir/ritonavir should follow the same dosing titration/maintenance regimen used
with antiepileptic drugs that induce glucuronidation and increase clearance [see Dosage and
Administration (2.1), Drug Interactions (7), and Clinical Pharmacology (12.3)].
10
Reference ID: 3757964
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Table 3. The Initial Weight-Based Dosing Guide for Patients Aged 2 to 12 Years Taking
Valproate (Weeks 1 to 4) with Epilepsy
If the patient’s weight is
Give this daily dose, using the most appropriate
combination of LAMICTAL 2- and 5-mg tablets
Greater than
And less than
Weeks 1 and 2
Weeks 3 and 4
6.7 kg
14 kg
2 mg every other day
2 mg every day
14.1 kg
27 kg
2 mg every day
4 mg every day
27.1 kg
34 kg
4 mg every day
8 mg every day
34.1 kg
40 kg
5 mg every day
10 mg every day
Usual Adjunctive Maintenance Dose for Epilepsy
The usual maintenance doses identified in Tables 1 and 2 are derived from dosing regimens
employed in the placebo-controlled adjunctive trials in which the efficacy of LAMICTAL was
established. In patients receiving multidrug regimens employing carbamazepine, phenytoin,
phenobarbital, or primidone without valproate, maintenance doses of adjunctive LAMICTAL as
high as 700 mg/day have been used. In patients receiving valproate alone, maintenance doses of
adjunctive LAMICTAL as high as 200 mg/day have been used. The advantage of using doses
above those recommended in Tables 1-4 has not been established in controlled trials.
2.3
Epilepsy—Conversion from Adjunctive Therapy to Monotherapy
The goal of the transition regimen is to attempt to maintain seizure control while mitigating the
risk of serious rash associated with the rapid titration of LAMICTAL.
The recommended maintenance dose of LAMICTAL as monotherapy is 500 mg/day given in 2
divided doses.
To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations
for LAMICTAL should not be exceeded [see Boxed Warning].
Conversion from Adjunctive Therapy with Carbamazepine, Phenytoin, Phenobarbital, or
Primidone to Monotherapy with LAMICTAL
After achieving a dose of 500 mg/day of LAMICTAL using the guidelines in Table 1, the
concomitant enzyme-inducing AED should be withdrawn by 20% decrements each week over a
4-week period. The regimen for the withdrawal of the concomitant AED is based on experience
gained in the controlled monotherapy clinical trial.
Conversion from Adjunctive Therapy with Valproate to Monotherapy with LAMICTAL
The conversion regimen involves the 4 steps outlined in Table 4.
11
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Table 4. Conversion from Adjunctive Therapy with Valproate to Monotherapy with
LAMICTAL in Patients Aged 16 Years and Older with Epilepsy
LAMICTAL
Valproate
Step 1
Achieve a dose of 200 mg/day according
to guidelines in Table 1.
Maintain established stable dose.
Step 2
Maintain at 200 mg/day.
Decrease dose by decrements no
greater than 500 mg/day/week to
500 mg/day and then maintain for 1
week.
Step 3
Increase to 300 mg/day and maintain for 1
week.
Simultaneously decrease to
250 mg/day and maintain for 1 week.
Step 4
Increase by 100 mg/day every week to
achieve maintenance dose of 500 mg/day.
Discontinue.
Conversion from Adjunctive Therapy with Antiepileptic Drugs other than Carbamazepine,
Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy with LAMICTAL
No specific dosing guidelines can be provided for conversion to monotherapy with LAMICTAL
with AEDs other than carbamazepine, phenytoin, phenobarbital, primidone, or valproate.
2.4
Bipolar Disorder
The goal of maintenance treatment with LAMICTAL is to delay the time to occurrence of mood
episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood
episodes with standard therapy [see Indications and Usage (1)].
Patients taking LAMICTAL for more than 16 weeks should be periodically reassessed to
determine the need for maintenance treatment.
Adults
The target dose of LAMICTAL is 200 mg/day (100 mg/day in patients taking valproate, which
decreases the apparent clearance of lamotrigine, and 400 mg/day in patients not taking valproate
and taking either carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as
rifampin and the protease inhibitor lopinavir/ritonavir that increase the apparent clearance of
lamotrigine). In the clinical trials, doses up to 400 mg/day as monotherapy were evaluated;
however, no additional benefit was seen at 400 mg/day compared with 200 mg/day [see Clinical
Studies (14.2)]. Accordingly, doses above 200 mg/day are not recommended.
Treatment with LAMICTAL is introduced, based on concurrent medications, according to the
regimen outlined in Table 5. If other psychotropic medications are withdrawn following
stabilization, the dose of LAMICTAL should be adjusted. In patients discontinuing valproate, the
dose of LAMICTAL should be doubled over a 2-week period in equal weekly increments (see
Table 6). In patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other
12
Reference ID: 3757964
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drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir
that induce lamotrigine glucuronidation, the dose of LAMICTAL should remain constant for the
first week and then should be decreased by half over a 2-week period in equal weekly
decrements (see Table 6). The dose of LAMICTAL may then be further adjusted to the target
dose (200 mg) as clinically indicated.
If other drugs are subsequently introduced, the dose of LAMICTAL may need to be adjusted. In
particular, the introduction of valproate requires reduction in the dose of LAMICTAL [see Drug
Interactions (7), Clinical Pharmacology (12.3)].
To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations
of LAMICTAL should not be exceeded [see Boxed Warning].
Table 5. Escalation Regimen for LAMICTAL in Adults with Bipolar Disorder
In Patients TAKING
Valproatea
In Patients
NOT TAKING
Carbamazepine,
Phenytoin,
Phenobarbital,
Primidone,b or
Valproatea
In Patients TAKING
Carbamazepine,
Phenytoin,
Phenobarbital, or
Primidoneb and NOT
TAKING Valproatea
Weeks 1 and 2
25 mg every other day
25 mg daily
50 mg daily
Weeks 3 and 4
25 mg daily
50 mg daily
100 mg daily,
in divided doses
Week 5
50 mg daily
100 mg daily
200 mg daily,
in divided doses
Week 6
100 mg daily
200 mg daily
300 mg daily,
in divided doses
Week 7
100 mg daily
200 mg daily
up to 400 mg daily,
in divided doses
a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of
lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].
b Drugs that induce lamotrigine glucuronidation and increase clearance, other than the
specified antiepileptic drugs, include estrogen-containing oral contraceptives, rifampin, and
the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Dosing
recommendations for oral contraceptives and the protease inhibitor atazanavir/ritonavir can
be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients
on rifampin and the protease inhibitor lopinavir/ritonavir should follow the same dosing
titration/maintenance regimen used with antiepileptic drugs that induce glucuronidation and
increase clearance [see Dosage and Administration (2.1), Drug Interactions (7), and
Clinical Pharmacology (12.3)].
13
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Table 6. Dosage Adjustments to LAMICTAL in Adults with Bipolar Disorder Following
Discontinuation of Psychotropic Medications
Discontinuation
of Psychotropic Drugs
(excluding Valproate,a
Carbamazepine,
Phenytoin, Phenobarbital,
or Primidoneb)
After Discontinuation
of Valproatea
After Discontinuation of
Carbamazepine,
Phenytoin, Phenobarbital,
or Primidoneb
Current Dose of
LAMICTAL (mg/day)
100
Current Dose of
LAMICTAL (mg/day)
400
Week 1
Maintain current dose
of LAMICTAL
150
400
Week 2
Maintain current dose
of LAMICTAL
200
300
Week 3
onward
Maintain current dose
of LAMICTAL
200
200
a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of
lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].
b Drugs that induce lamotrigine glucuronidation and increase clearance, other than the specified
antiepileptic drugs, include estrogen-containing oral contraceptives, rifampin, and the protease
inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Dosing recommendations for oral
contraceptives and the protease inhibitor atazanavir/ritonavir can be found in General Dosing
Considerations [see Dosage and Administration (2.1)]. Patients on rifampin and the protease
inhibitor lopinavir/ritonavir should follow the same dosing titration/maintenance regimen used
with antiepileptic drugs that induce glucuronidation and increase clearance [see Dosage and
Administration (2.1), Drug Interactions (7), and Clinical Pharmacology (12.3)].
2.5
Administration of LAMICTAL Chewable Dispersible Tablets
LAMICTAL chewable dispersible tablets may be swallowed whole, chewed, or dispersed in
water or diluted fruit juice. If the tablets are chewed, consume a small amount of water or diluted
fruit juice to aid in swallowing.
To disperse LAMICTAL chewable dispersible tablets, add the tablets to a small amount of liquid
(1 teaspoon, or enough to cover the medication). Approximately 1 minute later, when the tablets
are completely dispersed, swirl the solution and consume the entire quantity immediately. No
attempt should be made to administer partial quantities of the dispersed tablets.
2.6
Administration of LAMICTAL ODT Orally Disintegrating Tablets
LAMICTAL ODT orally disintegrating tablets should be placed onto the tongue and moved
around in the mouth. The tablet will disintegrate rapidly, can be swallowed with or without
water, and can be taken with or without food.
14
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3
DOSAGE FORMS AND STRENGTHS
3.1
Tablets
25 mg, white, scored, shield-shaped tablets debossed with “LAMICTAL” and “25.”
100 mg, peach, scored, shield-shaped tablets debossed with “LAMICTAL” and “100.”
150 mg, cream, scored, shield-shaped tablets debossed with “LAMICTAL” and “150.”
200 mg, blue, scored, shield-shaped tablets debossed with “LAMICTAL” and “200.”
3.2
Chewable Dispersible Tablets
2 mg, white to off-white, round tablets debossed with “LTG” over “2.”
5 mg, white to off-white, caplet-shaped tablets debossed with “GX CL2.”
25 mg, white, super elliptical-shaped tablets debossed with “GX CL5.”
3.3
Orally Disintegrating Tablets
25 mg, white to off-white, round, flat-faced, radius-edged tablets debossed with “LMT” on one
side and “25” on the other side.
50 mg, white to off-white, round, flat-faced, radius-edged tablets debossed with “LMT” on one
side and “50” on the other side.
100 mg, white to off-white, round, flat-faced, radius-edged tablets debossed with “LAMICTAL”
on one side and “100” on the other side.
200 mg, white to off-white, round, flat-faced, radius-edged tablets debossed with “LAMICTAL”
on one side and “200” on the other side.
4
CONTRAINDICATIONS
LAMICTAL is contraindicated in patients who have demonstrated hypersensitivity (e.g., rash,
angioedema, acute urticaria, extensive pruritus, mucosal ulceration) to the drug or its ingredients
[see Boxed Warning, Warnings and Precautions (5.1, 5.2)].
5
WARNINGS AND PRECAUTIONS
5.1
Serious Skin Rashes [see Boxed Warning]
Pediatric Population
The incidence of serious rash associated with hospitalization and discontinuation of LAMICTAL
in a prospectively followed cohort of pediatric patients (aged 2 to 17 years) is approximately
0.3% to 0.8%. One rash-related death was reported in a prospectively followed cohort of 1,983
pediatric patients (aged 2 to 16 years) with epilepsy taking LAMICTAL as adjunctive therapy.
Additionally, there have been rare cases of toxic epidermal necrolysis with and without
permanent sequelae and/or death in US and foreign postmarketing experience.
15
Reference ID: 3757964
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There is evidence that the inclusion of valproate in a multidrug regimen increases the risk of
serious, potentially life-threatening rash in pediatric patients. In pediatric patients who used
valproate concomitantly for epilepsy, 1.2% (6 of 482) experienced a serious rash compared with
0.6% (6 of 952) patients not taking valproate.
Adult Population
Serious rash associated with hospitalization and discontinuation of LAMICTAL occurred in
0.3% (11 of 3,348) of adult patients who received LAMICTAL in premarketing clinical trials of
epilepsy. In the bipolar and other mood disorders clinical trials, the rate of serious rash was
0.08% (1 of 1,233) of adult patients who received LAMICTAL as initial monotherapy and
0.13% (2 of 1,538) of adult patients who received LAMICTAL as adjunctive therapy. No
fatalities occurred among these individuals. However, in worldwide postmarketing experience,
rare cases of rash-related death have been reported, but their numbers are too few to permit a
precise estimate of the rate.
Among the rashes leading to hospitalization were Stevens-Johnson syndrome, toxic epidermal
necrolysis, angioedema, and those associated with multiorgan hypersensitivity [see Warnings
and Precautions (5.2)].
There is evidence that the inclusion of valproate in a multidrug regimen increases the risk of
serious, potentially life-threatening rash in adults. Specifically, of 584 patients administered
LAMICTAL with valproate in epilepsy clinical trials, 6 (1%) were hospitalized in association
with rash; in contrast, 4 (0.16%) of 2,398 clinical trial patients and volunteers administered
LAMICTAL in the absence of valproate were hospitalized.
Patients with History of Allergy or Rash to Other Antiepileptic Drugs
The risk of nonserious rash may be increased when the recommended initial dose and/or the rate
of dose escalation for LAMICTAL is exceeded and in patients with a history of allergy or rash to
other AEDs.
5.2
Multiorgan Hypersensitivity Reactions and Organ Failure
Multiorgan hypersensitivity reactions, also known as drug reaction with eosinophilia and
systemic symptoms (DRESS), have occurred with LAMICTAL. Some have been fatal or life
threatening. DRESS typically, although not exclusively, presents with fever, rash, and/or
lymphadenopathy in association with other organ system involvement, such as hepatitis,
nephritis, hematologic abnormalities, myocarditis, or myositis, sometimes resembling an acute
viral infection. Eosinophilia is often present. This disorder is variable in its expression, and other
organ systems not noted here may be involved.
Fatalities associated with acute multiorgan failure and various degrees of hepatic failure have
been reported in 2 of 3,796 adult patients and 4 of 2,435 pediatric patients who received
LAMICTAL in epilepsy clinical trials. Rare fatalities from multiorgan failure have also been
reported in postmarketing use.
16
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Isolated liver failure without rash or involvement of other organs has also been reported with
LAMICTAL.
It is important to note that early manifestations of hypersensitivity (e.g., fever,
lymphadenopathy) may be present even though a rash is not evident. If such signs or symptoms
are present, the patient should be evaluated immediately. LAMICTAL should be discontinued if
an alternative etiology for the signs or symptoms cannot be established.
Prior to initiation of treatment with LAMICTAL, the patient should be instructed that a rash or
other signs or symptoms of hypersensitivity (e.g., fever, lymphadenopathy) may herald a serious
medical event and that the patient should report any such occurrence to a healthcare provider
immediately.
5.3
Blood Dyscrasias
There have been reports of blood dyscrasias that may or may not be associated with multiorgan
hypersensitivity (also known as DRESS) [see Warnings and Precautions (5.2)]. These have
included neutropenia, leukopenia, anemia, thrombocytopenia, pancytopenia, and, rarely, aplastic
anemia and pure red cell aplasia.
5.4
Suicidal Behavior and Ideation
AEDs, including LAMICTAL, increase the risk of suicidal thoughts or behavior in patients
taking these drugs for any indication. Patients treated with any AED for any indication should be
monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or
any unusual changes in mood or behavior.
Pooled analyses of 199 placebo-controlled clinical trials (monotherapy and adjunctive therapy)
of 11 different AEDs showed that patients randomized to 1 of the AEDs had approximately
twice the risk (adjusted Relative Risk 1.8, 95% CI: 1.2, 2.7) of suicidal thinking or behavior
compared with patients randomized to placebo. In these trials, which had a median treatment
duration of 12 weeks, the estimated incidence of suicidal behavior or ideation among 27,863
AED-treated patients was 0.43%, compared with 0.24% among 16,029 placebo-treated patients,
representing an increase of approximately 1 case of suicidal thinking or behavior for every 530
patients treated. There were 4 suicides in drug-treated patients in the trials and none in
placebo-treated patients, but the number of events is too small to allow any conclusion about
drug effect on suicide.
The increased risk of suicidal thoughts or behavior with AEDs was observed as early as 1 week
after starting treatment with AEDs and persisted for the duration of treatment assessed. Because
most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts
or behavior beyond 24 weeks could not be assessed.
The risk of suicidal thoughts or behavior was generally consistent among drugs in the data
analyzed. The finding of increased risk with AEDs of varying mechanism of action and across a
17
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range of indications suggests that the risk applies to all AEDs used for any indication. The risk
did not vary substantially by age (5 to 100 years) in the clinical trials analyzed.
Table 7 shows absolute and relative risk by indication for all evaluated AEDs.
Table 7. Risk by Indication for Antiepileptic Drugs in the Pooled Analysis
Indication
Placebo
Patients with
Events per
1,000 Patients
Drug Patients
with Events
per 1,000
Patients
Relative Risk:
Incidence of
Events in Drug
Patients/
Incidence in
Placebo Patients
Risk Difference:
Additional Drug
Patients with
Events per
1,000 Patients
Epilepsy
1.0
3.4
3.5
2.4
Psychiatric
5.7
8.5
1.5
2.9
Other
1.0
1.8
1.9
0.9
Total
2.4
4.3
1.8
1.9
The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in
clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for
the epilepsy and psychiatric indications.
Anyone considering prescribing LAMICTAL or any other AED must balance the risk of suicidal
thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for
which AEDs are prescribed are themselves associated with morbidity and mortality and an
increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge
during treatment, the prescriber needs to consider whether the emergence of these symptoms in
any given patient may be related to the illness being treated.
Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal
thoughts and behavior and should be advised of the need to be alert for the emergence or
worsening of the signs and symptoms of depression, any unusual changes in mood or behavior,
the emergence of suicidal thoughts or suicidal behavior, or thoughts about self-harm. Behaviors
of concern should be reported immediately to healthcare providers.
5.5
Aseptic Meningitis
Therapy with LAMICTAL increases the risk of developing aseptic meningitis. Because of the
potential for serious outcomes of untreated meningitis due to other causes, patients should also
be evaluated for other causes of meningitis and treated as appropriate.
Postmarketing cases of aseptic meningitis have been reported in pediatric and adult patients
taking LAMICTAL for various indications. Symptoms upon presentation have included
headache, fever, nausea, vomiting, and nuchal rigidity. Rash, photophobia, myalgia, chills,
altered consciousness, and somnolence were also noted in some cases. Symptoms have been
18
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reported to occur within 1 day to one and a half months following the initiation of treatment. In
most cases, symptoms were reported to resolve after discontinuation of LAMICTAL.
Re-exposure resulted in a rapid return of symptoms (from within 30 minutes to 1 day following
re-initiation of treatment) that were frequently more severe. Some of the patients treated with
LAMICTAL who developed aseptic meningitis had underlying diagnoses of systemic lupus
erythematosus or other autoimmune diseases.
Cerebrospinal fluid (CSF) analyzed at the time of clinical presentation in reported cases was
characterized by a mild to moderate pleocytosis, normal glucose levels, and mild to moderate
increase in protein. CSF white blood cell count differentials showed a predominance of
neutrophils in a majority of the cases, although a predominance of lymphocytes was reported in
approximately one third of the cases. Some patients also had new onset of signs and symptoms
of involvement of other organs (predominantly hepatic and renal involvement), which may
suggest that in these cases the aseptic meningitis observed was part of a hypersensitivity reaction
[see Warnings and Precautions (5.2)].
5.6
Potential Medication Errors
Medication errors involving LAMICTAL have occurred. In particular, the names LAMICTAL or
lamotrigine can be confused with the names of other commonly used medications. Medication
errors may also occur between the different formulations of LAMICTAL. To reduce the potential
of medication errors, write and say LAMICTAL clearly. Depictions of the LAMICTAL tablets,
chewable dispersible tablets, and orally disintegrating tablets can be found in the Medication
Guide that accompanies the product to highlight the distinctive markings, colors, and shapes that
serve to identify the different presentations of the drug and thus may help reduce the risk of
medication errors. To avoid the medication error of using the wrong drug or formulation, patients
should be strongly advised to visually inspect their tablets to verify that they are LAMICTAL, as
well as the correct formulation of LAMICTAL, each time they fill their prescription.
5.7
Concomitant Use with Oral Contraceptives
Some estrogen-containing oral contraceptives have been shown to decrease serum concentrations
of lamotrigine [see Clinical Pharmacology (12.3)]. Dosage adjustments will be necessary in
most patients who start or stop estrogen-containing oral contraceptives while taking LAMICTAL
[see Dosage and Administration (2.1)]. During the week of inactive hormone preparation
(pill-free week) of oral contraceptive therapy, plasma lamotrigine levels are expected to rise, as
much as doubling at the end of the week. Adverse reactions consistent with elevated levels of
lamotrigine, such as dizziness, ataxia, and diplopia, could occur.
5.8
Withdrawal Seizures
As with other AEDs, LAMICTAL should not be abruptly discontinued. In patients with epilepsy
there is a possibility of increasing seizure frequency. In clinical trials in adults with bipolar
disorder, 2 patients experienced seizures shortly after abrupt withdrawal of LAMICTAL. Unless
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safety concerns require a more rapid withdrawal, the dose of LAMICTAL should be tapered over
a period of at least 2 weeks (approximately 50% reduction per week) [see Dosage and
Administration (2.1)].
5.9
Status Epilepticus
Valid estimates of the incidence of treatment-emergent status epilepticus among patients treated
with LAMICTAL are difficult to obtain because reporters participating in clinical trials did not
all employ identical rules for identifying cases. At a minimum, 7 of 2,343 adult patients had
episodes that could unequivocally be described as status epilepticus. In addition, a number of
reports of variably defined episodes of seizure exacerbation (e.g., seizure clusters, seizure
flurries) were made.
5.10
Sudden Unexplained Death in Epilepsy (SUDEP)
During the premarketing development of LAMICTAL, 20 sudden and unexplained deaths were
recorded among a cohort of 4,700 patients with epilepsy (5,747 patient-years of exposure).
Some of these could represent seizure-related deaths in which the seizure was not observed, e.g.,
at night. This represents an incidence of 0.0035 deaths per patient-year. Although this rate
exceeds that expected in a healthy population matched for age and sex, it is within the range of
estimates for the incidence of sudden unexplained death in epilepsy (SUDEP) in patients not
receiving LAMICTAL (ranging from 0.0005 for the general population of patients with epilepsy,
to 0.004 for a recently studied clinical trial population similar to that in the clinical development
program for LAMICTAL, to 0.005 for patients with refractory epilepsy). Consequently, whether
these figures are reassuring or suggest concern depends on the comparability of the populations
reported upon with the cohort receiving LAMICTAL and the accuracy of the estimates provided.
Probably most reassuring is the similarity of estimated SUDEP rates in patients receiving
LAMICTAL and those receiving other AEDs, chemically unrelated to each other, that underwent
clinical testing in similar populations. Importantly, that drug is chemically unrelated to
LAMICTAL. This evidence suggests, although it certainly does not prove, that the high SUDEP
rates reflect population rates, not a drug effect.
5.11
Addition of LAMICTAL to a Multidrug Regimen that Includes Valproate
Because valproate reduces the clearance of lamotrigine, the dosage of LAMICTAL in the
presence of valproate is less than half of that required in its absence [see Dosage and
Administration (2.2, 2.3, 2.4), Drug Interactions (7)].
5.12
Binding in the Eye and Other Melanin-Containing Tissues
Because lamotrigine binds to melanin, it could accumulate in melanin-rich tissues over time.
This raises the possibility that lamotrigine may cause toxicity in these tissues after extended use.
Although ophthalmological testing was performed in 1 controlled clinical trial, the testing was
inadequate to exclude subtle effects or injury occurring after long-term exposure. Moreover, the
20
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capacity of available tests to detect potentially adverse consequences, if any, of lamotrigine’s
binding to melanin is unknown [see Clinical Pharmacology (12.2)].
Accordingly, although there are no specific recommendations for periodic ophthalmological
monitoring, prescribers should be aware of the possibility of long-term ophthalmologic effects.
5.13
Laboratory Tests
False-Positive Drug Test Results
Lamotrigine has been reported to interfere with the assay used in some rapid urine drug screens,
which can result in false-positive readings, particularly for phencyclidine (PCP). A more specific
analytical method should be used to confirm a positive result.
Plasma Concentrations of Lamotrigine
The value of monitoring plasma concentrations of lamotrigine in patients treated with
LAMICTAL has not been established. Because of the possible pharmacokinetic interactions
between lamotrigine and other drugs, including AEDs (see Table 13), monitoring of the plasma
levels of lamotrigine and concomitant drugs may be indicated, particularly during dosage
adjustments. In general, clinical judgment should be exercised regarding monitoring of plasma
levels of lamotrigine and other drugs and whether or not dosage adjustments are necessary.
6
ADVERSE REACTIONS
The following adverse reactions are described in more detail in the Warnings and Precautions
section of the label:
• Serious skin rashes [see Warnings and Precautions (5.1)]
• Multiorgan hypersensitivity reactions and organ failure [see Warnings and Precautions (5.2)]
• Blood dyscrasias [see Warnings and Precautions (5.3)]
• Suicidal behavior and ideation [see Warnings and Precautions (5.4)]
• Aseptic meningitis [see Warnings and Precautions (5.5)]
• Withdrawal seizures [see Warnings and Precautions (5.8)]
• Status epilepticus [see Warnings and Precautions (5.9)]
• Sudden unexplained death in epilepsy [see Warnings and Precautions (5.10)]
6.1
Clinical Trial Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates
observed in the clinical trials of a drug cannot be directly compared with rates in the clinical
trials of another drug and may not reflect the rates observed in practice.
21
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Epilepsy
Most Common Adverse Reactions in All Clinical Trials: Adjunctive Therapy in Adults with
Epilepsy: The most commonly observed (≥5% for LAMICTAL and more common on drug than
placebo) adverse reactions seen in association with LAMICTAL during adjunctive therapy in
adults and not seen at an equivalent frequency among placebo-treated patients were: dizziness,
ataxia, somnolence, headache, diplopia, blurred vision, nausea, vomiting, and rash. Dizziness,
diplopia, ataxia, blurred vision, nausea, and vomiting were dose related. Dizziness, diplopia,
ataxia, and blurred vision occurred more commonly in patients receiving carbamazepine with
LAMICTAL than in patients receiving other AEDs with LAMICTAL. Clinical data suggest a
higher incidence of rash, including serious rash, in patients receiving concomitant valproate than
in patients not receiving valproate [see Warnings and Precautions (5.1)].
Approximately 11% of the 3,378 adult patients who received LAMICTAL as adjunctive therapy
in premarketing clinical trials discontinued treatment because of an adverse reaction. The
adverse reactions most commonly associated with discontinuation were rash (3.0%), dizziness
(2.8%), and headache (2.5%).
In a dose-response trial in adults, the rate of discontinuation of LAMICTAL for dizziness, ataxia,
diplopia, blurred vision, nausea, and vomiting was dose related.
Monotherapy in Adults with Epilepsy: The most commonly observed (≥5% for
LAMICTAL and more common on drug than placebo) adverse reactions seen in association with
the use of LAMICTAL during the monotherapy phase of the controlled trial in adults not seen at
an equivalent rate in the control group were vomiting, coordination abnormality, dyspepsia,
nausea, dizziness, rhinitis, anxiety, insomnia, infection, pain, weight decrease, chest pain, and
dysmenorrhea. The most commonly observed (≥5% for LAMICTAL and more common on drug
than placebo) adverse reactions associated with the use of LAMICTAL during the conversion to
monotherapy (add-on) period, not seen at an equivalent frequency among low-dose
valproate-treated patients, were dizziness, headache, nausea, asthenia, coordination abnormality,
vomiting, rash, somnolence, diplopia, ataxia, accidental injury, tremor, blurred vision, insomnia,
nystagmus, diarrhea, lymphadenopathy, pruritus, and sinusitis.
Approximately 10% of the 420 adult patients who received LAMICTAL as monotherapy in
premarketing clinical trials discontinued treatment because of an adverse reaction. The adverse
reactions most commonly associated with discontinuation were rash (4.5%), headache (3.1%),
and asthenia (2.4%).
Adjunctive Therapy in Pediatric Patients with Epilepsy: The most commonly observed
(≥5% for LAMICTAL and more common on drug than placebo) adverse reactions seen in
association with the use of LAMICTAL as adjunctive treatment in pediatric patients aged 2 to 16
years and not seen at an equivalent rate in the control group were infection, vomiting, rash, fever,
somnolence, accidental injury, dizziness, diarrhea, abdominal pain, nausea, ataxia, tremor,
asthenia, bronchitis, flu syndrome, and diplopia.
22
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In 339 patients aged 2 to 16 years with partial-onset seizures or generalized seizures of
Lennox-Gastaut syndrome, 4.2% of patients on LAMICTAL and 2.9% of patients on placebo
discontinued due to adverse reactions. The most commonly reported adverse reaction that led to
discontinuation of LAMICTAL was rash.
Approximately 11.5% of the 1,081 pediatric patients aged 2 to 16 years who received
LAMICTAL as adjunctive therapy in premarketing clinical trials discontinued treatment because
of an adverse reaction. The adverse reactions most commonly associated with discontinuation
were rash (4.4%), reaction aggravated (1.7%), and ataxia (0.6%).
Controlled Adjunctive Clinical Trials in Adults with Epilepsy: Table 8 lists adverse
reactions that occurred in adult patients with epilepsy treated with LAMICTAL in
placebo-controlled trials. In these trials, either LAMICTAL or placebo was added to the patient’s
current AED therapy.
Table 8. Adverse Reactions in Pooled, Placebo-Controlled Adjunctive Trials in Adult
Patients with Epilepsya,b
Body System/
Adverse Reaction
Percent of Patients
Receiving Adjunctive
LAMICTAL
(n = 711)
Percent of Patients
Receiving Adjunctive
Placebo
(n = 419)
Body as a whole
Headache
29
19
Flu syndrome
7
6
Fever
6
4
Abdominal pain
5
4
Neck pain
2
1
Reaction aggravated
(seizure exacerbation)
2
1
Digestive
Nausea
19
10
Vomiting
9
4
Diarrhea
6
4
Dyspepsia
5
2
Constipation
4
3
Anorexia
2
1
Musculoskeletal
Arthralgia
2
0
23
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Nervous
Dizziness
38
13
Ataxia
22
6
Somnolence
14
7
Incoordination
6
2
Insomnia
6
2
Tremor
4
1
Depression
4
3
Anxiety
4
3
Convulsion
3
1
Irritability
3
2
Speech disorder
3
0
Concentration disturbance
2
1
Respiratory
Rhinitis
14
9
Pharyngitis
10
9
Cough increased
8
6
Skin and appendages
Rash
Pruritus
10
3
5
2
Special senses
Diplopia
28
7
Blurred vision
16
5
Vision abnormality
3
1
Urogenital
Female patients only
Dysmenorrhea
Vaginitis
Amenorrhea
(n = 365)
7
4
2
(n = 207)
6
1
1
a Adverse reactions that occurred in at least 2% of patients treated with LAMICTAL and at a
greater incidence than placebo.
b Patients in these adjunctive trials were receiving 1 to 3 of the concomitant antiepileptic drugs
carbamazepine, phenytoin, phenobarbital, or primidone in addition to LAMICTAL or
placebo. Patients may have reported multiple adverse reactions during the trial or at
discontinuation; thus, patients may be included in more than 1 category.
In a randomized, parallel trial comparing placebo with 300 and 500 mg/day of LAMICTAL,
some of the more common drug-related adverse reactions were dose related (see Table 9).
24
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Table 9. Dose-Related Adverse Reactions from a Randomized, Placebo-Controlled,
Adjunctive Trial in Adults with Epilepsy
Adverse Reaction
Percent of Patients Experiencing Adverse Reactions
Placebo
(n = 73)
LAMICTAL
300 mg
(n = 71)
LAMICTAL
500 mg
(n = 72)
Ataxia
Blurred vision
Diplopia
Dizziness
Nausea
Vomiting
10
10
8
27
11
4
10
11
24
a
31
18
11
28
a,b
25
a,b
49
a,b
54
a,b
25
a
18
a
a Significantly greater than placebo group (P<0.05).
b Significantly greater than group receiving LAMICTAL 300 mg (P<0.05).
The overall adverse reaction profile for LAMICTAL was similar between females and males and
was independent of age. Because the largest non-Caucasian racial subgroup was only 6% of
patients exposed to LAMICTAL in placebo-controlled trials, there are insufficient data to
support a statement regarding the distribution of adverse reaction reports by race. Generally,
females receiving either LAMICTAL as adjunctive therapy or placebo were more likely to report
adverse reactions than males. The only adverse reaction for which the reports on LAMICTAL
were greater than 10% more frequent in females than males (without a corresponding difference
by gender on placebo) was dizziness (difference = 16.5%). There was little difference between
females and males in the rates of discontinuation of LAMICTAL for individual adverse
reactions.
Controlled Monotherapy Trial in Adults with Partial-Onset Seizures: Table 10 lists
adverse reactions that occurred in patients with epilepsy treated with monotherapy with
LAMICTAL in a double-blind trial following discontinuation of either concomitant
carbamazepine or phenytoin not seen at an equivalent frequency in the control group.
Table 10. Adverse Reactions in a Controlled Monotherapy Trial in Adult Patients with
Partial-Onset Seizuresa,b
Body System/
Adverse Reaction
Percent of Patients
Receiving LAMICTALc
as Monotherapy
(n = 43)
Percent of Patients
Receiving Low-Dose
Valproated Monotherapy
(n = 44)
Body as a whole
Pain
Infection
Chest pain
5
5
5
0
2
2
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Digestive
Vomiting
Dyspepsia
Nausea
9
7
7
0
2
2
Metabolic and nutritional
Weight decrease
5
2
Nervous
Coordination abnormality
Dizziness
Anxiety
Insomnia
7
7
5
5
0
0
0
2
Respiratory
Rhinitis
7
2
Urogenital (female patients only)
Dysmenorrhea
(n = 21)
5
(n = 28)
0
a Adverse reactions that occurred in at least 5% of patients treated with LAMICTAL and at a
greater incidence than valproate-treated patients.
b Patients in this trial were converted to LAMICTAL or valproate monotherapy from
adjunctive therapy with carbamazepine or phenytoin. Patients may have reported multiple
adverse reactions during the trial; thus, patients may be included in more than 1 category.
c Up to 500 mg/day.
d 1,000 mg/day.
Adverse reactions that occurred with a frequency of less than 5% and greater than 2% of patients
receiving LAMICTAL and numerically more frequent than placebo were:
Body as a Whole: Asthenia, fever.
Digestive: Anorexia, dry mouth, rectal hemorrhage, peptic ulcer.
Metabolic and Nutritional: Peripheral edema.
Nervous System: Amnesia, ataxia, depression, hypesthesia, libido increase, decreased reflexes,
increased reflexes, nystagmus, irritability, suicidal ideation.
Respiratory: Epistaxis, bronchitis, dyspnea.
Skin and Appendages: Contact dermatitis, dry skin, sweating.
Special Senses: Vision abnormality.
Incidence in Controlled Adjunctive Trials in Pediatric Patients with Epilepsy: Table 11
lists adverse reactions that occurred in 339 pediatric patients with partial-onset seizures or
generalized seizures of Lennox-Gastaut syndrome who received LAMICTAL up to
15 mg/kg/day or a maximum of 750 mg/day.
26
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Table 11. Adverse Reactions in Pooled, Placebo-Controlled Adjunctive Trials in
Pediatric Patients with Epilepsya
Body System/Adverse Reaction
Percent of Patients
Receiving LAMICTAL
(n = 168)
Percent of Patients
Receiving Placebo
(n = 171)
Body as a whole
Infection
20
17
Fever
15
14
Accidental injury
14
12
Abdominal pain
10
5
Asthenia
8
4
Flu syndrome
7
6
Pain
5
4
Facial edema
2
1
Photosensitivity
2
0
Cardiovascular
Hemorrhage
2
1
Digestive
Vomiting
20
16
Diarrhea
11
9
Nausea
10
2
Constipation
4
2
Dyspepsia
2
1
Hemic and lymphatic
Lymphadenopathy
2
1
Metabolic and nutritional
Edema
2
0
Nervous system
Somnolence
17
15
Dizziness
14
4
Ataxia
11
3
Tremor
10
1
Emotional lability
4
2
Gait abnormality
4
2
Thinking abnormality
3
2
Convulsions
2
1
Nervousness
2
1
Vertigo
2
1
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Respiratory
Pharyngitis
14
11
Bronchitis
7
5
Increased cough
7
6
Sinusitis
2
1
Bronchospasm
2
1
Skin
Rash
14
12
Eczema
2
1
Pruritus
2
1
Special senses
Diplopia
5
1
Blurred vision
4
1
Visual abnormality
2
0
Urogenital
Male and female patients
Urinary tract infection
3
0
a Adverse reactions that occurred in at least 2% of patients treated with LAMICTAL and at
a greater incidence than placebo.
Bipolar Disorder in Adults
The most common adverse reactions seen in association with the use of LAMICTAL as
monotherapy (100 to 400 mg/day) in adult patients (aged 18 to 82 years) with bipolar disorder in
the 2 double-blind placebo-controlled trials of 18 months’ duration are included in Table 12.
Adverse reactions that occurred in at least 5% of patients and were numerically more frequent
during the dose-escalation phase of LAMICTAL in these trials (when patients may have been
receiving concomitant medications) compared with the monotherapy phase were: headache
(25%), rash (11%), dizziness (10%), diarrhea (8%), dream abnormality (6%), and pruritus (6%).
During the monotherapy phase of the double-blind placebo-controlled trials of 18 months’
duration, 13% of 227 patients who received LAMICTAL (100 to 400 mg/day), 16% of 190
patients who received placebo, and 23% of 166 patients who received lithium discontinued
therapy because of an adverse reaction. The adverse reactions that most commonly led to
discontinuation of LAMICTAL were rash (3%) and mania/hypomania/mixed mood adverse
reactions (2%). Approximately 16% of 2,401 patients who received LAMICTAL (50 to
500 mg/day) for bipolar disorder in premarketing trials discontinued therapy because of an
adverse reaction, most commonly due to rash (5%) and mania/hypomania/mixed mood adverse
reactions (2%).
The overall adverse reaction profile for LAMICTAL was similar between females and males,
between elderly and nonelderly patients, and among racial groups.
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Table 12. Adverse Reactions in 2 Placebo-Controlled Trials in Adult Patients with
Bipolar I Disordera,b
Body System/Adverse Reaction
Percent of Patients
Receiving LAMICTAL
(n = 227)
Percent of Patients
Receiving Placebo
(n = 190)
General
Back pain
Fatigue
Abdominal pain
8
8
6
6
5
3
Digestive
Nausea
Constipation
Vomiting
14
5
5
11
2
2
Nervous System
Insomnia
Somnolence
Xerostomia (dry mouth)
10
9
6
6
7
4
Respiratory
Rhinitis
Exacerbation of cough
Pharyngitis
7
5
5
4
3
4
Skin
Rash (nonserious)c
7
5
a Adverse reactions that occurred in at least 5% of patients treated with LAMICTAL and at a
greater incidence than placebo.
b Patients in these trials were converted to LAMICTAL (100 to 400 mg/day) or placebo
monotherapy from add-on therapy with other psychotropic medications. Patients may have
reported multiple adverse reactions during the trial; thus, patients may be included in more
than 1 category.
c In the overall bipolar and other mood disorders clinical trials, the rate of serious rash was
0.08% (1 of 1,233) of adult patients who received LAMICTAL as initial monotherapy and
0.13% (2 of 1,538) of adult patients who received LAMICTAL as adjunctive therapy [see
Warnings and Precautions (5.1)].
Other reactions that occurred in 5% or more patients but equally or more frequently in the
placebo group included: dizziness, mania, headache, infection, influenza, pain, accidental injury,
diarrhea, and dyspepsia.
Adverse reactions that occurred with a frequency of less than 5% and greater than 1% of patients
receiving LAMICTAL and numerically more frequent than placebo were:
29
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General: Fever, neck pain.
Cardiovascular: Migraine.
Digestive: Flatulence.
Metabolic and Nutritional: Weight gain, edema.
Musculoskeletal: Arthralgia, myalgia.
Nervous System: Amnesia, depression, agitation, emotional lability, dyspraxia, abnormal
thoughts, dream abnormality, hypoesthesia.
Respiratory: Sinusitis.
Urogenital: Urinary frequency.
Adverse Reactions following Abrupt Discontinuation: In the 2 controlled clinical trials, there was
no increase in the incidence, severity, or type of adverse reactions in patients with bipolar
disorder after abruptly terminating therapy with LAMICTAL. In the clinical development
program in adults with bipolar disorder, 2 patients experienced seizures shortly after abrupt
withdrawal of LAMICTAL [see Warnings and Precautions (5.8)].
Mania/Hypomania/Mixed Episodes: During the double-blind placebo-controlled clinical trials in
bipolar I disorder in which adults were converted to monotherapy with LAMICTAL (100 to
400 mg/day) from other psychotropic medications and followed for up to 18 months, the rates of
manic or hypomanic or mixed mood episodes reported as adverse reactions were 5% for patients
treated with LAMICTAL (n = 227), 4% for patients treated with lithium (n = 166), and 7% for
patients treated with placebo (n = 190). In all bipolar controlled trials combined, adverse
reactions of mania (including hypomania and mixed mood episodes) were reported in 5% of
patients treated with LAMICTAL (n = 956), 3% of patients treated with lithium (n = 280), and
4% of patients treated with placebo (n = 803).
6.2
Other Adverse Reactions Observed in All Clinical Trials
LAMICTAL has been administered to 6,694 individuals for whom complete adverse reaction
data was captured during all clinical trials, only some of which were placebo controlled. During
these trials, all adverse reactions were recorded by the clinical investigators using terminology of
their own choosing. To provide a meaningful estimate of the proportion of individuals having
adverse reactions, similar types of adverse reactions were grouped into a smaller number of
standardized categories using modified COSTART dictionary terminology. The frequencies
presented represent the proportion of the 6,694 individuals exposed to LAMICTAL who
experienced an event of the type cited on at least 1 occasion while receiving LAMICTAL. All
reported adverse reactions are included except those already listed in the previous tables or
elsewhere in the labeling, those too general to be informative, and those not reasonably
associated with the use of the drug.
30
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Adverse reactions are further classified within body system categories and enumerated in order
of decreasing frequency using the following definitions: frequent adverse reactions are defined as
those occurring in at least 1/100 patients; infrequent adverse reactions are those occurring in
1/100 to 1/1,000 patients; rare adverse reactions are those occurring in fewer than 1/1,000
patients.
Body as a Whole
Infrequent: Allergic reaction, chills, malaise.
Cardiovascular System
Infrequent: Flushing, hot flashes, hypertension, palpitations, postural hypotension, syncope,
tachycardia, vasodilation.
Dermatological
Infrequent: Acne, alopecia, hirsutism, maculopapular rash, skin discoloration, urticaria.
Rare: Angioedema, erythema, exfoliative dermatitis, fungal dermatitis, herpes zoster,
leukoderma, multiforme erythema, petechial rash, pustular rash, Stevens-Johnson syndrome,
vesiculobullous rash.
Digestive System
Infrequent: Dysphagia, eructation, gastritis, gingivitis, increased appetite, increased salivation,
liver function tests abnormal, mouth ulceration.
Rare: Gastrointestinal hemorrhage, glossitis, gum hemorrhage, gum hyperplasia, hematemesis,
hemorrhagic colitis, hepatitis, melena, stomach ulcer, stomatitis, tongue edema.
Endocrine System
Rare: Goiter, hypothyroidism.
Hematologic and Lymphatic System
Infrequent: Ecchymosis, leukopenia.
Rare: Anemia, eosinophilia, fibrin decrease, fibrinogen decrease, iron deficiency anemia,
leukocytosis, lymphocytosis, macrocytic anemia, petechia, thrombocytopenia.
Metabolic and Nutritional Disorders
Infrequent: Aspartate transaminase increased.
Rare: Alcohol intolerance, alkaline phosphatase increase, alanine transaminase increase,
bilirubinemia, general edema, gamma glutamyl transpeptidase increase, hyperglycemia.
Musculoskeletal System
Infrequent: Arthritis, leg cramps, myasthenia, twitching.
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Rare: Bursitis, muscle atrophy, pathological fracture, tendinous contracture.
Nervous System
Frequent: Confusion, paresthesia.
Infrequent: Akathisia, apathy, aphasia, central nervous system depression, depersonalization,
dysarthria, dyskinesia, euphoria, hallucinations, hostility, hyperkinesia, hypertonia, libido
decreased, memory decrease, mind racing, movement disorder, myoclonus, panic attack,
paranoid reaction, personality disorder, psychosis, sleep disorder, stupor, suicidal ideation.
Rare: Choreoathetosis, delirium, delusions, dysphoria, dystonia, extrapyramidal syndrome,
faintness, grand mal convulsions, hemiplegia, hyperalgesia, hyperesthesia, hypokinesia,
hypotonia, manic depression reaction, muscle spasm, neuralgia, neurosis, paralysis, peripheral
neuritis.
Respiratory System
Infrequent: Yawn.
Rare: Hiccup, hyperventilation.
Special Senses
Frequent: Amblyopia.
Infrequent: Abnormality of accommodation, conjunctivitis, dry eyes, ear pain, photophobia, taste
perversion, tinnitus.
Rare: Deafness, lacrimation disorder, oscillopsia, parosmia, ptosis, strabismus, taste loss, uveitis,
visual field defect.
Urogenital System
Infrequent: Abnormal ejaculation, hematuria, impotence, menorrhagia, polyuria, urinary
incontinence.
Rare: Acute kidney failure, anorgasmia, breast abscess, breast neoplasm, creatinine increase,
cystitis, dysuria, epididymitis, female lactation, kidney failure, kidney pain, nocturia, urinary
retention, urinary urgency.
6.3
Postmarketing Experience
The following adverse reactions have been identified during postapproval use of LAMICTAL.
Because these reactions are reported voluntarily from a population of uncertain size, it is not
always possible to reliably estimate their frequency or establish a causal relationship to drug
exposure.
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Blood and Lymphatic
Agranulocytosis, hemolytic anemia, lymphadenopathy not associated with hypersensitivity
disorder.
Gastrointestinal
Esophagitis.
Hepatobiliary Tract and Pancreas
Pancreatitis.
Immunologic
Lupus-like reaction, vasculitis.
Lower Respiratory
Apnea.
Musculoskeletal
Rhabdomyolysis has been observed in patients experiencing hypersensitivity reactions.
Nervous System
Aggression, exacerbation of Parkinsonian symptoms in patients with pre-existing Parkinson’s
disease, tics.
Non-site Specific
Progressive immunosuppression.
7
DRUG INTERACTIONS
Significant drug interactions with LAMICTAL are summarized in this section. Additional details
of these drug interaction studies are provided in the Clinical Pharmacology section [see Clinical
Pharmacology (12.3)].
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Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug
Effect on
Concentration of
Lamotrigine or
Concomitant Drug
Clinical Comment
Estrogen-containing oral
contraceptive
preparations containing
30 mcg ethinylestradiol
and 150 mcg
levonorgestrel
↓ lamotrigine
↓ levonorgestrel
Decreased lamotrigine concentrations
approximately 50%.
Decrease in levonorgestrel component by
19%.
Carbamazepine and
carbamazepine epoxide
↓ lamotrigine
? carbamazepine
epoxide
Addition of carbamazepine decreases
lamotrigine concentration approximately
40%.
May increase carbamazepine epoxide
levels.
Lopinavir/ritonavir
↓ lamotrigine
Decreased lamotrigine concentration
approximately 50%.
Atazanavir/ritonavir
↓ lamotrigine
Decreased lamotrigine AUC
approximately 32%.
Phenobarbital/primidone
↓ lamotrigine
Decreased lamotrigine concentration
approximately 40%.
Phenytoin
↓ lamotrigine
Decreased lamotrigine concentration
approximately 40%.
Rifampin
↓ lamotrigine
Decreased lamotrigine AUC
approximately 40%.
Valproate
↑ lamotrigine
? valproate
Increased lamotrigine concentrations
slightly more than 2-fold.
There are conflicting study results
regarding effect of lamotrigine on
valproate concentrations: 1) a mean 25%
decrease in valproate concentrations in
healthy volunteers, 2) no change in
valproate concentrations in controlled
clinical trials in patients with epilepsy.
↓ = Decreased (induces lamotrigine glucuronidation).
↑ = Increased (inhibits lamotrigine glucuronidation).
? = Conflicting data.
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Effect of LAMICTAL on Organic Cationic Transporter 2 Substrates
Lamotrigine is an inhibitor of renal tubular secretion via organic cationic transporter 2 (OCT2)
proteins [see Clinical Pharmacology (12.3)]. This may result in increased plasma levels of
certain drugs that are substantially excreted via this route. Coadministration of LAMICTAL with
OCT2 substrates with a narrow therapeutic index (e.g., dofetilide) is not recommended.
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
As with other AEDs, physiological changes during pregnancy may affect lamotrigine
concentrations and/or therapeutic effect. There have been reports of decreased lamotrigine
concentrations during pregnancy and restoration of pre-partum concentrations after delivery.
Dosage adjustments may be necessary to maintain clinical response.
Pregnancy Category C
There are no adequate and well-controlled studies in pregnant women. In animal studies,
lamotrigine was developmentally toxic at doses lower than those administered clinically.
LAMICTAL should be used during pregnancy only if the potential benefit justifies the potential
risk to the fetus. When lamotrigine was administered to pregnant mice, rats, or rabbits during the
period of organogenesis (oral doses of up to 125, 25, and 30 mg/kg, respectively), reduced fetal
body weight and increased incidences of fetal skeletal variations were seen in mice and rats at
doses that were also maternally toxic. The no-effect doses for embryofetal developmental
toxicity in mice, rats, and rabbits (75, 6.25, and 30 mg/kg, respectively) are similar to (mice and
rabbits) or less than (rats) the human dose of 400 mg/day on a body surface area (mg/m2) basis.
In a study in which pregnant rats were administered lamotrigine (oral doses of 5 or 25 mg/kg)
during the period of organogenesis and offspring were evaluated postnatally, behavioral
abnormalities were observed in exposed offspring at both doses. The lowest effect dose for
developmental neurotoxicity in rats is less than the human dose of 400 mg/day on a mg/m2 basis.
Maternal toxicity was observed at the higher dose tested.
When pregnant rats were administered lamotrigine (oral doses of 5, 10, or 20 mg/kg) during the
latter part of gestation, increased offspring mortality (including stillbirths) was seen at all doses.
The lowest effect dose for peri/postnatal developmental toxicity in rats is less than the human
dose of 400 mg/day on a mg/m2 basis. Maternal toxicity was observed at the 2 highest doses
tested.
Lamotrigine decreases fetal folate concentrations in rat, an effect known to be associated with
adverse pregnancy outcomes in animals and humans.
Pregnancy Registry
To provide information regarding the effects of in utero exposure to LAMICTAL, physicians are
advised to recommend that pregnant patients taking LAMICTAL enroll in the North American
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Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll-free
number 1-888-233-2334 and must be done by patients themselves. Information on the registry
can also be found at the website http://www.aedpregnancyregistry.org.
8.2
Labor and Delivery
The effect of LAMICTAL on labor and delivery in humans is unknown.
8.3
Nursing Mothers
Lamotrigine is present in milk from lactating women taking LAMICTAL. Data from multiple
small studies indicate that lamotrigine plasma levels in human milk-fed infants have been
reported to be as high as 50% of the maternal serum levels. Neonates and young infants are at
risk for high serum levels because maternal serum and milk levels can rise to high levels
postpartum if lamotrigine dosage has been increased during pregnancy but not later reduced to
the pre-pregnancy dosage. Lamotrigine exposure is further increased due to the immaturity of the
infant glucuronidation capacity needed for drug clearance. Events including apnea, drowsiness,
and poor sucking have been reported in infants who have been human milk-fed by mothers using
lamotrigine; whether or not these events were caused by lamotrigine is unknown. Human
milk-fed infants should be closely monitored for adverse events resulting from lamotrigine.
Measurement of infant serum levels should be performed to rule out toxicity if concerns arise.
Human milk-feeding should be discontinued in infants with lamotrigine toxicity. Caution should
be exercised when LAMICTAL is administered to a nursing woman.
8.4
Pediatric Use
Epilepsy
LAMICTAL is indicated as adjunctive therapy in patients aged 2 years and older for
partial-onset seizures, the generalized seizures of Lennox-Gastaut syndrome, and PGTC seizures.
Safety and efficacy of LAMICTAL used as adjunctive treatment for partial-onset seizures were
not demonstrated in a small, randomized, double-blind, placebo-controlled withdrawal trial in
very young pediatric patients (aged 1 to 24 months). LAMICTAL was associated with an
increased risk for infectious adverse reactions (LAMICTAL 37%, placebo 5%), and respiratory
adverse reactions (LAMICTAL 26%, placebo 5%). Infectious adverse reactions included
bronchiolitis, bronchitis, ear infection, eye infection, otitis externa, pharyngitis, urinary tract
infection, and viral infection. Respiratory adverse reactions included nasal congestion, cough,
and apnea.
Bipolar Disorder
Safety and efficacy of LAMICTAL for the maintenance treatment of bipolar disorder were not
established in a double-blind, randomized withdrawal, placebo-controlled trial that evaluated 301
pediatric patients aged 10 to 17 years with a current manic/hypomanic, depressed, or mixed
mood episode as defined by DSM-IV-TR. In the randomized phase of the trial, adverse reactions
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that occurred in at least 5% of patients taking LAMICTAL (n = 87) and were twice as common
compared to patients taking placebo (n = 86) were influenza (LAMICTAL 8%, placebo 2%),
oropharyngeal pain (LAMICTAL 8%, placebo 2%), vomiting (LAMICTAL 6%, placebo 2%),
contact dermatitis (LAMICTAL 5%, placebo 2%), upper abdominal pain (LAMICTAL 5%,
placebo 1%), and suicidal ideation (LAMICTAL 5%, placebo 0%).
Juvenile Animal Data
In a juvenile animal study in which lamotrigine (oral doses of 5, 15, or 30 mg/kg) was
administered to young rats (postnatal days 7 to 62), decreased viability and growth were seen at
the highest dose tested and long-term behavioral abnormalities (decreased locomotor activity,
increased reactivity, and learning deficits in animals tested as adults) were observed at the 2
highest doses. The no-effect dose for adverse effects on neurobehavioral development is less
than the human dose of 400 mg/day on a mg/m2 basis.
8.5
Geriatric Use
Clinical trials of LAMICTAL for epilepsy and bipolar disorder did not include sufficient
numbers of patients aged 65 years and older to determine whether they respond differently from
younger patients or exhibit a different safety profile than that of younger patients. In general,
dose selection for an elderly patient should be cautious, usually starting at the low end of the
dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and
of concomitant disease or other drug therapy.
8.6
Hepatic Impairment
Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology
study in 24 subjects with mild, moderate, and severe liver impairment [see Clinical
Pharmacology (12.3)], the following general recommendations can be made. No dosage
adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance
doses should generally be reduced by approximately 25% in patients with moderate and severe
liver impairment without ascites and 50% in patients with severe liver impairment with ascites.
Escalation and maintenance doses may be adjusted according to clinical response [see Dosage
and Administration (2.1)].
8.7
Renal Impairment
Lamotrigine is metabolized mainly by glucuronic acid conjugation, with the majority of the
metabolites being recovered in the urine. In a small study comparing a single dose of lamotrigine
in subjects with varying degrees of renal impairment with healthy volunteers, the plasma half-life
of lamotrigine was approximately twice as long in the subjects with chronic renal failure [see
Clinical Pharmacology (12.3)].
Initial doses of LAMICTAL should be based on patients’ AED regimens; reduced maintenance
doses may be effective for patients with significant renal impairment. Few patients with severe
renal impairment have been evaluated during chronic treatment with lamotrigine. Because there
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structural formula
is inadequate experience in this population, LAMICTAL should be used with caution in these
patients [see Dosage and Administration (2.1)].
10
OVERDOSAGE
10.1
Human Overdose Experience
Overdoses involving quantities up to 15 g have been reported for LAMICTAL, some of which
have been fatal. Overdose has resulted in ataxia, nystagmus, seizures (including tonic-clonic
seizures), decreased level of consciousness, coma, and intraventricular conduction delay.
10.2
Management of Overdose
There are no specific antidotes for lamotrigine. Following a suspected overdose, hospitalization
of the patient is advised. General supportive care is indicated, including frequent monitoring of
vital signs and close observation of the patient. If indicated, emesis should be induced; usual
precautions should be taken to protect the airway. It should be kept in mind that
immediate-release lamotrigine is rapidly absorbed [see Clinical Pharmacology (12.3)]. It is
uncertain whether hemodialysis is an effective means of removing lamotrigine from the blood. In
6 renal failure patients, about 20% of the amount of lamotrigine in the body was removed by
hemodialysis during a 4-hour session. A Poison Control Center should be contacted for
information on the management of overdosage of LAMICTAL.
11
DESCRIPTION
LAMICTAL (lamotrigine), an AED of the phenyltriazine class, is chemically unrelated to
existing AEDs. Lamotrigine’s chemical name is 3,5-diamino-6-(2,3-dichlorophenyl)-as-triazine,
its molecular formula is C9H7N5Cl2, and its molecular weight is 256.09. Lamotrigine is a white
to pale cream-colored powder and has a pKa of 5.7. Lamotrigine is very slightly soluble in water
(0.17 mg/mL at 25°C) and slightly soluble in 0.1 M HCl (4.1 mg/mL at 25°C). The structural
formula is:
LAMICTAL tablets are supplied for oral administration as 25-mg (white), 100-mg (peach),
150-mg (cream), and 200-mg (blue) tablets. Each tablet contains the labeled amount of
lamotrigine and the following inactive ingredients: lactose; magnesium stearate; microcrystalline
cellulose; povidone; sodium starch glycolate; FD&C Yellow No. 6 Lake (100-mg tablet only);
ferric oxide, yellow (150-mg tablet only); and FD&C Blue No. 2 Lake (200-mg tablet only).
LAMICTAL chewable dispersible tablets are supplied for oral administration. The tablets
contain 2 mg (white), 5 mg (white), or 25 mg (white) of lamotrigine and the following inactive
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ingredients: blackcurrant flavor, calcium carbonate, low-substituted hydroxypropylcellulose,
magnesium aluminum silicate, magnesium stearate, povidone, saccharin sodium, and sodium
starch glycolate. The chewable dispersible tablets meet Organic Impurities Procedure 2 as
published in the current USP monograph for Lamotrigine Tablets for Oral Suspension.
LAMICTAL ODT orally disintegrating tablets are supplied for oral administration. The tablets
contain 25 mg (white to off-white), 50 mg (white to off-white), 100 mg (white to off-white), or
200 mg (white to off-white) of lamotrigine and the following inactive ingredients: artificial
cherry flavor, crospovidone, ethylcellulose, magnesium stearate, mannitol, polyethylene, and
sucralose.
LAMICTAL ODT orally disintegrating tablets are formulated using technologies (Microcaps®
and AdvaTab®) designed to mask the bitter taste of lamotrigine and achieve a rapid dissolution
profile. Tablet characteristics including flavor, mouth-feel, after-taste, and ease of use were rated
as favorable in a study in 108 healthy volunteers.
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
The precise mechanism(s) by which lamotrigine exerts its anticonvulsant action are unknown. In
animal models designed to detect anticonvulsant activity, lamotrigine was effective in preventing
seizure spread in the maximum electroshock (MES) and pentylenetetrazol (scMet) tests, and
prevented seizures in the visually and electrically evoked after-discharge (EEAD) tests for
antiepileptic activity. Lamotrigine also displayed inhibitory properties in the kindling model in
rats both during kindling development and in the fully kindled state. The relevance of these
models to human epilepsy, however, is not known.
One proposed mechanism of action of lamotrigine, the relevance of which remains to be
established in humans, involves an effect on sodium channels. In vitro pharmacological studies
suggest that lamotrigine inhibits voltage-sensitive sodium channels, thereby stabilizing neuronal
membranes and consequently modulating presynaptic transmitter release of excitatory amino
acids (e.g., glutamate and aspartate).
Effect of Lamotrigine on N-Methyl d-Aspartate-Receptor–Mediated Activity
Lamotrigine did not inhibit N-methyl d-aspartate (NMDA)-induced depolarizations in rat cortical
slices or NMDA-induced cyclic GMP formation in immature rat cerebellum, nor did lamotrigine
displace compounds that are either competitive or noncompetitive ligands at this glutamate
receptor complex (CNQX, CGS, TCHP). The IC 50 for lamotrigine effects on NMDA-induced
currents (in the presence of 3 µM of glycine) in cultured hippocampal neurons exceeded
100 µM.
The mechanisms by which lamotrigine exerts its therapeutic action in bipolar disorder have not
been established.
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12.2
Pharmacodynamics
Folate Metabolism
In vitro, lamotrigine inhibited dihydrofolate reductase, the enzyme that catalyzes the reduction of
dihydrofolate to tetrahydrofolate. Inhibition of this enzyme may interfere with the biosynthesis
of nucleic acids and proteins. When oral daily doses of lamotrigine were given to pregnant rats
during organogenesis, fetal, placental, and maternal folate concentrations were reduced.
Significantly reduced concentrations of folate are associated with teratogenesis [see Use in
Specific Populations (8.1)]. Folate concentrations were also reduced in male rats given repeated
oral doses of lamotrigine. Reduced concentrations were partially returned to normal when
supplemented with folinic acid.
Accumulation in Kidneys
Lamotrigine accumulated in the kidney of the male rat, causing chronic progressive nephrosis,
necrosis, and mineralization. These findings are attributed to α-2 microglobulin, a species- and
sex-specific protein that has not been detected in humans or other animal species.
Melanin Binding
Lamotrigine binds to melanin-containing tissues, e.g., in the eye and pigmented skin. It has been
found in the uveal tract up to 52 weeks after a single dose in rodents.
Cardiovascular
In dogs, lamotrigine is extensively metabolized to a 2-N-methyl metabolite. This metabolite
causes dose-dependent prolongation of the PR interval, widening of the QRS complex, and, at
higher doses, complete AV conduction block. Similar cardiovascular effects are not anticipated
in humans because only trace amounts of the 2-N-methyl metabolite (<0.6% of lamotrigine dose)
have been found in human urine [see Clinical Pharmacology (12.3)]. However, it is conceivable
that plasma concentrations of this metabolite could be increased in patients with a reduced
capacity to glucuronidate lamotrigine (e.g., in patients with liver disease, patients taking
concomitant medications that inhibit glucuronidation).
12.3
Pharmacokinetics
The pharmacokinetics of lamotrigine have been studied in subjects with epilepsy, healthy young
and elderly volunteers, and volunteers with chronic renal failure. Lamotrigine pharmacokinetic
parameters for adult and pediatric subjects and healthy normal volunteers are summarized in
Tables 14 and 16.
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Table 14. Mean Pharmacokinetic Parametersa in Healthy Volunteers and Adult Subjects
with Epilepsy
Adult Study Population
Number
of
Subjects
Tmax : Time of
Maximum
Plasma
Concentration
(h)
t½:
Elimination
Half-life
(h)
CL/F:
Apparent
Plasma
Clearance
(mL/min/kg)
Healthy volunteers taking no
other medications:
Single-dose LAMICTAL
179
2.2
32.8
0.44
(0.25-12.0)
(14.0-103.0)
(0.12-1.10)
Multiple-dose LAMICTAL
36
1.7
25.4
0.58
(0.5-4.0)
(11.6-61.6)
(0.24-1.15)
Healthy volunteers taking
valproate:
Single-dose LAMICTAL
6
1.8
48.3
0.30
(1.0-4.0)
(31.5-88.6)
(0.14-0.42)
Multiple-dose LAMICTAL
18
1.9
70.3
0.18
(0.5-3.5)
(41.9-113.5)
(0.12-0.33)
Subjects with epilepsy taking
valproate only:
Single-dose LAMICTAL
4
4.8
58.8
0.28
(1.8-8.4)
(30.5-88.8)
(0.16-0.40)
Subjects with epilepsy taking
carbamazepine, phenytoin,
phenobarbital, or primidoneb
plus valproate:
Single-dose LAMICTAL
25
3.8
(1.0-10.0)
27.2
(11.2-51.6)
0.53
(0.27-1.04)
Subjects with epilepsy taking
carbamazepine, phenytoin,
phenobarbital, or primidone:b
Single-dose LAMICTAL
24
2.3
14.4
1.10
(0.5-5.0)
(6.4-30.4)
(0.51-2.22)
Multiple-dose LAMICTAL
17
2.0
12.6
1.21
(0.75-5.93)
(7.5-23.1)
(0.66-1.82)
a The majority of parameter means determined in each study had coefficients of variation
between 20% and 40% for half-life and CL/F and between 30% and 70% for Tmax . The
overall mean values were calculated from individual study means that were weighted based on
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the number of volunteers/subjects in each study. The numbers in parentheses below each
parameter mean represent the range of individual volunteer/subject values across studies.
b Carbamazepine, phenytoin, phenobarbital, and primidone have been shown to increase the
apparent clearance of lamotrigine. Estrogen-containing oral contraceptives and other drugs,
such as rifampin and protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir, that
induce lamotrigine glucuronidation have also been shown to increase the apparent clearance
of lamotrigine [see Drug Interactions (7)].
Absorption
Lamotrigine is rapidly and completely absorbed after oral administration with negligible
first-pass metabolism (absolute bioavailability is 98%). The bioavailability is not affected by
food. Peak plasma concentrations occur anywhere from 1.4 to 4.8 hours following drug
administration. The lamotrigine chewable/dispersible tablets were found to be equivalent,
whether administered as dispersed in water, chewed and swallowed, or swallowed whole, to the
lamotrigine compressed tablets in terms of rate and extent of absorption. In terms of rate and
extent of absorption, lamotrigine orally disintegrating tablets, whether disintegrated in the mouth
or swallowed whole with water, were equivalent to the lamotrigine compressed tablets
swallowed with water.
Dose Proportionality
In healthy volunteers not receiving any other medications and given single doses, the plasma
concentrations of lamotrigine increased in direct proportion to the dose administered over the
range of 50 to 400 mg. In 2 small studies (n = 7 and 8) of patients with epilepsy who were
maintained on other AEDs, there also was a linear relationship between dose and lamotrigine
plasma concentrations at steady state following doses of 50 to 350 mg twice daily.
Distribution
Estimates of the mean apparent volume of distribution (Vd/F) of lamotrigine following oral
administration ranged from 0.9 to 1.3 L/kg. Vd/F is independent of dose and is similar following
single and multiple doses in both patients with epilepsy and in healthy volunteers.
Protein Binding
Data from in vitro studies indicate that lamotrigine is approximately 55% bound to human
plasma proteins at plasma lamotrigine concentrations from 1 to 10 mcg/mL (10 mcg/mL is 4 to 6
times the trough plasma concentration observed in the controlled efficacy trials). Because
lamotrigine is not highly bound to plasma proteins, clinically significant interactions with other
drugs through competition for protein binding sites are unlikely. The binding of lamotrigine to
plasma proteins did not change in the presence of therapeutic concentrations of phenytoin,
phenobarbital, or valproate. Lamotrigine did not displace other AEDs (carbamazepine,
phenytoin, phenobarbital) from protein-binding sites.
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Metabolism
Lamotrigine is metabolized predominantly by glucuronic acid conjugation; the major metabolite
is an inactive 2-N-glucuronide conjugate. After oral administration of 240 mg of 14C-lamotrigine
(15 µCi) to 6 healthy volunteers, 94% was recovered in the urine and 2% was recovered in the
feces. The radioactivity in the urine consisted of unchanged lamotrigine (10%), the 2-N
glucuronide (76%), a 5-N-glucuronide (10%), a 2-N-methyl metabolite (0.14%), and other
unidentified minor metabolites (4%).
Enzyme Induction
The effects of lamotrigine on the induction of specific families of mixed-function oxidase
isozymes have not been systematically evaluated.
Following multiple administrations (150 mg twice daily) to normal volunteers taking no other
medications, lamotrigine induced its own metabolism, resulting in a 25% decrease in t ½ and a
37% increase in CL/F at steady state compared with values obtained in the same volunteers
following a single dose. Evidence gathered from other sources suggests that self-induction by
lamotrigine may not occur when lamotrigine is given as adjunctive therapy in patients receiving
enzyme-inducing drugs such as carbamazepine, phenytoin, phenobarbital, primidone, or other
drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir
that induce lamotrigine glucuronidation [see Drug Interactions (7)].
Elimination
The elimination half-life and apparent clearance of lamotrigine following oral administration of
LAMICTAL to adult subjects with epilepsy and healthy volunteers is summarized in Table 14.
Half-life and apparent oral clearance vary depending on concomitant AEDs.
Drug Interactions
The apparent clearance of lamotrigine is affected by the coadministration of certain medications
[see Warnings and Precautions (5.7, 5.11), Drug Interactions (7)].
The net effects of drug interactions with lamotrigine are summarized in Tables 13 and 15,
followed by details of the drug interaction studies below.
Table 15. Summary of Drug Interactions with Lamotrigine
Drug
Drug Plasma
Concentration with
Adjunctive Lamotriginea
Lamotrigine Plasma
Concentration with
Adjunctive Drugsb
Oral contraceptives (e.g.,
ethinylestradiol/levonorgestrel)c
Aripiprazole
Atazanavir/ritonavir
Bupropion
↔d
Not assessed
↔f
Not assessed
↓
↔e
↓
↔
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Carbamazepine
Carbamazepine epoxideg
Felbamate
Gabapentin
Levetiracetam
Lithium
Lopinavir/ritonavir
Olanzapine
Oxcarbazepine
10-Monohydroxy oxcarbazepine
metaboliteh
Phenobarbital/primidone
Phenytoin
Pregabalin
Rifampin
Risperidone
9-Hydroxyrisperidonei
Topiramate
Valproate
Valproate + phenytoin and/or
carbamazepine
Zonisamide
↔
?
Not assessed
Not assessed
↔
↔
↔e
↔
↔
↔
↔
↔
↔
Not assessed
↔
↔
↔j
↓
Not assessed
Not assessed
↓
↔
↔
↔
Not assessed
↓
↔e
↔
↓
↓
↔
↓
Not assessed
↔
↑
↔
↔
a From adjunctive clinical trials and volunteer trials.
b Net effects were estimated by comparing the mean clearance values obtained in adjunctive
clinical trials and volunteer trials.
c The effect of other hormonal contraceptive preparations or hormone replacement therapy on
the pharmacokinetics of lamotrigine has not been systematically evaluated in clinical trials,
although the effect may be similar to that seen with the ethinylestradiol/levonorgestrel
combinations.
d Modest decrease in levonorgestrel.
e Slight decrease, not expected to be clinically meaningful.
f Compared with historical controls.
g Not administered, but an active metabolite of carbamazepine.
h Not administered, but an active metabolite of oxcarbazepine.
i Not administered, but an active metabolite of risperidone.
j Slight increase, not expected to be clinically meaningful.
↔ = No significant effect.
? = Conflicting data.
44
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Estrogen-Containing Oral Contraceptives
In 16 female volunteers, an oral contraceptive preparation containing 30 mcg ethinylestradiol
and 150 mcg levonorgestrel increased the apparent clearance of lamotrigine (300 mg/day) by
approximately 2-fold with mean decreases in AUC of 52% and in Cmax of 39%. In this study,
trough serum lamotrigine concentrations gradually increased and were approximately 2-fold
higher on average at the end of the week of the inactive hormone preparation compared with
trough lamotrigine concentrations at the end of the active hormone cycle.
Gradual transient increases in lamotrigine plasma levels (approximate 2-fold increase) occurred
during the week of inactive hormone preparation (pill-free week) for women not also taking a
drug that increased the clearance of lamotrigine (carbamazepine, phenytoin, phenobarbital,
primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and
atazanavir/ritonavir that induce lamotrigine glucuronidation) [see Drug Interactions (7)]. The
increase in lamotrigine plasma levels will be greater if the dose of LAMICTAL is increased in
the few days before or during the pill-free week. Increases in lamotrigine plasma levels could
result in dose-dependent adverse reactions.
In the same study, coadministration of lamotrigine (300 mg/day) in 16 female volunteers did not
affect the pharmacokinetics of the ethinylestradiol component of the oral contraceptive
preparation. There were mean decreases in the AUC and Cmax of the levonorgestrel component
of 19% and 12%, respectively. Measurement of serum progesterone indicated that there was no
hormonal evidence of ovulation in any of the 16 volunteers, although measurement of serum
FSH, LH, and estradiol indicated that there was some loss of suppression of the
hypothalamic-pituitary-ovarian axis.
The effects of doses of lamotrigine other than 300 mg/day have not been systematically
evaluated in controlled clinical trials.
The clinical significance of the observed hormonal changes on ovulatory activity is unknown.
However, the possibility of decreased contraceptive efficacy in some patients cannot be
excluded. Therefore, patients should be instructed to promptly report changes in their menstrual
pattern (e.g., break-through bleeding).
Dosage adjustments may be necessary for women receiving estrogen-containing oral
contraceptive preparations [see Dosage and Administration (2.1)].
Other Hormonal Contraceptives or Hormone Replacement Therapy
The effect of other hormonal contraceptive preparations or hormone replacement therapy on the
pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that
ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the
progestin-only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the
dosage of LAMICTAL in the presence of progestogens alone will likely not be needed.
45
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Aripiprazole
In 18 patients with bipolar disorder on a stable regimen of 100 to 400 mg/day of lamotrigine, the
lamotrigine AUC and Cmax were reduced by approximately 10% in patients who received
aripiprazole 10 to 30 mg/day for 7 days, followed by 30 mg/day for an additional 7 days. This
reduction in lamotrigine exposure is not considered clinically meaningful.
Atazanavir/Ritonavir
In a study in healthy volunteers, daily doses of atazanavir/ritonavir (300 mg/100 mg) reduced the
plasma AUC and C max of lamotrigine (single 100-mg dose) by an average of 32% and 6%,
respectively, and shortened the elimination half-lives by 27%. In the presence of
atazanavir/ritonavir (300 mg/100 mg), the metabolite-to-lamotrigine ratio was increased from
0.45 to 0.71 consistent with induction of glucuronidation. The pharmacokinetics of
atazanavir/ritonavir were similar in the presence of concomitant lamotrigine to the historical data
of the pharmacokinetics in the absence of lamotrigine.
Bupropion
The pharmacokinetics of a 100-mg single dose of lamotrigine in healthy volunteers (n = 12) were
not changed by coadministration of bupropion sustained-release formulation (150 mg twice
daily) starting 11 days before lamotrigine.
Carbamazepine
Lamotrigine has no appreciable effect on steady-state carbamazepine plasma concentration.
Limited clinical data suggest there is a higher incidence of dizziness, diplopia, ataxia, and
blurred vision in patients receiving carbamazepine with lamotrigine than in patients receiving
other AEDs with lamotrigine [see Adverse Reactions (6.1)]. The mechanism of this interaction is
unclear. The effect of lamotrigine on plasma concentrations of carbamazepine-epoxide is
unclear. In a small subset of patients (n = 7) studied in a placebo-controlled trial, lamotrigine had
no effect on carbamazepine-epoxide plasma concentrations, but in a small, uncontrolled study
(n = 9), carbamazepine-epoxide levels increased.
The addition of carbamazepine decreases lamotrigine steady-state concentrations by
approximately 40%.
Felbamate
In a trial in 21 healthy volunteers, coadministration of felbamate (1,200 mg twice daily) with
lamotrigine (100 mg twice daily for 10 days) appeared to have no clinically relevant effects on
the pharmacokinetics of lamotrigine.
Folate Inhibitors
Lamotrigine is a weak inhibitor of dihydrofolate reductase. Prescribers should be aware of this
action when prescribing other medications that inhibit folate metabolism.
46
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Gabapentin
Based on a retrospective analysis of plasma levels in 34 subjects who received lamotrigine both
with and without gabapentin, gabapentin does not appear to change the apparent clearance of
lamotrigine.
Levetiracetam
Potential drug interactions between levetiracetam and lamotrigine were assessed by evaluating
serum concentrations of both agents during placebo-controlled clinical trials. These data indicate
that lamotrigine does not influence the pharmacokinetics of levetiracetam and that levetiracetam
does not influence the pharmacokinetics of lamotrigine.
Lithium
The pharmacokinetics of lithium were not altered in healthy subjects (n = 20) by
coadministration of lamotrigine (100 mg/day) for 6 days.
Lopinavir/Ritonavir
The addition of lopinavir (400 mg twice daily)/ritonavir (100 mg twice daily) decreased the
AUC, Cmax, and elimination half-life of lamotrigine by approximately 50% to 55.4% in 18
healthy subjects. The pharmacokinetics of lopinavir/ritonavir were similar with concomitant
lamotrigine, compared with that in historical controls.
Olanzapine
The AUC and Cmax of olanzapine were similar following the addition of olanzapine (15 mg once
daily) to lamotrigine (200 mg once daily) in healthy male volunteers (n = 16) compared with the
AUC and Cmax in healthy male volunteers receiving olanzapine alone (n = 16).
In the same trial, the AUC and Cmax of lamotrigine were reduced on average by 24% and 20%,
respectively, following the addition of olanzapine to lamotrigine in healthy male volunteers
compared with those receiving lamotrigine alone. This reduction in lamotrigine plasma
concentrations is not expected to be clinically meaningful.
Oxcarbazepine
The AUC and Cmax of oxcarbazepine and its active 10-monohydroxy oxcarbazepine metabolite
were not significantly different following the addition of oxcarbazepine (600 mg twice daily) to
lamotrigine (200 mg once daily) in healthy male volunteers (n = 13) compared with healthy male
volunteers receiving oxcarbazepine alone (n = 13).
In the same trial, the AUC and Cmax of lamotrigine were similar following the addition of
oxcarbazepine (600 mg twice daily) to lamotrigine in healthy male volunteers compared with
those receiving lamotrigine alone. Limited clinical data suggest a higher incidence of headache,
dizziness, nausea, and somnolence with coadministration of lamotrigine and oxcarbazepine
compared with lamotrigine alone or oxcarbazepine alone.
47
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Phenobarbital, Primidone
The addition of phenobarbital or primidone decreases lamotrigine steady-state concentrations by
approximately 40%.
Phenytoin
Lamotrigine has no appreciable effect on steady-state phenytoin plasma concentrations in
patients with epilepsy. The addition of phenytoin decreases lamotrigine steady-state
concentrations by approximately 40%.
Pregabalin
Steady-state trough plasma concentrations of lamotrigine were not affected by concomitant
pregabalin (200 mg 3 times daily) administration. There are no pharmacokinetic interactions
between lamotrigine and pregabalin.
Rifampin
In 10 male volunteers, rifampin (600 mg/day for 5 days) significantly increased the apparent
clearance of a single 25-mg dose of lamotrigine by approximately 2-fold (AUC decreased by
approximately 40%).
Risperidone
In a 14 healthy volunteers study, multiple oral doses of lamotrigine 400 mg daily had no
clinically significant effect on the single-dose pharmacokinetics of risperidone 2 mg and its
active metabolite 9-OH risperidone. Following the coadministration of risperidone 2 mg with
lamotrigine, 12 of the 14 volunteers reported somnolence compared with 1 out of 20 when
risperidone was given alone, and none when lamotrigine was administered alone.
Topiramate
Topiramate resulted in no change in plasma concentrations of lamotrigine. Administration of
lamotrigine resulted in a 15% increase in topiramate concentrations.
Valproate
When lamotrigine was administered to healthy volunteers (n = 18) receiving valproate, the
trough steady-state valproate plasma concentrations decreased by an average of 25% over a
3-week period, and then stabilized. However, adding lamotrigine to the existing therapy did not
cause a change in valproate plasma concentrations in either adult or pediatric patients in
controlled clinical trials.
The addition of valproate increased lamotrigine steady-state concentrations in normal volunteers
by slightly more than 2-fold. In 1 trial, maximal inhibition of lamotrigine clearance was reached
at valproate doses between 250 and 500 mg/day and did not increase as the valproate dose was
further increased.
48
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Zonisamide
In a study in 18 patients with epilepsy, coadministration of zonisamide (200 to 400 mg/day) with
lamotrigine (150 to 500 mg/day for 35 days) had no significant effect on the pharmacokinetics of
lamotrigine.
Known Inducers or Inhibitors of Glucuronidation
Drugs other than those listed above have not been systematically evaluated in combination with
lamotrigine. Since lamotrigine is metabolized predominately by glucuronic acid conjugation,
drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of
lamotrigine and doses of lamotrigine may require adjustment based on clinical response.
Other
In vitro assessment of the inhibitory effect of lamotrigine at OCT2 demonstrate that lamotrigine,
but not the N(2)-glucuronide metabolite, is an inhibitor of OCT2 at potentially clinically relevant
concentrations, with IC50 value of 53.8 µM [see Drug Interactions (7)].
Results of in vitro experiments suggest that clearance of lamotrigine is unlikely to be reduced by
concomitant administration of amitriptyline, clonazepam, clozapine, fluoxetine, haloperidol,
lorazepam, phenelzine, sertraline, or trazodone.
Results of in vitro experiments suggest that lamotrigine does not reduce the clearance of drugs
eliminated predominantly by CYP2D6.
Specific Populations
Renal Impairment: Twelve volunteers with chronic renal failure (mean creatinine clearance:
13 mL/min, range: 6 to 23) and another 6 individuals undergoing hemodialysis were each given a
single 100-mg dose of lamotrigine. The mean plasma half-lives determined in the study were
42.9 hours (chronic renal failure), 13.0 hours (during hemodialysis), and 57.4 hours (between
hemodialysis) compared with 26.2 hours in healthy volunteers. On average, approximately 20%
(range: 5.6 to 35.1) of the amount of lamotrigine present in the body was eliminated by
hemodialysis during a 4-hour session [see Dosage and Administration (2.1)].
Hepatic Disease: The pharmacokinetics of lamotrigine following a single 100-mg dose of
lamotrigine were evaluated in 24 subjects with mild, moderate, and severe hepatic impairment
(Child-Pugh classification system) and compared with 12 subjects without hepatic impairment.
The subjects with severe hepatic impairment were without ascites (n = 2) or with ascites (n = 5).
The mean apparent clearances of lamotrigine in subjects with mild (n = 12), moderate (n = 5),
severe without ascites (n = 2), and severe with ascites (n = 5) liver impairment were 0.30 ± 0.09,
0.24 ± 0.1, 0.21 ± 0.04, and 0.15 ± 0.09 mL/min/kg, respectively, as compared with
0.37 ± 0.1 mL/min/kg in the healthy controls. Mean half-lives of lamotrigine in subjects with
mild, moderate, severe without ascites, and severe with ascites hepatic impairment were 46 ± 20,
49
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72 ± 44, 67 ± 11, and 100 ± 48 hours, respectively, as compared with 33 ± 7 hours in healthy
controls [see Dosage and Administration (2.1)].
Age: Pediatric Subjects: The pharmacokinetics of lamotrigine following a single 2-mg/kg dose
were evaluated in 2 studies in pediatric subjects (n = 29 for subjects aged 10 months to 5.9 years
and n = 26 for subjects aged 5 to 11 years). Forty-three subjects received concomitant therapy
with other AEDs and 12 subjects received lamotrigine as monotherapy. Lamotrigine
pharmacokinetic parameters for pediatric patients are summarized in Table 16.
Population pharmacokinetic analyses involving subjects aged 2 to 18 years demonstrated that
lamotrigine clearance was influenced predominantly by total body weight and concurrent AED
therapy. The oral clearance of lamotrigine was higher, on a body weight basis, in pediatric
patients than in adults. Weight-normalized lamotrigine clearance was higher in those subjects
weighing less than 30 kg compared with those weighing greater than 30 kg. Accordingly,
patients weighing less than 30 kg may need an increase of as much as 50% in maintenance doses,
based on clinical response, as compared with subjects weighing more than 30 kg being
administered the same AEDs [see Dosage and Administration (2.2)]. These analyses also
revealed that, after accounting for body weight, lamotrigine clearance was not significantly
influenced by age. Thus, the same weight-adjusted doses should be administered to children
irrespective of differences in age. Concomitant AEDs which influence lamotrigine clearance in
adults were found to have similar effects in children.
Table 16. Mean Pharmacokinetic Parameters in Pediatric Subjects with Epilepsy
Pediatric Study Population
Number of
Subjects
Tmax
(h)
t½
(h)
CL/F
(mL/min/kg)
Ages 10 months-5.3 years
Subjects taking carbamazepine,
phenytoin, phenobarbital, or
primidonea
Subjects taking antiepileptic drugs
with no known effect on the
apparent clearance of lamotrigine
Subjects taking valproate only
10
7
8
3.0
(1.0-5.9)
5.2
(2.9-6.1)
2.9
(1.0-6.0)
7.7
(5.7-11.4)
19.0
(12.9-27.1)
44.9
(29.5-52.5)
3.62
(2.44-5.28)
1.2
(0.75-2.42)
0.47
(0.23-0.77)
50
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Ages 5-11 years
Subjects taking carbamazepine,
7
1.6
7.0
2.54
phenytoin, phenobarbital, or
primidonea
(1.0-3.0)
(3.8-9.8)
(1.35-5.58)
Subjects taking carbamazepine,
8
3.3
19.1
0.89
phenytoin, phenobarbital, or
primidonea plus valproate
(1.0-6.4)
(7.0-31.2)
(0.39-1.93)
Subjects taking valproate only
b
3
4.5
65.8
0.24
(3.0-6.0)
(50.7-73.7)
(0.21-0.26)
Ages 13-18 years
Subjects taking carbamazepine,
phenytoin, phenobarbital, or
primidonea
11
___ c
___ c
1.3
Subjects taking carbamazepine,
phenytoin, phenobarbital, or
primidonea plus valproate
8
___ c
___ c
0.5
Subjects taking valproate only
4
___ c
___ c
0.3
a Carbamazepine, phenytoin, phenobarbital, and primidone have been shown to increase the
apparent clearance of lamotrigine. Estrogen-containing oral contraceptives, rifampin, and the
protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir have also been shown to
increase the apparent clearance of lamotrigine [see Drug Interactions (7)].
b Two subjects were included in the calculation for mean Tmax .
c Parameter not estimated.
Elderly: The pharmacokinetics of lamotrigine following a single 150-mg dose of
lamotrigine were evaluated in 12 elderly volunteers between the ages of 65 and 76 years (mean
creatinine clearance = 61 mL/min, range: 33 to 108 mL/min). The mean half-life of lamotrigine
in these subjects was 31.2 hours (range: 24.5 to 43.4 hours), and the mean clearance was
0.40 mL/min/kg (range: 0.26 to 0.48 mL/min/kg).
Gender: The clearance of lamotrigine is not affected by gender. However, during dose escalation
of lamotrigine in 1 clinical trial in patients with epilepsy on a stable dose of valproate (n = 77),
mean trough lamotrigine concentrations unadjusted for weight were 24% to 45% higher (0.3 to
1.7 mcg/mL) in females than in males.
Race: The apparent oral clearance of lamotrigine was 25% lower in non-Caucasians than
Caucasians.
51
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13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
No evidence of carcinogenicity was seen in mouse or rat following oral administration of
lamotrigine for up to 2 years at doses up to 30 mg/kg/day and 10 to 15 mg/kg/day in mouse and
rat, respectively. The highest doses tested are less than the human dose of 400 mg/day on a body
surface area (mg/m2) basis.
Lamotrigine was negative in in vitro gene mutation (Ames and mouse lymphoma tk) assays and
in clastogenicity (in vitro human lymphocyte and in vivo rat bone marrow) assays.
No evidence of impaired fertility was detected in rats given oral doses of lamotrigine up to
20 mg/kg/day. The highest dose tested is less than the human dose of 400 mg/day on a mg/m2
basis.
14
CLINICAL STUDIES
14.1
Epilepsy
Monotherapy with LAMICTAL in Adults with Partial-Onset Seizures Already Receiving
Treatment with Carbamazepine, Phenytoin, Phenobarbital, or Primidone as the Single
Antiepileptic Drug
The effectiveness of monotherapy with LAMICTAL was established in a multicenter
double-blind clinical trial enrolling 156 adult outpatients with partial-onset seizures. The patients
experienced at least 4 simple partial-onset, complex partial-onset, and/or secondarily generalized
seizures during each of 2 consecutive 4-week periods while receiving carbamazepine or
phenytoin monotherapy during baseline. LAMICTAL (target dose of 500 mg/day) or valproate
(1,000 mg/day) was added to either carbamazepine or phenytoin monotherapy over a 4-week
period. Patients were then converted to monotherapy with LAMICTAL or valproate during the
next 4 weeks, then continued on monotherapy for an additional 12-week period.
Trial endpoints were completion of all weeks of trial treatment or meeting an escape criterion.
Criteria for escape relative to baseline were: (1) doubling of average monthly seizure count, (2)
doubling of highest consecutive 2-day seizure frequency, (3) emergence of a new seizure type
(defined as a seizure that did not occur during the 8-week baseline) that is more severe than
seizure types that occur during study treatment, or (4) clinically significant prolongation of
generalized tonic-clonic seizures. The primary efficacy variable was the proportion of patients in
each treatment group who met escape criteria.
The percentages of patients who met escape criteria were 42% (32/76) in the group receiving
LAMICTAL and 69% (55/80) in the valproate group. The difference in the percentage of
patients meeting escape criteria was statistically significant (P = 0.0012) in favor of
LAMICTAL. No differences in efficacy based on age, sex, or race were detected.
52
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Patients in the control group were intentionally treated with a relatively low dose of valproate; as
such, the sole objective of this trial was to demonstrate the effectiveness and safety of
monotherapy with LAMICTAL, and cannot be interpreted to imply the superiority of
LAMICTAL to an adequate dose of valproate.
Adjunctive Therapy with LAMICTAL in Adults with Partial-Onset Seizures
The effectiveness of LAMICTAL as adjunctive therapy (added to other AEDs) was initially
established in 3 pivotal, multicenter, placebo-controlled, double-blind clinical trials in 355 adults
with refractory partial-onset seizures. The patients had a history of at least 4 partial-onset
seizures per month in spite of receiving 1 or more AEDs at therapeutic concentrations and in 2 of
the trials were observed on their established AED regimen during baselines that varied between 8
to 12 weeks. In the third trial, patients were not observed in a prospective baseline. In patients
continuing to have at least 4 seizures per month during the baseline, LAMICTAL or placebo was
then added to the existing therapy. In all 3 trials, change from baseline in seizure frequency was
the primary measure of effectiveness. The results given below are for all partial-onset seizures in
the intent-to-treat population (all patients who received at least 1 dose of treatment) in each trial,
unless otherwise indicated. The median seizure frequency at baseline was 3 per week while the
mean at baseline was 6.6 per week for all patients enrolled in efficacy trials.
One trial (n = 216) was a double-blind, placebo-controlled, parallel trial consisting of a 24-week
treatment period. Patients could not be on more than 2 other anticonvulsants and valproate was
not allowed. Patients were randomized to receive placebo, a target dose of 300 mg/day of
LAMICTAL, or a target dose of 500 mg/day of LAMICTAL. The median reductions in the
frequency of all partial-onset seizures relative to baseline were 8% in patients receiving placebo,
20% in patients receiving 300 mg/day of LAMICTAL, and 36% in patients receiving
500 mg/day of LAMICTAL. The seizure frequency reduction was statistically significant in the
500-mg/day group compared with the placebo group, but not in the 300-mg/day group.
A second trial (n = 98) was a double-blind, placebo-controlled, randomized, crossover trial
consisting of two 14-week treatment periods (the last 2 weeks of which consisted of dose
tapering) separated by a 4-week washout period. Patients could not be on more than 2 other
anticonvulsants and valproate was not allowed. The target dose of LAMICTAL was 400 mg/day.
When the first 12 weeks of the treatment periods were analyzed, the median change in seizure
frequency was a 25% reduction on LAMICTAL compared with placebo (P<0.001).
The third trial (n = 41) was a double-blind, placebo-controlled, crossover trial consisting of two
12-week treatment periods separated by a 4-week washout period. Patients could not be on more
than 2 other anticonvulsants. Thirteen patients were on concomitant valproate; these patients
received 150 mg/day of LAMICTAL. The 28 other patients had a target dose of 300 mg/day of
LAMICTAL. The median change in seizure frequency was a 26% reduction on LAMICTAL
compared with placebo (P<0.01).
53
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No differences in efficacy based on age, sex, or race, as measured by change in seizure
frequency, were detected.
Adjunctive Therapy with LAMICTAL in Pediatric Patients with Partial-Onset Seizures
The effectiveness of LAMICTAL as adjunctive therapy in pediatric patients with partial-onset
seizures was established in a multicenter, double-blind, placebo-controlled trial in 199 patients
aged 2 to 16 years (n = 98 on LAMICTAL, n = 101 on placebo). Following an 8-week baseline
phase, patients were randomized to 18 weeks of treatment with LAMICTAL or placebo added to
their current AED regimen of up to 2 drugs. Patients were dosed based on body weight and
valproate use. Target doses were designed to approximate 5 mg/kg/day for patients taking
valproate (maximum dose: 250 mg/day) and 15 mg/kg/day for the patients not taking valproate
(maximum dose: 750 mg/day). The primary efficacy endpoint was percentage change from
baseline in all partial-onset seizures. For the intent-to-treat population, the median reduction of
all partial-onset seizures was 36% in patients treated with LAMICTAL and 7% on placebo, a
difference that was statistically significant (P<0.01).
Adjunctive Therapy with LAMICTAL in Pediatric and Adult Patients with Lennox-Gastaut
Syndrome
The effectiveness of LAMICTAL as adjunctive therapy in patients with Lennox-Gastaut
syndrome was established in a multicenter, double-blind, placebo-controlled trial in 169 patients
aged 3 to 25 years (n = 79 on LAMICTAL, n = 90 on placebo). Following a 4-week,
single-blind, placebo phase, patients were randomized to 16 weeks of treatment with
LAMICTAL or placebo added to their current AED regimen of up to 3 drugs. Patients were
dosed on a fixed-dose regimen based on body weight and valproate use. Target doses were
designed to approximate 5 mg/kg/day for patients taking valproate (maximum dose: 200 mg/day)
and 15 mg/kg/day for patients not taking valproate (maximum dose: 400 mg/day). The primary
efficacy endpoint was percentage change from baseline in major motor seizures (atonic, tonic,
major myoclonic, and tonic-clonic seizures). For the intent-to-treat population, the median
reduction of major motor seizures was 32% in patients treated with LAMICTAL and 9% on
placebo, a difference that was statistically significant (P<0.05). Drop attacks were significantly
reduced by LAMICTAL (34%) compared with placebo (9%), as were tonic-clonic seizures (36%
reduction versus 10% increase for LAMICTAL and placebo, respectively).
Adjunctive Therapy with LAMICTAL in Pediatric and Adult Patients with Primary Generalized
Tonic-Clonic Seizures
The effectiveness of LAMICTAL as adjunctive therapy in patients with PGTC seizures was
established in a multicenter, double-blind, placebo-controlled trial in 117 pediatric and adult
patients aged 2 years and older (n = 58 on LAMICTAL, n = 59 on placebo). Patients with at least
3 PGTC seizures during an 8-week baseline phase were randomized to 19 to 24 weeks of
treatment with LAMICTAL or placebo added to their current AED regimen of up to 2 drugs.
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Patients were dosed on a fixed-dose regimen, with target doses ranging from 3 to 12 mg/kg/day
for pediatric patients and from 200 to 400 mg/day for adult patients based on concomitant AEDs.
The primary efficacy endpoint was percentage change from baseline in PGTC seizures. For the
intent-to-treat population, the median percent reduction in PGTC seizures was 66% in patients
treated with LAMICTAL and 34% on placebo, a difference that was statistically significant
(P = 0.006).
14.2
Bipolar Disorder
Adults
The effectiveness of LAMICTAL in the maintenance treatment of bipolar I disorder was
established in 2 multicenter, double-blind, placebo-controlled trials in adult patients (aged 18 to
82 years) who met DSM-IV criteria for bipolar I disorder. Trial 1 enrolled patients with a current
or recent (within 60 days) depressive episode as defined by DSM-IV and Trial 2 included
patients with a current or recent (within 60 days) episode of mania or hypomania as defined by
DSM-IV. Both trials included a cohort of patients (30% of 404 subjects in Trial 1 and 28% of
171 patients in Trial 2) with rapid cycling bipolar disorder (4 to 6 episodes per year).
In both trials, patients were titrated to a target dose of 200 mg of LAMICTAL as add-on therapy
or as monotherapy with gradual withdrawal of any psychotropic medications during an 8- to 16
week open-label period. Overall 81% of 1,305 patients participating in the open-label period
were receiving 1 or more other psychotropic medications, including benzodiazepines, selective
serotonin reuptake inhibitors (SSRIs), atypical antipsychotics (including olanzapine), valproate,
or lithium, during titration of LAMICTAL. Patients with a CGI-severity score of 3 or less
maintained for at least 4 continuous weeks, including at least the final week on monotherapy
with LAMICTAL, were randomized to a placebo-controlled double-blind treatment period for up
to 18 months. The primary endpoint was TIME (time to intervention for a mood episode or one
that was emerging, time to discontinuation for either an adverse event that was judged to be
related to bipolar disorder, or for lack of efficacy). The mood episode could be depression,
mania, hypomania, or a mixed episode.
In Trial 1, patients received double-blind monotherapy with LAMICTAL 50 mg/day (n = 50),
LAMICTAL 200 mg/day (n = 124), LAMICTAL 400 mg/day (n = 47), or placebo (n = 121).
LAMICTAL (200- and 400-mg/day treatment groups combined) was superior to placebo in
delaying the time to occurrence of a mood episode (Figure 1). Separate analyses of the 200- and
400-mg/day dose groups revealed no added benefit from the higher dose.
In Trial 2, patients received double-blind monotherapy with LAMICTAL (100 to 400 mg/day,
n = 59), or placebo (n = 70). LAMICTAL was superior to placebo in delaying time to occurrence
of a mood episode (Figure 2). The mean dose of LAMICTAL was about 211 mg/day.
Although these trials were not designed to separately evaluate time to the occurrence of
depression or mania, a combined analysis for the 2 trials revealed a statistically significant
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benefit for LAMICTAL over placebo in delaying the time to occurrence of both depression and
mania, although the finding was more robust for depression.
Figure 1: Kaplan-Meier Estimation of Cumulative Proportion of Patients with Mood
graph
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Figure 2: Kaplan-Meier Estimation of Cumulative Proportion of Patients with Mood
graph
16
HOW SUPPLIED/STORAGE AND HANDLING
LAMICTAL (lamotrigine) tablets
25 mg, white, scored, shield-shaped tablets debossed with “LAMICTAL” and “25”, bottles of
100 (NDC 0173-0633-02).
Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled
Room Temperature] in a dry place.
100 mg, peach, scored, shield-shaped tablets debossed with “LAMICTAL” and “100”, bottles of
100 (NDC 0173-0642-55).
150 mg, cream, scored, shield-shaped tablets debossed with “LAMICTAL” and “150”, bottles of
60 (NDC 0173-0643-60).
200 mg, blue, scored, shield-shaped tablets debossed with “LAMICTAL” and “200”, bottles of
60 (NDC 0173-0644-60).
Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled
Room Temperature] in a dry place and protect from light.
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LAMICTAL (lamotrigine) Starter Kit for Patients Taking Valproate (Blue Kit)
25 mg, white, scored, shield-shaped tablets debossed with “LAMICTAL” and “25”, blisterpack
of 35 tablets (NDC 0173-0633-10).
Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled
Room Temperature] in a dry place.
LAMICTAL (lamotrigine) Starter Kit for Patients Taking Carbamazepine, Phenytoin,
Phenobarbital, or Primidone and Not Taking Valproate (Green Kit)
25 mg, white, scored, shield-shaped tablets debossed with “LAMICTAL” and “25” and 100 mg,
peach, scored, shield-shaped tablets debossed with “LAMICTAL” and “100”, blisterpack of 98
tablets (84/25-mg tablets and 14/100-mg tablets) (NDC 0173-0817-28).
Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled
Room Temperature] in a dry place and protect from light.
LAMICTAL (lamotrigine) Starter Kit for Patients Not Taking Carbamazepine, Phenytoin,
Phenobarbital, Primidone, or Valproate (Orange Kit)
25 mg, white, scored, shield-shaped tablets debossed with “LAMICTAL” and “25” and 100 mg,
peach, scored, shield-shaped tablets debossed with “LAMICTAL” and “100”, blisterpack of 49
tablets (42/25-mg tablets and 7/100-mg tablets) (NDC 0173-0594-02).
Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled
Room Temperature] in a dry place and protect from light.
LAMICTAL (lamotrigine) chewable dispersible tablets
2 mg, white to off-white, round tablets debossed with “LTG” over “2”, bottles of 30 (NDC 0173
0699-00). ORDER DIRECTLY FROM GlaxoSmithKline 1-800-334-4153.
5 mg, white to off-white, caplet-shaped tablets debossed with “GX CL2”, bottles of 100 (NDC
0173-0526-00).
25 mg, white, super elliptical-shaped tablets debossed with “GX CL5”, bottles of 100 (NDC
0173-0527-00).
Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled
Room Temperature] in a dry place.
LAMICTAL ODT (lamotrigine) orally disintegrating tablets
25 mg, white to off-white, round, flat-faced, radius-edged tablets debossed with “LMT” on one
side and “25” on the other, Maintenance Packs of 30 (NDC 0173-0772-02).
50 mg, white to off-white, round, flat-faced, radius-edged tablets debossed with “LMT” on one
side and “50” on the other, Maintenance Packs of 30 (NDC 0173-0774-02).
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100 mg, white to off-white, round, flat-faced, radius-edged tablets debossed with “LAMICTAL”
on one side and “100” on the other, Maintenance Packs of 30 (NDC 0173-0776-02).
200 mg, white to off-white, round, flat-faced, radius-edged tablets debossed with “LAMICTAL”
on one side and “200” on the other, Maintenance Packs of 30 (NDC 0173-0777-02).
Store between 20°C and 25°C (68°F and 77°F); with excursions permitted between 15°C and
30°C (59°F and 86°F).
LAMICTAL ODT (lamotrigine) Patient Titration Kit for Patients Taking Valproate (Blue ODT
Kit)
25 mg, white to off-white, round, flat-faced, radius-edged tablets debossed with “LMT” on one
side and “25” on the other, and 50 mg, white to off-white, round, flat-faced, radius-edged tablets
debossed with “LMT” on one side and “50” on the other, blisterpack of 28 tablets (21/25-mg
tablets and 7/50-mg tablets) (NDC 0173-0779-00).
Store between 20°C and 25°C (68°F and 77°F); with excursions permitted between 15°C and
30°C (59°F and 86°F).
LAMICTAL ODT (lamotrigine) Patient Titration Kit for Patients Taking Carbamazepine,
Phenytoin, Phenobarbital, or Primidone and Not Taking Valproate (Green ODT Kit)
50 mg, white to off-white, round, flat-faced, radius-edged tablets debossed with “LMT” on one
side and “50” on the other, and 100 mg, white to off-white, round, flat-faced, radius-edged
tablets debossed with “LAMICTAL” on one side and “100” on the other, blisterpack of 56
tablets (42/50-mg tablets and 14/100-mg tablets) (NDC 0173-0780-00).
Store between 20°C and 25°C (68°F and 77°F); with excursions permitted between 15°C and
30°C (59°F and 86°F).
LAMICTAL ODT (lamotrigine) Patient Titration Kit for Patients Not Taking Carbamazepine,
Phenytoin, Phenobarbital, Primidone, or Valproate (Orange ODT Kit)
25 mg, white to off-white, round, flat-faced, radius-edged tablets debossed with “LMT” on one
side and “25” on the other, 50 mg, white to off-white, round, flat-faced, radius-edged tablets
debossed with “LMT” on one side and “50” on the other, and 100 mg, white to off-white, round,
flat-faced, radius-edged tablets debossed with “LAMICTAL” on one side and “100” on the
other, blisterpack of 35 (14/25-mg tablets, 14/50-mg tablets, and 7/100-mg tablets) (NDC 0173
0778-00).
Store between 20°C and 25°C (68°F and 77°F); with excursions permitted between 15°C and
30°C (59°F and 86°F).
Blisterpacks
If the product is dispensed in a blisterpack, the patient should be advised to examine the
blisterpack before use and not use if blisters are torn, broken, or missing.
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17
PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Rash
Prior to initiation of treatment with LAMICTAL, inform patients that a rash or other signs or
symptoms of hypersensitivity (e.g., fever, lymphadenopathy) may herald a serious medical event
and instruct them to report any such occurrence to their healthcare providers immediately.
Multiorgan Hypersensitivity Reactions, Blood Dyscrasias, and Organ Failure
Inform patients that multiorgan hypersensitivity reactions and acute multiorgan failure may
occur with LAMICTAL. Isolated organ failure or isolated blood dyscrasias without evidence of
multiorgan hypersensitivity may also occur. Instruct patients to contact their healthcare providers
immediately if they experience any signs or symptoms of these conditions [see Warnings and
Precautions (5.2, 5.3)].
Suicidal Thinking and Behavior
Inform patients, their caregivers, and families that AEDs, including LAMICTAL, may increase
the risk of suicidal thoughts and behavior. Instruct them to be alert for the emergence or
worsening of symptoms of depression, any unusual changes in mood or behavior, or the
emergence of suicidal thoughts or behavior or thoughts about self-harm. Instruct them to
immediately report behaviors of concern to their healthcare providers.
Worsening of Seizures
Instruct patients to notify their healthcare providers if worsening of seizure control occurs.
Central Nervous System Adverse Effects
Inform patients that LAMICTAL may cause dizziness, somnolence, and other symptoms and
signs of central nervous system depression. Accordingly, instruct them neither to drive a car nor
to operate other complex machinery until they have gained sufficient experience on LAMICTAL
to gauge whether or not it adversely affects their mental and/or motor performance.
Pregnancy and Nursing
Instruct patients to notify their healthcare providers if they become pregnant or intend to become
pregnant during therapy and if they intend to breastfeed or are breastfeeding an infant.
Encourage patients to enroll in the NAAED Pregnancy Registry if they become pregnant. This
registry is collecting information about the safety of antiepileptic drugs during pregnancy. To
enroll, patients can call the toll-free number 1-888-233-2334 [see Use in Specific Populations
(8.1)].
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Inform patients who intend to breastfeed that LAMICTAL is present in breast milk and advise
them to monitor their child for potential adverse effects of this drug. Discuss the benefits and
risks of continuing breastfeeding.
Oral Contraceptive Use
Instruct women to notify their healthcare providers if they plan to start or stop use of oral
contraceptives or other female hormonal preparations. Starting estrogen-containing oral
contraceptives may significantly decrease lamotrigine plasma levels and stopping
estrogen-containing oral contraceptives (including the pill-free week) may significantly increase
lamotrigine plasma levels [see Warnings and Precautions (5.7), Clinical Pharmacology (12.3)].
Also instruct women to promptly notify their healthcare providers if they experience adverse
reactions or changes in menstrual pattern (e.g., break-through bleeding) while receiving
LAMICTAL in combination with these medications.
Discontinuing LAMICTAL
Instruct patients to notify their healthcare providers if they stop taking LAMICTAL for any
reason and not to resume LAMICTAL without consulting their healthcare providers.
Aseptic Meningitis
Inform patients that LAMICTAL may cause aseptic meningitis. Instruct them to notify their
healthcare providers immediately if they develop signs and symptoms of meningitis such as
headache, fever, nausea, vomiting, stiff neck, rash, abnormal sensitivity to light, myalgia, chills,
confusion, or drowsiness while taking LAMICTAL.
Potential Medication Errors
To avoid a medication error of using the wrong drug or formulation, strongly advise patients to
visually inspect their tablets to verify that they are LAMICTAL, as well as the correct
formulation of LAMICTAL, each time they fill their prescription [see Dosage Forms and
Strengths (3.1, 3.2, 3.3), How Supplied/Storage and Handling (16)]. Refer the patient to the
Medication Guide that provides depictions of the LAMICTAL tablets, chewable dispersible
tablets, and orally disintegrating tablets.
LAMICTAL and LAMICTAL ODT are registered trademarks of the GSK group of companies.
The other brands listed are trademarks of their respective owners and are not trademarks of the
GSK group of companies. The makers of these brands are not affiliated with and do not endorse
the GSK group of companies or its products.
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Distributed by company logo
GlaxoSmithKline
Research Triangle Park, NC 27709
2015, the GSK group of companies. All rights reserved.
LMT:xPI
MEDICATION GUIDE
LAMICTAL® (la-MIK-tal) (lamotrigine) tablets
LAMICTAL® (lamotrigine) chewable dispersible tablets
LAMICTAL ODT® (lamotrigine) orally disintegrating tablets
What is the most important information I should know about LAMICTAL?
1. LAMICTAL may cause a serious skin rash that may cause you to be hospitalized or even
cause death.
There is no way to tell if a mild rash will become more serious. A serious skin rash can happen at any
time during your treatment with LAMICTAL, but is more likely to happen within the first 2 to 8 weeks
of treatment. Children and teenagers aged between 2 and 17 years have a higher chance of getting
this serious skin rash while taking LAMICTAL.
The risk of getting a serious skin rash is higher if you:
•
take LAMICTAL while taking valproate [DEPAKENE® (valproic acid) or DEPAKOTE® (divalproex
sodium)].
•
take a higher starting dose of LAMICTAL than your healthcare provider prescribed.
•
increase your dose of LAMICTAL faster than prescribed.
Call your healthcare provider right away if you have any of the following:
•
a skin rash
•
blistering or peeling of your skin
•
hives
•
painful sores in your mouth or around your eyes
These symptoms may be the first signs of a serious skin reaction. A healthcare provider should
examine you to decide if you should continue taking LAMICTAL.
2. Other serious reactions, including serious blood problems or liver problems. LAMICTAL can
also cause other types of allergic reactions or serious problems that may affect organs and other
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parts of your body like your liver or blood cells. You may or may not have a rash with these types of
reactions. Call your healthcare provider right away if you have any of these symptoms:
•
fever
•
frequent infections
•
severe muscle pain
•
swelling of your face, eyes, lips, or tongue
•
swollen lymph glands
•
unusual bruising or bleeding
•
weakness, fatigue
•
yellowing of your skin or the white part of your eyes
3. Like other antiepileptic drugs, LAMICTAL may cause suicidal thoughts or actions in a very
small number of people, about 1 in 500.
Call a healthcare provider right away if you have any of these symptoms, especially if they are
new, worse, or worry you:
•
thoughts about suicide or dying
•
attempt to commit suicide
•
new or worse depression
•
new or worse anxiety
•
feeling agitated or restless
•
panic attacks
•
trouble sleeping (insomnia)
•
new or worse irritability
•
acting aggressive, being angry, or violent
•
acting on dangerous impulses
•
an extreme increase in activity and talking (mania)
•
other unusual changes in behavior or mood
Do not stop LAMICTAL without first talking to a healthcare provider.
•
Stopping LAMICTAL suddenly can cause serious problems.
•
Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal
thoughts or actions, your healthcare provider may check for other causes.
How can I watch for early symptoms of suicidal thoughts and actions in myself or a family
member?
•
Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or
feelings.
•
Keep all follow-up visits with your healthcare provider as scheduled.
•
Call your healthcare provider between visits as needed, especially if you are worried about
symptoms.
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4. LAMICTAL may cause aseptic meningitis, a serious inflammation of the protective membrane
that covers the brain and spinal cord.
Call your healthcare provider right away if you have any of the following symptoms:
•
headache
•
fever
•
nausea
•
vomiting
•
stiff neck
•
rash
•
unusual sensitivity to light
•
muscle pains
•
chills
•
confusion
•
drowsiness
Meningitis has many causes other than LAMICTAL, which your doctor would check for if you
developed meningitis while taking LAMICTAL.
LAMICTAL can cause other serious side effects. For more information ask your healthcare
provider or pharmacist. Tell your healthcare provider if you have any side effect that bothers you. Be
sure to read the section below entitled “What are the possible side effects of LAMICTAL?”
5. People prescribed LAMICTAL have sometimes been given the wrong medicine because many
medicines have names similar to LAMICTAL, so always check that you receive LAMICTAL.
Taking the wrong medication can cause serious health problems. When your healthcare provider
gives you a prescription for LAMICTAL:
•
Make sure you can read it clearly.
•
Talk to your pharmacist to check that you are given the correct medicine.
•
Each time you fill your prescription, check the tablets you receive against the pictures of the
tablets below.
These pictures show the distinct wording, colors, and shapes of the tablets that help to identify the
right strength of LAMICTAL tablets, chewable dispersible tablets, and orally disintegrating tablets.
Immediately call your pharmacist if you receive a LAMICTAL tablet that does not look like one of
the tablets shown below, as you may have received the wrong medication.
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25 mg, white to off
50 mg, white to off
100 mg, white to off
200 mg, white to off-
white
white
white
white
Imprinted with LMT
Imprinted with
Imprinted with
Imprinted with
on one side
LMT on one side
LAMICTAL on one
LAMICTAL on one
25 on the other
50 on the other
side
side
100 on the other
200 on the other
LAMICTAL (lamotrigine) tablets
25 mg, white
100 mg, peach
150 mg, cream
200 mg, blue
Imprinted with
Imprinted with
Imprinted with
Imprinted with
LAMICTAL 25
LAMICTAL 100
LAMICTAL 150
LAMICTAL 200
LAMICTAL (lamotrigine) chewable dispersible tablets
2 mg, white
5 mg, white
25 mg, white
Imprinted with
Imprinted with
Imprinted with
LTG 2
GX CL2
GX CL5
LAMICTAL ODT (lamotrigine) orally disintegrating tablets
What is LAMICTAL?
LAMICTAL is a prescription medicine used:
•
together with other medicines to treat certain types of seizures (partial-onset seizures, primary
generalized tonic-clonic seizures, generalized seizures of Lennox-Gastaut syndrome) in people aged
2 years and older.
•
alone when changing from 1 other medicine used to treat partial-onset seizures in people aged 16
years and older.
•
for the long-term treatment of bipolar I disorder to lengthen the time between mood episodes in
people who have been treated for mood episodes with other medicine.
It is not known if LAMICTAL is safe or effective in people younger than 18 years with mood episodes such
as bipolar disorder or depression.
It is not known if LAMICTAL is safe or effective when used alone as the first treatment of seizures.
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It is not known if LAMICTAL is safe or effective for people with mood episodes who have not already
been treated with other medicines.
LAMICTAL should not be used for acute treatment of manic or mixed mood episodes.
Who should not take LAMICTAL?
You should not take LAMICTAL if you have had an allergic reaction to lamotrigine or to any of the inactive
ingredients in LAMICTAL. See the end of this leaflet for a complete list of ingredients in LAMICTAL.
What should I tell my healthcare provider before taking LAMICTAL?
Before taking LAMICTAL, tell your healthcare provider about all of your medical conditions, including if
you:
•
have had a rash or allergic reaction to another antiseizure medicine.
•
have or have had depression, mood problems, or suicidal thoughts or behavior.
•
have had aseptic meningitis after taking LAMICTAL or LAMICTAL XR (lamotrigine).
•
are taking oral contraceptives (birth control pills) or other female hormonal medicines. Do not start or
stop taking birth control pills or other female hormonal medicine until you have talked with your
healthcare provider. Tell your healthcare provider if you have any changes in your menstrual pattern
such as breakthrough bleeding. Stopping these medicines while you are taking LAMICTAL may
cause side effects (such as dizziness, lack of coordination, or double vision). Starting these
medicines may lessen how well LAMICTAL works.
•
are pregnant or plan to become pregnant. It is not known if LAMICTAL will harm your unborn baby. If
you become pregnant while taking LAMICTAL, talk to your healthcare provider about registering with
the North American Antiepileptic Drug Pregnancy Registry. You can enroll in this registry by calling
1-888-233-2334. The purpose of this registry is to collect information about the safety of antiepileptic
drugs during pregnancy.
•
are breastfeeding. LAMICTAL passes into breast milk and may cause side effects in a breastfed
baby. If you breastfeed while taking LAMICTAL, watch your baby closely for trouble breathing,
episodes of temporarily stopping breathing, sleepiness, or poor sucking. Call your baby’s healthcare
provider right away if you see any of these problems. Talk to your healthcare provider about the best
way to feed your baby if you take LAMICTAL.
Tell your healthcare provider about all the medicines you take or if you are planning to take a new
medicine, including prescription and over-the-counter medicines, vitamins, and herbal supplements.
If you use LAMICTAL with certain other medicines, they can affect each other, causing side effects.
How should I take LAMICTAL?
•
Take LAMICTAL exactly as prescribed.
•
Your healthcare provider may change your dose. Do not change your dose without talking to your
healthcare provider.
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•
Do not stop taking LAMICTAL without talking to your healthcare provider. Stopping LAMICTAL
suddenly may cause serious problems. For example, if you have epilepsy and you stop taking
LAMICTAL suddenly, you may have seizures that do not stop. Talk with your healthcare provider
about how to stop LAMICTAL slowly.
•
If you miss a dose of LAMICTAL, take it as soon as you remember. If it is almost time for your next
dose, just skip the missed dose. Take the next dose at your regular time. Do not take 2 doses at the
same time.
•
If you take too much LAMICTAL, call your healthcare provider or your local Poison Control Center or
go to the nearest hospital emergency room right away.
•
You may not feel the full effect of LAMICTAL for several weeks.
•
If you have epilepsy, tell your healthcare provider if your seizures get worse or if you have any new
types of seizures.
•
Swallow LAMICTAL Tablets whole.
•
If you have trouble swallowing LAMICTAL Tablets, tell your healthcare provider because there may
be another form of LAMICTAL you can take.
•
LAMICTAL ODT should be placed on the tongue and moved around the mouth. The tablet will rapidly
disintegrate, can be swallowed with or without water, and can be taken with or without food.
•
LAMICTAL chewable dispersible tablets may be swallowed whole, chewed, or mixed in water or fruit
juice mixed with water. If the tablets are chewed, drink a small amount of water or fruit juice mixed
with water to help in swallowing. To break up LAMICTAL chewable dispersible tablets, add the tablets
to a small amount of liquid (1 teaspoon, or enough to cover the medicine) in a glass or spoon. Wait at
least 1 minute or until the tablets are completely broken up, mix the solution together, and take the
whole amount right away.
•
If you receive LAMICTAL in a blisterpack, examine the blisterpack before use. Do not use if blisters
are torn, broken, or missing.
What should I avoid while taking LAMICTAL?
Do not drive, operate machinery, or do other dangerous activities until you know how LAMICTAL affects
you.
What are the possible side effects of LAMICTAL?
LAMICTAL can cause serious side effects.
See “What is the most important information I should know about LAMICTAL?”
Common side effects of LAMICTAL include:
•
dizziness
•
tremor
•
headache
•
rash
•
blurred or double vision
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•
fever
•
lack of coordination
•
abdominal pain
•
infections, including seasonal flu
•
sleepiness
•
back pain
•
nausea, vomiting
•
diarrhea
•
tiredness
•
insomnia
•
dry mouth
•
stuffy nose
•
sore throat
Tell your healthcare provider about any side effect that bothers you or that does not go away.
These are not all the possible side effects of LAMICTAL. For more information, ask your healthcare
provider or pharmacist.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA
1088.
How should I store LAMICTAL?
•
Store LAMICTAL at room temperature between 68°F and 77°F (20°C and 25°C).
•
Keep LAMICTAL and all medicines out of the reach of children.
General information about the safe and effective use of LAMICTAL.
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not
use LAMICTAL for a condition for which it was not prescribed. Do not give LAMICTAL to other people,
even if they have the same symptoms you have. It may harm them.
If you take a urine drug screening test, LAMICTAL may make the test result positive for another drug. If
you require a urine drug screening test, tell the healthcare professional administering the test that you are
taking LAMICTAL.
This Medication Guide summarizes the most important information about LAMICTAL. If you would like
more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist
for information about LAMICTAL that is written for healthcare professionals.
For more information, go to www.lamictal.com or call 1-888-825-5249.
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What are the ingredients in LAMICTAL?
LAMICTAL tablets
Active ingredient: lamotrigine.
Inactive ingredients: lactose; magnesium stearate, microcrystalline cellulose, povidone, sodium starch
glycolate, FD&C Yellow No. 6 Lake (100-mg tablet only), ferric oxide, yellow (150-mg tablet only), and
FD&C Blue No. 2 Lake (200-mg tablet only).
LAMICTAL chewable dispersible tablets
Active ingredient: lamotrigine.
Inactive ingredients: blackcurrant flavor, calcium carbonate, low-substituted hydroxypropylcellulose,
magnesium aluminum silicate, magnesium stearate, povidone, saccharin sodium, and sodium starch
glycolate.
LAMICTAL ODT orally disintegrating tablets
Active ingredient: lamotrigine.
Inactive ingredients: artificial cherry flavor, crospovidone, ethylcellulose, magnesium stearate, mannitol,
polyethylene, and sucralose.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
LAMICTAL and LAMICTAL ODT are registered trademarks of the GSK group of companies. The other
brands listed are trademarks of their respective owners and are not trademarks of the GSK group of
companies. The makers of these brands are not affiliated with and do not endorse the GSK group of
companies or its products.
company logo
GlaxoSmithKline
Research Triangle Park, NC 27709
2015, the GSK group of companies. All rights reserved.
May 2015
LMT:xMG
69
Reference ID: 3757964
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For current labeling information, please visit https://www.fda.gov/drugsatfda
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1
Physician Information
Women who use Depo-Provera Contraceptive Injection may lose significant bone
mineral density. Bone loss is greater with increasing duration of use and may not be
completely reversible.
It is unknown if use of Depo-Provera Contraceptive Injection during adolescence or
early adulthood, a critical period of bone accretion, will reduce peak bone mass and
increase the risk for osteoporotic fracture in later life.
Depo-Provera Contraceptive Injection should be used as a long-term birth control
method (e.g. longer than 2 years) only if other birth control methods are inadequate.
(See WARNINGS.)
Patients should be counseled that this product does not protect against HIV
infection (AIDS) and other sexually transmitted diseases.
DESCRIPTION
DEPO-PROVERA Contraceptive Injection (CI) contains medroxyprogesterone
acetate, a derivative of progesterone, as its active ingredient. Medroxyprogesterone
acetate is active by the parenteral and oral routes of administration. It is a white to off-
white; odorless crystalline powder that is stable in air and that melts between 200°C
and 210°C. It is freely soluble in chloroform, soluble in acetone and dioxane, sparingly
soluble in alcohol and methanol, slightly soluble in ether, and insoluble in water.
The chemical name for medroxyprogesterone acetate is pregn-4-ene-3,20-
dione, 17-(acetyloxy)-6-methyl-, (6α-).
The structural formula is as follows:
medroxyprogesterone acetate
DEPO-PROVERA CI for intramuscular (IM) injection is available in vials and
prefilled syringes, each containing 1 mL of medroxyprogesterone acetate sterile aqueous
suspension 150 mg/mL.
Each mL contains:
Medroxyprogesterone acetate
150 mg
Polyethylene glycol 3350
28.9 mg
Polysorbate 80
2.41 mg
Sodium chloride
8.68 mg
Methylparaben
1.37 mg
Propylparaben
0.150 mg
Water for injection
qs
When necessary, pH is adjusted with sodium hydroxide or hydrochloric acid, or
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both.
CLINICAL PHARMACOLOGY
DEPO-PROVERA CI (medroxyprogesterone acetate), when administered at the
recommended dose to women every 3 months, inhibits the secretion of gonadotropins
which, in turn, prevents follicular maturation and ovulation and results in endometrial
thinning. These actions produce its contraceptive effect.
Following a single 150 mg IM dose of DEPO-PROVERA Contraceptive
Injection, medroxyprogesterone acetate concentrations, measured by an extracted
radioimmunoassay procedure, increase for approximately 3 weeks to reach peak plasma
concentrations of 1 to 7 ng/mL. The levels then decrease exponentially until they
become undetectable (<100 pg/mL) between 120 to 200 days following injection. Using
an unextracted radioimmunoassay procedure for the assay of medroxyprogesterone
acetate in serum, the apparent half-life for medroxyprogesterone acetate following IM
administration of DEPO-PROVERA Contraceptive Injection is approximately 50 days.
Women with lower body weights conceive sooner than women with higher body
weights after discontinuing DEPO-PROVERA Contraceptive Injection.
The effect of hepatic and/or renal disease on the pharmacokinetics of DEPO-
PROVERA Contraceptive Injection is unknown.
INDICATIONS AND USAGE
DEPO-PROVERA CI is indicated only for the prevention of pregnancy. The
loss of bone mineral density (BMD) in women of all ages and the impact on peak bone
mass in adolescents should be considered, along with the decrease in BMD that occurs
during pregnancy and/or lactation, in the risk/benefit assessment for women who use
Depo-Provera CI long-term (see WARNINGS.) It is a long-term injectable
contraceptive in women when administered at 3-month (13-week) intervals. Dosage does
not need to be adjusted for body weight.
In five clinical studies using DEPO-PROVERA CI, the 12-month failure rate for
the group of women treated with DEPO-PROVERA CI was zero (no pregnancies
reported) to 0.7 by Life-Table method. Pregnancy rates with contraceptive measures are
typically reported for only the first year of use as shown in Table 1. Except for
intrauterine devices (IUD), implants, sterilization, and DEPO-PROVERA CI, the
efficacy of these contraceptive measures depends in part on the reliability of use. The
effectiveness of DEPO-PROVERA CI is dependent on the patient returning every 3
months (13 weeks) for reinjection.
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3
Table 1
Lowest Expected and Typical Failure Rates*
Expressed as Percent of Women Experiencing
an Accidental Pregnancy
in the First Year of Continuous Use
Method
Lowest
Expected
Typical
Injectable progestogen
DEPO-PROVERA
0.3
0.3
Implants
Norplant (6 capsules)
0.2†
0.2†
Female sterilization
0.2
0.4
Male sterilization
0.1
0.15
Pill
Combined
Progestogen only
0.1
0.5
3
Method
Lowest
Expected
Typical
IUD
Progestasert
Copper T 380A
2
0.8
3
Condom
2
12
Diaphragm
6
18
Cap
6
18
Spermicides
3
21
Sponge
Parous women
Nulliparous women
9
6
28
18
Periodic abstinence
1-9
20
Withdrawal
4
18
No method
85
85
Source: Trussell et al1
* Lowest expected - when used exactly as directed.
Typical - includes those not following directions exactly.
† from Norplant® package insert.
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4
CONTRAINDICATIONS
1. Known or suspected pregnancy or as a diagnostic test for pregnancy.
2. Undiagnosed vaginal bleeding.
3. Known or suspected malignancy of breast.
4. Active thrombophlebitis, or current or past history of thromboembolic disorders, or
cerebral vascular disease.
5. Significant liver disease.
6. Known hypersensitivity to DEPO-PROVERA CI (medroxyprogesterone acetate or
any of its other ingredients).
WARNINGS
1. Loss of Bone Mineral Density
Use of Depo-Provera CI reduces serum estrogen levels and is associated with
significant loss of bone mineral density (BMD) as bone metabolism accommodates
to a lower estrogen level. This loss of BMD is of particular concern during
adolescence and early adulthood, a critical period of bone accretion. It is
unknown if use of Depo-Provera CI by younger women will reduce peak bone
mass and increase the risk for osteoporotic fracture in later life. In both adults
and adolescents, the decrease in BMD appears to be at least partially reversible
after Depo-Provera CI is discontinued and ovarian estrogen production increases.
A study to assess the reversibility of loss of BMD in adolescents is ongoing.
Depo-Provera CI should be used as a long-term birth control method (e.g. longer
than 2 years) only if other birth control methods are inadequate. BMD should be
evaluated when a woman needs to continue to use Depo-Provera CI long term.
In adolescents, interpretation of BMD results should take into account patient age
and skeletal maturity.
Other birth control methods should be considered in the risk/benefit analysis for
the use of Depo-Provera CI in women with osteoporosis risk factors. Depo-
Provera CI can pose an additional risk in patients with risk factors for
osteoporosis (e.g., metabolic bone disease, chronic alcohol and/or tobacco use,
anorexia nervosa, strong family history of osteoporosis or chronic use of drugs
that can reduce bone mass such as anticonvulsants or corticosteroids). Although
there are no studies addressing whether calcium and Vitamin D may lessen BMD
loss in women using Depo-Provera CI, all patients should have adequate calcium
and Vitamin D intake.
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5
BMD Changes in Adult Women
In a controlled, clinical study, adult women using Depo-Provera CI for up to 5
years showed spine and hip BMD mean decreases of 5-6%, compared to no
significant change in BMD in the control group. The decline in BMD was more
pronounced during the first two years of use, with smaller declines in subsequent
years. Mean changes in lumbar spine BMD of –2.86%, -4.11%, -4.89%, -4.93%
and –5.38% after 1, 2, 3, 4, and 5 years, respectively, were observed. Mean
decreases in BMD of the total hip and femoral neck were similar.
After stopping use of Depo-Provera CI (150 mg), there was partial recovery of
BMD toward baseline values during the 2-year post-therapy period. Longer
duration of treatment was associated with less complete recovery during this 2-
year period following the last injection. Table 2 shows the extent of recovery of
BMD for women who completed 5 years of treatment.
Table 2. Mean Percent Change from Baseline in BMD in Adults by Skeletal Site
and Cohort
Time in Study
Spine
Total Hip
Femoral Neck
Depo-
Provera*
Control**
Depo-
Provera*
Control**
Depo-
Provera*
Control**
5 years
n=33
-5.38%
n=105
0.43%
n=21
-5.16%
n=65
0.19%
n=34
-6.12%
n=106
-0.27%
7 years
n=12
-3.13%
n=60
0.53%
n=7
-1.34%
n=39
0.94%
n=13
-5.38%
n=63
-0.11%
*The treatment group consisted of women who received Depo-Provera Contraceptive Injection for
5 years and were then followed for 2 years post-use.
**The control group consisted of women who did not use hormonal contraception and were
followed for 7 years.
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BMD Changes in Adolescent Females (12-18 years of age)
Preliminary results from an ongoing, open-label, self-selected, non-randomized
clinical study of adolescent females (12-18 years) also showed that Depo-Provera
CI use was associated with a significant decline in BMD from baseline (Table 3).
In general, adolescents increase bone density during the period of growth
following menarche, as seen in the untreated cohort. However, the two cohorts
were not matched at baseline for age, gynecologic age, race, BMD and other
factors that influence the rate of acquisition of bone mineral density, with the
result that they differed with respect to these demographic factors.
Preliminary data from the small number of adolescents participating in the 2-year
post-use observation period demonstrated partial recovery of BMD.
Table 3. Mean Percent Change from Baseline in BMD in Adolescents by Skeletal
Site and Cohort
Duration of Treatment
Depo-Provera CI
(150 mg IM)
Unmatched, Untreated
Cohort
N
Mean % Change
N
Mean % Change
Total Hip BMD
Week 60 (1.2 years)
Week 144 (2.8 years)
Week 240 (4.6 years)
103
45
9
-2.82
-6.16
-6.92
171
111
69
1.32
1.74
1.12
Femoral Neck BMD
Week 60
Week 144
Week 240
103
45
9
-3.05
-6.01
-6.06
171
111
69
1.87
2.54
1.45
Lumbar Spine BMD
Week 60
Week 144
Week 240
104
46
9
-2.42
-2.78
-4.17
171
111
70
3.47
5.41
5.12
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2. Bleeding Irregularities
Most women using DEPO-PROVERA CI experience disruption of menstrual bleeding
patterns. Altered menstrual bleeding patterns include irregular or unpredictable
bleeding or spotting, or rarely, heavy or continuous bleeding. If abnormal bleeding
persists or is severe, appropriate investigation should be instituted to rule out the
possibility of organic pathology, and appropriate treatment should be instituted when
necessary.
As women continue using DEPO-PROVERA CI, fewer experience irregular
bleeding and more experience amenorrhea. By month 12 amenorrhea was reported by
55% of women, and by month 24 amenorrhea was reported by 68% of women using
DEPO-PROVERA CI.2
3. Cancer Risks
Long-term case-controlled surveillance of users of DEPO-PROVERA CI found slight or
no increased overall risk of breast cancer3 and no overall increased risk of ovarian,4
liver,5 or cervical6 cancer and a prolonged, protective effect of reducing the risk of
endometrial7 cancer in the population of users.
A pooled analysis14 from two case-control studies, the World Health
Organization Study3 and the New Zealand Study13, reported the relative risk (RR) of
breast cancer for women who had ever used DEPO-PROVERA CI as 1.1 (95%
confidence interval (CI) 0.97 to 1.4). Overall, there was no increase in risk with
increasing duration of use of DEPO-PROVERA CI. The RR of breast cancer for women
of all ages who had initiated use of DEPO-PROVERA CI within the previous 5 years
was estimated to be 2.0 (95% CI 1.5 to 2.8).
The World Health Organization Study3, a component of the pooled analysis14
described above, showed an increased RR of 2.19 (95% CI 1.23 to 3.89) of breast
cancer associated with use of DEPO-PROVERA CI in women whose first exposure to
drug was within the previous 4 years and who were under 35 years of age. However,
the overall RR for ever-users of DEPO-PROVERA CI was only 1.2 (95% CI 0.96 to
1.52).
[NOTE: A RR of 1.0 indicates neither an increased nor a decreased risk of
cancer associated with the use of the drug, relative to no use of the drug. In the case of
the subpopulation with a RR of 2.19, the 95% CI is fairly wide and does not include the
value of 1.0, thus inferring an increased risk of breast cancer in the defined subgroup
relative to nonusers. The value of 2.19 means that women whose first exposure to drug
was within the previous 4 years and who are under 35 years of age have a 2.19 fold
(95% CI 1.23 to 3.89-fold) increased risk of breast cancer relative to nonusers. The
National Cancer Institute8 reports an average annual incidence rate for breast cancer for
US women, all races, age 30 to 34 years of 26.7 per 100,000. A RR of 2.19, thus,
increases the possible risk from 26.7 to 58.5 cases per 100,000 women. The attributable
risk, thus, is 31.8 per 100,000 women per year.]
A statistically insignificant increase in RR estimates of invasive squamous-cell
cervical cancer has been associated with the use of DEPO-PROVERA CI in women
who were first exposed before the age of 35 years (RR 1.22 to 1.28 and 95% CI 0.93 to
1.70). The overall, nonsignificant relative rate of invasive squamous-cell cervical
cancer in women who ever used DEPO-PROVERA CI was estimated to be 1.11 (95%
CI 0.96 to 1.29). No trends in risk with duration of use or times since initial or most
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recent exposure were observed.
4. Thromboembolic Disorders
The physician should be alert to the earliest manifestations of thrombotic disorders
(thrombophlebitis, pulmonary embolism, cerebrovascular disorders, and retinal
thrombosis). Should any of these occur or be suspected, the drug should not be
readministered.
5. Ocular Disorders
Medication should not be readministered pending examination if there is a sudden partial
or complete loss of vision or if there is a sudden onset of proptosis, diplopia, or migraine.
If examination reveals papilledema or retinal vascular lesions, medication should not be
readministered.
6. Unexpected Pregnancies
To ensure that DEPO-PROVERA CI is not administered inadvertently to a pregnant
woman, the first injection must be given ONLY during the first 5 days of a normal
menstrual period; ONLY within the first 5-days postpartum if not breast-feeding, and if
exclusively breast-feeding, ONLY at the sixth postpartum week (see DOSAGE AND
ADMINISTRATION).
Neonates from unexpected pregnancies that occur 1 to 2 months after injection of
DEPO-PROVERA CI may be at an increased risk of low birth weight, which, in turn, is
associated with an increased risk of neonatal death. The attributable risk is low because
such pregnancies are uncommon.9,10
A significant increase in incidence of polysyndactyly and chromosomal anomalies
was observed among infants of users of DEPO-PROVERA CI, the former being most
pronounced in women under 30 years of age. The unrelated nature of these defects, the
lack of confirmation from other studies, the distant preconceptual exposure to DEPO-
PROVERA CI, and the chance effects due to multiple statistical comparisons, make a
causal association unlikely.11
Neonates exposed to medroxyprogesterone acetate in utero and followed to
adolescence, showed no evidence of any adverse effects on their health including their
physical, intellectual, sexual, or social development.
Several reports suggest an association between intrauterine exposure to
progestational drugs in the first trimester of pregnancy and genital abnormalities in male
and female fetuses. The risk of hypospadias (five to eight per 1,000 male births in the
general population) may be approximately doubled with exposure to these drugs. There
are insufficient data to quantify the risk to exposed female fetuses, but because some of
these drugs induce mild virilization of the external genitalia of the female fetus and
because of the increased association of hypospadias in the male fetus, it is prudent to
avoid the use of these drugs during the first trimester of pregnancy.
To ensure that DEPO-PROVERA CI is not administered inadvertently to a
pregnant woman, it is important that the first injection be given only during the first 5
days after the onset of a normal menstrual period within 5 days postpartum if not breast-
feeding and if breast-feeding, at the sixth week postpartum (see DOSAGE AND
ADMINISTRATION).
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7. Ectopic Pregnancy
Health-care providers should be alert to the possibility of an ectopic pregnancy among
women using DEPO-PROVERA CI who become pregnant or complain of severe
abdominal pain.
8. Lactation
Detectable amounts of drug have been identified in the milk of mothers receiving DEPO-
PROVERA CI. In nursing mothers treated with DEPO-PROVERA CI, milk composition,
quality, and amount are not adversely affected. Neonates and infants exposed to
medroxyprogesterone from breast milk have been studied for developmental and
behavioral effects through puberty. No adverse effects have been noted.
9. Anaphylaxis and Anaphylactoid Reaction
Anaphylaxis and anaphylactoid reaction have been reported with the use of DEPO-
PROVERA CI. If an anaphylactic reaction occurs appropriate therapy should be
instituted. Serious anaphylactic reactions require emergency medical treatment.
PRECAUTIONS
GENERAL
1. Physical Examination
It is good medical practice for all women to have annual history and physical
examinations, including women using DEPO-PROVERA CI. The physical examination,
however, may be deferred until after initiation of DEPO PROVERA CI if requested by
the woman and judged appropriate by the clinician. The physical examination should
include special reference to blood pressure, breasts, abdomen and pelvic organs,
including cervical cytology and relevant laboratory tests. In case of undiagnosed,
persistent or recurrent abnormal vaginal bleeding, appropriate measures should be
conducted to rule out malignancy. Women with a strong family history of breast cancer
or who have breast nodules should be monitored with particular care.
2. Fluid Retention
Because progestational drugs may cause some degree of fluid retention, conditions that
might be influenced by this condition, such as epilepsy, migraine, asthma, and cardiac or
renal dysfunction, require careful observation.
3. Weight Changes
There is a tendency for women to gain weight while on therapy with DEPO-PROVERA
CI. From an initial average body weight of 136 lb, women who completed 1 year of
therapy with DEPO-PROVERA CI gained an average of 5.4 lb. Women who completed
2 years of therapy gained an average of 8.1 lb.
Women who completed 4 years gained an average of 13.8 lb. Women who
completed 6 years gained an average of 16.5 lb. Two percent of women withdrew from a
large-scale clinical trial because of excessive weight gain.
4. Return of Fertility
DEPO-PROVERA CI has a prolonged contraceptive effect. In a large US study of
women who discontinued use of DEPO-PROVERA CI to become pregnant, data are
available for 61% of them. Based on Life-Table analysis of these data, it is expected that
68% of women who do become pregnant may conceive within 12 months, 83% may
conceive within 15 months, and 93% may conceive within 18 months from the last
injection. The median time to conception for those who do conceive is 10 months
following the last injection with a range of 4 to 31 months, and is unrelated to the
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duration of use. No data are available for 39% of the patients who discontinued DEPO-
PROVERA CI to become pregnant and who were lost to follow-up or changed their
mind.
5. CNS Disorders and Convulsions
Patients who have a history of psychic depression should be carefully observed and the
drug not be readministered if the depression recurs.
There have been a few reported cases of convulsions in patients who were treated
with DEPO-PROVERA CI. Association with drug use or pre-existing conditions is not
clear.
6. Carbohydrate Metabolism
A decrease in glucose tolerance has been observed in some patients on DEPO-
PROVERA CI treatment. The mechanism of this decrease is obscure. For this reason,
diabetic patients should be carefully observed while receiving such therapy.
7. Liver Function
If jaundice develops, consideration should be given to not readministering the drug.
8. Protection Against Sexually Transmitted Diseases
Patients should be counseled that this product does not protect against HIV infection
(AIDS) and other sexually transmitted diseases.
DRUG INTERACTIONS
Aminoglutethimide administered concomitantly with the DEPO-PROVERA CI
may significantly depress the serum concentrations of medroxyprogesterone acetate.12
Users of DEPO-PROVERA CI should be warned of the possibility of decreased efficacy
with the use of this or any related drugs.
LABORATORY TEST INTERACTIONS
The pathologist should be advised of progestin therapy when relevant specimens
are submitted.
The following laboratory tests may be affected by progestins including DEPO-
PROVERA CI:
(a)
Plasma and urinary steroid levels are decreased (eg, progesterone,
estradiol, pregnanediol, testosterone, cortisol).
(b)
Gonadotropin levels are decreased.
(c)
Sex-hormone-binding-globulin concentrations are decreased.
(d)
Protein-bound iodine and butanol extractable protein-bound iodine may
increase.
T3-uptake values may decrease.
(e)
Coagulation test values for prothrombin (Factor II), and
Factors VII, VIII, IX, and X may increase.
(f)
Sulfobromophthalein and other liver function test values may be
increased.
(g)
The effects of medroxyprogesterone acetate on lipid metabolism are
inconsistent. Both increases and decreases in total cholesterol,
triglycerides, low-density lipoprotein (LDL) cholesterol, and high-
density lipoprotein (HDL) cholesterol have been observed in studies.
CARCINOGENESIS
See “WARNINGS” section 3.
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11
PREGNANCY
Pregnancy Category X. See “WARNINGS” section 6.
NURSING MOTHERS
See “WARNINGS” section 8.
PEDIATRIC USE
Depo-Provera CI is not indicated before menarche. Use of Depo-Provera CI is associated
with significant loss of BMD. This loss of BMD is of particular concern during
adolescence and early adulthood, a critical period of bone accretion. In adolescents,
interpretation of BMD results should take into account patient age and skeletal
maturity. It is unknown if use of Depo-Provera CI by younger women will reduce peak
bone mass and increase the risk of osteoporotic fractures in later life. Other than
concerns about loss of BMD, the safety and effectiveness are expected to be the same for
postmenarchal adolescents and adult women.
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INFORMATION FOR THE PATIENT
See Patient Labeling.
Patient labeling is included with each single-dose vial and prefilled syringe of
DEPO-PROVERA CI to help describe its characteristics to the patient. It is
recommended that prospective users be given this labeling and be informed about the
risks and benefits associated with the use of DEPO-PROVERA CI, as compared with
other forms of contraception or with no contraception at all. It is recommended that
physicians or other health-care providers responsible for those patients advise them at the
beginning of treatment that their menstrual cycle may be disrupted and that irregular and
unpredictable bleeding or spotting results, and that this usually decreases to the point of
amenorrhea as treatment with DEPO-PROVERA CI continues, without other therapy
being required.
ADVERSE REACTIONS
In the largest clinical trial with DEPO-PROVERA CI, over 3,900 women, who
were treated for up to 7 years, reported the following adverse reactions, which may or
may not be related to the use of DEPO-PROVERA CI.
The following adverse reactions were reported by more than 5% of subjects:
Menstrual irregularities (bleeding or amenorrhea, or both)
Abdominal pain or discomfort
Weight changes
Dizziness
Headache
Asthenia (weakness or fatigue)
Nervousness
Adverse reactions reported by 1% to 5% of subjects using DEPO-PROVERA
Contraceptive Injection were:
Decreased libido or anorgasmia
Pelvic pain
Backache
Breast pain
Leg cramps
No hair growth or alopecia
Depression
Bloating
Nausea
Rash
Insomnia
Edema
Leukorrhea
Hot flashes
Acne
Arthralgia
Vaginitis
Events reported by fewer than 1% of subjects included: galactorrhea, melasma,
chloasma, convulsions, changes in appetite, gastrointestinal disturbances, jaundice,
genitourinary infections, vaginal cysts, dyspareunia, paresthesia, chest pain, pulmonary
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13
embolus, allergic reactions, anemia, drowsiness, syncope, dyspnea and asthma,
tachycardia, fever, excessive sweating and body odor, dry skin, chills, increased libido,
excessive thirst, hoarseness, pain at injection site, blood dyscrasia, rectal bleeding,
changes in breast size, breast lumps or nipple bleeding, axillary swelling, breast cancer,
prevention of lactation, sensation of pregnancy, lack of return to fertility, paralysis,
facial palsy, scleroderma, osteoporosis, uterine hyperplasia, cervical cancer, varicose
veins, dysmenorrhea, hirsutism, unexpected pregnancy, thrombophlebitis, deep vein
thrombosis.
Postmarketing Experience
There have been rare cases of osteoporosis including osteoporotic fractures
reported postmarketing in patients taking Depo-Provera CI. In addition, there have been
voluntary reports of anaphylaxis and anaphylactoid reaction associated with the use of
Depo-Provera CI.
DOSAGE AND ADMINISTRATION
Both the 1 mL vial and the 1 mL prefilled syringe of DEPO-PROVERA CI
should be vigorously shaken just before use to ensure that the dose being administered
represents a uniform suspension.
The recommended dose is 150 mg of DEPO-PROVERA CI every 3 months (13
weeks) administered by deep, IM injection in the gluteal or deltoid muscle. To ensure
the patient is not pregnant at the time of the first injection, the first injection MUST be
given ONLY during the first 5 days of a normal menstrual period; ONLY within the
first 5-days postpartum if not breast-feeding; and if exclusively breast-feeding, ONLY at
the sixth postpartum week. If the time interval between injections is greater than 13
weeks, the physician should determine that the patient is not pregnant before
administering the drug. The efficacy of DEPO-PROVERA CI depends on adherence to
the dosage schedule of administration.
HOW SUPPLIED
DEPO-PROVERA CI (medroxyprogesterone acetate sterile aqueous suspension
150 mg/mL) is available as:
NDC 0009-0746-30
1 mL vial
NDC 0009-0746-35
25 x 1 mL vials
NDC 0009-7376-01
1 mL prefilled syringe
NDC 0009-7376-02
6 x 1 mL prefilled syringes
NDC 0009-7376-03
24 x 1 mL prefilled syringes
DEPO-PROVERA CI prefilled syringes are available packaged with 22-gauge x 1
1/2 inch BD SafetyGlideTM Needles in the following presentations:
NDC 0009-7376-04
1 mL prefilled syringe
NDC 0009-7376-05
6 x 1 mL prefilled syringes
NDC 0009-7376-06
24 x 1 mL prefilled syringes
Store at controlled room temperature 20° to 25°C (68° to 77°F) [see USP].
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
14
REFERENCES
1. Trussell J, Hatcher RA, Cates W Jr, Stewart FH, Kost K. A guide to interpreting
contraceptive efficacy studies. Obstet Gynecol. 1990; 76:558-567.
2. Schwallie PC, Assenzo JR. Contraceptive use-efficacy study utilizing
medroxyprogesterone acetate administered as an intramuscular injection once every
90 days. Fertil Steril. 1973; 24:331-339.
3. WHO Collaborative Study of Neoplasia and Steroid Contraceptives. Breast cancer and
depot-medroxyprogesterone acetate: a multi-national study. Lancet. 1991; 338:833-
838.
4. WHO Collaborative Study of Neoplasia and Steroid Contraceptives. Depot-
medroxyprogesterone acetate (DMPA) and risk of epithelial ovarian cancer. Int J
Cancer. 1991; 49:191-195.
5. WHO Collaborative Study of Neoplasia and Steroid Contraceptives. Depot-
medroxyprogesterone acetate (DMPA) and risk of liver cancer. Int J Cancer. 1991;
49:182185.
6. WHO Collaborative Study of Neoplasia and Steroid Contraceptives. Depot-
medroxyprogesterone acetate (DMPA) and risk of invasive squamous-cell cervical
cancer. Contraception. 1992; 45:299-312.
7. WHO Collaborative Study of Neoplasia and Steroid Contraceptives. Depot-
medroxyprogesterone acetate (DMPA) and risk of endometrial cancer. Int J Cancer.
1991; 49:186-190.
8. Surveillance, Epidemiology, and End Results: Incidence and Mortality Data, 1973-
1977. National Cancer Institute Monograph, 57: June 1981. (NIH publication No. 81-
2330).
9. Gray RH, Pardthaisong T. In Utero exposure to steroid contraceptives and survival
during infancy. Am J Epidemiol. 1991; 134:804-811.
10. Pardthaisong T, Gray RH. In Utero exposure to steroid contraceptives and outcome
of pregnancy. Am J Epidemiol. 1991; 134:795-803.
11. Pardthaisong T, Gray RH, McDaniel EB, Chandacham A. Steroid contraceptive use
and pregnancy outcome. Teratology. 1988; 38:51-58.
12. Van Deijk WA, Biljham GH, Mellink WAM, Meulenberg PMM. Influence of
aminoglutethimide on plasma levels of medroxyprogesterone acetate: its correlation
with serum cortisol. Cancer Treatment Reports. 1985; 69:1, 85-90.
13. Paul C, Skegg DCG, Spears GFS. Depot medroxyprogesterone (Depo-Provera) and
risk of breast cancer. Br Med J. 1989; 299:759-762.
14. Skegg DCG, Noonan EA, Paul C, Spears GFS, Meirik O, Thomas DB. Depot
Medroxyprogesterone Acetate and Breast Cancer: A Pooled Analysis from the World
Health Organization and New Zealand Studies. JAMA. 1995; 273(10):799-804.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
15
Rx only
DEPO-PROVERA Contraceptive Injection 1 mL vials are manufactured by:
Pharmacia & Upjohn Company
Kalamazoo, MI 49001, USA
DEPO-PROVERA Contraceptive Injection 1 mL prefilled syringes are manufactured
by:
Pharmacia & Upjohn, N.V./S.A.
Puurs, Belgium
for:
Pharmacia & Upjohn Company
A subsidiary of Pharmacia Corporation
Kalamazoo, MI 49001, USA
LAB-0149-2.1
Revised November 2004
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
Patient Labeling
Use of Depo-Provera Contraceptive Injection may cause you to lose calcium stored
in your bones. The longer you use Depo-Provera Contraceptive Injection the more
calcium you are likely to lose. The calcium may not return completely once you stop
using Depo-Provera Contraceptive Injection.
Loss of calcium may cause weak, porous bones (osteoporosis) that could increase the
risk that your bones might break, especially after menopause. It is not known
whether your risk of developing osteoporosis may be greater if you are a teenager
when you start to use Depo-Provera Contraceptive Injection.
You should use Depo-Provera Contraceptive Injection long term (for example, more
than two years) only if other methods of birth control are not right for you. (See
“Risks of Using Depo-Provera Contraceptive Injection”)
This product is intended to prevent pregnancy. It does not protect against HIV
infection (AIDS) and other sexually transmitted diseases.
Introduction
Every woman who considers using DEPO-PROVERA Contraceptive Injection
needs to understand the benefits and risks of this form of birth control and to discuss
them with her health-care provider. This leaflet is intended to give you much of the
information you will need in order to decide if DEPO-PROVERA Contraceptive
Injection is the right choice for you. Your health-care provider will help you to compare
DEPO-PROVERA Contraceptive Injection with other contraceptive methods and will
answer any questions you have after you have read this information.
DEPO-PROVERA Contraceptive Injection is given as an intramuscular injection
(a shot) in the buttock or upper arm once every 3 months (13 weeks). Promptly at the end
of the 3-month interval, you will need to return to your health-care provider for your next
injection in order to continue your contraceptive protection.
DEPO-PROVERA Contraceptive
Injection
contains medroxyprogesterone
acetate, a chemical similar to (but not the same as) the natural hormone progesterone that
is produced by your ovaries during the second half of your menstrual cycle. DEPO-
PROVERA Contraceptive Injection acts by preventing your egg cells from ripening. If an
egg is not released from the ovaries during your menstrual cycle, it cannot become
fertilized by sperm and result in pregnancy. DEPO-PROVERA Contraceptive Injection
also causes changes in the lining of your uterus that make it less likely for pregnancy to
occur.
Effectiveness of DEPO-PROVERA Contraceptive Injection
To ensure that DEPO-PROVERA Contraceptive Injection is not administered
inadvertently to a pregnant woman, the first injection must be given ONLY during the
first 5 days of a normal menstrual period; ONLY within the first 5-days postpartum if not
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For current labeling information, please visit https://www.fda.gov/drugsatfda
2
breast-feeding, and if exclusively breast-feeding, ONLY at the sixth postpartum week
(see Administration of DEPO-PROVERA Contraceptive Injection). The efficacy of
DEPO-PROVERA Contraceptive Injection depends on adherence to the recommended
dosage schedule.
DEPO-PROVERA Contraceptive Injection is over 99% effective, making it one
of the most reliable methods of birth control available. This means that the average
annual pregnancy rate is less than one for every 100 women who use DEPO-PROVERA
Contraceptive Injection. The effectiveness of most contraceptive methods depends, in
part, on how reliably each woman uses the method. The effectiveness of DEPO-
PROVERA Contraceptive Injection depends only on the patient returning every 3 months
(13 weeks) for her next injection.
The following table shows the percent of women who become pregnant while
using different kinds of contraceptive methods. It gives both the lowest expected rate of
pregnancy (the rate expected in women who use each method exactly as it should be
used) and the typical rate of pregnancy (which includes women who became pregnant
because they forgot to use their birth control or because they did not follow the directions
exactly).
Percent of Women Experiencing an Accidental Pregnancy in the First Year of
Continuous Use
Method
Lowest
Typical
DEPO-PROVERA
0.3
0.3
Implants (Norplant)
0.2*
0.2*
Female sterilization
0.2
0.4
Male sterilization
0.1
0.15
Oral contraceptives (pill)
—
3
Combined
0.1
—
Progestogen only
0.5
—
IUD
—
3
Progestasert
2
—
Copper T 380A
0.8
—
Condom (without spermicide)
2
12
Diaphragm (with spermicide)
6
18
Cervical cap
6
18
Withdrawal
4
18
Periodic abstinence
1-9
20
Spermicide alone
3
21
Vaginal sponge
—
—
used before childbirth
6
18
used after childbirth
9
28
No method
85
85
Source: Trussell et al; Obstet Gynecol 1990;76:558-567.
* From Norplant® package insert.
Who Should Not Use DEPO-PROVERA Contraceptive Injection
Certain women should not use DEPO-PROVERA Contraceptive Injection. You
should not use DEPO-PROVERA Contraceptive Injection if you have any of the
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
3
following conditions:
• if you think you might be pregnant
• if you have any vaginal bleeding without a known reason
• if you have had cancer of the breast
• if you have had a stroke
• if you have or have had blood clots (phlebitis) in your legs
• if you have problems with your liver or liver disease
• if you are allergic to DEPO-PROVERA Contraceptive Injection
(medroxyprogesterone acetate or any of its other ingredients)
Other Things to Consider Before Choosing DEPO-PROVERA Contraceptive
Injection
Before your doctor prescribes DEPO-PROVERA Contraceptive Injection, you
will have a physical examination. It is important to tell your doctor or health-care
provider if you have any of the following:
• a family history of cancer of the breast
• an abnormal mammogram (breast X-ray), fibrocystic breast disease, breast
nodules or lumps, or bleeding from your nipples
• kidney disease
• irregular or scanty menstrual periods
• high blood pressure
• migraine headaches
• asthma
• epilepsy (convulsions or seizures)
• diabetes or a family history of diabetes
• a history of depression
• if you are taking any prescription or over-the-counter medications
This product is intended to prevent pregnancy. It does not protect against transmission of
HIV (AIDS) and other sexually transmitted diseases such as chlamydia, genital herpes,
genital warts, gonorrhea, hepatitis B, and syphilis.
Return of Fertility
Because DEPO-PROVERA Contraceptive Injection is a long-acting birth control
method, it takes some time after your last injection for its effect to wear off. Based on the
results from a large study done in the United States, of those women who stop using
DEPO-PROVERA Contraceptive Injection in order to become pregnant, about half of
those who become pregnant do so in about 10 months after their last injection; about two-
thirds of those who become pregnant do so in about 12 months, about 83% of those who
become pregnant do so in about 15 months, and about 93% of those who become
pregnant do so in about 18 months after their last injection. The length of time you use
DEPO-PROVERA Contraceptive Injection has no effect on how long it takes you to
become pregnant after you stop using it.
Risks of Using DEPO-PROVERA Contraceptive Injection
1. Losing Calcium from Your Bones
Depo-Provera CI use may decrease the amount of calcium in your bones. The longer
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
4
you are on Depo-Provera CI the more calcium you may lose. This increases the risk of
your bones weakening if you use Depo-Provera CI continuously for a long time (for more
than 2 years). The loss of calcium may increase your risk of osteoporosis and broken
bones, particularly after your menopause.
Calcium is generally added to the bones during teenage years. The decrease of calcium
in your bones is of most concern if you are a teenager or have the following risk factors:
-
bone disease
-
anorexia nervosa (an eating disorder)
-
a strong family history of osteoporosis
-
drug use that can lower the amount of calcium in bones (drugs for epilepsy or
steroids), or
-
drinking a lot of alcohol or smoking a lot.
If you need a birth control method for more than 2 years, your healthcare provider may
ask you to switch to another birth control method or ask you to have a test of your bones
before continuing Depo-Provera CI, especially if you have other risks for weak bones.
When Depo-Provera CI is stopped, the calcium in bones begins to come back. Your
healthcare provider may tell you take calcium and Vitamin D as this may lessen the loss
of calcium from your bones.
2. Irregular Menstrual Bleeding
The side effect reported most frequently by women who use DEPO-PROVERA
Contraceptive Injection for contraception is a change in their normal menstrual cycle.
During the first year of using DEPO-PROVERA Contraceptive Injection, you might have
one or more of the following changes:
• irregular or unpredictable bleeding or spotting,
• an increase or decrease in menstrual bleeding, or
• no bleeding at all.
Unusually heavy or continuous bleeding, however, is not a usual effect of DEPO-
PROVERA Contraceptive Injection and if this happens you should see your health-care
provider right away.
With continued use of DEPO-PROVERA Contraceptive Injection, bleeding
usually decreases and many women stop having periods completely. In clinical studies of
DEPO-PROVERA Contraceptive Injection, 55% of the women studied reported no
menstrual bleeding (amenorrhea) after 1 year of use and 68% of the women studied
reported no menstrual bleeding after 2 years of use.
The reason that your periods stop is because DEPO-PROVERA Contraceptive
Injection causes a resting state in your ovaries. When your ovaries do not release an egg
monthly, the regular monthly growth of the lining of your uterus does not occur and,
therefore, the bleeding that comes with your normal menstruation does not take place.
When you stop using DEPO-PROVERA Contraceptive Injection your menstrual period
will usually, in time, return to its normal cycle.
3. Cancer
Studies of women who have used different forms of contraception found that women who
used DEPO-PROVERA Contraceptive Injection for contraception had no increased
overall risk of developing cancer of the breast, ovary, uterus, cervix, or liver. However,
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5
women under 35 years of age whose first exposure to DEPO-PROVERA Contraceptive
Injection was within the previous 4 to 5 years may have a slightly increased risk of
developing breast cancer similar to that seen with oral contraceptives. You should discuss
this with your health-care provider.
4. Unexpected Pregnancy
Because DEPO-PROVERA Contraceptive Injection is such an effective contraceptive
method, the risk of unexpected pregnancy for women who get their shots regularly (every
3 months [13 weeks] ) is very low. While there have been reports of an increased risk of
low birth weight and neonatal infant death or other health problems in infants conceived
close to the time of injection, such pregnancies are uncommon. If you think you may
have become pregnant while using DEPO-PROVERA Contraceptive Injection for
contraception, see your health-care provider as soon as possible.
5. Allergic Reactions
Severe allergic reactions known as anaphylaxis and anaphylactoid reactions have also
been reported in some women using DEPO-PROVERA Contraceptive Injection.
6. Other Risks
Women who use hormone-based contraceptives may have an increased risk of blood clots
or stroke. Also, if a contraceptive method fails, there is a possibility that the fertilized egg
will begin to develop outside of the uterus (ectopic pregnancy). While these events are
rare, you should tell your health-care provider if you have any of the Warning Signals
listed in the next section.
Warning Signals
If any of these problems occur following an injection of DEPO-PROVERA
Contraceptive Injection, call your healthcare provider immediately:
• Sharp chest pain, coughing up of blood, or sudden shortness of breath (indicating
a possible clot in the lung)
• Sudden severe headache or vomiting, dizziness or fainting, problems with your
eyesight or speech, weakness, or numbness in an arm or leg (indicating a possible
stroke)
• Severe pain or swelling in the calf (indicating a possible clot in the leg)
• Unusually heavy vaginal bleeding
• Severe pain or tenderness in the lower abdominal area
• Persistent pain, pus, or bleeding at the injection site
Side Effects of DEPO-PROVERA Contraceptive Injection
1. Weight Gain
You may experience a weight gain while you are using DEPO-PROVERA Contraceptive
Injection. About two-thirds of the women who used DEPO-PROVERA Contraceptive
Injection in the clinical trials reported a weight gain of about 5 pounds during the first
year of use. You may continue to gain weight after the first year. Women in one large
study who used DEPO-PROVERA Contraceptive Injection for 2 years gained an average
total of 8.1 pounds over those 2 years, or approximately 4 pounds per year. Women who
continued for 4 years gained an average total of 13.8 pounds over those 4 years, or
approximately 3.5 pounds per year. Women who continued for 6 years gained an average
total of 16.5 pounds over those 6 years, or approximately 2.75 pounds per year.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
6
2. Other Side Effects
In a clinical study of over 3,900 women who used DEPO-PROVERA Contraceptive
Injection for up to 7 years, some women reported the following effects that may or may
not have been related to their use of DEPO-PROVERA Contraceptive Injection:
• irregular menstrual bleeding
• amenorrhea
• headache
• nervousness
• abdominal cramps
• dizziness
• weakness or fatigue
• decreased sexual desire
• leg cramps
• nausea
• vaginal discharge or irritation
• breast swelling and tenderness
• bloating
• swelling of the hands or feet
• backache
• depression
• insomnia
• acne
• pelvic pain
• no hair growth or excessive hair
loss
• rash
• hot flashes
• joint pain
Other problems were reported by very few of the women in the clinical trials, but
some of these could be serious. These include: convulsions, jaundice, urinary tract
infections, allergic reactions, fainting, paralysis, osteoporosis, lack of return to fertility,
deep vein thrombosis, pulmonary embolus, breast cancer, or cervical cancer. If these or
any other problems occur during your use of DEPO-PROVERA Contraceptive Injection,
discuss them with your health-care provider.
General Precautions
1. Missed Periods
During the time you are using DEPO-PROVERA Contraceptive Injection for
contraception, you may skip a period, or your periods may stop completely. If you have
been receiving your injection of DEPO-PROVERA Contraceptive Injection regularly
every 3 months (13 weeks), then you are probably not pregnant. However, if you think
that you may be pregnant, see your health-care provider.
2. Laboratory Test Interactions
If you are scheduled for any laboratory tests, tell your health-care provider that you are
using DEPO-PROVERA Contraceptive Injection for contraception. Certain blood tests
are affected by hormones such as DEPO-PROVERA Contraceptive Injection.
3. Drug Interactions
Cytadren (aminoglutethimide) is an anticancer drug that
may significantly decrease the effectiveness of DEPOPROVERA Contraceptive Injection
if the two drugs are given during the same time.
4. Nursing Mothers
Although DEPO-PROVERA Contraceptive Injection can be passed to the nursing infant
in the breast milk, no harmful effects have been found in these children. DEPO-
PROVERA Contraceptive Injection does not prevent the breasts from producing milk, so
it can be used by nursing mothers. However, to minimize the amount of DEPO-
PROVERA Contraceptive Injection that is passed to the infant in the first weeks after
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
7
birth, you should wait until 6 weeks after childbirth before you start using DEPO-
PROVERA Contraceptive Injection for contraception.
Administration of DEPO-PROVERA Contraceptive Injection
The recommended dose of DEPO-PROVERA Contraceptive Injection is 150 mg
every 3 months (13 weeks) given in a single intramuscular injection in the buttock or
upper arm. To ensure that you are not pregnant at the time of the first injection, it is
essential that the injection be given ONLY during the first 5 days of a normal menstrual
period. If used following the delivery of a child, the first injection of DEPO-PROVERA
Contraceptive Injection MUST be given within 5 days after childbirth if you are not
breast-feeding, or if you are exclusively breast-feeding, the injection MUST be given 6
weeks after childbirth. If you wait longer than 3 months (13 weeks) between injections,
or longer than 6 weeks after delivery, your health-care provider should determine that
you are not pregnant before giving you your injection of DEPO-PROVERA
Contraceptive Injection.
Rx only
Pharmacia & Upjohn Company
A subsidiary of Pharmacia Corporation
Kalamazoo, MI 49001, USA
Revised October 2004
815 463 612
692819
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:47:13.554890
|
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|
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1
Physician Information
Women who use Depo-Provera Contraceptive Injection may lose significant bone
mineral density. Bone loss is greater with increasing duration of use and may not be
completely reversible.
It is unknown if use of Depo-Provera Contraceptive Injection during adolescence or
early adulthood, a critical period of bone accretion, will reduce peak bone mass and
increase the risk for osteoporotic fracture in later life.
Depo-Provera Contraceptive Injection should be used as a long-term birth control
method (e.g. longer than 2 years) only if other birth control methods are inadequate.
(See WARNINGS.)
Patients should be counseled that this product does not protect against HIV
infection (AIDS) and other sexually transmitted diseases.
DESCRIPTION
DEPO-PROVERA Contraceptive Injection (CI) contains medroxyprogesterone
acetate, a derivative of progesterone, as its active ingredient. Medroxyprogesterone
acetate is active by the parenteral and oral routes of administration. It is a white to off-
white; odorless crystalline powder that is stable in air and that melts between 200°C
and 210°C. It is freely soluble in chloroform, soluble in acetone and dioxane, sparingly
soluble in alcohol and methanol, slightly soluble in ether, and insoluble in water.
The chemical name for medroxyprogesterone acetate is pregn-4-ene-3,20-
dione, 17-(acetyloxy)-6-methyl-, (6α-).
The structural formula is as follows:
medroxyprogesterone acetate
DEPO-PROVERA CI for intramuscular (IM) injection is available in vials and
prefilled syringes, each containing 1 mL of medroxyprogesterone acetate sterile aqueous
suspension 150 mg/mL.
Each mL contains:
Medroxyprogesterone acetate
150 mg
Polyethylene glycol 3350
28.9 mg
Polysorbate 80
2.41 mg
Sodium chloride
8.68 mg
Methylparaben
1.37 mg
Propylparaben
0.150 mg
Water for injection
qs
When necessary, pH is adjusted with sodium hydroxide or hydrochloric acid, or
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2
both.
CLINICAL PHARMACOLOGY
DEPO-PROVERA CI (medroxyprogesterone acetate), when administered at the
recommended dose to women every 3 months, inhibits the secretion of gonadotropins
which, in turn, prevents follicular maturation and ovulation and results in endometrial
thinning. These actions produce its contraceptive effect.
Following a single 150 mg IM dose of DEPO-PROVERA Contraceptive
Injection, medroxyprogesterone acetate concentrations, measured by an extracted
radioimmunoassay procedure, increase for approximately 3 weeks to reach peak plasma
concentrations of 1 to 7 ng/mL. The levels then decrease exponentially until they
become undetectable (<100 pg/mL) between 120 to 200 days following injection. Using
an unextracted radioimmunoassay procedure for the assay of medroxyprogesterone
acetate in serum, the apparent half-life for medroxyprogesterone acetate following IM
administration of DEPO-PROVERA Contraceptive Injection is approximately 50 days.
Women with lower body weights conceive sooner than women with higher body
weights after discontinuing DEPO-PROVERA Contraceptive Injection.
The effect of hepatic and/or renal disease on the pharmacokinetics of DEPO-
PROVERA Contraceptive Injection is unknown.
INDICATIONS AND USAGE
DEPO-PROVERA CI is indicated only for the prevention of pregnancy. The
loss of bone mineral density (BMD) in women of all ages and the impact on peak bone
mass in adolescents should be considered, along with the decrease in BMD that occurs
during pregnancy and/or lactation, in the risk/benefit assessment for women who use
Depo-Provera CI long-term (see WARNINGS.) It is a long-term injectable
contraceptive in women when administered at 3-month (13-week) intervals. Dosage does
not need to be adjusted for body weight.
In five clinical studies using DEPO-PROVERA CI, the 12-month failure rate for
the group of women treated with DEPO-PROVERA CI was zero (no pregnancies
reported) to 0.7 by Life-Table method. Pregnancy rates with contraceptive measures are
typically reported for only the first year of use as shown in Table 1. Except for
intrauterine devices (IUD), implants, sterilization, and DEPO-PROVERA CI, the
efficacy of these contraceptive measures depends in part on the reliability of use. The
effectiveness of DEPO-PROVERA CI is dependent on the patient returning every 3
months (13 weeks) for reinjection.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
3
Table 1
Lowest Expected and Typical Failure Rates*
Expressed as Percent of Women Experiencing
an Accidental Pregnancy
in the First Year of Continuous Use
Method
Lowest
Expected
Typical
Injectable progestogen
DEPO-PROVERA
0.3
0.3
Implants
Norplant (6 capsules)
0.2†
0.2†
Female sterilization
0.2
0.4
Male sterilization
0.1
0.15
Pill
Combined
Progestogen only
0.1
0.5
3
Method
Lowest
Expected
Typical
IUD
Progestasert
Copper T 380A
2
0.8
3
Condom
2
12
Diaphragm
6
18
Cap
6
18
Spermicides
3
21
Sponge
Parous women
Nulliparous women
9
6
28
18
Periodic abstinence
1-9
20
Withdrawal
4
18
No method
85
85
Source: Trussell et al1
* Lowest expected - when used exactly as directed.
Typical - includes those not following directions exactly.
† from Norplant® package insert.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
4
CONTRAINDICATIONS
1. Known or suspected pregnancy or as a diagnostic test for pregnancy.
2. Undiagnosed vaginal bleeding.
3. Known or suspected malignancy of breast.
4. Active thrombophlebitis, or current or past history of thromboembolic disorders, or
cerebral vascular disease.
5. Significant liver disease.
6. Known hypersensitivity to DEPO-PROVERA CI (medroxyprogesterone acetate or
any of its other ingredients).
WARNINGS
1. Loss of Bone Mineral Density
Use of Depo-Provera CI reduces serum estrogen levels and is associated with
significant loss of bone mineral density (BMD) as bone metabolism accommodates
to a lower estrogen level. This loss of BMD is of particular concern during
adolescence and early adulthood, a critical period of bone accretion. It is
unknown if use of Depo-Provera CI by younger women will reduce peak bone
mass and increase the risk for osteoporotic fracture in later life. In both adults
and adolescents, the decrease in BMD appears to be at least partially reversible
after Depo-Provera CI is discontinued and ovarian estrogen production increases.
A study to assess the reversibility of loss of BMD in adolescents is ongoing.
Depo-Provera CI should be used as a long-term birth control method (e.g. longer
than 2 years) only if other birth control methods are inadequate. BMD should be
evaluated when a woman needs to continue to use Depo-Provera CI long term.
In adolescents, interpretation of BMD results should take into account patient age
and skeletal maturity.
Other birth control methods should be considered in the risk/benefit analysis for
the use of Depo-Provera CI in women with osteoporosis risk factors. Depo-
Provera CI can pose an additional risk in patients with risk factors for
osteoporosis (e.g., metabolic bone disease, chronic alcohol and/or tobacco use,
anorexia nervosa, strong family history of osteoporosis or chronic use of drugs
that can reduce bone mass such as anticonvulsants or corticosteroids). Although
there are no studies addressing whether calcium and Vitamin D may lessen BMD
loss in women using Depo-Provera CI, all patients should have adequate calcium
and Vitamin D intake.
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5
BMD Changes in Adult Women
In a controlled, clinical study, adult women using Depo-Provera CI for up to 5
years showed spine and hip BMD mean decreases of 5-6%, compared to no
significant change in BMD in the control group. The decline in BMD was more
pronounced during the first two years of use, with smaller declines in subsequent
years. Mean changes in lumbar spine BMD of –2.86%, -4.11%, -4.89%, -4.93%
and –5.38% after 1, 2, 3, 4, and 5 years, respectively, were observed. Mean
decreases in BMD of the total hip and femoral neck were similar.
After stopping use of Depo-Provera CI (150 mg), there was partial recovery of
BMD toward baseline values during the 2-year post-therapy period. Longer
duration of treatment was associated with less complete recovery during this 2-
year period following the last injection. Table 2 shows the extent of recovery of
BMD for women who completed 5 years of treatment.
Table 2. Mean Percent Change from Baseline in BMD in Adults by Skeletal Site
and Cohort
Time in Study
Spine
Total Hip
Femoral Neck
Depo-
Provera*
Control**
Depo-
Provera*
Control**
Depo-
Provera*
Control**
5 years
n=33
-5.38%
n=105
0.43%
n=21
-5.16%
n=65
0.19%
n=34
-6.12%
n=106
-0.27%
7 years
n=12
-3.13%
n=60
0.53%
n=7
-1.34%
n=39
0.94%
n=13
-5.38%
n=63
-0.11%
*The treatment group consisted of women who received Depo-Provera Contraceptive Injection for
5 years and were then followed for 2 years post-use.
**The control group consisted of women who did not use hormonal contraception and were
followed for 7 years.
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BMD Changes in Adolescent Females (12-18 years of age)
Preliminary results from an ongoing, open-label, self-selected, non-randomized
clinical study of adolescent females (12-18 years) also showed that Depo-Provera
CI use was associated with a significant decline in BMD from baseline (Table 3).
In general, adolescents increase bone density during the period of growth
following menarche, as seen in the untreated cohort. However, the two cohorts
were not matched at baseline for age, gynecologic age, race, BMD and other
factors that influence the rate of acquisition of bone mineral density, with the
result that they differed with respect to these demographic factors.
Preliminary data from the small number of adolescents participating in the 2-year
post-use observation period demonstrated partial recovery of BMD.
Table 3. Mean Percent Change from Baseline in BMD in Adolescents by Skeletal
Site and Cohort
Duration of Treatment
Depo-Provera CI
(150 mg IM)
Unmatched, Untreated
Cohort
N
Mean % Change
N
Mean % Change
Total Hip BMD
Week 60 (1.2 years)
Week 144 (2.8 years)
Week 240 (4.6 years)
103
45
9
-2.82
-6.16
-6.92
171
111
69
1.32
1.74
1.12
Femoral Neck BMD
Week 60
Week 144
Week 240
103
45
9
-3.05
-6.01
-6.06
171
111
69
1.87
2.54
1.45
Lumbar Spine BMD
Week 60
Week 144
Week 240
104
46
9
-2.42
-2.78
-4.17
171
111
70
3.47
5.41
5.12
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7
2. Bleeding Irregularities
Most women using DEPO-PROVERA CI experience disruption of menstrual bleeding
patterns. Altered menstrual bleeding patterns include irregular or unpredictable
bleeding or spotting, or rarely, heavy or continuous bleeding. If abnormal bleeding
persists or is severe, appropriate investigation should be instituted to rule out the
possibility of organic pathology, and appropriate treatment should be instituted when
necessary.
As women continue using DEPO-PROVERA CI, fewer experience irregular
bleeding and more experience amenorrhea. By month 12 amenorrhea was reported by
55% of women, and by month 24 amenorrhea was reported by 68% of women using
DEPO-PROVERA CI.2
3. Cancer Risks
Long-term case-controlled surveillance of users of DEPO-PROVERA CI found slight or
no increased overall risk of breast cancer3 and no overall increased risk of ovarian,4
liver,5 or cervical6 cancer and a prolonged, protective effect of reducing the risk of
endometrial7 cancer in the population of users.
A pooled analysis14 from two case-control studies, the World Health
Organization Study3 and the New Zealand Study13, reported the relative risk (RR) of
breast cancer for women who had ever used DEPO-PROVERA CI as 1.1 (95%
confidence interval (CI) 0.97 to 1.4). Overall, there was no increase in risk with
increasing duration of use of DEPO-PROVERA CI. The RR of breast cancer for women
of all ages who had initiated use of DEPO-PROVERA CI within the previous 5 years
was estimated to be 2.0 (95% CI 1.5 to 2.8).
The World Health Organization Study3, a component of the pooled analysis14
described above, showed an increased RR of 2.19 (95% CI 1.23 to 3.89) of breast
cancer associated with use of DEPO-PROVERA CI in women whose first exposure to
drug was within the previous 4 years and who were under 35 years of age. However,
the overall RR for ever-users of DEPO-PROVERA CI was only 1.2 (95% CI 0.96 to
1.52).
[NOTE: A RR of 1.0 indicates neither an increased nor a decreased risk of
cancer associated with the use of the drug, relative to no use of the drug. In the case of
the subpopulation with a RR of 2.19, the 95% CI is fairly wide and does not include the
value of 1.0, thus inferring an increased risk of breast cancer in the defined subgroup
relative to nonusers. The value of 2.19 means that women whose first exposure to drug
was within the previous 4 years and who are under 35 years of age have a 2.19 fold
(95% CI 1.23 to 3.89-fold) increased risk of breast cancer relative to nonusers. The
National Cancer Institute8 reports an average annual incidence rate for breast cancer for
US women, all races, age 30 to 34 years of 26.7 per 100,000. A RR of 2.19, thus,
increases the possible risk from 26.7 to 58.5 cases per 100,000 women. The attributable
risk, thus, is 31.8 per 100,000 women per year.]
A statistically insignificant increase in RR estimates of invasive squamous-cell
cervical cancer has been associated with the use of DEPO-PROVERA CI in women
who were first exposed before the age of 35 years (RR 1.22 to 1.28 and 95% CI 0.93 to
1.70). The overall, nonsignificant relative rate of invasive squamous-cell cervical
cancer in women who ever used DEPO-PROVERA CI was estimated to be 1.11 (95%
CI 0.96 to 1.29). No trends in risk with duration of use or times since initial or most
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8
recent exposure were observed.
4. Thromboembolic Disorders
The physician should be alert to the earliest manifestations of thrombotic disorders
(thrombophlebitis, pulmonary embolism, cerebrovascular disorders, and retinal
thrombosis). Should any of these occur or be suspected, the drug should not be
readministered.
5. Ocular Disorders
Medication should not be readministered pending examination if there is a sudden partial
or complete loss of vision or if there is a sudden onset of proptosis, diplopia, or migraine.
If examination reveals papilledema or retinal vascular lesions, medication should not be
readministered.
6. Unexpected Pregnancies
To ensure that DEPO-PROVERA CI is not administered inadvertently to a pregnant
woman, the first injection must be given ONLY during the first 5 days of a normal
menstrual period; ONLY within the first 5-days postpartum if not breast-feeding, and if
exclusively breast-feeding, ONLY at the sixth postpartum week (see DOSAGE AND
ADMINISTRATION).
Neonates from unexpected pregnancies that occur 1 to 2 months after injection of
DEPO-PROVERA CI may be at an increased risk of low birth weight, which, in turn, is
associated with an increased risk of neonatal death. The attributable risk is low because
such pregnancies are uncommon.9,10
A significant increase in incidence of polysyndactyly and chromosomal anomalies
was observed among infants of users of DEPO-PROVERA CI, the former being most
pronounced in women under 30 years of age. The unrelated nature of these defects, the
lack of confirmation from other studies, the distant preconceptual exposure to DEPO-
PROVERA CI, and the chance effects due to multiple statistical comparisons, make a
causal association unlikely.11
Neonates exposed to medroxyprogesterone acetate in utero and followed to
adolescence, showed no evidence of any adverse effects on their health including their
physical, intellectual, sexual, or social development.
Several reports suggest an association between intrauterine exposure to
progestational drugs in the first trimester of pregnancy and genital abnormalities in male
and female fetuses. The risk of hypospadias (five to eight per 1,000 male births in the
general population) may be approximately doubled with exposure to these drugs. There
are insufficient data to quantify the risk to exposed female fetuses, but because some of
these drugs induce mild virilization of the external genitalia of the female fetus and
because of the increased association of hypospadias in the male fetus, it is prudent to
avoid the use of these drugs during the first trimester of pregnancy.
To ensure that DEPO-PROVERA CI is not administered inadvertently to a
pregnant woman, it is important that the first injection be given only during the first 5
days after the onset of a normal menstrual period within 5 days postpartum if not breast-
feeding and if breast-feeding, at the sixth week postpartum (see DOSAGE AND
ADMINISTRATION).
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9
7. Ectopic Pregnancy
Health-care providers should be alert to the possibility of an ectopic pregnancy among
women using DEPO-PROVERA CI who become pregnant or complain of severe
abdominal pain.
8. Lactation
Detectable amounts of drug have been identified in the milk of mothers receiving DEPO-
PROVERA CI. In nursing mothers treated with DEPO-PROVERA CI, milk composition,
quality, and amount are not adversely affected. Neonates and infants exposed to
medroxyprogesterone from breast milk have been studied for developmental and
behavioral effects through puberty. No adverse effects have been noted.
9. Anaphylaxis and Anaphylactoid Reaction
Anaphylaxis and anaphylactoid reaction have been reported with the use of DEPO-
PROVERA CI. If an anaphylactic reaction occurs appropriate therapy should be
instituted. Serious anaphylactic reactions require emergency medical treatment.
PRECAUTIONS
GENERAL
1. Physical Examination
It is good medical practice for all women to have annual history and physical
examinations, including women using DEPO-PROVERA CI. The physical examination,
however, may be deferred until after initiation of DEPO PROVERA CI if requested by
the woman and judged appropriate by the clinician. The physical examination should
include special reference to blood pressure, breasts, abdomen and pelvic organs,
including cervical cytology and relevant laboratory tests. In case of undiagnosed,
persistent or recurrent abnormal vaginal bleeding, appropriate measures should be
conducted to rule out malignancy. Women with a strong family history of breast cancer
or who have breast nodules should be monitored with particular care.
2. Fluid Retention
Because progestational drugs may cause some degree of fluid retention, conditions that
might be influenced by this condition, such as epilepsy, migraine, asthma, and cardiac or
renal dysfunction, require careful observation.
3. Weight Changes
There is a tendency for women to gain weight while on therapy with DEPO-PROVERA
CI. From an initial average body weight of 136 lb, women who completed 1 year of
therapy with DEPO-PROVERA CI gained an average of 5.4 lb. Women who completed
2 years of therapy gained an average of 8.1 lb.
Women who completed 4 years gained an average of 13.8 lb. Women who
completed 6 years gained an average of 16.5 lb. Two percent of women withdrew from a
large-scale clinical trial because of excessive weight gain.
4. Return of Fertility
DEPO-PROVERA CI has a prolonged contraceptive effect. In a large US study of
women who discontinued use of DEPO-PROVERA CI to become pregnant, data are
available for 61% of them. Based on Life-Table analysis of these data, it is expected that
68% of women who do become pregnant may conceive within 12 months, 83% may
conceive within 15 months, and 93% may conceive within 18 months from the last
injection. The median time to conception for those who do conceive is 10 months
following the last injection with a range of 4 to 31 months, and is unrelated to the
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10
duration of use. No data are available for 39% of the patients who discontinued DEPO-
PROVERA CI to become pregnant and who were lost to follow-up or changed their
mind.
5. CNS Disorders and Convulsions
Patients who have a history of psychic depression should be carefully observed and the
drug not be readministered if the depression recurs.
There have been a few reported cases of convulsions in patients who were treated
with DEPO-PROVERA CI. Association with drug use or pre-existing conditions is not
clear.
6. Carbohydrate Metabolism
A decrease in glucose tolerance has been observed in some patients on DEPO-
PROVERA CI treatment. The mechanism of this decrease is obscure. For this reason,
diabetic patients should be carefully observed while receiving such therapy.
7. Liver Function
If jaundice develops, consideration should be given to not readministering the drug.
8. Protection Against Sexually Transmitted Diseases
Patients should be counseled that this product does not protect against HIV infection
(AIDS) and other sexually transmitted diseases.
DRUG INTERACTIONS
Aminoglutethimide administered concomitantly with the DEPO-PROVERA CI
may significantly depress the serum concentrations of medroxyprogesterone acetate.12
Users of DEPO-PROVERA CI should be warned of the possibility of decreased efficacy
with the use of this or any related drugs.
LABORATORY TEST INTERACTIONS
The pathologist should be advised of progestin therapy when relevant specimens
are submitted.
The following laboratory tests may be affected by progestins including DEPO-
PROVERA CI:
(a)
Plasma and urinary steroid levels are decreased (eg, progesterone,
estradiol, pregnanediol, testosterone, cortisol).
(b)
Gonadotropin levels are decreased.
(c)
Sex-hormone-binding-globulin concentrations are decreased.
(d)
Protein-bound iodine and butanol extractable protein-bound iodine may
increase.
T3-uptake values may decrease.
(e)
Coagulation test values for prothrombin (Factor II), and
Factors VII, VIII, IX, and X may increase.
(f)
Sulfobromophthalein and other liver function test values may be
increased.
(g)
The effects of medroxyprogesterone acetate on lipid metabolism are
inconsistent. Both increases and decreases in total cholesterol,
triglycerides, low-density lipoprotein (LDL) cholesterol, and high-
density lipoprotein (HDL) cholesterol have been observed in studies.
CARCINOGENESIS
See “WARNINGS” section 3.
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11
PREGNANCY
Pregnancy Category X. See “WARNINGS” section 6.
NURSING MOTHERS
See “WARNINGS” section 8.
PEDIATRIC USE
Depo-Provera CI is not indicated before menarche. Use of Depo-Provera CI is associated
with significant loss of BMD. This loss of BMD is of particular concern during
adolescence and early adulthood, a critical period of bone accretion. In adolescents,
interpretation of BMD results should take into account patient age and skeletal
maturity. It is unknown if use of Depo-Provera CI by younger women will reduce peak
bone mass and increase the risk of osteoporotic fractures in later life. Other than
concerns about loss of BMD, the safety and effectiveness are expected to be the same for
postmenarchal adolescents and adult women.
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12
INFORMATION FOR THE PATIENT
See Patient Labeling.
Patient labeling is included with each single-dose vial and prefilled syringe of
DEPO-PROVERA CI to help describe its characteristics to the patient. It is
recommended that prospective users be given this labeling and be informed about the
risks and benefits associated with the use of DEPO-PROVERA CI, as compared with
other forms of contraception or with no contraception at all. It is recommended that
physicians or other health-care providers responsible for those patients advise them at the
beginning of treatment that their menstrual cycle may be disrupted and that irregular and
unpredictable bleeding or spotting results, and that this usually decreases to the point of
amenorrhea as treatment with DEPO-PROVERA CI continues, without other therapy
being required.
ADVERSE REACTIONS
In the largest clinical trial with DEPO-PROVERA CI, over 3,900 women, who
were treated for up to 7 years, reported the following adverse reactions, which may or
may not be related to the use of DEPO-PROVERA CI.
The following adverse reactions were reported by more than 5% of subjects:
Menstrual irregularities (bleeding or amenorrhea, or both)
Abdominal pain or discomfort
Weight changes
Dizziness
Headache
Asthenia (weakness or fatigue)
Nervousness
Adverse reactions reported by 1% to 5% of subjects using DEPO-PROVERA
Contraceptive Injection were:
Decreased libido or anorgasmia
Pelvic pain
Backache
Breast pain
Leg cramps
No hair growth or alopecia
Depression
Bloating
Nausea
Rash
Insomnia
Edema
Leukorrhea
Hot flashes
Acne
Arthralgia
Vaginitis
Events reported by fewer than 1% of subjects included: galactorrhea, melasma,
chloasma, convulsions, changes in appetite, gastrointestinal disturbances, jaundice,
genitourinary infections, vaginal cysts, dyspareunia, paresthesia, chest pain, pulmonary
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13
embolus, allergic reactions, anemia, drowsiness, syncope, dyspnea and asthma,
tachycardia, fever, excessive sweating and body odor, dry skin, chills, increased libido,
excessive thirst, hoarseness, pain at injection site, blood dyscrasia, rectal bleeding,
changes in breast size, breast lumps or nipple bleeding, axillary swelling, breast cancer,
prevention of lactation, sensation of pregnancy, lack of return to fertility, paralysis,
facial palsy, scleroderma, osteoporosis, uterine hyperplasia, cervical cancer, varicose
veins, dysmenorrhea, hirsutism, unexpected pregnancy, thrombophlebitis, deep vein
thrombosis.
Postmarketing Experience
There have been rare cases of osteoporosis including osteoporotic fractures
reported postmarketing in patients taking Depo-Provera CI. In addition, there have been
voluntary reports of anaphylaxis and anaphylactoid reaction associated with the use of
Depo-Provera CI.
DOSAGE AND ADMINISTRATION
Both the 1 mL vial and the 1 mL prefilled syringe of DEPO-PROVERA CI
should be vigorously shaken just before use to ensure that the dose being administered
represents a uniform suspension.
The recommended dose is 150 mg of DEPO-PROVERA CI every 3 months (13
weeks) administered by deep, IM injection in the gluteal or deltoid muscle. To ensure
the patient is not pregnant at the time of the first injection, the first injection MUST be
given ONLY during the first 5 days of a normal menstrual period; ONLY within the
first 5-days postpartum if not breast-feeding; and if exclusively breast-feeding, ONLY at
the sixth postpartum week. If the time interval between injections is greater than 13
weeks, the physician should determine that the patient is not pregnant before
administering the drug. The efficacy of DEPO-PROVERA CI depends on adherence to
the dosage schedule of administration.
HOW SUPPLIED
DEPO-PROVERA CI (medroxyprogesterone acetate sterile aqueous suspension
150 mg/mL) is available as:
NDC 0009-0746-30
1 mL vial
NDC 0009-0746-35
25 x 1 mL vials
NDC 0009-7376-01
1 mL prefilled syringe
NDC 0009-7376-02
6 x 1 mL prefilled syringes
NDC 0009-7376-03
24 x 1 mL prefilled syringes
DEPO-PROVERA CI prefilled syringes are available packaged with 22-gauge x 1
1/2 inch BD SafetyGlideTM Needles in the following presentations:
NDC 0009-7376-04
1 mL prefilled syringe
NDC 0009-7376-05
6 x 1 mL prefilled syringes
NDC 0009-7376-06
24 x 1 mL prefilled syringes
Store at controlled room temperature 20° to 25°C (68° to 77°F) [see USP].
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For current labeling information, please visit https://www.fda.gov/drugsatfda
14
REFERENCES
1. Trussell J, Hatcher RA, Cates W Jr, Stewart FH, Kost K. A guide to interpreting
contraceptive efficacy studies. Obstet Gynecol. 1990; 76:558-567.
2. Schwallie PC, Assenzo JR. Contraceptive use-efficacy study utilizing
medroxyprogesterone acetate administered as an intramuscular injection once every
90 days. Fertil Steril. 1973; 24:331-339.
3. WHO Collaborative Study of Neoplasia and Steroid Contraceptives. Breast cancer and
depot-medroxyprogesterone acetate: a multi-national study. Lancet. 1991; 338:833-
838.
4. WHO Collaborative Study of Neoplasia and Steroid Contraceptives. Depot-
medroxyprogesterone acetate (DMPA) and risk of epithelial ovarian cancer. Int J
Cancer. 1991; 49:191-195.
5. WHO Collaborative Study of Neoplasia and Steroid Contraceptives. Depot-
medroxyprogesterone acetate (DMPA) and risk of liver cancer. Int J Cancer. 1991;
49:182185.
6. WHO Collaborative Study of Neoplasia and Steroid Contraceptives. Depot-
medroxyprogesterone acetate (DMPA) and risk of invasive squamous-cell cervical
cancer. Contraception. 1992; 45:299-312.
7. WHO Collaborative Study of Neoplasia and Steroid Contraceptives. Depot-
medroxyprogesterone acetate (DMPA) and risk of endometrial cancer. Int J Cancer.
1991; 49:186-190.
8. Surveillance, Epidemiology, and End Results: Incidence and Mortality Data, 1973-
1977. National Cancer Institute Monograph, 57: June 1981. (NIH publication No. 81-
2330).
9. Gray RH, Pardthaisong T. In Utero exposure to steroid contraceptives and survival
during infancy. Am J Epidemiol. 1991; 134:804-811.
10. Pardthaisong T, Gray RH. In Utero exposure to steroid contraceptives and outcome
of pregnancy. Am J Epidemiol. 1991; 134:795-803.
11. Pardthaisong T, Gray RH, McDaniel EB, Chandacham A. Steroid contraceptive use
and pregnancy outcome. Teratology. 1988; 38:51-58.
12. Van Deijk WA, Biljham GH, Mellink WAM, Meulenberg PMM. Influence of
aminoglutethimide on plasma levels of medroxyprogesterone acetate: its correlation
with serum cortisol. Cancer Treatment Reports. 1985; 69:1, 85-90.
13. Paul C, Skegg DCG, Spears GFS. Depot medroxyprogesterone (Depo-Provera) and
risk of breast cancer. Br Med J. 1989; 299:759-762.
14. Skegg DCG, Noonan EA, Paul C, Spears GFS, Meirik O, Thomas DB. Depot
Medroxyprogesterone Acetate and Breast Cancer: A Pooled Analysis from the World
Health Organization and New Zealand Studies. JAMA. 1995; 273(10):799-804.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
15
Rx only
DEPO-PROVERA Contraceptive Injection 1 mL vials are manufactured by:
Pharmacia & Upjohn Company
Kalamazoo, MI 49001, USA
DEPO-PROVERA Contraceptive Injection 1 mL prefilled syringes are manufactured
by:
Pharmacia & Upjohn, N.V./S.A.
Puurs, Belgium
for:
Pharmacia & Upjohn Company
A subsidiary of Pharmacia Corporation
Kalamazoo, MI 49001, USA
LAB-0149-2.1
Revised November 2004
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
Patient Labeling
Use of Depo-Provera Contraceptive Injection may cause you to lose calcium stored
in your bones. The longer you use Depo-Provera Contraceptive Injection the more
calcium you are likely to lose. The calcium may not return completely once you stop
using Depo-Provera Contraceptive Injection.
Loss of calcium may cause weak, porous bones (osteoporosis) that could increase the
risk that your bones might break, especially after menopause. It is not known
whether your risk of developing osteoporosis may be greater if you are a teenager
when you start to use Depo-Provera Contraceptive Injection.
You should use Depo-Provera Contraceptive Injection long term (for example, more
than two years) only if other methods of birth control are not right for you. (See
“Risks of Using Depo-Provera Contraceptive Injection”)
This product is intended to prevent pregnancy. It does not protect against HIV
infection (AIDS) and other sexually transmitted diseases.
Introduction
Every woman who considers using DEPO-PROVERA Contraceptive Injection
needs to understand the benefits and risks of this form of birth control and to discuss
them with her health-care provider. This leaflet is intended to give you much of the
information you will need in order to decide if DEPO-PROVERA Contraceptive
Injection is the right choice for you. Your health-care provider will help you to compare
DEPO-PROVERA Contraceptive Injection with other contraceptive methods and will
answer any questions you have after you have read this information.
DEPO-PROVERA Contraceptive Injection is given as an intramuscular injection
(a shot) in the buttock or upper arm once every 3 months (13 weeks). Promptly at the end
of the 3-month interval, you will need to return to your health-care provider for your next
injection in order to continue your contraceptive protection.
DEPO-PROVERA Contraceptive
Injection
contains medroxyprogesterone
acetate, a chemical similar to (but not the same as) the natural hormone progesterone that
is produced by your ovaries during the second half of your menstrual cycle. DEPO-
PROVERA Contraceptive Injection acts by preventing your egg cells from ripening. If an
egg is not released from the ovaries during your menstrual cycle, it cannot become
fertilized by sperm and result in pregnancy. DEPO-PROVERA Contraceptive Injection
also causes changes in the lining of your uterus that make it less likely for pregnancy to
occur.
Effectiveness of DEPO-PROVERA Contraceptive Injection
To ensure that DEPO-PROVERA Contraceptive Injection is not administered
inadvertently to a pregnant woman, the first injection must be given ONLY during the
first 5 days of a normal menstrual period; ONLY within the first 5-days postpartum if not
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2
breast-feeding, and if exclusively breast-feeding, ONLY at the sixth postpartum week
(see Administration of DEPO-PROVERA Contraceptive Injection). The efficacy of
DEPO-PROVERA Contraceptive Injection depends on adherence to the recommended
dosage schedule.
DEPO-PROVERA Contraceptive Injection is over 99% effective, making it one
of the most reliable methods of birth control available. This means that the average
annual pregnancy rate is less than one for every 100 women who use DEPO-PROVERA
Contraceptive Injection. The effectiveness of most contraceptive methods depends, in
part, on how reliably each woman uses the method. The effectiveness of DEPO-
PROVERA Contraceptive Injection depends only on the patient returning every 3 months
(13 weeks) for her next injection.
The following table shows the percent of women who become pregnant while
using different kinds of contraceptive methods. It gives both the lowest expected rate of
pregnancy (the rate expected in women who use each method exactly as it should be
used) and the typical rate of pregnancy (which includes women who became pregnant
because they forgot to use their birth control or because they did not follow the directions
exactly).
Percent of Women Experiencing an Accidental Pregnancy in the First Year of
Continuous Use
Method
Lowest
Typical
DEPO-PROVERA
0.3
0.3
Implants (Norplant)
0.2*
0.2*
Female sterilization
0.2
0.4
Male sterilization
0.1
0.15
Oral contraceptives (pill)
—
3
Combined
0.1
—
Progestogen only
0.5
—
IUD
—
3
Progestasert
2
—
Copper T 380A
0.8
—
Condom (without spermicide)
2
12
Diaphragm (with spermicide)
6
18
Cervical cap
6
18
Withdrawal
4
18
Periodic abstinence
1-9
20
Spermicide alone
3
21
Vaginal sponge
—
—
used before childbirth
6
18
used after childbirth
9
28
No method
85
85
Source: Trussell et al; Obstet Gynecol 1990;76:558-567.
* From Norplant® package insert.
Who Should Not Use DEPO-PROVERA Contraceptive Injection
Certain women should not use DEPO-PROVERA Contraceptive Injection. You
should not use DEPO-PROVERA Contraceptive Injection if you have any of the
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
3
following conditions:
• if you think you might be pregnant
• if you have any vaginal bleeding without a known reason
• if you have had cancer of the breast
• if you have had a stroke
• if you have or have had blood clots (phlebitis) in your legs
• if you have problems with your liver or liver disease
• if you are allergic to DEPO-PROVERA Contraceptive Injection
(medroxyprogesterone acetate or any of its other ingredients)
Other Things to Consider Before Choosing DEPO-PROVERA Contraceptive
Injection
Before your doctor prescribes DEPO-PROVERA Contraceptive Injection, you
will have a physical examination. It is important to tell your doctor or health-care
provider if you have any of the following:
• a family history of cancer of the breast
• an abnormal mammogram (breast X-ray), fibrocystic breast disease, breast
nodules or lumps, or bleeding from your nipples
• kidney disease
• irregular or scanty menstrual periods
• high blood pressure
• migraine headaches
• asthma
• epilepsy (convulsions or seizures)
• diabetes or a family history of diabetes
• a history of depression
• if you are taking any prescription or over-the-counter medications
This product is intended to prevent pregnancy. It does not protect against transmission of
HIV (AIDS) and other sexually transmitted diseases such as chlamydia, genital herpes,
genital warts, gonorrhea, hepatitis B, and syphilis.
Return of Fertility
Because DEPO-PROVERA Contraceptive Injection is a long-acting birth control
method, it takes some time after your last injection for its effect to wear off. Based on the
results from a large study done in the United States, of those women who stop using
DEPO-PROVERA Contraceptive Injection in order to become pregnant, about half of
those who become pregnant do so in about 10 months after their last injection; about two-
thirds of those who become pregnant do so in about 12 months, about 83% of those who
become pregnant do so in about 15 months, and about 93% of those who become
pregnant do so in about 18 months after their last injection. The length of time you use
DEPO-PROVERA Contraceptive Injection has no effect on how long it takes you to
become pregnant after you stop using it.
Risks of Using DEPO-PROVERA Contraceptive Injection
1. Losing Calcium from Your Bones
Depo-Provera CI use may decrease the amount of calcium in your bones. The longer
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
4
you are on Depo-Provera CI the more calcium you may lose. This increases the risk of
your bones weakening if you use Depo-Provera CI continuously for a long time (for more
than 2 years). The loss of calcium may increase your risk of osteoporosis and broken
bones, particularly after your menopause.
Calcium is generally added to the bones during teenage years. The decrease of calcium
in your bones is of most concern if you are a teenager or have the following risk factors:
-
bone disease
-
anorexia nervosa (an eating disorder)
-
a strong family history of osteoporosis
-
drug use that can lower the amount of calcium in bones (drugs for epilepsy or
steroids), or
-
drinking a lot of alcohol or smoking a lot.
If you need a birth control method for more than 2 years, your healthcare provider may
ask you to switch to another birth control method or ask you to have a test of your bones
before continuing Depo-Provera CI, especially if you have other risks for weak bones.
When Depo-Provera CI is stopped, the calcium in bones begins to come back. Your
healthcare provider may tell you take calcium and Vitamin D as this may lessen the loss
of calcium from your bones.
2. Irregular Menstrual Bleeding
The side effect reported most frequently by women who use DEPO-PROVERA
Contraceptive Injection for contraception is a change in their normal menstrual cycle.
During the first year of using DEPO-PROVERA Contraceptive Injection, you might have
one or more of the following changes:
• irregular or unpredictable bleeding or spotting,
• an increase or decrease in menstrual bleeding, or
• no bleeding at all.
Unusually heavy or continuous bleeding, however, is not a usual effect of DEPO-
PROVERA Contraceptive Injection and if this happens you should see your health-care
provider right away.
With continued use of DEPO-PROVERA Contraceptive Injection, bleeding
usually decreases and many women stop having periods completely. In clinical studies of
DEPO-PROVERA Contraceptive Injection, 55% of the women studied reported no
menstrual bleeding (amenorrhea) after 1 year of use and 68% of the women studied
reported no menstrual bleeding after 2 years of use.
The reason that your periods stop is because DEPO-PROVERA Contraceptive
Injection causes a resting state in your ovaries. When your ovaries do not release an egg
monthly, the regular monthly growth of the lining of your uterus does not occur and,
therefore, the bleeding that comes with your normal menstruation does not take place.
When you stop using DEPO-PROVERA Contraceptive Injection your menstrual period
will usually, in time, return to its normal cycle.
3. Cancer
Studies of women who have used different forms of contraception found that women who
used DEPO-PROVERA Contraceptive Injection for contraception had no increased
overall risk of developing cancer of the breast, ovary, uterus, cervix, or liver. However,
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5
women under 35 years of age whose first exposure to DEPO-PROVERA Contraceptive
Injection was within the previous 4 to 5 years may have a slightly increased risk of
developing breast cancer similar to that seen with oral contraceptives. You should discuss
this with your health-care provider.
4. Unexpected Pregnancy
Because DEPO-PROVERA Contraceptive Injection is such an effective contraceptive
method, the risk of unexpected pregnancy for women who get their shots regularly (every
3 months [13 weeks] ) is very low. While there have been reports of an increased risk of
low birth weight and neonatal infant death or other health problems in infants conceived
close to the time of injection, such pregnancies are uncommon. If you think you may
have become pregnant while using DEPO-PROVERA Contraceptive Injection for
contraception, see your health-care provider as soon as possible.
5. Allergic Reactions
Severe allergic reactions known as anaphylaxis and anaphylactoid reactions have also
been reported in some women using DEPO-PROVERA Contraceptive Injection.
6. Other Risks
Women who use hormone-based contraceptives may have an increased risk of blood clots
or stroke. Also, if a contraceptive method fails, there is a possibility that the fertilized egg
will begin to develop outside of the uterus (ectopic pregnancy). While these events are
rare, you should tell your health-care provider if you have any of the Warning Signals
listed in the next section.
Warning Signals
If any of these problems occur following an injection of DEPO-PROVERA
Contraceptive Injection, call your healthcare provider immediately:
• Sharp chest pain, coughing up of blood, or sudden shortness of breath (indicating
a possible clot in the lung)
• Sudden severe headache or vomiting, dizziness or fainting, problems with your
eyesight or speech, weakness, or numbness in an arm or leg (indicating a possible
stroke)
• Severe pain or swelling in the calf (indicating a possible clot in the leg)
• Unusually heavy vaginal bleeding
• Severe pain or tenderness in the lower abdominal area
• Persistent pain, pus, or bleeding at the injection site
Side Effects of DEPO-PROVERA Contraceptive Injection
1. Weight Gain
You may experience a weight gain while you are using DEPO-PROVERA Contraceptive
Injection. About two-thirds of the women who used DEPO-PROVERA Contraceptive
Injection in the clinical trials reported a weight gain of about 5 pounds during the first
year of use. You may continue to gain weight after the first year. Women in one large
study who used DEPO-PROVERA Contraceptive Injection for 2 years gained an average
total of 8.1 pounds over those 2 years, or approximately 4 pounds per year. Women who
continued for 4 years gained an average total of 13.8 pounds over those 4 years, or
approximately 3.5 pounds per year. Women who continued for 6 years gained an average
total of 16.5 pounds over those 6 years, or approximately 2.75 pounds per year.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
6
2. Other Side Effects
In a clinical study of over 3,900 women who used DEPO-PROVERA Contraceptive
Injection for up to 7 years, some women reported the following effects that may or may
not have been related to their use of DEPO-PROVERA Contraceptive Injection:
• irregular menstrual bleeding
• amenorrhea
• headache
• nervousness
• abdominal cramps
• dizziness
• weakness or fatigue
• decreased sexual desire
• leg cramps
• nausea
• vaginal discharge or irritation
• breast swelling and tenderness
• bloating
• swelling of the hands or feet
• backache
• depression
• insomnia
• acne
• pelvic pain
• no hair growth or excessive hair
loss
• rash
• hot flashes
• joint pain
Other problems were reported by very few of the women in the clinical trials, but
some of these could be serious. These include: convulsions, jaundice, urinary tract
infections, allergic reactions, fainting, paralysis, osteoporosis, lack of return to fertility,
deep vein thrombosis, pulmonary embolus, breast cancer, or cervical cancer. If these or
any other problems occur during your use of DEPO-PROVERA Contraceptive Injection,
discuss them with your health-care provider.
General Precautions
1. Missed Periods
During the time you are using DEPO-PROVERA Contraceptive Injection for
contraception, you may skip a period, or your periods may stop completely. If you have
been receiving your injection of DEPO-PROVERA Contraceptive Injection regularly
every 3 months (13 weeks), then you are probably not pregnant. However, if you think
that you may be pregnant, see your health-care provider.
2. Laboratory Test Interactions
If you are scheduled for any laboratory tests, tell your health-care provider that you are
using DEPO-PROVERA Contraceptive Injection for contraception. Certain blood tests
are affected by hormones such as DEPO-PROVERA Contraceptive Injection.
3. Drug Interactions
Cytadren (aminoglutethimide) is an anticancer drug that
may significantly decrease the effectiveness of DEPOPROVERA Contraceptive Injection
if the two drugs are given during the same time.
4. Nursing Mothers
Although DEPO-PROVERA Contraceptive Injection can be passed to the nursing infant
in the breast milk, no harmful effects have been found in these children. DEPO-
PROVERA Contraceptive Injection does not prevent the breasts from producing milk, so
it can be used by nursing mothers. However, to minimize the amount of DEPO-
PROVERA Contraceptive Injection that is passed to the infant in the first weeks after
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
7
birth, you should wait until 6 weeks after childbirth before you start using DEPO-
PROVERA Contraceptive Injection for contraception.
Administration of DEPO-PROVERA Contraceptive Injection
The recommended dose of DEPO-PROVERA Contraceptive Injection is 150 mg
every 3 months (13 weeks) given in a single intramuscular injection in the buttock or
upper arm. To ensure that you are not pregnant at the time of the first injection, it is
essential that the injection be given ONLY during the first 5 days of a normal menstrual
period. If used following the delivery of a child, the first injection of DEPO-PROVERA
Contraceptive Injection MUST be given within 5 days after childbirth if you are not
breast-feeding, or if you are exclusively breast-feeding, the injection MUST be given 6
weeks after childbirth. If you wait longer than 3 months (13 weeks) between injections,
or longer than 6 weeks after delivery, your health-care provider should determine that
you are not pregnant before giving you your injection of DEPO-PROVERA
Contraceptive Injection.
Rx only
Pharmacia & Upjohn Company
A subsidiary of Pharmacia Corporation
Kalamazoo, MI 49001, USA
Revised October 2004
815 463 612
692819
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:47:13.657262
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/020246s013lbl.pdf', 'application_number': 20246, 'submission_type': 'SUPPL ', 'submission_number': 13}
|
12,369
|
5R4606
15
Depo-Provera®
Contraceptive Injection
Patients should be counseled that this product does not protect against HIV infection (AIDS) and other sexually
transmitted diseases.
DESCRIPTION
DEPO-PROVERA Contraceptive Injection contains medroxyprogesterone acetate, a derivative of progesterone, as its active
ingredient. Medroxyprogesterone acetate is active by the parenteral and oral routes of administration. It is a white to off-white,
odorless crystalline powder that is stable in air and that melts between 200° C and 210° C. It is freely soluble in chloroform,
soluble in acetone and dioxane, sparingly soluble in alcohol and methanol, slightly soluble in ether, and insoluble in water.
The chemical name for medroxyprogesterone acetate is pregn-4-ene-3,20-dione, 17-(acetyloxy)-6-methyl-, (6α)-. The
structural formula is as follows:
medroxyprogesterone acetate
DEPO-PROVERA Contraceptive Injection for intramuscular (IM) injection is available in vials and prefilled syringes, each
containing 1 mL of medroxyprogesterone acetate sterile aqueous suspension 150 mg/mL.
Each mL contains:
Medroxyprogesterone acetate
150 mg
Polyethylene glycol 3350
28.9 mg
Polysorbate 80
2.41 mg
Sodium chloride
8.68 mg
Methylparaben
1.37 mg
Propylparaben
0.150 mg
Water for injection
qs
When necessary, pH is adjusted with sodium hydroxide or hydrochloric acid, or both.
CLINICAL PHARMACOLOGY
DEPO-PROVERA Contraceptive Injection (medroxyprogesterone acetate), when administered at the recommended dose to
women every 3 months, inhibits the secretion of gonadotropins which, in turn, prevents follicular maturation and ovulation
and results in endometrial thinning. These actions produce its contraceptive effect.
Following a single 150 mg IM dose of DEPO-PROVERA Contraceptive Injection, medroxyprogesterone acetate concentrations,
measured by an extracted radioimmunoassay procedure, increase for approximately 3 weeks to reach peak plasma
concentrations of 1 to 7 ng/mL. The levels then decrease exponentially until they become undetectable (< 100 pg/mL) between
120 to 200 days following injection. Using an unextracted radioimmunoassay procedure for the assay of medroxyprogesterone
acetate in serum, the apparent half-life for medroxyprogesterone acetate following IM administration of DEPO-PROVERA
Contraceptive Injection is approximately 50 days.
Women with lower body weights conceive sooner than women with higher body weights after discontinuing DEPO-PROVERA
medroxyprogesterone acetate injectable suspension, USP
Physician Information
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Layout and/or size adjusted for
ease of reading and printing.
Contraceptive Injection.
The effect of hepatic and/or renal disease on the pharmacokinetics of DEPO-PROVERA Contraceptive Injection is unknown.
INDICATIONS AND USAGE
DEPO-PROVERA Contraceptive Injection is indicated only for the prevention of pregnancy. To ensure that DEPO-PROVERA
Contraceptive Injection is not administered inadvertently to a pregnant woman, the first injection must be given ONLY during
the first 5 days of a normal menstrual period; ONLY within the first 5-days postpartum if not breast-feeding, and if exclusively
breast-feeding, ONLY at the sixth postpartum week. The efficacy of DEPO-PROVERA Contraceptive Injection depends on
adherence to the recommended dosage schedule (see DOSAGE AND ADMINISTRATION). It is a long-term injectable contraceptive
in women when administered at 3-month (13-week) intervals. Dosage does not need to be adjusted for body weight.
In five clinical studies using DEPO-PROVERA Contraceptive Injection, the 12-month failure rate for the group of women
treated with DEPO-PROVERA Contraceptive Injection was zero (no pregnancies reported) to 0.7 by Life-Table method.
Pregnancy rates with contraceptive measures are typically reported for only the first year of use as shown in Table 1. Except for
intrauterine devices (IUD), implants, sterilization, and DEPO-PROVERA Contraceptive Injection, the efficacy of these
contraceptive measures depends in part on the reliability of use. The effectiveness of DEPO-PROVERA Contraceptive Injection is
dependent on the patient returning every 3 months (13 weeks) for reinjection.
Table 1
Lowest Expected and Typical Failure Rates*
Expressed as Percent of Women Experiencing
an Accidental Pregnancy
in the First Year of Continuous Use
Lowest
Method
Expected
Typical
Injectable progestogen
DEPO-PROVERA
0.3
0.3
Implants
Norplant (6 capsules)
0.2 †
0.2 †
Female sterilization
0.2
0.4
Male sterilization
0.1
0.15
Pill
3
Combined
0.1
Progestogen only
0.5
IUD
3
Progestasert
2
Copper T 380A
0.8
Condom
2
12
Diaphragm
6
18
Cap
6
18
Spermicides
3
21
Sponge
Parous women
9
28
Nulliparous women
6
18
Periodic abstinence
1-9
20
Withdrawal
4
18
No method
85
85
Source: Trussell et al1
* Lowest expected - when used exactly as directed.
Typical - includes those not following directions exactly.
† from Norplant® package insert.
CONTRAINDICATIONS
1. Known or suspected pregnancy or as a diagnostic test for pregnancy.
2. Undiagnosed vaginal bleeding.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
3. Known or suspected malignancy of breast.
4. Active thrombophlebitis, or current or past history of thromboembolic disorders, or cerebral vascular disease.
5. Liver dysfunction or disease.
6. Known hypersensitivity to DEPO-PROVERA Contraceptive Injection (medroxyprogesterone acetate or any of its other
ingredients).
WARNINGS
1. Bleeding Irregularities
Most women using DEPO-PROVERA Contraceptive Injection experience disruption of menstrual bleeding patterns. Altered
menstrual bleeding patterns include irregular or unpredictable bleeding or spotting, or rarely, heavy or continuous bleeding. If
abnormal bleeding persists or is severe, appropriate investigation should be instituted to rule out the possibility of organic
pathology, and appropriate treatment should be instituted when necessary.
As women continue using DEPO-PROVERA Contraceptive Injection, fewer experience irregular bleeding and more experience
amenorrhea. By month 12 amenorrhea was reported by 55% of women, and by month 24 amenorrhea was reported by 68% of
women using DEPO-PROVERA Contraceptive Injection.2
2. Bone Mineral Density Changes
Use of DEPO-PROVERA Contraceptive Injection may be considered among the risk factors for development of osteoporosis. The
rate of bone loss is greatest in the early years of use and then subsequently approaches the normal rate of age related fall.
3. Cancer Risks
Long-term case-controlled surveillance of users of DEPO-PROVERA Contraceptive Injection found slight or no increased overall
risk of breast cancer3 and no overall increased risk of ovarian,4 liver,5 or cervical6 cancer and a prolonged, protective effect of
reducing the risk of endometrial7 cancer in the population of users.
A pooled analysis14 from two case-control studies, the World Health Organization Study3 and the New Zealand Study13,
reported the relative risk (RR) of breast cancer for women who had ever used DEPO-PROVERA Contraceptive Injection as
1.1 (95% confidence interval (CI) 0.97 to 1.4). Overall, there was no increase in risk with increasing duration of use of
DEPO-PROVERA Contraceptive Injection. The RR of breast cancer for women of all ages who had initiated use of DEPO-PROVERA
Contraceptive Injection within the previous 5 years was estimated to be 2.0 (95% CI 1.5 to 2.8). The World Health Organization
Study3, a component of the pooled analysis14 described above, showed an increased RR of 2.19 (95% CI 1.23 to 3.89) of breast
cancer associated with use of DEPO-PROVERA Contraceptive Injection in women whose first exposure to drug was within the
previous 4 years and who were under 35 years of age. However, the overall RR for ever-users of DEPO-PROVERA Contraceptive
Injection was only 1.2 (95% CI 0.96 to 1.52).
[NOTE: A RR of 1.0 indicates neither an increased nor a decreased risk of cancer associated with the use of the drug, relative
to no use of the drug. In the case of the subpopulation with a RR of 2.19, the 95% CI is fairly wide and does not include the
value of 1.0, thus inferring an increased risk of breast cancer in the defined subgroup relative to nonusers. The value of 2.19
means that women whose first exposure to drug was within the previous 4 years and who are under 35 years of age have a
2.19-fold (95% CI 1.23 to 3.89-fold) increased risk of breast cancer relative to nonusers. The National Cancer Institute8 reports an
average annual incidence rate for breast cancer for US women, all races, age 30 to 34 years of 26.7 per 100,000. A RR of 2.19,
thus, increases the possible risk from 26.7 to 58.5 cases per 100,000 women. The attributable risk, thus, is 31.8 per 100,000
women per year.]
A statistically insignificant increase in RR estimates of invasive squamous-cell cervical cancer has been associated with the use
of DEPO-PROVERA Contraceptive Injection in women who were first exposed before the age of 35 years (RR 1.22 to 1.28 and
95% CI 0.93 to 1.70). The overall, nonsignificant relative rate of invasive squamous-cell cervical cancer in women who ever used
DEPO-PROVERA Contraceptive Injection was estimated to be 1.11 (95% CI 0.96 to 1.29). No trends in risk with duration of use or
times since initial or most recent exposure were observed.
4. Thromboembolic Disorders
The physician should be alert to the earliest manifestations of thrombotic disorders (thrombophlebitis, pulmonary embolism,
cerebrovascular disorders, and retinal thrombosis). Should any of these occur or be suspected, the drug should not be
readministered.
5. Ocular Disorders
Medication should not be readministered pending examination if there is a sudden partial or complete loss of vision or if there
is a sudden onset of proptosis, diplopia, or migraine. If examination reveals papilledema or retinal vascular lesions, medication
should not be readministered.
6. Unexpected Pregnancies
To ensure that DEPO-PROVERA Contraceptive Injection is not administered inadvertently to a pregnant woman, the first
injection must be given ONLY during the first 5 days of a normal menstrual period; ONLY within the first 5-days postpartum if
not breast-feeding, and if exclusively breast-feeding, ONLY at the sixth postpartum week (see DOSAGE AND ADMINISTRATION).
Neonates from unexpected pregnancies that occur 1 to 2 months after injection of DEPO-PROVERA Contraceptive Injection
may be at an increased risk of low birth weight, which, in turn, is associated with an increased risk of neonatal death. The
attributable risk is low because such pregnancies are uncommon.9,10
A significant increase in incidence of polysyndactyly and chromosomal anomalies was observed among infants of users of
DEPO-PROVERA Contraceptive Injection, the former being most pronounced in women under 30 years of age. The unrelated
nature of these defects, the lack of confirmation from other studies, the distant preconceptual exposure to DEPO-PROVERA
Contraceptive Injection, and the chance effects due to multiple statistical comparisons, make a causal association unlikely.11
Neonates exposed to medroxyprogesterone acetate in utero and followed to adolescence, showed no evidence of any
adverse effects on their health including their physical, intellectual, sexual, or social development.
Several reports suggest an association between intrauterine exposure to progestational drugs in the first trimester of
pregnancy and genital abnormalities in male and female fetuses. The risk of hypospadias (five to eight per 1,000 male births in
the general population) may be approximately doubled with exposure to these drugs. There are insufficient data to quantify the
risk to exposed female fetuses, but because some of these drugs induce mild virilization of the external genitalia of the female
fetus and because of the increased association of hypospadias in the male fetus, it is prudent to avoid the use of these drugs
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
during the first trimester of pregnancy.
To ensure that DEPO-PROVERA Contraceptive Injection is not administered inadvertently to a pregnant woman, it is important
that the first injection be given only during the first 5 days after the onset of a normal menstrual period within 5 days
postpartum if not breast-feeding and if breast-feeding, at the sixth week postpartum (see DOSAGE AND ADMINISTRATION).
7. Ectopic Pregnancy
Health-care providers should be alert to the possibility of an ectopic pregnancy among women using DEPO-PROVERA
Contraceptive Injection who become pregnant or complain of severe abdominal pain.
8. Lactation
Detectable amounts of drug have been identified in the milk of mothers receiving DEPO-PROVERA Contraceptive Injection. In
nursing mothers treated with DEPO-PROVERA Contraceptive Injection, milk composition, quality, and amount are not adversely
affected. Neonates and infants exposed to medroxyprogesterone from breast milk have been studied for developmental and
behavioral effects through puberty. No adverse effects have been noted.
9. Anaphylaxis and Anaphylactoid Reaction
Anaphylaxis and anaphylactoid reaction have been reported with the use of DEPO-PROVERA Contraceptive Injection. If an
anaphylactic reaction occurs appropriate therapy should be instituted. Serious anaphylactic reactions require emergency
medical treatment.
PRECAUTIONS
GENERAL
1. Physical Examination
It is good medical practice for all women to have annual history and physical examinations, including women using
DEPO-PROVERA Contraceptive Injection. The physical examination, however, may be deferred until after initation of
DEPO-PROVERA if requested by the woman and judged appropriate by the clinician. The physical examination should include
special reference to blood pressure, breasts, abdomen and pelvic organs, including cervical cytology and relevant labortory
tests. In case of undiagnosed, persistent or recurrent abnormal vaginal bleeding, appropriate measures should be conducted to
rule out malignancy. Women with a strong family history of breast cancer or who have breast nodules should be monitored
with particular care.
2. Fluid Retention
Because progestational drugs may cause some degree of fluid retention, conditions that might be influenced by this condition,
such as epilepsy, migraine, asthma, and cardiac or renal dysfunction, require careful observation.
3. Weight Changes
There is a tendency for women to gain weight while on therapy with DEPO-PROVERA Contraceptive Injection. From an initial
average body weight of 136 lb, women who compled 1 year of therapy with DEPO-PROVERA Contraceptive Injection gained an
average of 5.4 lb. Women who completed 2 years of therapy gained an average of 8.1 lb.
Women who completed 4 years gained an average of 13.8 lb. Women who completed 6 years gained an average of 16.5 lb.
Two percent of women withdrew from a large-scale clinical trial because of excessive weight gain.
4. Return of Fertility
DEPO-PROVERA Contraceptive Injection has a prolonged contraceptive effect. In a large US study of women who discontinued
use of DEPO-PROVERA Contraceptive Injection to become pregnant, data are available for 61% of them. Based on Life-Table
analysis of these data, it is expected that 68% of women who do become pregnant may conceive within 12 months, 83% may
conceive within 15 months, and 93% may conceive within 18 months from the last injection. The median time to conception
for those who do conceive is 10 months following the last injection with a range of 4 to 31 months, and is unrelated to the
duration of use. No data are available for 39% of the patients who discontinued DEPO-PROVERA Contraceptive Injection to
become pregnant and who were lost to follow-up or changed their mind.
5. CNS Disorders and Convulsions
Patients who have a history of psychic depression should be carefully observed and the drug not be readministered if the
depression recurs.
There have been a few reported cases of convulsions in patients who were treated with DEPO-PROVERA Contraceptive
Injection. Association with drug use or pre-existing conditions is not clear.
6. Carbohydrate Metabolism
A decrease in glucose tolerance has been observed in some patients on DEPO-PROVERA Contraceptive Injection treatment. The
mechanism of this decrease is obscure. For this reason, diabetic patients should be carefully observed while receiving such
therapy.
7. Liver Function
If jaundice develops, consideration should be given to not readministering the drug.
8. Protection Against Sexually Transmitted Diseases
Patients should be counseled that this product does not protect against HIV infection (AIDS) and other sexually transmitted
diseases.
DRUG INTERACTIONS
Aminoglutethimide administered concomitantly with the DEPO-PROVERA Contraceptive Injection may significantly depress
the serum concentrations of medroxyprogesterone acetate.12 Users of DEPO-PROVERA Contraceptive Injection should be
warned of the possibility of decreased efficacy with the use of this or any related drugs.
Depo-Provera®
Contraceptive Injection
medroxyprogesterone acetate injectable suspension, USP
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
LABORATORY TEST INTERACTIONS
The pathologist should be advised of progestin therapy when relevant specimens are submitted.
The following laboratory tests may be affected by progestins including DEPO-PROVERA Contraceptive Injection:
(a) Plasma and urinary steroid levels are decreased (eg, progesterone, estradiol, pregnanediol, testosterone, cortisol).
(b)Gonadotropin levels are decreased.
(c) Sex-hormone-binding-globulin concentrations are decreased.
(d)Protein-bound iodine and butanol extractable protein-bound iodine may increase.
T3-uptake values may decrease.
(e) Coagulation test values for prothrombin (Factor II), and Factors VII, VIII, IX, and X may increase.
(f) Sulfobromophthalein and other liver function test values may be increased.
(g)The effects of medroxyprogesterone acetate on lipid metabolism are inconsistent. Both increases and decreases in total
colesterol, triglycerides, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol have been
observed in studies.
CARCINOGENESIS
See "WARNINGS" section 3.
PREGNANCY
Pregnancy Category X. See "WARNINGS" section 6.
NURSING MOTHERS
See "WARNINGS" section 8.
PEDIATRIC USE
Saftey and effectiveness in pediatric patients have not been established. See "WARNINGS" section 6.
INFORMATION FOR THE PATIENT
See Patient Labeling.
Patient labeling is included with each single-dose vial of DEPO-PROVERA Contraceptive Injection to help describe its
characteristics to the patient. It is recommended that prospective users be given this labeling and be informed about the risks
and benefits associated with the use of DEPO-PROVERA Contraceptive Injection, as compared with other forms of
contraception or with no contraception at all. It is recommended that physicians or other health-care providers responsible for
those patients advise them at the beginning of treatment that their menstrual cycle may be disrupted and that irregular and
unpredictable bleeding or spotting results, and that this usually decreases to the point of amenorrhea as treatment with
DEPO-PROVERA Contraceptive Injection continues, without other therapy being required.
ADVERSE REACTIONS
In the largest clinical trial with DEPO-PROVERA Contraceptive Injection, over 3,900 women, who were treated for up to
7 years, reported the following adverse reactions, which may or may not be related to the use of DEPO-PROVERA Contraceptive
Injection.
The following adverse reactions were reported by more than 5% of subjects:
Menstrual irregularities (bleeding or amenorrhea, or both)
Abdominal pain or discomfort
Weight changes
Dizziness
Headache
Asthenia (weakness or fatigue)
Nervousness
Adverse reactions reported by 1% to 5% of subjects using DEPO-PROVERA Contraceptive Injection were:
Decreased libido or anorgasmia
Pelvic pain
Backache
Breast pain
Leg cramps
No hair growth or alopecia
Depression
Bloating
Nausea
Rash
Insomnia
Edema
Leukorrhea
Hot flashes
Acne
Arthralgia
Vaginitis
Events reported by fewer than 1% of subjects included: galactorrhea, melasma, chloasma, convulsions, changes in appetite,
gastrointestinal disturbances, jaundice, genitourinary infections, vaginal cysts, dyspareunia, paresthesia, chest pain, pulmonary
embolus, allergic reactions, anemia, drowsiness, syncope, dyspnea and asthma, tachycardia, fever, excessive sweating and body
odor, dry skin, chills, increased libido, excessive thirst, hoarseness, pain at injection site, blood dyscrasia, rectal bleeding,
changes in breast size, breast lumps or nipple bleeding, axillary swelling, breast cancer, prevention of lactation, sensation of
pregnancy, lack of return to fertility, paralysis, facial palsy, scleroderma, osteoporosis, uterine hyperplasia, cervical cancer,
varicose veins, dysmenorrhea, hirsutism, unexpected pregnancy, thrombophlebitis, deep vein thrombosis.
In addition, voluntary reports have been received of anaphylaxis and anaphylactoid reaction with use of DEPO-PROVERA
Contraceptive Injection.
DOSAGE AND ADMINISTRATION
Both the 1 mL vial and the 1 mL prefilled syringe of DEPO-PROVERA Contraceptive Injection should be vigorously shaken just
before use to ensure that the dose being administered represents a uniform suspension.
The recommended dose is 150 mg of DEPO-PROVERA Contraceptive Injection every 3 months (13 weeks) administered by
deep, IM injection in the gluteal or deltoid muscle. To ensure the patient is not pregnant at the time of the first injection, the
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
first injection MUST be given ONLY during the first 5 days of a normal menstrual period; ONLY within the first 5-days
postpartum if not breast-feeding; and if exclusively breast-feeding, ONLY at the sixth postpartum week. If the time interval
between injections is greater than 13 weeks, the physician should determine that the patient is not pregnant before
administering the drug. The efficacy of DEPO-PROVERA Contraceptive Injection depends on adherence to the dosage schedule
of administration.
Instructions for using the BD SafetyGlide™ Needle*:
Hold syringe upright and remove protective cap. Attach the BD SafetyGlide™ Needle to the syringe barrel. Remove the
protective shield from the needle. Administer dose. Immediately after use, activate the needle protection device by pushing
the lever arm completely forward. Visually confirm that the lever arm has fully advanced and the needle tip is completely
covered. Discard appropriately.
HOW SUPPLIED
DEPO-PROVERA Contraceptive Injection (medroxyprogesterone acetate injectable suspension 150 mg/mL) is available as:
NDC 0009-0746-30
1 mL
vial
NDC 0009-0746-35
25 x 1 mL
vials
NDC 0009-7376-02
6 x 1 mL
prefilled syringes
NDC 0009-7376-03
24 x 1 mL
prefilled syringes
DEPO-PROVERA Contraceptive Injection prefilled syringes are available packaged with 22-gauge x 1 1/2 inch BD SafetyGlide™
Needles in the following presentations:
NDC 0009-7376-04
1 mL
prefilled syringe
NDC 0009-7376-05
6 x 1 mL
prefilled syringes
NDC 0009-7376-06
24 x 1 mL
prefilled syringes
Store at controlled room temperature 20° to 25° C (68° to 77° F)[see USP].
REFERENCES
1.
Trussell J, Hatcher RA, Cates W Jr, Stewart FH, Kost K. A guide to interpreting contraceptive efficacy studies. Obstet Gynecol.
1990; 76:558-567.
2.
Schwallie PC, Assenzo JR. Contraceptive use-efficacy study utilizing medroxyprogesterone acetate administered as an
intramuscular injection once every 90 days. Fertil Steril. 1973; 24:331-339.
3.
WHO Collaborative Study of Neoplasia and Steroid Contraceptives. Breast cancer and depot-medroxyprogesterone acetate: a
multi-national study. Lancet. 1991; 338:833-838.
4.
WHO Collaborative Study of Neoplasia and Steroid Contraceptives. Depot-medroxyprogesterone acetate (DMPA) and risk of
epithelial ovarian cancer. Int J Cancer. 1991; 49:191-195.
5.
WHO Collaborative Study of Neoplasia and Steroid Contraceptives. Depot-medroxyprogesterone acetate (DMPA) and risk of
liver cancer. Int J Cancer. 1991; 49:182-185.
6.
WHO Collaborative Study of Neoplasia and Steroid Contraceptives. Depot-medroxyprogesterone acetate (DMPA) and risk of
invasive squamous-cell cervical cancer. Contraception. 1992; 45:299-312.
7.
WHO Collaborative Study of Neoplasia and Steroid Contraceptives. Depot-medroxyprogesterone acetate (DMPA) and risk of
endometrial cancer. Int J Cancer. 1991; 49:186-190.
8.
Surveillance, Epidemiology, and End Results: Incidence and Mortality Data, 1973-1977. National Cancer Institute Monograph,
57: June 1981. (NIH publication No. 81-2330).
9.
Gray RH, Pardthaisong T. In Utero exposure to steroid contraceptives and survival during infancy. Am J Epidemiol. 1991;
134:804-811.
10. Pardthaisong T, Gray RH. In Utero exposure to steroid contraceptives and outcome of pregnancy. Am J Epidemiol. 1991;
134:795-803.
11. Pardthaisong T, Gray RH, McDaniel EB, Chandacham A. Steroid contraceptive use and pregnancy outcome. Teratology. 1988;
38:51-58.
12. Van Deijk WA, Biljham GH, Mellink WAM, Meulenberg PMM. Influence of aminoglutethimide on plasma levels of
medroxyprogesterone acetate: its correlation with serum cortisol. Cancer Treatment Reports. 1985; 69:1, 85-90.
13. Paul C, Skegg DCG, Spears GFS. Depot medroxyprogesterone (Depo-Provera) and risk of breast cancer. Br Med J.1989;
299:759-762.
14. Skegg DCG, Noonan EA, Paul C, Spears GFS, Meirik O, Thomas DB. Depot Medroxyprogesterone Acetate and Breast Cancer: A
Pooled Analysis from the World Health Organization and New Zealand Studies. JAMA. 1995; 273(10):799-804.
DEPO-PROVERA Contraceptive Injection 1 mL vials are manufactured by:
Pharmacia & Upjohn Company
A subsidiary of Pharmacia Corporation
Kalamazoo, MI 49001, USA
DEPO-PROVERA Contraceptive Injection 1 mL prefilled syringes are manufactured by:
Pharmacia N.V./S.A.
Puurs, Belgium
for:
Pharmacia & Upjohn Company
A subsidiary of Pharmacia Corporation
Kalamazoo, MI 49001, USA
* BD SafetyGlide™ Needle is a trademark of Becton, Dickinson and Company.
Revised June 2002
815 459 614E
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Depo-Provera® Contraceptive Injection
medroxyprogesterone acetate injectable suspension, USP
This product is intended to prevent pregnancy. It does not protect against HIV infection (AIDS) and other sexually
transmitted diseases.
Patient Labeling
Introduction
Every woman who considers using DEPO-PROVERA Contraceptive Injection needs to understand the benefits and risks of this
form of birth control and to discuss them with her health-care provider. This leaflet is intended to give you much of the
information you will need in order to decide if DEPO-PROVERA Contraceptive Injection is the right choice for you. Your
health-care provider will help you to compare DEPO-PROVERA Contraceptive Injection with other contraceptive methods and
will answer any questions you have after you have read this information.
DEPO-PROVERA Contraceptive Injection is given as an intramuscular injection (a shot) in the buttock or upper arm once every
3 months (13 weeks). Promptly at the end of the 3-month interval, you will need to return to your health-care provider for your
next injection in order to continue your contraceptive protection.
DEPO-PROVERA Contraceptive Injection contains medroxyprogesterone acetate, a chemical similar to (but not the same as)
the natural hormone progesterone that is produced by your ovaries during the second half of your menstrual cycle.
DEPO-PROVERA Contraceptive Injection acts by preventing your egg cells from ripening. If an egg is not released from the
ovaries during your menstrual cycle, it cannot become fertilized by sperm and result in pregnancy. DEPO-PROVERA
Contraceptive Injection also causes changes in the lining of your uterus that make it less likely for pregnancy to occur.
Effectiveness of DEPO-PROVERA Contraceptive Injection
To ensure that DEPO-PROVERA Contraceptive Injection is not administered inadvertently to a pregnant woman, the first
injection must be given ONLY during the first 5 days of a normal menstrual period; ONLY within the first 5-days postpartum if
not breast-feeding, and if exclusively breast-feeding, ONLY at the sixth postpartum week (see Administration of DEPO-PROVERA
Contraceptive Injection). The efficacy of DEPO-PROVERA Contraceptive Injection depends on adherence to the recommended
dosage schedule.
DEPO-PROVERA Contraceptive Injection is over 99% effective, making it one of the most reliable methods of birth control
available. This means that the average annual pregnancy rate is less than one for every 100 women who use DEPO-PROVERA
Contraceptive Injection. The effectiveness of most contraceptive methods depends, in part, on how reliably each woman uses
the method. The effectiveness of DEPO-PROVERA Contraceptive Injection depends only on the patient returning every
3 months (13 weeks) for her next injection.
The following table shows the percent of women who become pregnant while using different kinds of contraceptive
methods. It gives both the lowest expected rate of pregnancy (the rate expected in women who use each method exactly as it
should be used) and the typical rate of pregnancy (which includes women who became pregnant because they forgot to use
their birth control or because they did not follow the directions exactly).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Percent of Women Experiencing an Accidental Pregnancy in the First Year of Continuous Use
Lowest
Method
Expected
Typical
DEPO-PROVERA
0.3
0.3
Implants (Norplant)
0.2*
0.2*
Female sterilization
0.2
0.4
Male sterilization
0.1
0.15
Oral contraceptives (pill)
-
3
Combined
0.1
-
Progestogen only
0.5
-
IUD
-
3
Progestasert
2
-
Copper T 380A
0.8
-
Condom (without spermicide)
2
12
Diaphragm (with spermicide)
6
18
Cervical cap
6
18
Withdrawal
4
18
Periodic abstinence
1-9
20
Spermicide alone
3
21
Vaginal sponge
-
-
Used before childbirth
6
18
Used after childbirth
9
28
No method
85
85
Source: Trussell et al; Obstet Gynecol 1990;76:558-567.
* From Norplant® package insert.
Who Should Not Use DEPO-PROVERA Contraceptive Injection
Certain women should not use DEPO-PROVERA Contraceptive Injection. You should not use DEPO-PROVERA Contraceptive
Injection if you have any of the following conditions:
• if you think you might be pregnant
• if you have any vaginal bleeding without a known reason
• if you have had cancer of the breast
• if you have had a stroke
• if you have or have had blood clots (phlebitis) in your legs
• if you have problems with your liver or liver disease
• if you are allergic to DEPO-PROVERA Contraceptive Injection (medroxyprogesterone acetate or any of its other ingredients)
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Other Things to Consider Before Choosing DEPO-PROVERA Contraceptive Injection
Before your doctor prescribes DEPO-PROVERA Contraceptive Injection, you will have a physical examination. It is important to
tell your doctor or health-care provider if you have any of the following:
• a family history of cancer of the breast
• an abnormal mammogram (breast X-ray), fibrocystic breast disease, breast nodules or lumps, or bleeding from your nipples
• kidney disease irregular or scanty menstrual periods
• high blood pressure
• migraine headaches
• asthma
• epilepsy (convulsions or seizures)
• diabetes or a family history of diabetes
• a history of depression
• if you are taking any prescription or over-the-counter medications
This product is intended to prevent pregnancy. It does not protect against transmission of HIV (AIDS) and other sexually
transmitted diseases such as chlamydia, genital herpes, genital warts, gonorrhea, hepatitis B, and syphilis.
Return of Fertility
Because DEPO-PROVERA Contraceptive Injection is a long-acting birth control method, it takes some time after your last
injection for its effect to wear off. Based on the results from a large study done in the United States, of those women who stop
using DEPO-PROVERA Contraceptive Injection in order to become pregnant, about half of those who become pregnant do so in
about 10 months after their last injection; about two-thirds of those who become pregnant do so in about 12 months, about
83% of those who become pregnant do so in about 15 months, and about 93% of those who become pregnant do so in about
18 months after their last injection. The length of time you use DEPO-PROVERA Contraceptive Injection has no effect on how
long it takes you to become pregnant after you stop using it.
Risks of Using DEPO-PROVERA Contraceptive Injection
1. Irregular Menstrual Bleeding
The side effect reported most frequently by women who use DEPO-PROVERA Contraceptive Injection for contraception is a
change in their normal menstrual cycle. During the first year of using DEPO-PROVERA Contraceptive Injection, you might have
one or more of the following changes:
• irregular or unpredictable bleeding or spotting,
• an increase or decrease in menstrual bleeding, or
• no bleeding at all.
Unusually heavy or continuous bleeding, however, is not a usual effect of DEPO-PROVERA Contraceptive Injection and if this
happens you should see your health-care provider right away.
With continued use of DEPO-PROVERA Contraceptive Injection, bleeding usually decreases and many women stop having
periods completely. In clinical studies of DEPO-PROVERA Contraceptive Injection, 55% of the women studied reported no
menstrual bleeding (amenorrhea) after 1 year of use and 68% of the women studied reported no menstrual bleeding after
2 years of use.
The reason that your periods stop is because DEPO-PROVERA Contraceptive Injection causes a resting state in your ovaries.
When your ovaries do not release an egg monthly, the regular monthly growth of the lining of your uterus does not occur and,
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
therefore, the bleeding that comes with your normal menstruation does not take place. When you stop using DEPO-PROVERA
Contraceptive Injection your menstrual period will usually, in time, return to its normal cycle.
2. Bone Mineral Changes
Use of DEPO-PROVERA Contraceptive Injection may be associated with a decrease in the amount of mineral stored in your
bones. This could increase your risk of developing bone fractures. The rate of bone mineral loss is greatest in the early years of
DEPO-PROVERA Contraceptive Injection use but, after that, it begins to resemble the normal rate of age-related bone mineral
loss.
3. Cancer
Studies of women who have used different forms of contraception found that women who used DEPO-PROVERA Contraceptive
Injection for contraception had no increased overall risk of developing cancer of the breast, ovary, uterus, cervix, or liver.
However, women under 35 years of age whose first exposure to DEPO-PROVERA Contraceptive Injection was within the
previous 4 to 5 years may have a slightly increased risk of developing breast cancer similar to that seen with oral contraceptives.
You should discuss this with your health-care provider.
4. Unexpected Pregnancy
Because DEPO-PROVERA Contraceptive Injection is such an effective contraceptive method, the risk of unexpected pregnancy
for women who get their shots regularly (every 3 months [13 weeks]) is very low. While there have been reports of an increased
risk of low birth weight and neonatal infant death or other health problems in infants conceived close to the time of injection,
such pregnancies are uncommon. If you think you may have become pregnant while using DEPO-PROVERA Contraceptive
Injection for contraception, see your health-care provider as soon as possible.
5. Allergic Reactions
Severe allergic reactions known as anaphylaxis and anaphylactoid reactions have also been reported in some women using
DEPO-PROVERA Contraceptive Injection.
6. Other Risks
Women who use hormone-based contraceptives may have an increased risk of blood clots or stroke. Also, if a contraceptive
method fails, there is a possibility that the fertilized egg will begin to develop outside of the uterus (ectopic pregnancy). While
these events are rare, you should tell your health-care provider if you have any of the Warning Signals listed in the next section.
Warning Signals
If any of these problems occur following an injection of DEPO-PROVERA Contraceptive Injection, call your health-care provider
immediately:
• Sharp chest pain, coughing up of blood, or sudden shortness of breath (indicating a possible clot in the lung)
• Sudden severe headache or vomiting, dizziness or fainting, problems with your eyesight or speech, weakness, or numbness
in an arm or leg (indicating a possible stroke)
• Severe pain or swelling in the calf (indicating a possible clot in the leg)
• Unusually heavy vaginal bleeding
Depo-Provera®
Contraceptive Injection
medroxyprogesterone acetate injectable suspension, USP
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• Severe pain or tenderness in the lower abdominal area
• Persistent pain, pus, or bleeding at the injection site
Side Effects of DEPO-PROVERA Contraceptive Injection
1. Weight Gain
You may experience a weight gain while you are using DEPO-PROVERA Contraceptive Injection. About two-thirds of the women
who used DEPO-PROVERA Contraceptive Injection in the clinical trials reported a weight gain of about 5 pounds during the first
year of use. You may continue to gain weight after the first year. Women in one large study who used DEPO-PROVERA
Contraceptive Injection for 2 years gained an average total of 8.1 pounds over those 2 years, or approximately 4 pounds per
year. Women who continued for 4 years gained an average total of 13.8 pounds over those 4 years, or approximately
3.5 pounds per year. Women who continued for 6 years gained an average total of 16.5 pounds over those 6 years, or
approximately 2.75 pounds per year.
2. Other Side Effects
In a clinical study of over 3,900 women who used DEPO-PROVERA Contraceptive Injection for up to 7 years, some women
reported the following effects that may or may not have been related to their use of DEPO-PROVERA Contraceptive Injection:
• irregular menstrual bleeding
• bloating
• amenorrhea
• swelling of the hands or feet
• headache
• backache
• nervousness
• depression
• abdominal cramps
• insomnia
• dizziness
• acne
• weakness or fatigue
• pelvic pain
• decreased sexual desire
• no hair growth or excessive
• leg cramps
hair loss
• nausea
• rash
• vaginal discharge or irritation
• hot flashes
• breast swelling and tenderness
• joint pain
Other problems were reported by very few of the women in the clinical trials, but some of these could be serious. These
include: convulsions, jaundice, urinary tract infections, allergic reactions, fainting, paralysis, osteoporosis, lack of return to
fertility, deep vein thrombosis, pulmonary embolus, breast cancer, or cervical cancer. If these or any other problems occur
during your use of DEPO-PROVERA Contraceptive Injection, discuss them with your health-care provider.
General Precautions
1. Missed Periods
During the time you are using DEPO-PROVERA Contraceptive Injection for contraception, you may skip a period, or your periods
may stop completely. If you have been receiving your injection of DEPO-PROVERA Contraceptive Injection regularly every
3 months (13 weeks), then you are probably not pregnant. However, if you think that you may be pregnant, see your
health-care provider.
2. Laboratory Test Interactions
If you are scheduled for any laboratory tests, tell your health-care provider that you are using DEPO-PROVERA Contraceptive
Injection for contraception. Certain blood tests are affected by hormones such as DEPO-PROVERA Contraceptive Injection.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5R4606
3. Drug Interactions
Cytadren (aminoglutethimide) is an anticancer drug that may significantly decrease the effectiveness of DEPO-PROVERA
Contraceptive Injection if the two drugs are given during the same time.
4. Nursing Mothers
Although DEPO-PROVERA Contraceptive Injection can be passed to the nursing infant in the breast milk, no harmful effects
have been found in these children. DEPO-PROVERA Contraceptive Injection does not prevent the breasts from producing milk,
so it can be used by nursing mothers. However, to minimize the amount of DEPO-PROVERA Contraceptive Injection that is
passed to the infant in the first weeks after birth, you should wait until 6 weeks after childbirth before you start using
DEPO-PROVERA Contraceptive Injection for contraception.
Administration of DEPO-PROVERA Contraceptive Injection
The recommended dose of DEPO-PROVERA Contraceptive Injection is 150 mg every 3 months (13 weeks) given in a single
intramuscular injection in the buttock or upper arm. To ensure that you are not pregnant at the time of the first injection, it is
essential that the injection be given ONLY during the first 5 days of a normal menstrual period. If used following the delivery of
a child, the first injection of DEPO-PROVERA Contraceptive Injection MUST be given within 5 days after childbirth if you are not
breast-feeding, or if you are exclusively breast-feeding, the injection MUST be given 6 weeks after childbirth. If you wait longer
than 3 months (13 weeks) between injections, or longer than 6 weeks after delivery, your health-care provider should
determine that you are not pregnant before giving you your injection of DEPO-PROVERA Contraceptive Injection.
Pharmacia & Upjohn Company
A subsidiary of Pharmacia Corporation
Kalamazoo, MI 49001, USA
Revised June 2002
815 459 614E
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:47:13.698651
|
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|
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